Clinical trial NCT03066609
Conditions: Plaque Psoriasis
Keywords: Plaque psoriasis Secukinumab Skin condition skin disease itching psoriasis vulgaris immune-mediated systemic disease skin lesions scaly patches papules psoriasis
Sponsor: Novartis Pharmaceuticals
Start date: 2017-02-28; Completion date: 2018-11-20
Enrollment: 543 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine if secukinumab is effective and safe in the treatment of plaque type psoriasis

Detailed description:

Arms: arm 1: Secukinumab 150mg s.c. arm 2: Secukinumab 300mg s.c. arm 3: Placebo to secukinumab s.c
Interventions: intervention 1: Secukinumab 150 mg s.c. intervention 2: Secukinumab 300 mg s.c. intervention 3: Placebo
Intervention descriptions: intervention 1: 150 mg s.c. at randomization, Weeks 1, 2, 3, 4 and every 4 weeks till Week 48 intervention 2: 300 mg s.c. at randomization, Weeks 1, 2, 3, 4 and every 4 weeks till Week 48 intervention 3: Placebo 150 or 300 mg s.c at randomization, Weeks 1, 2, 3, 4, and 8. PASI responders at week 12 continued to receive placebo till Week 48. PASI non-responders at Week 12 received Secukinumab 300mg at Weeks 12, 13, 14, 15, 16 and every 4 weeks till Week 48

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
Secukinumab (AIN457)
Clinical Trial Protocol CAIN457A2318 / NCT03066609
A randomized, double-blind, placebo controlled, 
multicenter study of subcutaneous secukinumab, to 
demonstrate efficacy after twelve weeks of treatment and 
to assess safety, tolerability and long-term efficacy up to 
one year in subjects with moderate to severe chronic 
plaque-type psoriasis with or without psoriatic arthritis 
comorbidity 
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2016-000524-25
Version number:
v01 Clean
Clinical trial phase:
III
Release date:
09-June-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 03 (August 2015)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 01 .........................................................................................................................10
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.2
Purpose ..................................................................................................................17
2
Study objectives and endpoints .........................................................................................17
2.1
Primary objective...................................................................................................17
2.2
Secondary objectives .............................................................................................17
18
3
Investigational plan ...........................................................................................................18
3.1
Study design...........................................................................................................18
3.2
Rationale for study design .....................................................................................21
3.3
Rationale for dose/regimen, route of administration and duration of treatment....22
3.4
Rationale for choice of comparator .......................................................................23
3.5
Purpose and timing of interim analyses/design adaptations..................................24
3.6
Risks and benefits..................................................................................................24
4
Population..........................................................................................................................25
4.1
Inclusion criteria ....................................................................................................25
4.2
Exclusion criteria...................................................................................................26
5
Treatment...........................................................................................................................28
5.1
Study treatment......................................................................................................28
5.1.1
Investigational and control drugs..........................................................28
5.1.2
Additional treatment..............................................................................28
5.1.3
Treatment arms......................................................................................28
5.2
Treatment assignment and randomization.............................................................29
5.3
Treatment blinding.................................................................................................29
5.4
Treating the patient................................................................................................30
5.5
Subject numbering.................................................................................................30
5.5.1
Dispensing the study drug.....................................................................30
5.5.2
Handling of study and additional treatment..........................................30
5.5.3
Instructions for prescribing and taking study treatment........................31


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5.5.4
Permitted dose adjustments and interruptions of study treatment ........32
5.5.5
Rescue medication ................................................................................32
5.5.6
Concomitant medication .......................................................................32
5.5.7
Prohibited medication ...........................................................................32
5.5.8
Emergency breaking of assigned treatment code..................................34
5.6
Study Completion and Discontinuation.................................................................35
5.6.1
Study completion and post-study treatment..........................................35
5.6.2
Discontinuation of Study Treatment .....................................................35
5.6.3
Withdrawal of informed consent...........................................................36
5.6.4
Loss to follow-up ..................................................................................36
5.6.5
Early study termination by the sponsor.................................................37
6
Visit schedule and assessments .........................................................................................37
6.1
Information to be collected on screening failures..................................................43
6.2
Patient demographics/other baseline characteristics .............................................43
6.2.1
Demographics .......................................................................................43
6.2.2
Psoriasis medical history / Previous psoriasis therapies .......................43
6.2.3
Smoking history ....................................................................................43
6.2.4
Co-morbidities – cardiovascular medical history .................................43
6.2.5
Relevant medical history/current medical conditions...........................44
6.2.6
Determination of the tuberculosis status...............................................44
6.2.7
Diagnosis of psoriatic arthritis (PsA) – CASPAR ................................46
6.2.8
Other baseline characteristics................................................................47
6.3
Treatment exposure and compliance .....................................................................47
6.4
Efficacy..................................................................................................................47
6.4.1
Investigator Global Assessment (IGA mod 2011)................................48
6.4.2
Assessment of total Body surface Area (BSA) and Psoriasis Area 
Severity Index .......................................................................................48
50
51
6.4.5
Assessment of the American College of Rheumatology (ACR) 
response in subjects with psoriatic arthritis ..........................................51
6.4.6
Appropriateness of efficacy assessments..............................................51
6.5
Safety.....................................................................................................................51
6.5.1
Physical examination ............................................................................52
6.5.2
Vital signs..............................................................................................52
6.5.3
Height and weight .................................................................................52
6.5.4
Laboratory evaluations..........................................................................53


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6.5.5
Electrocardiogram (ECG) .....................................................................54
6.5.6
Pregnancy..............................................................................................54
6.5.7
Appropriateness of safety measurements..............................................55
6.6
Other assessments..................................................................................................55
6.6.1
Clinical Outcome Assessments (COAs) ...............................................55
58
6.6.3
Fasting Laboratory evaluations.............................................................58
58
59
59
7
Safety monitoring ..............................................................................................................59
7.1
Adverse events.......................................................................................................59
7.2
Serious adverse events...........................................................................................61
7.2.1
Definition of SAE .................................................................................61
7.2.2
SAE reporting........................................................................................62
7.3
Reporting of study treatment errors including misuse/abuse ................................63
7.4
Pregnancy reporting...............................................................................................63
8
Data review and database management.............................................................................63
8.1
Site monitoring ......................................................................................................63
8.2
Data collection.......................................................................................................64
8.3
Database management and quality control............................................................64
8.4
Data Monitoring Committee..................................................................................65
8.5
Adjudication Committee........................................................................................65
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Patient demographics and other baseline characteristics.......................................66
9.3
Treatments .............................................................................................................66
9.4
Analysis of the primary variable(s) .......................................................................67
9.4.1
Variable(s).............................................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................68
9.4.4
Sensitivity analyses ...............................................................................69
9.5
Analysis of secondary variables ............................................................................70
9.5.1
Efficacy variables..................................................................................70
9.5.2
Safety variables .....................................................................................72
73


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73
9.5.5
DNA......................................................................................................73
9.5.6
Biomarkers ............................................................................................73
.73
73
9.7
Interim analyses .....................................................................................................73
9.8
Sample size calculation..........................................................................................73
10 Ethical considerations........................................................................................................75
10.1
Regulatory and ethical compliance........................................................................75
10.2
Informed consent procedures.................................................................................75
10.3
Responsibilities of the investigator and IRB/IEC..................................................75
10.4
Publication of study protocol and results...............................................................76
10.5
Quality Control and Quality Assurance.................................................................76
11 Protocol adherence ............................................................................................................76
11.1
Protocol Amendments ...........................................................................................76
12 References .........................................................................................................................77
13 Appendix 1: Clinically notable laboratory values and vital signs.....................................80
14 Appendix 2: The classification criteria for psoriatic arthritis (CASPAR) ........................80
.82
.83
83
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List of tables
Table 5-1
Prohibited treatment..............................................................................33
Table 6-1
Assessment schedule.............................................................................39
Table 6-2
The IGA mod 2011 rating scale............................................................48
Table 6-3
The PASI scoring system ......................................................................49
Table 9-1
Response reference for sample size calculation based on Phase III 
trials.......................................................................................................74
82
82
List of figures
Figure 3-1
Study design..........................................................................................20
Figure 3-2
Simulated PASI 75 response rates ........................................................23
Figure 6-1
Tuberculosis screening flowchart .........................................................46
Figure 9-1
Testing strategy.....................................................................................68


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List of abbreviations
AE
Adverse Event
AI
Auto-injector
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
CFR
US Code of Federal Regulations 
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CS
Corticosteroids
CRO
Contract Research Organization
CTC
Common Terminology Criteria
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
e.g.
example
EU
European Union
FAS
Full Analysis Set
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice
HAQ-DI
Health Assessment Questionnaire© – Disability Index
GGT
Gamma –glutamyl transferase
hCG
Human chorionic gonadotropin
hsCRP
high sensitivity C-reactive protein
HIV
Human Immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IGA mod 2011
Investigator’s Global Assessment modified 2011
IL
interleukin
IN
Investigator Notification
i.v.
intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
LYO
lyophilized powder
MedDRA
Medical dictionary for regulatory activities 
OC/RDC
Oracle Clinical/Remote Data Capture 
PASI
Psoriasis Area and Severity Index
PFS
Pre-filled syringe
PhGA  
physician global assessment
PtGA
patient’s global assessment


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PRO
Patient Reported Outcome
PUVA
Photochemotherapy (e.g. psoralen + UVA treatment)
QFT
QuantiFERON TB-Gold test
SAE
Serious Adverse Event
s.c.
Subcutaneous
SUSAR
Suspected Unexpected Serious Adverse Reactions
TB
tuberculosis
TBL
Total Bilirubin
TCS
Topical Corticosteroid
Th17
T helper 17 cells
TNF
Tumor necrosis factor
UV
Ultraviolet
UVA
Ultraviolet A, long wave 400 nm–315 nm
UVB
Ultraviolet B, medium wave 315 nm–280 nm
WBC
White blood cells / leukocytes
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
Cohort 
A specific group of patients/subjects fulfilling certain criteria
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 100 
mg once a day, 75 mg twice a day)
Enrollment
Point/time of patient entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients/subjects 
with established disease and in those with newly-diagnosed disease.
Patient/subject ID 
A unique number assigned to each patient upon signing the informed 
consent 
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), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the patient permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study is defined as when a patient does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
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Amendment 01
Amendment rationale 
The aim of this amendment is to introduce a provision for a Week 16 analysis. This analysis 
will include primary endpoint data at Week 12 and in addition data at Week 16 visit. 
This amendment also introduces the provision for additional subsequent interim analyses that 
may be conducted to fulfill any request from Health Authorities. 
At the time of this amendment release, the enrollment into the study is ongoing. 
In addition, this amendment is used to clarify minor inconsistencies between various protocol 
sections, and correct minor errors; these do not affect the study design or population.
Changes to the protocol
The major changes made to the protocol are listed below:

Section 3.5 Purpose and timing of interim analyses/design adaptations
Amended to introduce a Week 16 analysis and the provision for additional subsequent 
interim analyses that may be conducted to fulfill any HA requests 

Section 5.3 Treatment blinding
Updated to introduce unblinding of designated Novartis personnel who may be involved 
in the Week 16 analysis and additional subsequent interim analyses that may be conducted 
to fulfill any HA requests

Section 5.5.3 Instructions for prescribing and taking study medication
Clarification regarding order of assessments prior to injection of study treatment
    

Section 9 Data analysis
Amended to include Week 16 visit analysis and the provision for additional subsequent 
interim analyses that may be conducted to fulfill any HA requests

Section 9.7 Interim analyses
Amended to include Week 16 visit analysis and the provision for additional subsequent 
interim analyses that may be conducted to fulfill any HA requests.
This protocol amendment also includes corrections of minor errors/inconsistencies across 
sections of the protocol and changes to align with the study design and increase clarity of the 
text. 


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Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC and HA approval where 
needed and according to local regulations, prior to implementation. The changes herein do 
NOT affect the trial specific model ICF.
Protocol summary
Protocol number
AIN457A2318
Title
A randomized, double-blind, placebo controlled, multicenter study of 
subcutaneous secukinumab, to demonstrate efficacy after twelve weeks of 
treatment and to assess safety, tolerability and long-term efficacy up to one 
year in subjects with moderate to severe chronic plaque-type psoriasis with 
or without psoriatic arthritis comorbidity
Brief title
Study of efficacy and safety of secukinumab in subjects with moderate to 
severe chronic plaque-type psoriasis
Sponsor and Clinical 
Phase
Novartis / Phase 3
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to demonstrate superiority of secukinumab at 
Week 12 in subjects with moderate to severe chronic plaque-type psoriasis 
in terms of both PASI 75 and IGA mod 2011 0 or 1 response, compared to 
placebo, and to assess the maintenance of efficacy of secukinumab until 
Week 52. In addition, the study will assess efficacy of secukinumab 
compared to placebo in treating subjects with psoriatic arthritis comorbidity 
in terms of ACR 20/50/70 response and ACR components at Week 12 and 
over time until Week 52. The study will also assess the safety and
tolerability of secukinumab with prefilled syringe in the patient population 
over the study period. 
Primary Objective(s) 
To demonstrate the superiority of secukinumab in subjects with moderate 
to severe chronic plaque-type psoriasis in terms of both PASI 75 and IGA 
mod 2011 0 or 1 response (co-primary endpoints) at Week 12 compared to 
placebo.
Secondary Objectives

To demonstrate the superiority of secukinumab in terms of PASI 90 
response at Week 12 compared to placebo.

To assess the efficacy of secukinumab in maintaining PASI 75 
response at Week 52 in subjects who were PASI 75 responders at 
Week 12  or IGA mod 2011 0 or 1 response at Week 52 in subjects 
who were IGA mod 2011 0 or 1 responders at Week 12.

To assess the efficacy of secukinumab in terms of PASI score, IGA 


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mod 2011 score, PASI 50/75/90/100 and IGA mod 2011 0 or 1 
response over time up to Week 12 compared to placebo and over time 
up to Week 52

To assess the efficacy of secukinumab in terms of time to PASI 75 
response up to Week 12 compared to placebo.

To investigate the clinical safety and tolerability of secukinumab, as 
assessed by vital signs, clinical laboratory variables, ECG and 
adverse events monitoring compared to placebo.

To assess the efficacy of secukinumab in treating psoriatic arthritis in 
subjects with this comorbidity at Baseline in terms of American 
College of Rheumatology (ACR) 20/50/70 response over time up to 
Week 52. 
Study design
This is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group trial in approximately 536 subjects with moderate to severe 
chronic plaque-type psoriasis with or without psoriatic arthritis comorbidity. 
It is expected that subjects will be enrolled at around 45 study sites in 
China and other countries 
Randomization will be stratified by geographical region and presence of 
psoriatic arthritis at Baseline. Subjects will be randomized using a 2:1:1 
ratio into one of the treatment groups: secukinumab 300 mg s.c., 
secukinumab 150 mg s.c., and placebo s.c.
Population
The study population will consist of a representative group of male and 
female adult out-patients with moderate to severe chronic plaque-type 
psoriasis, poorly controlled by topical treatments and/or phototherapy 
and/or previous systemic therapy. As this study may be used to support the 
registration of secukinumab in China, the majority of the patients will be 
enrolled in China, for example approximately 80% from China and the rest 
from other countries.  
Key Inclusion criteria
1.
Subjects must be able to understand and communicate with the 
investigator and comply with the requirements of the study and must 
give a written, signed and dated informed consent before any study 
related activity is performed. Where relevant, a legal representative will 
also sign the informed study consent according to local laws and 
regulations.
2.
Men or women at least 18 years of age at time of screening.
3.
Chronic plaque-type psoriasis present for at least 6 months and 
diagnosed before Baseline.
4.
Moderate to severe psoriasis as defined at Baseline by:

PASI score of 12 or greater, and

IGA mod 2011 score of 3 or greater (based on a static scale of 0 –
4), and

Body Surface Area (BSA) affected by plaque-type psoriasis of 10% 
or greater.
5.
Candidate for systemic therapy. This is defined as a subject having 
moderate to severe chronic plaque-type psoriasis that is inadequately 
controlled by

topical treatment and/or,

phototherapy and/or,

previous systemic therapy.


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Key Exclusion criteria
1.
Forms of psoriasis other than chronic plaque-type (e.g., pustular, 
erythrodermic and guttate psoriasis) at Screening or Baseline.
2.
Drug-induced psoriasis.
3.
Ongoing use of prohibited treatments. 
4.
Previous exposure to secukinumab (AIN457) or any other biologic drug 
directly targeting IL-17 or the IL-17 receptor.
5.
Use of other investigational drugs at the time of enrollment, or within 5 
half-lives of enrollment, or within 30 days until the expected 
pharmacodynamic effect has returned to baseline, whichever is longer; 
or longer if required by local regulations.
6.
Pregnant or nursing (lactating) women, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test.
Study treatment

Investigational therapy: secukinumab 150 mg and 300 mg s.c

Reference therapy: placebo s.c.
Efficacy assessments

Investigator’s Global Assessment for psoriasis (IGA mod 2011; scale
from 0 – 4)

Psoriasis Area and Severity Index (PASI; score from 0 – 72)

ACR response
Key safety 
assessments

Evaluation of all AEs and SAEs including injection site reactions, 
hypersensitivity reactions and occurrence of infections.

Physical examination

Vital signs

Weight

Laboratory evaluations (Hematology, Clinical chemistry)

Urinalysis

ECG

Other assessments

Clinician Reported Outcomes

Patient Reported Outcomes

Data analysis
The primary endpoint (PASI 75 and IGA mod 2011 0 or 1 response at 
Week 12) will be evaluated using an exact logistic regression model with 
treatment group, baseline body weight, geographical region, presence of 
psoriatic arthritis, and baseline PASI score as explanatory variables. Odds 
ratios will be computed for comparisons of secukinumab dose regimens 
versus placebo utilizing the exact logistic regression model fitted. In case of 
rates of 0% or 100% in one of the treatment groups, Fisher’s exact test will 
be applied.
Key words
psoriasis, PASI, IGA mod 2011, psoriatic arthritis, secukinumab


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1
Introduction
1.1
Background 
Psoriasis is a chronic, relapsing, immune mediated multi-system disorder primarily affecting 
the dermis and epidermis. Skin lesions are classified as erythemato-squamous, which 
indicates that both the vasculature (erythema) and the epidermis (increased scale formation) 
are involved. The prevalence of psoriasis in different populations can vary between 0 and 12% 
(Schon and Boehncke 2005), with estimates of 2.8% in western populations (Naldi 2004; 
Farber 1998) and 0.47% in China (Ding 2012).
Plaque psoriasis (also called plaque-type or chronic plaque) is the most frequent clinical 
presentation, also called psoriasis vulgaris. The erythematous plaques are well defined with 
sharp borders. The silvery grey scale on the surface of the lesions is easily removed. Sharply 
demarcated lesions can present on the extensor surfaces of the knees and elbows and on the 
trunk. Lesions are often symmetrically distributed. The size of the lesions is highly variable. 
Psoriasis may also occur on the scalp, palms and/or soles (palmoplantar psoriasis), nails and 
in skin folds (intertrigo psoriasis).  
The etiology of psoriasis is unknown. Accumulating evidence indicates that psoriasis is a 
multifactorial disorder caused by the concerted action of multiple disease genes in a single 
individual, triggered by environmental factors. Genetic factors influence the pattern of 
psoriasis, severity and the age of onset (Griffiths and Barker 2007).  In recent years, increased 
attention has been paid to comorbidities of psoriasis. A distinct pattern of chronic disorders 
was found to be significantly associated with psoriasis, including arterial hypertension, 
hyperlipidemia, and coronary heart disease. Psoriatic arthritis (PsA) is a particular instance of 
comorbidity in psoriasis. This chronic, immune-mediated inflammatory disease encompasses 
a spectrum of overlapping clinical entities (Moll and Wright 1973) belonging to a group of 
conditions referred to as seronegative spondylarthropathies (SpA) and possibly mediated via a 
common pathway including the IL-23/IL-17 axis. The prevalence varies from 20–420 per    
100,000 population across the world (Dhir et al 2013) with the limited data from Asia 
(Alamanos Y et al 2008). Based on the population-based surveys in China, the prevalence of 
PsA appeared to be similar to the rest of the world, ranging from 10 to 100 per 100,000 
population (Zeng QY et al 2008). However, among the Japanese population, there is a 64- and 
180-fold lower incidence with prevalence between 0.1 and 1 per 100,000 population as 
compared with the median incidence and prevalence of all other studies (Hukuda S et al 2001, 
Dhir et al 2013). In addition, a multi-ethnic study reported that PsA was significantly more 
common among the Indian population than the ethnic distribution of the Singapore population 
(Thumboo J et al 1997).
Other reports refer to prevalence of PsA between 6% and 42% in psoriatic patients in Europe,
USA and South Africa (Gladman et al 2005). However, the overall numbers are lower in 
Asian countries. PsA was observed in 9% of the patients with psoriasis in Iran (Jamshidi F et 
al 2008), Korea (Baek HJ et al 2000), and India (Prasad PV et al 2007); 5% in China (Fan X 
et al 2007); 2% in Turkey (Kundakci N et al 2002), and 1% in Japan (Kawada A et al 2003).  
Also, a study conducted in Singapore reported that the Indian population with psoriasis had 
twice the risk of developing PsA when compared with the Chinese population (Thumboo J et 
al 1997) with the amplitude of variations possibly reflecting differences in diagnostic 


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complexities and ethnicities difference. Psoriatic arthritis is associated with significant 
morbidity and disability and thus, it constitutes a major socioeconomic burden. 
Once psoriasis appears as a localized disease, it persists throughout life, manifesting itself at 
unpredictable intervals. Spontaneous remissions of varying duration do occur with varying 
frequencies. Data relative to permanent remissions, either spontaneous or induced, appears to 
be unavailable in the literature.
Therefore, psoriasis represents a lifelong condition for the patient. A study reported reduction 
in physical functioning and mental functioning comparable to that seen in cancer, arthritis, 
hypertension, heart disease, diabetes and depression (Rapp et al 1999).
The patient and his or her family must learn to deal with the illness and its treatment in such a 
manner as to reduce the potential negative influence on self-esteem. Both the appearance of 
the affected areas and the chronic nature of the disease impose a heavy psychological burden. 
In addition to dermatological care, attention must be given to the emotional problems that 
may be created in the patient and the family (Christophers and Mrowietz 2003; de Waardvan 
der Spek and Oranje 2006).
Secukinumab (AIN457) is a recombinant high-affinity fully human monoclonal anti-human 
Interleukin-17A antibody of the IgG1/κ-class. Secukinumab binds to human IL-17A and 
neutralizes the bioactivity of this cytokine.
IL-17A is the central cytokine of a newly defined subset of inflammatory T cells, the Th17 
cells which, in several animal models, are pivotal in several autoimmune and inflammatory 
processes. IL-17A is mainly produced by memory effector CD4+ and CD8+ T lymphocytes. 
IL-17A is being recognized as one of the principal pro-inflammatory cytokines in immune 
mediated inflammatory diseases. Its neutralization is expected to treat the underlying 
pathophysiology of immune mediated disease, and as a consequence provide relief of 
symptoms.
To confirm the findings of basic research and early clinical studies regarding the crucial role 
of interleukin-17A in psoriasis, 2 randomized, phase 3 trials were conducted to assess the 
efficacy and safety of secukinumab, at a dose of 300 mg or 150 mg, administered as induction 
therapy (with assessment at Week 12) and maintenance therapy (with assessment at week 52) 
in patients with moderate-to-severe plaque psoriasis. The CAIN457A2302/ERASURE 
(Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) study 
compared secukinumab with placebo, and the CAIN457A2303/FIXTURE (Full Year 
Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to 
Determine Efficacy in Psoriasis) study compared secukinumab with placebo and etanercept, 
the first tumor necrosis factor (TNF) inhibitor approved by the Food and Drug Administration 
for moderate-to-severe plaque psoriasis. The studies evaluating pre-filled syringe (PFS) and 
auto-injector (AI) forms of secukinumab administration (Studies CAIN457A2308 and 
CAIN457A2309) showed no new or unexpected administration and immune reactions 
compared to the profile seen in studies using lyophilized powder (LYO) (e.g., Studies 
CAIN457A2302 and CAIN457A2303).
The results of these phase 3 studies validate interleukin-17A as an important therapeutic target 
in moderate-to-severe plaque psoriasis, confirming earlier findings from basic research and 
phase 2 trials of secukinumab that suggested that interleukin-17A plays a role in the 
pathogenesis of psoriasis. The superiority of secukinumab over these comparators (both 
placebo and etanercept) was shown in both studies. Secukinumab was associated with a rapid 


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reduction in psoriasis symptoms, elicited significantly greater PASI 75 rates and higher rates 
of 0 or 1 responses on the modified investigator's global assessment than placebo at week 12, 
and with continued treatment was associated with sustained high response rates in a majority 
of patients through week 52. The FIXTURE study showed the superior efficacy of 
secukinumab over the TNF inhibitor etanercept over a period of 52 weeks, a duration that 
exceeds the 12-week study duration in a previous phase 3, blinded, direct comparison of two 
biologic therapies for psoriasis. The safety data from the completed and ongoing studies 
including AE and SAE data, laboratory parameters and immunogenicity data demonstrate a 
good safety profile which included an observed risk of infections in particular candida 
infections and neutropenia or hypersensitivity reactions that can be seen with administration 
of foreign proteins. Most of the infections were non-serious, mild to moderate in severity, 
clinically easily manageable and did not lead to treatment discontinuation. Cases of 
neutropenia were uncommon, generally mild to moderate and transient and did not lead to 
treatment discontinuation, and only a few cases were timely associated with non-serious 
infections.
The results of a proof-of-concept study in patients with moderate to severe psoriatic arthritis 
(CAIN457A2206) suggest that secukinumab was well tolerated and demonstrated preliminary 
evidence for therapeutic benefit. ACR response rates under secukinumab and placebo did not 
differ significantly at week 6, however the onset of secukinumab action was more rapid, with 
ACR20 and ACR50 responses occurring as early as two weeks after the beginning of therapy 
and numerically greater reductions in ACR20, ACR50 and ACR70 responses under 
secukinumab compared to placebo at almost every time point up to week 24. Acute phase 
reactant CRP was reduced at week 6 of the treatment. Also, the data that is available from the 
ongoing phase 3 FUTURE 2 study suggests that secukinumab can improve the signs and 
symptoms in patients with psoriatic arthritis.  All studied doses 75 mg, 150 mg and 300 mg s.c. 
showed significantly higher ACR 20 response rates at Week 24 (29.3%, 51% and 54% 
respectively) compared to placebo (15.3%) (McInnes et al 2015).
As of 25 June 2015, approximately 12,000 subjects (healthy subjects and patients) have been 
enrolled in Novartis sponsored clinical studies with secukinumab, with over 9,600 subjects 
having received secukinumab treatment at doses ranging from 0.1 mg/kg to 30 mg/kg 
intravenously (i.v.), and from 25 mg to 300 mg subcutaneously (s.c.), given as single or 
multiple doses. As of 25 July 2015, there are 79 completed and multiple ongoing trials 
conducted with secukinumab in indications including psoriasis, psoriatic arthritis, uveitis, 
multiple sclerosis, rheumatoid arthritis, rheumatic polymyalgia, type I diabetes mellitus, 
asthma, and ankylosing spondylitis. Full safety results including all reported AEs are currently 
available for completed studies across different indications.  The Investigator’s Brochure (IB) 
provides a more detailed review of the pre-clinical and clinical information on secukinumab.
Results are available from a bioequivalence study (CAIN457A2106) in which the 
pharmacokinetics, safety and tolerability of a pre-filled syringe (test) and the lyophilisate 
formulation (reference) were compared. Secukinumab (reference, 300 mg or test, 300 mg) 
was subcutaneously injected (2x 1 mL) to the abdominal region of 150 healthy volunteers in a 
randomized, open label, single dose, and parallel group study. Serum concentrations were 
measured up to 112 days post dose by ELISA. The primary outcome was assessed via 
geometric mean ratios of the log-transformed Cmax, AUClast and AUCinf as PK parameters. 
The geometric mean ratios (90% CIs) of the test to reference formulation for Cmax, AUClast 


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and AUCinf were 1.04 (0.96-1.12), 1.01 (0.93-1.08) and 1.00 (0.92-1.08), respectively. The 
confidence intervals were entirely within the 0.8-1.25 boundaries and therefore, the prefilled 
syringe met the standard criteria for assuming bioequivalence. Further, phase III data with the 
liquid formulation are now available that demonstrate the safe and effective use of both liquid 
forms i.e. prefilled syringe (Study A2308) and autoinjector (Study A2309). 
In addition, pooled data from two phase III studies (Study A2302 and A2303) presented 
analysis of 443 Asian subjects with moderate to severe plaque psoriasis. Similar to the overall 
population, PASI 75 responses in Asian subjects were significantly higher in secukinumab 
300mg (74.4%) and 150mg (67.5%) treatment arms compared with placebo (6.8%; p <  0001, 
both doses) or etanercept treatment (27.4%; p < 0001, both doses) at Week 12. Also, IGA 0/1 
after 12 weeks was significantly higher in secukinumab 300 and 150mg groups (52.8% and 
46.0% respectively) compared with 2.6% in placebo group (p < 0001, both secukinumab 
doses) or 17.8% in the etanercept treatment arm (p < 0001 for both secukinumab doses). 
Moreover, PASI 90 responses were also significantly higher in the secukinumab 300 mg 
(53.6%) and 150 mg (40.5%) arms when compared with placebo (0.9%) or etanercept (13.7%) 
treatment at week 12. In addition, PASI 75 and PASI 90 responses were consistently higher in 
the 300 mg group when compared with the 150 mg group. Clinical responses to secukinumab 
were increased at Week 16 and sustained after Week 52. The most common AEs with either 
secukinumab dose were infections and infestations, including nasopharyngitis. In summary, in 
this 52 weeks pooled analysis, secukinumab demonstrated consistent efficacy and safety 
profile that is comparable to the overall population in the phase III studies.
1.2
Purpose 
The purpose of this study is to demonstrate superiority of secukinumab at Week 12 in subjects 
with moderate to severe chronic plaque-type psoriasis in terms of both PASI 75 and IGA mod 
2011 0 or 1 response, compared to placebo, and to assess the maintenance of efficacy of 
secukinumab until Week 52. In addition, the study will assess efficacy of secukinumab in 
treating subjects with psoriatic arthritis comorbidity in terms of ACR 20/50/70 response and 
ACR components at Week 12 compared to placebo and over time until Week 52. The study 
will also assess the safety and tolerability of secukinumab with prefilled syringe in the patient 
population over the study period. Efficacy and safety data from this global study will 
primarily be used to support the registration of secukinumab in China, for the treatment of 
moderate to severe chronic plaque-type psoriasis and psoriatic arthritis comorbidity.
2
Study objectives and endpoints
2.1
Primary objective
To demonstrate the superiority of secukinumab in subjects with moderate to severe chronic 
plaque-type psoriasis in terms of both PASI 75 and IGA mod 2011 0 or 1 response (co-
primary endpoints) at Week 12 compared to placebo.
2.2
Secondary objectives

To demonstrate the superiority of secukinumab in terms of PASI 90 response at Week 12 
compared to placebo.


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
To assess the efficacy of secukinumab in maintaining PASI 75 response at Week 52 in 
subjects who were PASI 75 responders at Week 12  or  IGA mod 2011 0 or 1 response at 
Week 52 in subjects who were IGA mod 2011 0 or 1 responders at Week 12.

To assess the efficacy of secukinumab in terms of PASI score, IGA mod 2011 score, 
PASI 50/75/90/100 and IGA mod 2011 0 or 1 response over time up to Week 12 
compared to placebo and over time up to Week 52.

To assess the efficacy of secukinumab in terms of time to PASI 75 response up to Week 
12 compared to placebo.

To investigate the clinical safety and tolerability of secukinumab, as assessed by vital 
signs, clinical laboratory variables, ECG and adverse events monitoring compared to 
placebo.

To assess the efficacy of secukinumab in treating psoriatic arthritis in subjects with this 
comorbidity at Baseline in terms of American College of Rheumatology (ACR) 20/50/70 
response over time up to Week 52. 
3
Investigational plan
3.1
Study design
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in 
approximately 536 subjects with moderate to severe chronic plaque-type psoriasis with or 
without psoriatic arthritis comorbidity. It is expected that subjects will be enrolled at around 
45 study sites in China and other countries.
The study consists of four epochs: Screening (of at least 1 week and up to 4 weeks), Induction 
(of 12 weeks), Maintenance (of 40 weeks), and Follow-up epoch (of 8 weeks). An outline of 
the study is presented in Figure 3-1 and a detailed visit and assessment schedule is presented 
in Table 6-1.
Safety, efficacy
will be performed 
according to the schedule presented in Table 6-1.


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Randomization will be stratified by geographical region and presence of psoriatic arthritis at 
Baseline. Subjects will be randomized using a 2:1:1 ratio into one of the treatment groups 
below:

Secukinumab 300 mg regimen group: secukinumab 300 mg s.c. (two injections of 
secukinumab 150 mg dose) once weekly for four weeks (at Baseline, Weeks 1, 2, and 3), 
followed by dosing every four weeks, starting at Week 4 and until Week 48, except for 
Weeks 13, 14, and 15 where they will receive a weekly dose of placebo (two injections 
per dose) to maintain the blind.

Secukinumab 150 mg regimen group: secukinumab 150 mg (one injection of 
secukinumab 150 mg and one placebo secukinumab injection) once weekly for four weeks 
(at Baseline, Weeks 1, 2, and 3), followed by dosing every four weeks, starting at Week 4 
and until Week 48, except for Weeks 13, 14, and 15 where they will receive a weekly dose 
of placebo (two injections per dose) to maintain the blind.

Placebo group: placebo secukinumab (two placebo injections per dose) once per week for 
four weeks (at Baseline, Weeks 1, 2, and 3), followed by dosing every four weeks (Weeks 
4 and 8). Prior to receiving the Week 12 dose, all subjects in the placebo group will be 
assigned to the following treatment groups based on PASI 75 response status at Week 12, 
as follows:

PASI 75 responders (per definition in Section 6.4.2) will continue on placebo and 
will receive their placebo injections on Weeks 12, 13, 14, 15, and then every four 
weeks starting at Week 16 until Week 48. 

PASI 75 non-responders (per definition in Section 6.4.2) will be reassigned to 300 
mg secukinumab regimen group and receive their treatment on Weeks 12, 13, 14, 15 
and then every four weeks starting at Week 16 until Week 48.


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Figure 3-1
Study design 
Screening (Screening to Baseline)
The screening epoch of at least 1 week and up to 4 weeks will be used to assess eligibility of 
the subjects and to taper subjects off disallowed medications. 
Induction epoch (Baseline to Week 12 pre-dose)
The Induction epoch is defined as Baseline through Week 12 (prior to Week 12 dose). At the 
start of the Induction epoch, eligible subjects will be randomized in a 2:1:1 ratio into one of 
three treatment groups (secukinumab 300 mg, secukinumab 150 mg or placebo group 
respectively). During the Induction epoch, subjects will be visiting the study site at Baseline 
and Weeks 1, 2, 3, 4, 8 and 12.
During the Induction epoch, all three treatment groups will receive study treatment and/or 
placebo weekly for four weeks (Baseline and Weeks 1, 2 and 3) and then one dose of study 
treatment and/or placebo at Weeks 4 and 8 (last dose during the Induction epoch).
Assessments for the primary endpoint will be performed at Week 12 for all treatment arms 
prior to the dose at Week 12.
In addition, for subjects who discontinue study treatment prematurely for any reason before 
the end of the induction epoch, visit Week 12 (planned End of Induction Epoch (EOI)) should 
be performed approximately four weeks after their last dose of study treatment (secukinumab 
or placebo) and then the subject should enter the follow-up epoch.


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Maintenance epoch (Week 12 dosing to Week 52)
The Maintenance epoch is defined from dosing at Week 12 (first dose of the Maintenance 
epoch) through Week 52. At Week 12, non-responders of the induction placebo treatment 
group will be reassigned to 300 mg secukinumab, as described above. Initially they will 
receive an active loading regimen with 5 weekly doses, identical to the induction epoch for 
those subjects who were initially randomized to receive secukinumab. To ensure a double-
blind design, all subjects in the other treatment arms will receive as well 5 weekly doses 
starting Week 12 up to Week 16, that will either be active or placebo doses, depending on 
their 4-weekly treatment schedule (150 mg or 300 mg secukinumab groups will receive 4-
weekly active treatment at Week 12 and Week 16, and placebo treatment at Week 13, 14 and 
15 and placebo PASI 75 responders will receive only placebo). The dose given at Week 12 is 
the first dose of the maintenance epoch and is followed by doses of secukinumab study 
treatment and / or placebo weekly up to Week 16, as described above, and every four weeks 
up to Week 48 for all treatment arms. The Week 52 Visit is the end of maintenance visit 
(EOM).
Subjects who complete the maintenance treatment epoch will enter the post-treatment follow-
up epoch or join a possible extension study, if available.
In addition, for subjects who discontinue study treatment prematurely for any reason before 
the end of the maintenance epoch, visit Week 52 (planned End of Maintenance Epoch (EOM) 
visit) should be performed approximately four weeks after their last dose of study treatment 
(secukinumab or placebo) and then the subject should enter the follow-up epoch.
Follow-up epoch (Week 52 to Week 60)
Subjects who discontinue the study prematurely for any reason will have EOI/EOM visits, 
approximately 4 weeks after receiving the last dose of study treatment and should enter the 
follow up epoch.
The treatment-free follow-up visits (no study treatment administered during follow-up epoch) 
will be at Week 56 (Follow-up visit F4, which is 4 weeks after the EOM visit but 8 weeks 
post last dose of secukinumab or placebo secukinumab) and Week 60 (Follow-up visit F8 (or 
End of Follow-up (EOF)), which is 8 weeks after the EOM visit  but 12 weeks post last dose 
of secukinumab or placebo.
3.2
Rationale for study design
The double-blind, randomized, parallel-group, placebo-controlled design used in this study is 
aligned with similar phase III trials of other systemic therapies for psoriasis and psoriatic 
arthritis including biologics and immunomodulatory drugs, and complies with guidelines and 
feedback of the Health Authorities, including the United States Food and Drug Administration 
(FDA), the European Medicines Agency (EMA) and the Pharmaceuticals, Medical Devices 
Agency of Japan (PMDA) and CFDA requirement in use of biologic drug. Primary endpoint 
of the trial is assessed after 12 weeks, allowing for comparisons of efficacy at a point in time 
which is common to all currently approved/available systemic therapies of psoriasis. The total 
study duration, including one year of treatment plus the follow-up period, will allow for the 
assessment of long term safety and efficacy. Blinding is maintained beyond the primary 
endpoint, to ensure reliable efficacy measures beyond the induction period of 12 weeks. 


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Regular assessments of disease activity and clinical status ensure close monitoring of subject 
safety and give steady occasions to both the subjects and the investigators to decide if 
continuous participation in the study does benefit the subjects.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The proposal to use doses of 300 mg and 150 mg s.c. administered with a loading regimen for 
induction, and treatment every four weeks for maintenance is based on a wealth of dose -
response relationship data from four phase II studies of secukinumab in psoriasis 
(CAIN457A2102, CAIN457A2211,CAIN457A2212, CAIN457A2220), and the results from 
several phase III studies (CAIN457A2302, CAIN457A2303, 
CAIN457A2304,CAIN457A2307, CAIN457A2308, CAIN457A2309); ~4160 subjects 
randomized, and ~3310 subjects exposed to secukinumab).
The proposal to use a dose of 300 mg s.c. administered with a weekly regimen (randomization, 
week 1, week 2, and week 3) followed by and treatment every 4 weeks thereafter (started at 
week 4) is based on the outcome of the Phase III studies (CAIN457A2302 and 
CAIN457A2303).
Study CAIN457A1101 in healthy Japanese male subjects did not show differential ethnic 
sensitivity to study materials. Hence, it is considered appropriate to treat the Asian population 
with the same doses as the non-Asian population.
The proposed induction regimen is also supported by analyses using data from four of the 
psoriasis studies (CAIN457A2102, CAIN457A2211, CAIN457A2212, and CAIN457A2220), 
which predict a notably better PASI 75 response rate of the proposed loading regimen after 
twelve weeks of treatment (see Figure 3-2) when compared to the response rates observed in 
study CAIN457A2211. In contrast, the predicted efficacy of a 75 mg dose also depicted in the 
graph does not promise to deliver acceptable efficacy.


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Figure 3-2
Simulated PASI 75 response rates
a) Simulated PASI 75 response rates for the two doses proposed to be utilized in phase III (150 mg 
and 300 mg), plus for the rejected dose of 75 mg, for a treatment duration of twelve weeks with the 
proposed induction regimen (subcutaneous administration at Weeks 0, 1, 2, 3, 4, and 8).
b) Shown are the simulated response rates at the time point of twelve weeks, with the respective 95% 
prediction intervals.
The purpose of a maintenance regimen is to maintain subjects within clinically meaningful 
limits of responsiveness to the treatment. For psoriasis, successful maintenance is usually 
defined as maintaining the subjects on PASI 75 response at least.
Secukinumab 300 mg has been accepted as the recommended dose in all countries with a 
regulatory approval in psoriasis to date. 
3.4
Rationale for choice of comparator
Due to the nature of psoriasis and the outcome measures used (PASI and IGA mod 2011 
scores), a placebo arm is necessary to obtain reliable efficacy measurements. Moreover the 
inclusion of a placebo group is in accordance with health authority guidelines and feedback 
(see CHMP guidelines for psoriasis (CHMP/EWP/2454/02 2004).  The choice of placebo 
control is a standard requirement to ascertain study sensitivity due to the seasonal and 
fluctuating character of chronic plaque-type psoriasis.  
The continuation of the placebo group up to the primary endpoint at Week 12 is accepted for 
the indication of psoriasis. Subjects who do respond to placebo treatment (based on 
achievement of a PASI 75 response) will remain in the placebo arm beyond Week 12 and not 


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be re-assigned to secukinumab for the maintenance period, as they do not require active 
treatment.  This will ensure continuous blinding of allocation beyond the induction period. 
3.5
Purpose and timing of interim analyses/design adaptations
A Week 16 analysis is planned after all subjects have completed their Week 16 visit. This 
analysis will include primary endpoint data analysis at Week 12 visit, and in addition, Week 
16 visit data
. There is no intention to modify 
study design based on the Week 16 analysis. Additional subsequent interim analyses may be 
conducted to fulfill any requests from Health Authorities. Full analysis of all data will be 
performed at the end of the study. 
3.6
Risks and benefits 
Secukinumab (Cosentyx®) with a recommended dose of 300 mg was approved in 2014 in 
Japan, in 2015 in the US, in the EU, in Switzerland and other countries for the treatment of 
adults with moderate to severe plaque psoriasis. Secukinumab 150 mg is available as a 
powder for solution for injection, and as a solution for injection in pre-filled syringe or pre-
filled pen.  
Non-clinical studies and phase 2 and 3 clinical studies in adults have not shown any 
impediment to using secukinumab subcutaneously in human. In total approximately 4,500 
patients with moderate to severe plaque psoriasis were included in studies in the registration 
program. This included 3,430 patients treated with secukinumab in 10 phase 2/3 studies, 
2,727 of whom were treated for at least 6 months and 2,029 of whom were treated for at least 
48 weeks. 
In adult studies, secukinumab has shown an excellent efficacy profile in the treatment of 
moderate to severe chronic plaque psoriasis. Superiority of secukinumab 150 mg and 300 mg 
doses to placebo was demonstrated for the co-primary efficacy criteria of PASI 75 and IGA 
mod 2011 0 or 1 at 12 weeks in all 4 pivotal placebo-controlled trials (>62% for PASI 75 
and >48% for IGA mod 2011 0 or 1). Secukinumab at both doses was also found to be 
superior in efficacy compared to etanercept and placebo with a rapid onset of action in the 
etanercept and placebo-controlled studies, CAIN457A2302 and CAIN457A2303. 
Potential risks for subjects are as outlined in the approved product labeling. At this time, 
safety data including (1) AE data, laboratory parameters, available immunogenicity data from 
the completed studies, and (2) SAE data from the phase 3 studies do not show any other safety 
risk apart from the approved safety profile. The safety data from the completed and ongoing 
studies demonstrate a good safety profile which included an observed risk of infections in 
particular candida infections, neutropenia or hypersensitivity reactions that can be seen with 
administration of foreign proteins. Most of the infections were non-serious, mild to moderate 
in severity, clinically easily manageable and did not lead to treatment discontinuation. Cases 
of neutropenia were uncommon, generally mild to moderate and transient and did not lead to 
treatment discontinuation, and only a few cases were temporally associated with non-serious 
infections.
Subjects with pre-existing malignancies within the past 5 years are generally excluded from 
studies with secukinumab although there is no scientific basis to suggest that secukinumab 
would increase the risk for malignancies. 


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Based upon the results of the toxicology studies demonstrating lack of effect of secukinumab 
on fertility and embryo-fetal development, women of child bearing potential (WoCBP) can be 
included in studies with secukinumab, but pregnancy should be avoided by proven effective 
measures. No contraceptive measures are required for males participating in studies with 
secukinumab.
Subjects of Asian ethnicity who suffer from psoriasis have been included in several phase III 
studies. Across studies, subjects have been recruited in India, Japan, the Philippines, 
Singapore, South Korea, Taiwan, and Vietnam. Study CAIN457A1101 in healthy Japanese 
male subjects did not show differential ethnic sensitivity to study materials.
4
Population
The study population will consist of a representative group of male and female adult with 
moderate to severe chronic plaque-type psoriasis, poorly controlled by topical treatments 
and/or phototherapy and/or previous systemic therapy.
Disease severity in these subjects must justify systemic treatment. The requirement of PASI of 
at least 12 AND IGA mod 2011 of at least 3 AND a total BSA of minimum 10% reflects 
published guidelines (CHMP/EWP/2454/02 2004) and the outcome of discussions with health 
authorities. It is expected that between 10% and 30% of the recruited subjects will have 
psoriatic arthritis as comorbidity.
Approximately 536 subjects will be randomized in a 2:1:1 ratio into one of three treatment 
groups (secukinumab 300 mg, secukinumab 150 mg or placebo group) at approximately 45 
study sites. As this study may be used to support the registration of secukinumab in China and 
other countries, the majority of the patients will be enrolled in China, for example: 
approximately 80% from China and the rest from other countries.  Anticipating a screen 
failure rate around 30%, it is planned to screen a total of around 766 subjects. Subjects who 
drop out after randomization will not be replaced.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Subjects must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study related activity is performed. Where relevant, a legal 
representative will also sign the informed study consent according to local laws and 
regulations.
2. Men and women at least 18 years of age at the time of screening.
3. Chronic plaque-type psoriasis present for at least 6 months and diagnosed before Baseline.
4. Moderate to severe psoriasis as defined at Baseline by:

PASI score of 12 or greater, and

IGA mod 2011 score of 3 or greater (based on a scale of 0 – 4), and

Body Surface Area (BSA) affected by plaque-type psoriasis of 10% or greater.
5. Candidate for systemic therapy. This is defined as a subject having moderate to severe 
chronic plaque-type psoriasis that is inadequately controlled by:

topical treatment, and/or


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
phototherapy, and/or

previous systemic therapy.
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and 
guttate psoriasis) at Screening or Baseline.
2. Drug-induced psoriasis (i.e., new onset or current exacerbation from beta-blockers, 
calcium channel inhibitors or lithium) at Baseline.
3. Ongoing use of prohibited treatments. Washout periods detailed in the protocol have to be 
adhered to (Table 5-1). Subjects not willing to limit UV light exposure (e.g., sunbathing 
and / or the use of tanning devices) during the course of the study will be considered not 
eligible for this study since UV light exposure is prohibited.
Note: administration of live vaccines 6 weeks prior to Randomization or during the study 
period is also prohibited. 
4. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting 
IL-17 or the IL-17 receptor.
5. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days until the expected pharmacodynamic effect has returned to 
baseline, whichever is longer; or longer if required by local regulations
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
7. 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 (e.g. 20 weeks in EU).. 
Effective contraception methods include:

Total abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence, (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization: have had a surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking the 
study treatment; in case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 

Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other forms
or hormonal contraception that have complete efficacy (failure < 1%), e.g., hormone


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vaginal ring or transdermal hormone contraception or placement of an intrauterine 
device (IUD) or intrauterine system (IUS)
In case of use of oral contraception, women should have been stable on the same pill for a
minimum of 12 weeks before taking study treatment.
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

Surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy 
or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child-bearing potential.
8. Active ongoing inflammatory diseases other than psoriasis that might confound the 
evaluation of the benefit of secukinumab therapy. Also, underlying conditions (including, 
but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, 
endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator 
significantly immunocompromises the subject and/or places the subject at unacceptable 
risk for receiving an immunomodulatory therapy. In addition, current severe progressive 
or uncontrolled diseases which renders the subject unsuitable for the trial or puts the 
subject at increased risk, including 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 
9. Presence of:

Significant medical problems, including but not limited to the following: uncontrolled 
hypertension (systolic ≥ 160 mmHg and/or diastolic ≥ 95 mmHg), congestive heart 
failure (New York Heart Association status of class III or IV).

Subjects with a serum creatinine level exceeding 2.0 mg/dl (176.8 μmol/L).

Screening total white blood cell (WBC) count <2,500/μl, or platelets <100,000/μl or 
neutrophils <1,500/μl or hemoglobin <8.5 g/dl at screening
10. Chest X-ray, computed tomography (CT scan), or MRI with evidence of ongoing 
infectious or malignant process, obtained within 12 weeks prior to screening, and 
evaluated by a qualified physician.
11. Active systemic infections during the last two weeks (exception: common cold) prior to 
Baseline or any infection that reoccurs on a regular basis.
12. History of chronic or recurrent infectious disease, or evidence of tuberculosis infection as 
defined by a positive QuantiFERON® TB-Gold test (QFT) at screening. Subjects with a 
positive or indeterminate QFT result may participate in the study if full tuberculosis work 
up (according to local practice/guidelines) was completed within 12 weeks prior to 
Baseline and establishes conclusively that the subject has no evidence of active 
tuberculosis. If presence of latent tuberculosis is established, then treatment must have 
been initiated and maintained according to local country guidelines prior to Baseline.
13. History or current infection with human immunodeficiency virus (HIV) or hepatitis C; or 
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14. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for Bowen's disease, basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed).
15. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins).
16. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
Baseline.
17. History of hypersensitivity to any of study drug constituent 
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following study treatments:

Investigational therapy: secukinumab

Reference therapy: placebo
Secukinumab 150 mg syringes for s.c. injection will be provided in a 150mg 1 mL pre-filled 
syringe.
Secukinumab placebo for s.c. injection will be provided as a 1 mL pre-filled syringe matching 
the appearance of 150 mg secukinumab syringe; each placebo pre-filled syringe contains a 
mixture of inactive excipients, matching the composition of the secukinumab 150 mg dose. 
5.1.2
Additional treatment 
No additional treatment beyond investigational treatment described in Section 5.1.1 is used in 
this trial.
5.1.3
Treatment arms
At Baseline, approximately 536 subjects will be assigned to one of the following 3 treatment 
arms in a ratio of 2:1:1:

Secukinumab 300 mg regimen group: secukinumab 300 mg (two injections of the 150 
mg dose) administered at Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
and 48, and Placebo (two injections per dose) administered at Weeks 13, 14, and 15.

Secukinumab 150 mg regimen group: secukinumab 150 mg (one injection of the 150 
mg dose + one injection of placebo) administered at Baseline, Weeks 1, 2, 3, 4, 8, 12, 16, 
20, 24, 28, 32, 36, 40, 44, and 48, and Placebo (two injections per dose) administered at 
Weeks 13, 14 and 15.

Placebo group: placebo secukinumab (two injections per dose) administered at Baseline, 
Weeks 1, 2, 3, 4, and 8.


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Based on their response to the treatment during the Induction epoch of the study, assessed at 
the Week 12 visit, subjects on placebo will either remain on placebo during the Maintenance 
epoch of the study or be re-assigned to secukinumab 300 mg, as follows:

Placebo PASI 75 Non-responder (per definition in Section 6.4.2): secukinumab 300 mg 
(two injections of the 150 mg dose) administered at Weeks 12, 13, 14, 15, 16, 20, 24, 28, 
32, 36, 40, 44, and 48.

Placebo PASI 75 Responder (per definition in Section 6.4.2): placebo secukinumab (two 
injections per dose) administered at Weeks 12, 13, 14, 15, 16, 20, 24, 28, 32, 36, 40, 44 
and 48.
5.2
Treatment assignment and randomization 
At Baseline visit all eligible subjects will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. Randomization will be stratified by geographical region 
and presence of psoriatic arthritis collected at the Randomization Visit. The investigator or 
his/her delegate will contact the IRT after confirming that the patient fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the patient which 
will be used to link the subject to a treatment arm and will specify a unique medication 
number for the packages of investigational treatment to be dispensed to the subject. The 
randomization number will not be communicated to the caller.
The randomization numbers will be generated using the following procedure, to ensure that 
treatment assignment is unbiased and concealed from subjects 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 arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to packs containing the investigational drug(s).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Group.
5.3
Treatment blinding 
Subjects, investigator staff, persons performing the assessments and data analyst will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding, and will not be accessible by anyone else involved in the study. (2) the identity of 
the treatments will be concealed by the use of investigational treatment that are all identical in 
packaging, labeling, schedule of administration, appearance, taste and odor.
Unblinding will only occur in the case of subject emergencies (see Section 5.5.8) and at the 
conclusion of the study. 
The appropriate personnel from the study site and Novartis will assess whether study 
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inadvertently for any reason. Study treatment must be discontinued after emergency 
unblinding. However for the purpose of Week 16 analysis as well as for any additional
subsequent interim analyses that may be requested by Health Authorities, designated Novartis 
staff may be unblinded after Week 16 data base lock and subsequent locks, if any, to perform 
the analyses. Subjects, site staff, and study monitors will continue to remain blinded until 
study completion
5.4
Treating the patient 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5
Subject numbering 
Each subject is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a subject, the Subject Number will not be reused. 
Upon signing the informed consent form, the subject is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the patient to register them into the IRT. The site must 
select the CRF book with a matching Subject Number from the OC/RDC system to enter data. 
If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
epoch Study Disposition CRF.
5.5.1
Dispensing the study drug 
Each study site will be supplied with study drug in packaging of identical appearance.
The study drug packaging has a 2-part label. A unique randomization number is printed on 
each part of this label which corresponds to one of the 3 treatment arms.  Investigator staff 
will identify the study drug package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the patient, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number. 
5.5.2
Handling of study and additional treatment 
5.5.2.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels. Clinical supplies are to be dispensed only in accordance 
with the protocol. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the patient except for the medication number.


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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.
5.5.2.2
Handling of additional treatment 
Not applicable.
5.5.3
Instructions for prescribing and taking study treatment 
Each subject will require two boxes of syringe set (PFS) per dose throughout the study: 

Two secukinumab 150 mg PFS  (300 mg treatment arm) OR

One secukinumab 150 mg PFS and one secukinumab placebo 150 mg PFS (150 mg 
treatment arm) OR

Two secukinumab placebo 150 mg PFS (placebo treatment arm)
All study treatment kits assigned to the subject during the study will be captured in the IRT.
The syringes with the ready-to-use study treatment solution (PFS) will be provided. Study 
treatment will be administered subcutaneously throughout the study.
All doses of study treatment that are administered at the study site should be performed after 
the study assessments for the visit have been completed. The first study treatment 
administration will occur at the Randomization/baseline Visit, after all study scheduled 
assessments have been performed (and inclusion/exclusion criteria confirmed) and only after 
the scheduled blood samples have been drawn. 
The study treatment solution must be injected in non-affected areas of the skin. If possible, 
throughout the trial administer the study treatment to one of the following body regions, 
rotating the injection site from visit to visit: right thigh, left thigh, right stomach, left stomach, 
upper outer arm (when assisted by attendant).
Prior to administration the boxes containing the PFS with study treatment solution should be 
allowed to come to room temperature unopened before administration. Used PFS should be 
disposed immediately after use in a sharps container OR according to the regulatory needs of 
the respective countries. For details please refer to the “Patient Instructions For Self-
Administration”.
All doses of study treatment (secukinumab and placebo) will be administered at the study site, 
it is preferred that subject self-inject. However, if the subject is not able or not willing to self-
administer, administration will be performed by study site staff. At the randomization/baseline 
visit the subjects will be instructed by the site staff walking them through the “Patient 
Instructions For Self-Administration” on how to self-inject via PFS. For subjects willing to 
self-inject, the first administration should be performed under guidance and supervision of a 
site staff member. 
At all study site visits when pre-dose blood samples have to be drawn (Table 6-1), the study 
treatment will be injected only after the blood samples have been taken.


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At each site visit, all study assessments, including the completion of 
 
Patient’s global assessment (PtGA) Disease Activity and PtGA Pain questionnaires (as 
reported by subjects), should be completed prior to the injection of study treatment.
All dates and times of injections during the study must be recorded on the Dosage 
Administration Record eCRF. 
All kits of study treatment assigned by the IRT will be recorded in the IRT.
The investigator must promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed.
5.5.4
Permitted dose adjustments and interruptions of study treatment 
Investigational or other treatment dose adjustments and/or interruptions are not permitted.
5.5.5
Rescue medication
Rescue medication for psoriasis is not permitted in this study.
5.5.6
Concomitant medication 
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.
5.5.7
Prohibited medication
Use of any treatments displayed in Table 5-1 that could confound the efficacy are NOT
allowed during the study for any indication and wash-out periods for these treatments are 
indicated in Table 5-1.
The investigator should instruct the subject to notify the study site about any new treatments 
he/she takes after the start of the study treatment. All prohibited medications and significant 
non-drug therapies administered after the subject starts treatment with study treatment must be 
listed on the Concomitant medications eCRF or the Procedures eCRF.    
The use of the treatments listed in Table 5-1 is prohibited AFTER randomization for any 
indication, including psoriasis. These treatments need to be washed out before randomization 
as indicated. If the use of these treatments is required, then the subject should NOT be 
randomized into the study. If a prohibited treatment listed in Table 5-1 was used during the 
study, the subject must discontinue use of the prohibited treatment if he/she wishes to 
continue in the study.  At the discretion of the investigator, if the subject’s use during the 
study of a prohibited treatment listed in Table 5-1 presents undue safety risk for the subject, 
the subject should be discontinued from study treatment as per Section 5.6.2. If the subject 


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received a live virus vaccination during the study, the subject must discontinue study 
treatment.
During the screening, subjects will be allowed to use some active topical treatments for any 
indication in the following body regions: face, scalp, and genito-anal area. The active topical 
treatments are limited to: mild or moderate potency CS. The subject should stop using topical 
CS at least the day preceding randomization and is not allowed to use these topical CS for any 
indication at any time after randomization except as specified in the footnote for Table 5-1. 
Use of topical CS must be recorded on the Concomitant medications eCRF.
For all other body regions, a washout period of 2 weeks applies for all active topical 
treatments for any indication.
After the screening the use of concomitant medication for psoriasis in all body regions is 
restricted to bland emollients (not supplied by Novartis) and other non-medicated 
interventions (not listed in Table 5-1). The definition of “bland” excludes all topical 
medications that contain pharmacologically active ingredients. The use of bland emollients 
should be avoided during the 12 hours preceding a scheduled study visit. 
Table 5-1
Prohibited treatment
Prohibited treatmentsa, b
Washout period (before 
Baseline)
Alefacept, briakinumab, efalizumab, ustekinumab
6 months
Biological immunomodulating agents other than the above 
(e.g., adalimumab, etanercept, infliximab)
12 weeks
Other systemic immunomodulating treatmentsc
(e.g., MTX, cyclosporine A, corticosteroids, cyclophosphamide) 
4 weeks
Other systemic psoriasis treatments (e.g., retinoids, fumarates, 
apremilast)
4 weeks
Photochemotherapy (e.g., PUVA)  
4 weeks
Phototherapy (e.g., UVA, UVB) 
2 weeks
Topical treatment which is likely to impact the signs and 
symptoms of psoriasis (e.g., corticosteroids[CS], vitamin D 
analogues, pimecrolimus, retinoids, salicylvaseline, salicylic 
acid, lactic acid, tacrolimus, tar, urea, -hydroxy or fruit 
acids)d,e, f
2 weeks
Live vaccinations
6 weeks
Any investigational treatment (including IL23p19) or 
participation in any interventional trial
4 weeks or 5 half-lives 
(whichever is longer)


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Prohibited treatmentsa, b
Washout period (before 
Baseline)
Traditional Chinese medicine treatments of psoriasis and/or 
psoriatic arthritisg 
4 weeks
a If the prohibited treatment was used during the study for any indication, the subject must discontinue 
use of the prohibited treatment if he/she wishes to continue in the study.  
b In case of undue safety risk for the subject, the subject should discontinue study treatment at the 
discretion of the investigator.  If the subject received a live virus vaccination during the study, the 
subject must discontinue study treatment.
c Including intra-articular or peri-articular injections. Note that inhaled CS with only a topical effect (e.g., 
to treat asthma) are not considered “systemic immunomodulating treatments” and are therefore 
acceptable as co-medication. 
d Mild to moderate topical corticosteroids (CS) are allowed only during the screening , if used 
exclusively on the face, scalp and/or genito-anal area.  
e Mild to moderate topical CS in the screening should be stopped  at least the day  prior to 
randomization. 
f Topical corticosteroids and other topical treatments will be allowed during the maintenance epoch 
only if (all must  apply):
•medication was started after the Week 12 visit was completed;
•medication was used for 14 consecutive calendar days or less;
•medication was used for an indication other than psoriasis and not on the area affected with 
psoriasis.
g Traditional Chinese medicine (TCM) is defined as a compendium of methods popular in Chinese 
tradition for the treatment of a wide range of conditions. TCM practitioners use herbal remedies, 
acupuncture, massage, mind-body and dietary therapies, and other methods. In the United States, 
TCM is considered part of complementary and alternative medicines (CAM).
There is no restriction on the use of anti-histamines and on the use of corticosteroids in the 
eye, nose or ear.
Subjects who are receiving treatments known to worsen psoriasis (e.g. beta-blockers, lithium) 
should be on stable dose for at least 4 weeks before Randomization Visit and during the study.
Exposure to light
Subjects need to be advised to limit exposure to UV light (including sunbathing and/or use of 
UV tanning devices) during the study to avoid possible effect on psoriasis.
5.5.8
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a patient, he/she must provide 
the requested patient identifying information and confirm the necessity to break the treatment 
code for the patient. The investigator will then receive details of the investigational drug 
treatment for the specified patient and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

patient number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
Study treatment must be discontinued after emergency unblinding.
The appropriate personnel from the study site and Novartis will assess whether study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
5.6
Study Completion and Discontinuation 
5.6.1
Study completion and post-study treatment 
A subject will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.
5.6.2
Discontinuation of Study Treatment 
Subjects may voluntarily discontinue study treatment for any reason at any time. 
The investigator/qualified site staff should discontinue study treatment for a given subject if, 
on balance, he/she believes that continuation would be detrimental to the subject’s well-being.
If discontinuation occurs for any reason in the induction or maintenance epoch, the 
investigator/qualified site staff must make every effort to determine the primary reason for a 
subject’s discontinuation from the study.  This information will then be recorded by 
investigator/qualified site staff on the applicable end of study epoch eCRF. 
Study treatment must be discontinued under the following circumstances: 

Emergence of the following AEs: AEs that in the judgment of the investigator/qualified 
site staff, taking into account the subject’s overall status, prevent the subject from 
continuing study treatment (for example sepsis).

Any laboratory abnormality that in the judgment of the investigator/qualified site staff, 
and taking into consideration the subject’s overall status, prevents the subject from 
continuing study treatment. 

Pregnancy (see Section 6.5.6 and Section 7.4) 

Use of ongoing prohibited treatment as per recommendations in Section 5.5.8. 

Emergency unblinding.

Any protocol deviation that results in a significant risk to patient’s safety.
Subjects discontinued from study treatment will NOT be considered discontinued from the 
study. On the applicable end of treatment epoch eCRF (EOI and EOM completion eCRFs), 
the investigator/qualified site staff must record the date and primary reason for stopping study 
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At the time of the study treatment discontinuation visit, if it has been approximately 4 weeks 
post last dose of study treatment then the assessments described at the EOI Visit Week 12 (for 
early discontinuation during induction epoch) or the EOM Visit Week 52 (for early 
discontinuation during maintenance epoch) should be completed at this visit and the subject 
should then return per appropriate schedule for the visits F4 and F8.
If it has not been approximately 4 weeks post last dose of study treatment at the time of the 
study treatment discontinuation visit, then the subject should be scheduled to return 4 weeks 
post last dose for their EOI or EOM visit as appropriate, respectively, and then the subject 
should return per appropriate schedule for follow up visits F4 and F8.
The investigator must contact the IRT as soon as possible, to register the subject’s early 
completion of the study (induction or maintenance epochs, respectively) due to study 
treatment discontinuation. 
Study treatment must be discontinued after emergency unblinding.
The appropriate personnel from the study site and Novartis will assess whether study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason.
5.6.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
and

Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the patient’s decision to withdraw his/her consent and record 
this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in 
Table 6-1.
5.6.4
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 


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telephone calls, registered letters, etc. A patient cannot be considered as lost to follow-up until 
the time point of his/her scheduled end of study visit has passed.
5.6.5
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
An ‘S’ indicates the data for that assessment are in the source documents at the site. 
Subjects should be seen for all visits on the designated day or as closely as possible to the 
original planned visit schedule. 
If for any reason the subject is a screen failure, the subject may be rescreened. There is no 
restriction on the number of times a potential subject may be rescreened or on how much time 
must pass from the date of screen failure and the date of rescreening. 
If a subject rescreens for the study, then the subject must sign a new ICF and be issued a new 
subject number prior to any screening assessment being conducted for the subject under the 
new screening subject number. For all subjects, the investigator/qualified site staff will record 
if the subject was rescreened on the rescreening CRF and any applicable screening numbers 
the subject was issued prior to the current screening number.
The date of the new informed consent signature must be entered on the Informed consent CRF 
to correspond to the new screening subject number. Informed Consent for a rescreened subject 
must be obtained prior to performing any study-related assessment or collecting any data for 
the Screening Visit. For rescreening, all screening assessments must be performed as per 
protocol, except for the tuberculosis (TB) work up, if applicable, if performed not more than 
12 weeks before randomization.
If the date of a TB work up is less than 12 weeks from the projected randomization date, then 
it is not required that the TB work up be repeated. However, the subject must repeat the 
Quantiferon® test performed by the central laboratory. 
During the treatment period, subjects may be seen at an unscheduled visit, e.g., if they 
experience deterioration of psoriasis and/or psoriatic arthritis, or AEs that in the opinion of the 
investigator need intervention or repeated laboratory testing. During these unscheduled visits, 
study treatment will NOT be administered.
Subjects who discontinue study treatment will continue to be followed for safety assessments. 
They are not considered withdrawn from the study.
Subjects who discontinue study treatment before completing the study, and those who 
prematurely withdraw from the study for any reason should be scheduled for a study visit 4 
weeks after their last study treatment administration, at which time all the assessments listed 


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for EOI (Week 12)/ EOM (Week 52) will be performed. Then, subjects should return to the 
study site for further assessments as indicated under the follow-up visits (F4 and F8). 
If a subject refuses to return for these assessments or are unable to do so, every effort should 
be made to contact them or a knowledgeable informant by telephone or by sending 
appropriate correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g., 
potential occurrence of AE or SAE) and the primary reason for a subject’s premature 
withdrawal should be determined.
At a minimum, subjects who pre-maturely discontinue the treatment will be contacted for 
safety evaluations during the 12 weeks following the last dose of study treatment, including 
final contact at the 12 week point. Documentation of attempts to contact the subject should be 
recorded in the subject record.
Suggested order of assessments:
The recommended order of assessments, as applicable at the respective visits, is:

Patient-reported outcomes (PROs) prior to any assessments made by the investigator, in 
the following order: 
 and in subjects with psoriatic arthritis only:
PtGA 
Disease Activity, PtGA Pain.

Investigator assessments in the following order: IGA mod 2011, PASI, PhGA PsA 
Activity (in subjects with psoriatic arthritis only).

Tender and swollen joint count* 

All remaining procedures (e.g., laboratory sample collection, vital signs) must be 
completed prior to study treatment administration.

PASI and IGA mod 2011 assessments are recommended to be recorded in the eCRF 
before contacting IRT (at Baseline and Week 12 visit).

Contact IRT to register the subject visit.

Study treatment administration.
* At baseline tender and swollen joint count assessment will be completed before initiating 
PROs and PhGA PsA in order to decide if a subject should complete the PROs related to 
psoriatic arthritis. 


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Table 6-1
Assessment schedule
Epoch
Scr
Induction
Maintenance
Unschedule
d  visit d
FUc
Week (relative to baseline)
≥-4 
to
≤-1
B
1
2
3
4
8
12a
13
14
15
16
20
24
28
32
36
40
44
48
52b
56
60
Day 
≥-
28 
to
≤-7
1
8
15
22
29
57
85
92
99
106
113
141
169
197
225
253
281
309
337
365
393
421
Informed consent
X
Subject demographics
X
Inclusion / exclusion criteria1
X
S
Smoking history
X
Medical history of Ps and PsA / 
previous therapies
X
Other medical history, including 
Cardiovascular history, and 
prior medications
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
S
S
S
S
S
S
S
S
S
S
S
S
S
Height
X
Weight
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (local laboratory)
X
X
X
X
X
Hematology / blood chemistry2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lab samples2: 
plasma glucose, lipid panel
X
hsCRP2
X
X
X
X
X
X
X


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Protocol No. CAIN457A2318
Epoch
Scr
Induction
Maintenance
Unschedule
d  visit d
FUc
Week (relative to baseline)
≥-4 
to
≤-1
B
1
2
3
4
8
12a
13
14
15
16
20
24
28
32
36
40
44
48
52b
56
60
Day 
≥-
28 
to
≤-7
1
8
15
22
29
57
85
92
99
106
113
141
169
197
225
253
281
309
337
365
393
421
QuantiFERON® TB-Gold test2
X3
X
Hepatitis and HIV screen,9
X
Serum pregnancy test2,4
X
X4
Urine pregnancy test (local lab)4
X
X
X
X
X
X
X
Chest X-ray6
S
ECG (standard 12 lead)
X
X
X
X
X
X
X
PASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IGA mod 2011
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CASPAR10
X
Swollen/tender joint count8, 10
X
X
X
X
X
PtGA-A (VAS)8
X
X
X
X
X
PtGA-P (VAS)8
X
X
X
X
X
PhGA PsA (VAS)8
X
X
X
X
X
ESR8,11
X
X
X
X
X
HAQ-DI8
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. CAIN457A2318
Epoch
Scr
Induction
Maintenance
Unschedule
d  visit d
FUc
Week (relative to baseline)
≥-4 
to
≤-1
B
1
2
3
4
8
12a
13
14
15
16
20
24
28
32
36
40
44
48
52b
56
60
Day 
≥-
28 
to
≤-7
1
8
15
22
29
57
85
92
99
106
113
141
169
197
225
253
281
309
337
365
393
421
SAE assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization via IRT12
X
X
Dispense study treatment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening epoche-CRF
Completion
X
End of induction:
submit induction epoch 
completion  eCRF and call IRT 
Xa
End of maintenance:
submit maintenance epoch 
completion eCRF and call IRT
X
End of follow-up:
submit follow-up epoch 
completion eCRF
X
B=Baseline, Scr=screening, hsCRP=high sensitivity C-reactive protein, eCRF=electronic case report form, SAE=serious adverse event, 
 
 VAS=visual analog scale, IRT=interactive response technology, Ps=psoriasis, PsA=psoriatic arthritis
X = to be recorded in the clinical database; S = to be recorded in source documentation only
a All induction epoch assessments must be performed prior to dosing. 
b During Visit Week 52, subjects will have their last assessments performed for the maintenance treatment epoch and will enter the post-treatment follow up epoch or
join a possible extension study, if available (only applicable for completers of the maintenance epoch. Visit Week 52 is also to be done for early study discontinuations 
from the maintenance epoch.
c
All subjects who discontinue prematurely from the induction or maintenance epochs should enter the follow-up epoch. 


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Protocol No. CAIN457A2318
Epoch
Scr
Induction
Maintenance
Unschedule
d  visit d
FUc
Week (relative to baseline)
≥-4 
to
≤-1
B
1
2
3
4
8
12a
13
14
15
16
20
24
28
32
36
40
44
48
52b
56
60
Day 
≥-
28 
to
≤-7
1
8
15
22
29
57
85
92
99
106
113
141
169
197
225
253
281
309
337
365
393
421
d The assessment(s) to perform at unscheduled visits are at the investigator’s discretion.
1 The outcome of these assessments is filed with the source documentation. Data regarding the Inclusion/Exclusion screen are captured in the eCRF.
2 Samples will be shipped to and analyzed by a central laboratory. 
3 If the first QuantiFERON® TB-Gold In-Tube test is indeterminate, the investigator may choose to perform a second QuantiFERON® TB-Gold In-Tube test (as part of an 
unscheduled visit) or refer the subject for tuberculosis workup per local guidelines. If the result of any QuantiFERON® TB-Gold In-Tube test is “positive” or the results 
of 2 successive QuantiFERON® TB-Gold In-Tube tests are ”indeterminate”, the subject must be referred to have a tuberculosis workup per local guidelines (if no 
workup within 12 weeks prior to randomization is available). The subject will not be eligible for randomization if active tuberculosis is present or if latent tuberculosis is 
present and is untreated according to local guidelines. No QuantiFERON® TB-Gold In-Tube test is to be conducted after the subject is randomized.
4 In case of positive urine pregnancy test, study treatment must be withheld and serum pregnancy test is performed at the same visit. Urine testing for pregnancy is not 
required for sterile or post-menopausal women.
5
6   No new chest X-ray is needed in subjects with chest X-ray or chest CT scan or MRI performed within 12 weeks of screening. 
7
8 ACR criteria component. Only in subjects with psoriatic arthritis (PsA) and who have at least 3 tender and 3 swollen joints at baseline (at baseline tender and swollen 
joint assessment will be performed for all subjects with medical history of PsA).
9 Screening for hepatitis and HIV is required. Hepatitis testing will include hepatitis B surface antigen (HBsAg) and HCV antibodies. Positive HIV screening will be 
confirmed by alternative technique available at the laboratory, e.g., Western blot. 
10 Conducted at baseline on all subjects with medical history of PsA.
11 Central lab will supply kits for ESR however the ESR test will be conducted at the site.
12 The PASI score and Investigator’s Global Assessment eCRF must be completed prior to contacting IRT for randomization. At the screening visit, the investigator must 
confirm that the subject meets IGA mod 2011, PASI and BSA eligibility before randomizing the subject. At the Week 12 visit, PASI 75 status from the PASI score 
eCRF must be available for entry into IRT.  


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6.1
Information to be collected on screening failures 
Subjects who sign the informed consent form and discontinue prior to randomization at 
Baseline are considered screening failures.
If a subject discontinues before entering the double-blind treatment period, the IRT must be 
notified within 5 days and the reason for not being randomized will be entered on the 
Screening Phase Disposition electronic Case Report Form (eCRF). The Screening visit date, 
the Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion Criteria eCRF and 
Subject rescreening eCRF must be completed. The Adverse Event eCRF and an SAE form 
should be completed for any serious adverse event (SAEs) that occurred during the screening 
epoch. The Withdrawal of consent eCRF should be completed if consent was withdrawn 
during the screening epoch before the subject was randomized.  The Death eCRF should be 
completed in the case of a death during the screening epoch.  
All patients who have signed informed consent but not entered into the next epoch will have 
the study completion page for the screening epoch, demographics, inclusion/exclusion, and 
serious adverse event (SAE) data collected. Adverse events that are not SAEs will be 
followed by the investigator and collected only in the source data.
6.2
Patient demographics/other baseline characteristics 
6.2.1
Demographics
Subject demographic data will include: date of birth (might be restricted to the year only due 
to applicable local data protection regulations), sex, race, ethnicity, and child-bearing 
potential (for females only).
6.2.2
Psoriasis medical history / Previous psoriasis therapies
The following information should be collected and entered in the Psoriasis history eCRF in 
addition to pre-psoriasis therapies: 

The start date of plaque psoriasis.

The date of first diagnosis of psoriatic arthritis (by a physician).

The previous treatments of psoriasis/psoriatic arthritis (including previous use of biologic 
therapies, as well as phototherapy and/or photo chemotherapy) and the reason for 
discontinuation.

Relevant psoriasis/psoriatic arthritis medical history and current medical condition, e.g., 
status of TNFα inhibitor responsiveness. 
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 medical history
Any information pertaining to cardiovascular medical history should be assessed prior to 
randomization.


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6.2.5
Relevant medical history/current medical conditions
Relevant medical history and current medical conditions present before signing the informed 
consent should be recorded in the Medical History eCRF.
Relevant medical history/current medical condition data includes data up to 6 months prior to 
signing of the informed consent and until the start of study treatment. Whenever possible, 
diagnoses and not symptoms should be recorded.
Any information pertaining to psoriasis or cardiovascular medical history assessed prior to 
randomization should be reported.
Chest X-ray 
No new chest X-ray is needed in subjects with chest X-ray or chest CT scan or MRI 
performed within 12 weeks of screening.  This is aimed to detect ongoing infection and 
particularly tuberculosis or malignancy.
If the chest X-ray, CT scan, or MRI evaluated by a qualified physician reveals an evidence of 
untreated infections or malignancies the subject will not be enrolled into the study.
Hepatitis and human immunodeficiency virus (HIV) screen
Screening for hepatitis and HIV is required.
6.2.6
Determination of the tuberculosis status
Determination of the tuberculosis (TB) status will be required before administration of study 
treatment and should be performed as defined by local guidelines. The TB status must be 
determined by medical history, signs, symptoms, TB testing (QuantiFERON-TB Gold assay). 
QuantiFERON TB-Gold In-Tube assay
A QuantiFERON® TB-Gold In-Tube assay (QFT) to screen a population for latent 
tuberculosis infection (Doherty et al 2008) will be used at screening to evaluate the subjects’ 
eligibility for the study. This blood-based assay is specific for Mycobacterium tuberculosis 
and is not influenced by previous Bacillus Calmette-Guérin vaccination or by exposure to 
other Mycobacteria species. Furthermore, 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 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 
to investigators in the study-specific laboratory manual.
Positive or indeterminate tests must be recorded on the source document. The workflow of 
sample handling in case of positive or indeterminate test results is provided in Figure 6-1. 

If the test result is negative, the subject may be randomized.

If the test result is positive, the investigator should perform workup for the test result 
as per local procedures. If a TB workup was conducted prior to screening the subject, 
results of the workup can be used to assess eligibility if the workup was conducted 
within 12 weeks prior to randomization.
o
Subjects 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.


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o
Subjects positive for active TB per workup are not eligible for the study.
o
Subjects negative for TB (no signs of latent or active TB) per workup may be 
randomized to the trial.

If the test result is indeterminate, the investigator may repeat the test once or may 
proceed directly to perform workup for the test result as per local procedures. This 
action is at the discretion of the investigator. If a TB workup was conducted prior to the 
screening the subject, results of the workup can be used to assess eligibility if the 
workup was conducted within 12 weeks prior to randomization.
o
If the second test is negative, the subject may be randomized.
o
If the second test is positive or indeterminate, the investigator should perform 
workup as per local guidelines. Subject 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. 
Subjects positive for active TB per workup are not eligible for the study. Subjects 
negative for TB per workup (no signs of latent or active TB) may be randomized 
to the trial.

If eligibility is being assessed with only 1 test result and a TB workup (i.e., no second 
TB test will be performed), the TB test to assess eligibility must have been done via the 
central laboratory for the study within the screening epoch (within 4 weeks prior to 
randomization) and TB workup will only be considered if it was completed within 12 
weeks prior to randomization. Subjects 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. Subjects 
positive for active TB per workup are not eligible for the study. Subjects negative for 
TB per workup (no signs of latent or active TB) may be randomized to the trial.


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Figure 6-1
Tuberculosis screening flowchart
6.2.7
Diagnosis of psoriatic arthritis (PsA) – CASPAR  
All subjects with a medical history of PsA during the screening epoch will be assessed to 
establish if there is a diagnosis of PsA per the ClASsification of Psoriatic ARthritis (CASPAR) 
criteria according to (Taylor et al 2006). The CASPAR assessment data are to be available to 
the study investigator prior to the randomization visit as specified in Table 6-1.


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In order to establish the diagnosis of psoriatic arthritis, at least 3 points out of the five 
ClASsification of Psoriatic ARthritis (CASPAR) criteria according to (Taylor et al 2006) must 
be met (see Appendix 2): 
1. Evidence of current psoriasis, or personal history of psoriasis, or a family history of 
psoriasis

Current psoriasis is defined as psoriatic skin or scalp disease present today as judged 
by a rheumatologist or dermatologist (2 points)

Personal history of psoriasis is defined as a history of psoriasis that may be obtained 
from a subject, family physician, dermatologist, rheumatologist, or other qualified 
health care provider (1 point, unless current psoriasis was present)

A family history of psoriasis is defined as a history of psoriasis in a first- or second-
degree relative according to the subject (1 point, unless current psoriasis was present 
or personal history of psoriasis
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 but 
preferably by an Enzyme-Linked Immunosorbent Assay (ELISA) or nephelometry, 
according to the local laboratory reference range (1 point)
4. Either current dactylitis (defined as swelling of an entire digit), OR a history of dactylitis 
(recorded by a rheumatologist) (1 point)
5. Radiographic evidence of juxtaarticular 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).
6.2.8
Other baseline characteristics
Baseline characteristic data to be collected on all subjects include (all laboratory results are
central except where indicated): ECG, vital signs; hematology; clinical chemistry; local
urinalysis; serum pregnancy test; past medical history record of HIV, hepatitis B or hepatitis C 
status; 
 PASI; IGA mod 2011; 
; Swollen/tender joint count, HAQ-DI, 
PtGA-Activity, PtGA-Pain and PhGA PsA.
6.3
Treatment exposure and compliance 
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record eCRF page. Compliance to the planned administration schedule is
expected to be high since the study treatment will be administered in the presence of the
investigator or study personnel. Compliance will also be assessed by means of site and 
subject-specific drug accountability by Novartis study personnel during the site 
monitoring visits using medication pack numbers, Drug Label Form information and
information collected by IRT.
6.4
Efficacy
All efficacy assessments should be performed by qualified site personnel. The following order
should be applied when performing the efficacy assessments at study visits:

Investigator’s Global Assessment for general psoriasis (IGA mod 2011; scale from 0 – 4)


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
Psoriasis Area and Severity Index (PASI; score from 0 – 72)

ACR response (in subjects with PsA)
6.4.1
Investigator Global Assessment (IGA mod 2011)
IGA mod 2011 will be conducted for overall psoriatic disease as indicated in Table 6-1 and 
Table 6-2. It is recommended that the same evaluator conduct the assessment throughout the
study whenever possible.
In collaboration with health authorities, in particular the FDA, the IGA mod 2011 scale (see 
Table 6-2) has been developed based on a previous version of the scale used in secukinumab 
phase 2 studies. The only change from the phase 2 scale to phase 3 scale was to condense 
the very severe and severe subjects into one category “severe”. The explanations/descriptions 
of the points on the scale have been improved to ensure appropriate differentiation between 
them.
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.
Table 6-2
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 eligible to participate in the study if the subject has an 
IGA mod 2011 score at baseline of 3 or 4.
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.
6.4.2
Assessment of total Body surface Area (BSA) and Psoriasis Area 
Severity Index
The PASI assessment will be completed as indicated in Table 6-1.  Whenever possible, the 
same evaluator should perform this PASI assessment at all visits.
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of 
areas affected, including head, trunk, upper limbs and lower limbs (see below for PASI 
assessment).  The following calculations will be done:  Each reported percentage will be 
multiplied by its respective body region corresponding factor (head = 0.1, trunk = 0.3, upper 


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limbs = 0.2, lower limbs = 0.4).  The resulting 4 percentages will be added up to estimate the 
total BSA affected by plaque-type psoriasis.  The PASI scoring system is further described in 
Table 6-3.
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 6-3.  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:
1. The neck is assessed as part of the head.
2. The axillae and groin are assessed as part of the trunk.
3. The buttocks are assessed as part of the lower limbs.
When scoring the severity of erythema, scales should not be removed.
Table 6-3
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=no 
involvement
1=>0-<10%
2=10-<30%
3=30-<50%
4=50-<70%
5=70-<90%
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=no 
involvement
1=>0-<10%
2=10-<30%
3=30-<50%
4=50-<70%
5=70-<90%
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=no 
involvement
1=>0-<10%
2=10-<30%
3=30-<50%
4=50-<70%
5=70-<90%
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=no 
involvement
1=>0-<10%
2=10-<30%
3=30-<50%
4=50-<70%


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5=70-<90%
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
The keys for the letters are provided in Table 6-3.  
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0.
A subject will be considered as a PASI 75 responder if he/she achieves a reduction of 75% or
more of the PASI score, compared to baseline, at a given time point.
At the end of the induction epoch, the PASI score will be calculated and subjects will be 
classified as PASI 75 responders or PASI 75 non-responders according to the definitions
stated below. Therefore, at EOI Visit Week 12, the investigator or qualified designee should
ensure that all the information required for the PASI calculation was entered into the PASI
Score eCRF at EOI Visit Week 12 and that a PASI score and PASI 75 responder status is
available prior to contacting IRT. The investigator or qualified designee will enter the EOI
Visit Week 12 PASI 75 responder status into the IRT system at EOI Visit Week 12 prior to
dosing.
During the study, at each visit, the PASI score will be calculated and response will be 
classified according to the definitions from CHMP guidelines for psoriasis CHMP/EWP/2454/ 
02 2004.

PASI 50 response: subjects achieving ≥ 50% improvement (reduction) in PASI score 
compared to baseline 

PASI 75 response: subjects achieving ≥ 75% improvement (reduction) in PASI score 
compared to baseline 

PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
compared to baseline 

PASI 100 response/remission: complete clearing of psoriasis (PASI=0)
In addition to the assessment of PASI, the investigator will assess whether new pustular 
psoriasis, or new erythrodermic psoriasis, or more inflammatorypsoriasis occurred (yes/no).


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6.4.5
Assessment of the American College of Rheumatology (ACR) 
response in subjects with psoriatic arthritis
Assessments related to psoriatic arthritis will be performed as indicated in Table 6-1. 
Evaluations to determine ACR response (ACR 20/50/70) include tender and swollen joint 
counts, HAQ-DI, PtGA Activity, PtGA Pain, PhGA PsA and acute phase reactant (ESR and 
hsCRP).  
The elements of the ACR scoring system are used in the same way as in standard trials of 
rheumatoid arthritis, with the exception of the number of joints tested, to include distal 
interphalangeal joints of the feet and carpometacarpal joints of the hands, i.e., 76 joints for 
tenderness and 78 joints for swelling. ACR 20, 50 or 70 responses correspond, respectively, to 
at least 20%, 50% or 70% improvement in comparison with baseline in the number of tender 
and swollen joint counts, in addition to similar improvements in at least three of five domains-
HAQ-DI measure of disability, acute phase reactant (CRP or ESR) and the VAS scores of 
PtGA Activity, PtGA Pain and PhGA PsA. 
6.4.6
Appropriateness of efficacy assessments 
The PASI score, the assessment of the severity of the psoriasis symptoms and the extent to 
which the subject’s body area is affected by the disease, is considered acceptable by health 
authorities (CHMP/EWP/2454/02 2004) to assess efficacy in conjunction with Investigator’s 
Global Assessment mod 2011 (IGA mod 2011). The efficacy assessments in patients with 
PsA co-morbidity are standardized measures used across many psoriatic arthritis trials and 
may be used to complement the knowledge base pertaining to the condition, as well as for 
regulatory filing.
6.5
Safety 
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 all AEs and SAEs including injection site hypersensitivityreactions, vital 
signs, laboratory assessments and occurrence of infections.

Physical examination

Vital signs

Height and weight

Laboratory evaluations (Hematology, Clinical chemistry, Urinalysis)

ECG

Pregnancy


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6.5.1
Physical examination
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, and extremities, vascular and neurological systems 
will be performed as indicated in Table 6-1
If indicated, based on medical history and/or symptoms, additional exams will be performed 
at the discretion of the investigator.
Whenever possible, assessments for an individual subject should be performed by the same 
member of the study site staff throughout the study.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the start of the study, i.e. all findings 
prior to signing the informed consent form (ICF), must be included in the Medical History 
screen in the subject’s eCRF. Significant findings after enrollment into the study that meets 
the definition of an adverse event must be recorded on the Adverse Event eCRF.
6.5.2
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 6-1. Whenever possible, assessments should be
performed by the same study site staff member throughout the study.
After the subject has been sitting for about five minutes, with back supported and both feet
placed on the floor, systolic and diastolic blood pressure will be measured twice and will
be recorded in the source documentation (measurements separated by 1 to 2 minutes)
using a validated device, with an appropriately sized cuff (Mancia et al 2007). In case the
cuff sizes available are not large enough for the subject’s arm circumference, a
sphygmomanometer with an appropriately sized cuff may be used. Both measurements will 
be entered on the Vital Signs eCRF. If possible, assessments should be performed by the same 
study site staff member throughout the study. 
Normal blood pressure will be defined as a systolic pressure of 90 to < 120mmHg, and a 
diastolic blood pressure of 60 to <80 mmHg under measurement conditions as outlined above. 
Notable blood pressure will be hypertension (systolic ≥ 140 mmHg and/or diastolic >90 
mmHg) or hypotension (systolic <90 mmHg and/or diastolic <60 mmHg). A blood 
pressure indicative of pre-hypertension (systolic 120 to <140 mmHg and/or diastolic 80 to < 
90 mmHg) will not be regarded as notable (Chobanian et al 2003).
A normal pulse rate will be defined as a rate of 60 to 100 beats per minute under the 
measurement conditions outlined above. Notable pulse rates are a rate below 60 bpm 
(bradycardia) or above 100 bpm (tachycardia).
No specific action is pre-defined within this protocol to respond to specific abnormal vital 
signs, as it will be decided by the investigator whether and which specific action needs to be 
taken to respond to any abnormal values, taking into account the overall status of the subject.
6.5.3
Height and weight 
Height and body weight will be measured as listed in Table 6-1.
Height and body weight will be measured in indoor clothing, but without shoes. Whenever,
possible, body weight assessments should be performed by the same study site staff 
member; the same scale should be used throughout the study.


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6.5.4
Laboratory evaluations
Subjects should avoid smoking within the hour preceding blood drawing.
A central laboratory will be used for analysis of all specimens listed below, unless noted 
otherwise. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual. Refer to the Laboratory 
Manual for identification of laboratory reference range values and the schema for notification of site 
staff and Novartis for out of range values. 
Appendix 1 shows the extended laboratory ranges that are considered clinically notable.
No specific action is pre-defined within this protocol to respond to specific abnormal 
laboratory values, as it will be decided by the investigator whether and which specific action 
needs to be taken to respond to any abnormal values, taking into account the overall status of 
the subject.
6.5.4.1
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured at all scheduled study visits, within the visit window suggested
in Table 6-1.
6.5.4.2
Clinical chemistry
Serum chemistry will include urea, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), 
GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, total 
protein, albumin, and uric acid. Serum chemistry will be measured at all scheduled study 
visits within the visit window specified in Table 6-1.
6.5.4.3
Urinalysis
Dipsticks will be provided by the central laboratory to the study sites for local urinalysis 
assessments. The sites will record the results in the appropriate eCRF page for each subject. 
Standard dipstick measurements for specific gravity, protein, glucose, pH, blood, urine blood 
dipstick (non-hemolyzed), urine blood dipstick (hemolyzed), bilirubin, ketones and WBC will 
be done at baseline as indicated in Table 6-1.


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6.5.5
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed as indicated in Table 6-1.
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. 
Although there is no exclusion criterion based on ECG results, the baseline ECG at the 
Randomization Visit must be reviewed locally for major abnormalities prior to dosing. 
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/ Current medical conditions/AE CRF / e(CRF) page as appropriate.
6.5.6
Pregnancy 
A serum β-hCG test will be performed in all women of child bearing potential as indicated in 
Table 6-1.
All women who are not sterile and all women who are not post-menopausal at screening will 
have a local urine pregnancy test as indicated in Table 6-1.
Any woman with a confirmed positive pregnancy test during screening is not eligible for 
randomization. A positive urine pregnancy test during the treatment periods of the study 


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requires immediate interruption of study treatment until a serum β-hCG is performed and
found to be negative. If the serum β-hCG test is positive, the subject must be discontinued
from the study treatment.
6.5.7
Appropriateness of safety measurements 
The safety measures used in this study are reliable and relevant standard measures for a 
biologic immunomodulating agent in psoriasis.  
6.6
Other assessments
The following additional assessments will be performed:

Clinician Reported Outcomes (swollen/tender joint count; PhGA PsA)

Patient Reported Outcomes (
 the following only in subjects with PsA- HAQ-DI, 
Patient’s global assessment of disease activity (Pt-GA Activity) and  Patient’s global 
assessment of pain (Pt-GA Pain)

Fasting laboratory evaluations

6.6.1
Clinical Outcome Assessments (COAs)
6.6.1.1
Clinician Reported Outcomes (ClinRO)
Tender 78-joint count and swollen 76-joint count (subjects with PsA only)
The assessment of tender (78 joints) and swollen (76 joints) joint count will be performed as 
indicated in Table 6-1 at baseline for all subjects with a medical history of PsA and later only 
for subject with PsA and who have at least 3 tender and 3 swollen joints at baseline. 
Whenever possible, the same evaluator should perform this assessment at all required visits.
The distal interphalangeal joints of the feet and the two first carpometacarpal joints of the 
hands are added to the usual ACR joint count of 68 tender and 66 swollen joints, to yield 78 
and 76 joint counts, respectively. Thus, the joints assessed for tenderness include the 8 distal 
interphalangeal, 10 proximal interphalangeal 10 metacarpophalangeal, and the 2 first 
carpometacarpal joints of the hands, and 10 metatarsophalangeal, 10 proximal interphalangeal 
and 8 distal interphalangeal joints of the feet, the 2 wrists, 2 elbows, 2 shoulders, 2
acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 hip, 2 knee, 2 talo-tibial, and 2 
mid-tarsal joints. All of these except for the hips are assessed for swelling. Joint tenderness
and swelling 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 are recorded for the joints which are positive. Data are 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. 
In addition, also the total number of tender and swollen joints (right and left) and the total 
number of right and left missing or not applicable tender and swollen joints will be recorded 
on the Tender and Swollen Joint Count (78/76) eCRF.


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Physician’s global assessment of disease activity, PhGA PsA (subjects with 
PsA only)
When a subject has PsA at baseline defined as at least 3 points out of the CASPAR criteria 
and at least 3 tender and 3 swollen joints at baseline, the rheumatologist or a qualified trained 
physician will complete the Physician’s Global Assessment of disease activity (PhGA PsA) 
using a visual analog scale (VAS) as indicated in Table 6-1.  Whenever possible, the same 
evaluator should perform this assessment at all indicated visits.
The investigator will be presented with the question ‘Considering all the ways psoriatic 
arthritis affects your patient, please indicate by tapping  on the horizontal line how would you 
rate his or her current condition?’  The investigator or qualified designee will then record the 
response using 100 mm VAS ranging from “very good” to “very poor” on the VAS.
To enhance objectivity, the investigator or qualified designee must not be aware of the 
specific subject assessments 
HAQ-DI, PtGA Activity and the PtGA Pain, prior to 
performing his own assessment on that subject. 
6.6.1.2
Patient Reported Outcomes (PRO)
The impact of study treatment on patient’s health status will be assessed by the following 
measures:
Health Assessment Questionnaire- Disability Index (HAQ-DI) (subjects with PsA 
only)
The Health Assessment Questionnaire (HAQ©) was developed by Stanford University and is 
one of the most widely used measures to assess the long-term influence of chronic disease on 
a subject's level of functional ability and activity restriction. Although originally developed 
for use in subjects with rheumatic disease, the HAQ has been employed across a large variety 


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of disease areas. The disability assessment component of the HAQ (Health Assessment 
Questionnaire© – Disability Index), the HAQ-DI, assesses a subject's level of functional 
ability and includes questions of fine movements of the upper extremity, locomotor activities 
of the lower extremity, and activities that involve both upper and lower extremities. There are 
20 items in eight categories of functioning including dressing & grooming, arising, 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 (without any difficulty [0]), with some difficulty (1), with 
much difficulty (2), and unable to do (3). The HAQ-DI also includes questions about the use 
of ‘aids or devices’ and aid from other people to supplement the answers given to the 20 items. 
The purpose of the HAQ-DI in this study is to assess the functional ability of subjects with 
PsA.
The HAQ-DI questionnaire will be completed as indicated in Table 6-1 by all subjects with  
PsA at baseline defined as at least 3 points out of 5 CASPAR criteria and at least 3 tender and 
3 swollen joints at baseline.  
Patient’s global assessments (subjects with PsA only)
When a subject has PsA at baseline defined as at least 3 points of the CASPAR criteria and at 
least 3 tender and 3 swollen joints at baseline, the subject will be asked to complete the 
following non-validated instruments as indicated in Table 6-1:

Patient’s Global Assessment of disease activity (PtGA Activity)
As indicated in Table 6-1, subject with PsA will be asked to complete the Patient’s Global 
Assessment of disease activity (PtGA Activity) using a visual analog scale (VAS).  
The subject will be presented with the question ‘Considering all the ways your psoriatic
arthritis affects you, please indicate by tapping on the horizontal line how well you are 
doing today.’  The subject will then record a self-assessment of disease activity using 100 
mm VAS ranging from “very good” to “very poor” on the VAS.

Patient’s Global Assessment of psoriatic arthritis pain (PtGA Pain)
As indicated in Table 6-1, subject with PsA will be asked to complete the Patient’s Global 
Assessment of psoriatic arthritis pain (PtGA Pain) using a visual analog scale (VAS).  
The subject will be presented with the question ‘Please indicate by tapping on the 
horizontal line the most pain you had from your psoriatic arthritis over the last 24 hours’.  
The subject will then record pain associated with psoriasis using 100 mm VAS ranging 
from “no pain” to “unbearable pain” on the VAS.
Completed questionnaires will be reviewed and examined by the investigator only after the 
clinical efficacy assessments (PASI and IGA), for responses that may indicate potential AEs 
or SAEs. The investigator should review not only the responses to the questions in the 
questionnaire but also for any unsolicited comments written by the subject. If AEs or SAEs 
are confirmed, then the physician must record the events as per instructions given in Section 7
of the protocol. Investigator should not encourage the subject to change the responses reported 
in the completed questionnaires.
6.6.1.3
Performance Outcomes (PerfO)
Not applicable.


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6.6.1.4
Observer Reported Outcomes (ObsRO)
Not applicable.
6.6.1.5
Proxy Reported Outcomes 
Not applicable.
6.6.2
Resource utilization
Not applicable.
6.6.3
Fasting Laboratory evaluations 
Fasting (8 hour duration with water ad libitum) laboratory evaluations will be assessed at 
baseline as indicated in Table 6-1. 
Subjects should avoid smoking within the hour preceding the blood draws. 
A central laboratory will be used for analysis of all fasting laboratory specimens. Details of 
the collections, shipment of samples and reporting of results by the central laboratory are 
provided to the investigators in the Laboratory Manual.
6.6.3.1
Plasma glucose
Fasting plasma glucose will be taken as a fasting blood sample as indicated in Table 6-1.
6.6.3.2
Lipid panel
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol,  triglycerides, lipoprotein (a), apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be measured from a fasting blood sample as indicated in Table 6-1.


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6.6.5
DNA sampling
Pharmacogenetics
Not applicable.
6.6.6
Other biomarkers 
Not applicable.
7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 


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by the patient during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information:

the severity grade:

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (yes/no)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
and which seriousness criteria have been met

action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

study treatment dosage increased/reduced

study treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

patient hospitalized/patient’s hospitalization prolonged (see Section 7.2 for definition of 
SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown).
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Worsening of psoriasis in this study is evaluated via the use of PASI, IGA mod 2011
 
 and is not expected to be captured as an AE in the eCRF. Exceptions 


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include cases when a) a new type of psoriasis is diagnosed e.g. guttate psoriasis) or b) the 
worsening of psoriasis is so severe that a qualitatively different status is reached.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the patient.
The investigator must also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (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 


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immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks following the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after the 12 weeks period following the last administration of study 
treatment should only be reported to Novartis if the investigator suspects a causal relationship 
to study treatment. Any SAEs reported up to the subject’s last visit will be reported in the AE 
eCRF. SAEs beyond that date will only be recorded in the Novartis Drug Safety and 
Epidemiology database.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete 
the SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to 
be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs.  The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
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7.3
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an 
AE/SAE.
Treatment error 
type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
7.4
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
8
Data review and database management 
8.1
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and 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 


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treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization.   
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the 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/subjects will be disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the database. The signed copy of the 
Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.


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Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed locally. 
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an Interactive Response Technology (IRT).  
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
Development management.
8.4
Data Monitoring Committee 
Data Monitoring Committee (DMC) is planned in this study. Details regarding the DMC will 
be available in the relevant DMC charter. 
8.5
Adjudication Committee 
An independent adjudication committee may be established. Details regarding the 
adjudication process will be available in the relevant Adjudication Committee charter. 
9
Data analysis 
The final analysis will be conducted on all subject data at the time the trial ends. 
A Week 16 analysis is planned to be performed after all subjects have completed Week 16 
visit.
 
 Additional 
subsequent interim analyses may be performed to fulfill any requests from Health Authority. 
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
Treatment groups for analyses will include: 

Induction epoch: secukinumab 150 mg, secukinumab 300 mg and placebo.

Maintenance epoch: secukinumab 150 mg, secukinumab 300 mg and placebo, as well as 
placebo-secukinumab 300 mg.
Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, lower quartile, median, upper quartile, maximum. Summary statistics for discrete 
variables will be presented in contingency tables and will include absolute and relative 
frequencies.
If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed.
9.1
Analysis sets 
The following analysis sets will be used in this trial:


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Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be 
excluded from the randomized set. 
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set 
to whom study treatment has been assigned. Following the intent-to-treat principle, subjects 
will be analyzed according to the treatment assigned to at randomization. 
Safety set (SAF): The safety set includes all subjects who took at least one dose of study
treatment during the treatment period. Subjects will be analyzed according to treatment 
received.
9.2
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and for all subjects.
Medical history
Any condition entered as medical history or current medical conditions at baseline will be 
coded using the MedDRA dictionary. Medical history will be summarized by system organ 
class and preferred term in the MedDRA dictionary. Summaries for psoriasis specific medical 
history will be provided as well.
9.3
Treatments 
Study treatments
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 by means 
of contingency tables. 
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number of subjects with exposure of at least certain thresholds (e.g., any 
exposure, ≥1 week, ≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, etc.) will be displayed.
Prior and concomitant treatments
Prior and concomitant treatments will be summarized by treatment group in separate tables 
for the safety set.
Prior treatments are defined as treatments taken and stopped prior to first dose of study 
treatment. Any treatment given at least once between the day of first dose of randomized 
study treatment and the last day of study visit will be a concomitant treatment, including those 
which were started pre-baseline and continued into the treatment period.
Treatments will be presented in alphabetical order, by ATC codes and main groups. Tables 
will also show the overall number and percentage of subjects receiving at least one treatment 
of a particular ATC code and at least one treatment in a particular anatomical main group.


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Psoriasis specific prior treatments will be presented as well including number of prior 
systemic and biologic psoriasis therapies as well as reason for discontinuation.
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized.
9.4
Analysis of the primary variable(s)
This section will detail the statistical analysis of the primary endpoint. Details of the 
hypothesis testing strategy including primary and secondary endpoints to handle multiplicity 
are provided in Section 9.5.1
9.4.1
Variable(s)
The co-primary efficacy variables are PASI 75 response at Week 12 and IGA mod 2011 0 or 
1 response at Week 12. The secondary variable is PASI 90 response at Week 12.
The analysis of the co-primary and secondary variables will be based on the FAS.
9.4.2
Statistical model, hypothesis, and method of analysis
The statistical hypotheses for PASI 75 response at Week 12 and IGA mod 2011 0 or 1 
response at Week 12 being tested is that any of the secukinumab groups are not superior to 
placebo in the proportion of subjects with PASI 75 response and IGA mod 2011 0 or 1 
response at Week 12.
Let pj denote the proportion of PASI 75 responders at Week 12 for treatment group j and rj
denote the proportion of IGA mod 2011 0 or 1 responders at Week 12 for treatment group j, 
j=0, 1, 2, where 

0 corresponds to placebo,

1 corresponds to secukinumab 150 mg,

2 corresponds to secukinumab 300 mg.
The following hypotheses will be tested
H1: p1 – p0 ≤ 0 versus HA1: p1 – p0 > 0,
H2: p2 – p0 ≤ 0 versus HA2: p2 – p0 > 0,
H3: r1 – r0 ≤ 0 versus HA3: r1 – r0 > 0,
H4: r2 – r0 ≤ 0 versus HA4: r2 – r0 > 0.
In other words:
H1:
secukinumab 150 mg is not superior to placebo with respect to PASI 75 response at 
Week 12
H2:
secukinumab 300 mg is not superior to placebo with respect to PASI 75 response at 
Week 12
H3:
secukinumab 150 mg is not superior to placebo with respect to IGA mod 2011 0 or 1 
response at Week 12
H4:
secukinumab 300 mg is not superior to placebo with respect to IGA mod 2011 0 or 1 
response at Week 12
The primary endpoint (PASI 75 and IGA mod 2011 0 or 1 response at Week 12) will be 
evaluated using an exact logistic regression model with treatment group, baseline body weight, 
geographical region, presence of psoriatic arthritis, and baseline PASI score as explanatory 


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variables. Odds ratios will be computed for comparisons of secukinumab dose regimens 
versus placebo utilizing the exact logistic regression model fitted. In case of rates of 0% or 
100% in one of the treatment groups, Fisher’s exact test will be applied.
PASI 90 response at Week 12 will be evaluated analogously to PASI 75 and IGA mod 2011 0 
or 1 response at Week 12 (i.e., exact logistic regression analysis) and the following 
hypotheses will be tested:
H5:
secukinumab 150 mg is not superior to placebo with respect PASI 90 response at 
Week 12
H6:
secukinumab 300 mg is not superior to placebo with respect PASI 90 response at 
Week 12
The graphical approach of Bretz et al. 2009 for sequentially rejective testing procedures is 
used to illustrate the testing strategy:
Figure 9-1
Testing strategy
One-sided p-values will be derived. The family-wise error will be set to α=2.5% (one-sided). 
The hypotheses are mapped into two sets (H1, H3, and H5) or (H2, H4, and H6) such that 
hypotheses within a set correspond to the same secukinumab dose regimen (150 mg or 300 
mg). In essence, the type-I-error probability will be equally split for both sets of hypotheses 
and within each set the hypotheses are tested sequentially as follows:
Within each pair of hypotheses (H1 or H3) and (H2 or H4) each hypothesis is tested at α/2. 
Only if both hypotheses of a pair are rejected, the testing sequence will continue and the PASI 
90 comparisons of secukinumab versus placebo are tested, H5 or H6 will be tested at α/2
(one-sided).
If all hypotheses within a set referring to a secukinumab dose regimen have been rejected, i.e., 
(H1, H3, and H5) or (H2, H4, and H6), the corresponding type-I-error probability can be 
passed on to the other group of hypotheses, and if needed, hypotheses can be retested at a new 
significance level.
9.4.3
Handling of missing values/censoring/discontinuations
Response variables based on PASI score and IGA mod 2011 score will be imputed with 
multiple imputation (MI) as primary imputation method for the missing values.
Multiple imputation (MI) is a simulation based approach where missing values are replaced 
by multiple Bayesian draws from the conditional distribution of missing data given the 
observed data and covariates, creating multiple completed data sets. These completed data 
sets can then be analyzed using standard methods. Within this analysis the PASI score or IGA 


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mod 2011 categories 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.
Non-responder imputation will be used as sensitivity method: Missing values with respect to 
response variables based on PASI score and IGA 2011 categories will be imputed with non-
response regardless to the reason for missing data (e.g. premature study discontinuation, 
missed visit, administrative issues), exceptions will apply to the following:

If a subject dropped out the study prior to last scheduled visit and being responder 
consecutively at least for two preceding visits, the subject will be imputed as 
responder for the last scheduled visit.

If a subject who was responder at visit x-1 and visit x+1 but has missing data at visit x, 
then the subject will be imputed as responder for visit x, except for the missing data at 
last visit in the treatment period.
Summary tables for PASI scores and IGA mod 2011 categories will be imputed using MI.
Inferential analysis of percentage change in PASI score will be done using a mix-effects 
repeated measures model (MMRM) which is valid under the missing at random (MAR) 
assumption.
Missing data for ACR response variables will be handled based on a three tiered approach for 
drop-outs, complete missing data, and partial missing data.
1. Subjects who drop out of the trial for any reason will be considered non-responders from 
the time they drop out through week 52.
2. Subjects 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 core set variables) at baseline and 
at the specific time point will be classified as non-responders.
For subjects who switch treatment after induction period, values of induction period are not 
carried forward to maintenance period.
Following the intent-to-treat principle for subjects who prematurely discontinue treatment, but 
who are observed in the follow-up period, efficacy data collected in follow-up periods will be 
linked to planned but missed study visits as well.
Baseline values will not be carried forward.
9.4.4
Sensitivity analyses 
Sensitivity analyses will be performed as follows:
PASI 75 and IGA mod 2011 0 or 1 response at Week 12 will be evaluated using an exact 
logistic regression model with non-responder imputations instead of multiple imputations for 
missing values.


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9.5
Analysis of secondary variables
9.5.1
Efficacy variables 
Maintenance of PASI 75 response after 52 weeks of treatment
Summary statistics as well as 95% confidence intervals will be presented for maintenance of 
PASI 75 response at Week 52 for the subset of subjects with PASI 75 response at Week 12 in 
the secukinumab treatment groups.
In addition, Kaplan-Meier estimates including 95% confidence intervals for cumulative rate of 
subjects losing PASI 75 response up to Week 52 will be calculated for the subset of subjects 
with PASI 75 response at Week 12 in the secukinumab treatment groups.
Maintenance of IGA 0 or 1 response after 52 weeks of treatment
The same analyses as planned for maintenance of PASI 75 response will be performed for 
IGA 0 or 1 response after 52 weeks of treatment, but analyses will be based on the subset of 
subjects with IGA 0 or 1 response at Week 12.
PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response over
time
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1
response by visit will be presented in contingency tables and will include absolute and relative
frequencies. Confidence intervals for response rates will be derived as well based on the score
method including continuity correction (Newcombe 1998).
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response at each visit
up to Week 12, each secukinumab dose regimen will be compared to placebo using an exact 
logistic regression model with treatment group, baseline body weight, geographical region, 
presence of psoriatic arthritis, and baseline PASI score as explanatory variables. 
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response the placebo-
adjusted response rates including 95% confidence interval will be derived by visit up to Week 
12. In addition, Fisher’s exact test will be applied to pairwise treatment group comparisons to 
placebo.
Figures will be provided as well displaying estimates for responder rates by treatment
including confidence intervals.
PASI score over time
Summary statistics will be provided for absolute PASI scores as well as for percent change 
from baseline by visit and treatment group. Figures will also be provided.
The percentage change from baseline of PASI score at different time points will be analyzed 
via mixed model repeated measures (MMRM). Treatment group, visit, geographical region, 
presence of psoriatic arthritis and baseline PASI score will be fitted as continuous covariate. 
Treatment group by visit and visit by baseline PASI score will be included as interaction term 
in the model. An unstructured correlation matrix will be used thus allowing adjustment for 
correlations between time points within patients. 


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IGA mod 2011 score over time
Summary statistics for the IGA mod 2011 score over time will be presented by visit and 
treatment group in contingency tables.
Time to PASI 75 response
Number and percentage of subjects with PASI 75 response based on the number of subjects in 
the FAS at risk as denominator will be provided by treatment group.
Between-treatment differences will be evaluated using a log-rank test, stratified by 
geographical region, presence of psoriatic arthritis, to compare the cumulative rates between 
secukinumab treatment groups versus placebo. The hazard ratios for the comparisons and 95% 
confidence intervals will be computed using a stratified cox proportional hazards regression 
model with treatment and baseline PASI as explanatory variable and stratified by 
geographical region, presence of psoriatic arthritis.
Subjects without PASI 75 response will be considered as censored at Week 12.
Psoriatic arthritis
Summary statistics will be derived for
 
ACR 20 / 50 / 70 responses as well as for ACR component 
variables.
Relationship between response to secukinumab treatment and having failed to 
respond to previous biologic psoriasis therapy
Response variables PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 by visit 
will be tabulated versus previous systemic psoriasis therapy and response to previous biologic 
therapy, by treatment group.


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9.5.2
Safety variables 
All safety evaluations will be performed on the Safety set.
Adverse events
Treatment emergent adverse events will be summarized. Only primary paths within MedDRA 
will be considered for adverse event reporting. The definition for “treatment emergent” is as 
follows:

Events started after the first dose of study medication or events present prior to the 
first dose of study medication but increased in severity based on preferred term

Started prior to the last dose plus 84 days (inclusive)
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having at least one AE, having an AE in each primary system organ class and 
having each individual AE (preferred term). 
Summaries will also be presented for AEs by severity and for study treatment related AEs. If 
a 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 death, serious adverse event, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment 
(including study treatment discontinuation).
Exposure adjusted incidence rates will be provided for selected adverse events. 
Laboratory data
The summary of laboratory evaluation will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented by laboratory test group, laboratory tests 
(i.e., lab parameters) and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post baseline.
For each lab parameter, the maximum change (maximum decrease and maximum increase) 
from baseline will be analyzed analogously.
In addition, shift tables will be provided for all lab parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme post-baseline laboratory test value. Shift 
tables with respect to Common Toxicity grade Criteria (CTC) and normal ranges will be 
provided by laboratory test and treatment group.
Vital signs
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed by vital sign and treatment group. 


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Change from baseline will only be summarized for subjects with both baseline and post-
baseline values.
ECG
Summary statistics will be presented for ECG variables by visit and treatment group.
9.5.3
Resource utilization
Not applicable. 
9.5.5
DNA 
Not applicable.
9.5.6
Biomarkers 
Not applicable.
9.7
Interim analyses
In addition to Week 16 analysis, additional subsequent interim analyses may be performed to 
fulfill any requests from Health Authorities. The treatment blinding after the Week 16 and any 
subsequent data base locks for interim analyses that may be requested by Health Authorities,
is discussed in Section 5.3  
9.8
Sample size calculation
This global study aims at complementing the safety and efficacy knowledge on  secukinumab 
with data obtained from patients in China and other countries. The planned cohort sizes 
address this objective, in particular with respect to safety data.
At Baseline, subjects will be randomized to one of the two secukinumab treatment regimens 
or to placebo in a 2:1:1 ratio (300mg Secukinumab: 150mg Secukinumab: placebo). After the 


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first 12 weeks of treatment, non-responders under placebo will be re-assigned to 300 mg
secukinumab treatment regimen.
Reported PASI 75 response rate to placebo is generally in the range of 3% to 7% (Papp 2006; 
Menter 2008; Leonardi 2008; Papp 2008) whilst in a recent phase III trial, observed PASI 75 
response rate to placebo in Chinese subjects after twelve weeks of treatment was above 11% 
("Safety and effectiveness of ustekinumab/stelara in Chinese patients with psoriasis", 
ClinicalTrials.gov Identifier: NCT01008995). It is estimated that in the present study, up to 10% 
of the subjects under placebo will achieve a PASI 75 response during the first twelve weeks of 
treatment (induction period).
According to CFDA requirement in use of biologic drug, it is planned to randomize 536
subjects at Baseline, i.e., using a 2:1:1 ratio, 268 patients for 300 mg secukinumab regimen 
and 134 patients for 150 mg secukinumab regimen and placebo group, respectively.
The PASI 75 and IGA mod 2011 0 or 1 response rates of secukinumab regimens at Week 12 
are assessed based on Phase III trials. PASI 75 response rates at Week 12 are approximately 
79.4% (95% C.I: [76.2, 82.4]) for the 300 mg secukinumab regimen and 69.2% (95% C.I: 
[65.6, 72.6]) for the 150 mg secukinumab regimen. IGA mod 2011 0 or 1 response rates at 
Week 12 are approximately 65.0% (95% C.I: [61.3, 68.6]) for the 300 mg secukinumab 
regimen and 51.4% (95% C.I: [47.7, 55.2]) for the 150 mg secukinumab regimen.
Since two secukinumab dose regimens will be tested in parallel versus placebo with respect to 
the co-primary endpoints, PASI 75 response and IGA mod 2011 0 or 1 response after 12 
weeks of treatment, the type-I-error for each comparison will be split to α/2 (family-wise 
α=2.5%, one-sided). With 536 (using a 2:1:1 ratio) subjects and assuming a response rate in 
the placebo group of 10% for PASI 75 response and IGA mod 2011 0 or 1 response, the 
power to demonstrate a response rate of 65.6% for PASI 75 and 47.7% for IGA mod 2011 0 
or 1 in the secukinumab groups is above 99%, based on Fisher’s exact test (nQuery Advisor 
7.0, two group Fisher’s-exact test of equal proportions).
The PASI 90 response rates of secukinumab regimens are approximately 56.6% (95% C.I: 
[52.8, 60.3]) for the 300 mg secukinumab regimen and 41.1% (95% C.I: [37.4, 44.9]) for the 
150 mg secukinumab regimen.
With respect to the secondary endpoint of PASI 90 response at week 12 and with sample size 
of 536 (using a 2:1:1 ratio), the power to detect differences in response rates for each 
secukinumab dose regimen versus placebo is above 99%, based on Fisher’s exact test with 
type-I-error of α/2 (family-wise α=2.5%, one-sided) for each comparison and placebo 
response rate of 5%.
Table 9-1
Response reference for sample size calculation based on Phase III 
trials
Response at Week 12
AIN457 150 mg
AIN457 300 mg
IGA 0/1
( 51.4) ( 47.7,  55.2)
( 65.0) ( 61.3,  68.6)   
PASI 75
( 69.2) ( 65.6,  72.6)  
( 79.4) ( 76.2,  82.4)   
PASI 90
( 41.1) ( 37.4,  44.9)  
( 56.6) ( 52.8,  60.3)


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


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10.4
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those 
involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients/subjects 
should be administered as deemed necessary on a case by case basis. Under no circumstances 
is an investigator allowed to collect additional data or conduct any additional procedures for 
any research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
11.1
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients/subjects may be implemented immediately provided the health authorities 
are subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring must be followed.


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12
References 
Alamanos Y, Voulgari PV, Drosos AA (2008)  Incidence and Prevalence of Psoriatic Arthritis: 
A Systematic Review. J.Rheumatology; 35; 1354-1358.
Baek JH, Yoo CD, Shin KC et al. (2000) Spondylitis is the most common pattern of psoriatic 
artheritis in Korea. 19: 89-94.
Bretz F, Maurer W, Brannath W et al., (2009) A graphical approach to sequentially rejective
multiple test procedures. Statist.Med.;28:586-604.
Chobanian AV, Bakris GL, Black HR et al.,(2003) Seventh Reort of the Joint National 
Committee on Prevention ,Detection,Evaluation,and Treatment of High Blood Pressure. 
Hypertension; 42:1206-1252.
Christophers E, Mrowietz U (2003) Psoriasis. In: Freedberg IM, Eisen AZ, Wolff K, et al (eds) 
Fitzpatrick’s Dermatology In General Medicine. 6th ed; New York: McGraw-Hill: p.407-427
Committee for medicinal products for human use (CHMP).  European Medicines Agency for 
the Evaluation of Medicines for Human Use.  (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis.  CHMP/EWP/2454/02 document. 
London, UK.
Dhir V, Aggarwal A (2013) Psoriatic Arthritis: a Critical Review. Clinic Rev Allerg Immunol; 
44:141-148
Ding X, Wang T, Shen Y et al (2012) Prevalence of psoriasis in China: A population-based 
study in six cities. Eur J Dermatol; 22(5): 663-7.
Doherty SD, Van Voohees A, Lebwohl MG et al (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 – 217.
Farber EM (1998) Juvenile psoriasis: Early interventions can reduce risks for problems later. 
Postgraduate Medicine; 103(4):89-100.
Fredriksson T, Pettersson U (1978) Severe Psoriasis – Oral Therapy with a New Retinoid. 
Dermatologica: 157: 238-244.
Fan X, Yang S, Sun LD et al. (2007) Coparison of Clinical Features of HLA-Cw*0602-
Positive and Negative Psoriasis Patients in a Han Chinese Population. Acta Derm Venereol; 
87: 335-340.
Gladmann DD, Antoni C, Mease P et al. (2005) Psoriatic arthritis: epidemiology, clinical 
features, course, and outcome. Ann Rheum Dis; 64 Suppl 2:ii 14-7.
Gottlieb AB, Griffiths CEM, Ho VC et al. ( 2005) Oral pimecrolimus in the treatment of 
moderate to severe Chronic plaque-type psoriasis: a double –blind, multicenter, randomized, 
dose-finding trail. British association of Dermatology; 152.1219-1217.
Griffiths CEM, Barker JNWN (2007) Pathogenesis and clinical features of psoriasis. Lancet; 
370: 263 – 271.


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Hukuda S, Minami M, Saito T et al. (2001) Spondyloarthropathies in Japan: nationwide 
questionnaire performed by the Japan Anklylosing Spondylitis Society. J Rheumatol; 28; 554-
559.
Kawada A,  Tezuka T, Nakamizo Y et al. (2003)  A survey of psoriasis patients in Japan from 
1982 to 2001. J. of Dermatological Science; 31, 59-64.
Kundakci N, Tursen U, Babiker MOA et al. (2002) The evaluation of the sociodemographic 
and clinical features of Turkish psoriasis patients. Intern Journal of Dermatology, 41:220-224.
Jamshidi F, Bouzari N, Seirafi H et al.(2008) The Prevalence of Psoriatic Arthrites in 
Psoriatic Patients in Tehran, Iran. Arch. Iranian Med ; 11(2) :162-165.
Langley RG, Elewski BE, Lebwohl M et al. (2014) Secukinumab in Plaque Psoriasis-Results 
of Two Phase 3 Trials. N ENGL J MED 371;4.
Leonradi C., Menter A., Hamilton T., Caro I., Xing B., Gottlieb AB. (2008) Efalizumab: 
results of a 3-year continuous dosing study for the long-term control of psoriasis Br J 
Dermatol. May; 158(5):1107-16. doi: 10.1111/j.1365-2133.2008.08548.x. Epub 2008 Mar 27
Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert rev. Mol. Diagn; 8(3). 247-255.
Mancia G, Backer GD, Dominiczak A et al. (2007) The Task Force for the Management of 
Arterial Hypertension of the European Society of Hypertension (ESH) and of the European 
Society of Cardiology (ESC). Journal of Hypertension ; 25: 1105-1187.
McInnes IB , Mease PJ, Kirkham B et al., (2015) Secukinumab, a human anti-interleukin-17A 
monoclonal antibody, in patients with psoriatic arthritis (FUTURE2): a randomized, double –
blind, placebo-controlled, phase 3 trial. The Lancet; 386:1137- 1146.
Moll JMH and Wright V (1973) Psoriatic arthritis. Seminars in Arthritis and Rheumatism; 
3(1): 55-78.
Naldi L (2004)  Epidemiology of Psoriasis. Current Drug Targets- Inflammation and Allergy; 
(3) 2: 121-128
Newcombe RG (1998) Improved confidence intervals for the difference between binomial 
proportions based on paired data Stat Med. 1998 Nov 30; 17 (22):2635-50Oranje AP, 
Devillers AC, Kunz B, Jones SL, DeRaeve L, Van Gysel D, de Waard-van der Spek FB, 
Grimalt R, Torrelo A, Stevens J, Harper J. (2006) Treatment of patients with atopic dermatitis 
using wet-wrap dressings with diluted steroids and/or emollients. An expert panel's opinion 
and review of the literature J Eur Acad Dermatol Venereol. Nov; 20 (10):1277-86
Papp KA, (2006) The long-term efficacy and safety of new biological therapies for psoriasis. 
Arch Dermatol Res ; 298:7-15
Prasad P, Bikku B, Kaviarasan P K, Senthilnathan A. (2007) A clinical study of psoriatic 
arthropathy. Indian J Dermatol Venereol Leprol; 73:166-70
Papp KA, Langley RG, Lebwohl M et al. (2008) Efficacy and Safety of ustekinumab, a 
human interleukin-12/23 monoclonal antibody,in patients with psoriasis:52-week results from 
a randomized, double-blind,placebo-controlled trial(PHOENIX 2). Lancet; 371:1675-84
Rapp SR, Feldman SR, Exum ML, et al (1999) Psoriasis causes as much disability as other 
major medical diseases. J Am Acad Dematol; 41:401-7.


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Schon MP and Henning Boehncke W (2005) Psoriasis. NEJM; 352; 18:1899-1912.
Taylor W, Gladman D, Helliwell P, et al. (2006);  CASPAR Study Group. Classification 
criteria for psoriatic arthritis: development of new criteria from a large international study. 
Arthritis Rheum; 54(8): 2665-73
Thumboo J, Tham SN, Tay YK, et al., (1997) Patterns of Psoriatic Artheritis in Orientals. J 
Rheumatol; 24:1949-53.
Weisman S, Pollack CR, Gottschalk (2003) Psoriais disease severity measures : comparing 
efficacy of treatments for severe psoriasis.  Journam of Dermatological Treatment ; 14,158-
165
Zeng YQ, Chen R, Darmawan J et al. (2008) Rheumatic Diseases in China. Arthritis Research 
&Therapy; 10:R17


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13
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. Notable values for blood pressure and pulse are presented in Section 6.5.2.
No specific action is pre-defined within this protocol to respond to specific abnormal 
laboratory values, as it will be decided by the investigator whether & which specific action 
needs to be taken to respond to any abnormal values, taking into account the overall status of 
the subject.
Liver Function and Related Variables
Alanine transaminase (ALT) (SGPT):
> 3 x Upper Limit of Normal (ULN)
Aspartate transaminase (AST) (SGOT):
> 3 x ULN
Total bilirubin:
> 2 x ULN
Alkaline phosphatase:
> 2.5 x ULN
Renal Function and Electrolyte Variables
Creatinine (serum):
> 1.5 x ULN
Potassium:
> 6 mmol/L or < 3 mmol/L
Sodium:
> 160 mmol/L or < 115 mmol/L
Hematology Variables
Hemoglobin:
≥ 20 g/dL decrease from baseline
Platelet count:
< Lower Limit of Normal (LLN)
White blood cell count:
< 0.8 x LLN
Neutrophils:
< 0.9 x LLN
Eosinophils:
> 1.1 x ULN
Lymphocytes:
> 1.1 x ULN
Urinalysis Variable
Protein urine dipstick:
++*
* ++ is ≥ 100 mg/dL
14
Appendix 2: The classification criteria for psoriatic arthritis 
(CASPAR)
To meet the ClASsification of Psoriatic ARthritis (CASPAR) criteria for the diagnosis of 
psoriatic arthritis according to Taylor et al, 2006, a subject must cumulate at least 3 points 
from the following 5 categories:
1. Evidence of current psoriasis, or personal history of psoriasis, or family history of 
psoriasis:

Current psoriasis is defined as psoriatic skin or scalp disease present today, as judged 
by a rheumatologist or dermatologist (2 points).


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
Personal history of psoriasis is defined as history of psoriasis that may be obtained 
from a patient, a family physician, dermatologist, rheumatologist, or other qualified 
health care provider (1 point, unless current psoriasis).

Family history of psoriasis is defined as history of psoriasis in a first- or second-
degree relative according to the subject (1 point, unless current psoriasis or personal 
history of psoriasis).
2. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination (1 point).
3. Negative test result for the presence of rheumatoid factor by any method except latex        
(1 point).
4. Either current dactylitis, defined as swelling of an entire digit, or 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 (excluding osteophyte formation) on plain radiographs of 
the hand or the foot (1 point).
Total score: _______  
All study subjects are expected to have current psoriasis, thus 2 points should be recorded for 
question 1 of the assessment.  Personal history of psoriasis and family history of psoriasis will 
be recorded in the Investigator Comments section of the CASPAR eCRF however these will 
not be taken into account for the subtotal score of question 1 and will not contribute to the 
total score calculated on the eCRF.
The CASPAR eCRF will populate automatically the total score cumulated by a subject. If the 
total score is ≥3, the subject meets CASPAR criteria.


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SAP_001.pdf: 
Clinical Development 
AIN457/ Secukinumab/Cosentyx® 
CAIN457A2318 / NCT03066609
A randomized, double-blind, placebo controlled, 
multicenter study of subcutaneous secukinumab, to 
demonstrate efficacy after twelve weeks of treatment and 
to assess safety, tolerability and long-term efficacy up to 
one year in subjects with moderate to severe chronic 
plaque-type psoriasis with or without psoriatic arthritis 
comorbidity 
Statistical Analysis Plan (SAP) 
Author: 
Document type: 
SAP Amendment 2 
Document status: 
Final 
Release date: 
11-Jan-2019
Number of pages: 
57 
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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Document History – Changes compared to previous final version of SAP 
 
Date 
Reason for update 
Section and title impacted (Current) 
22-Feb-2017 
Final  
 
5-Dec-2017 
Protocol 
amendment 
Primary endpoint analysis added for authority interactions for 
2.14 part 
 
Imputation rule 
updated 
First diagnosis date of PSO and PsA were added in 5.14 part 
7-Feb-2018 
Analysis set update 
Detailed information of analysis set during different treatment 
period were added in 2.2 part 
 
 
 
Baseline PsA 
removed from 
analysis model 
Baseline PsA was removed from the analyses models since 
too few subjects with baseline PsA, part 2.5 and 2.6 were 
impacted. 
11-Jan-2019 
Amendment final        Section 4 Change to protocol specified analyses 
Added the definition of Entire study period. 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 8 
2.1 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 16 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ....................... 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary objective .......................................................................... 18 
2.5.1 
Primary and key secondary endpoints ................................................... 18 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 23 
2.5.4 
Supportive analyses ............................................................................... 24 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 24 
2.6.1 
Secondary endpoints  ............................................................................ 24 
2.6.2 
Secondary statistical model, and method of analysis ............................ 28 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 28 
2.6.4 
Overview of analysis methods of efficacy variables ............................. 28 
2.7 
Safety analyses ....................................................................................................... 29 
2.7.1 
Adverse events (AEs) ............................................................................ 29 
2.7.2 
Deaths .................................................................................................... 32 
2.7.3 
Laboratory data ..................................................................................... 32 
2.7.4 
Other safety data ................................................................................... 36 
 
 37 
 
 37 
2.10 
Patient-reported outcomes ..................................................................................... 37 
 
 37 
2.10.2 
Health Assessment Questionnaire- Disability Index (HAQ-DI) 
(subjects with PsA only) ....................................................................... 39 


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2.10.3 
Patient’s global assessments (subjects with PsA only) ......................... 41 
2.10.4 
Handling of missing values/censoring/discontinuations ....................... 41 
 
 41 
 
 41 
2.13 
DMC ...................................................................................................................... 41 
2.14 
Interim analysis ...................................................................................................... 41 
3 
Sample size calculation ..................................................................................................... 42 
4 
Change to protocol specified analyses .............................................................................. 43 
5 
Appendix ........................................................................................................................... 43 
5.1 
Imputation rules ..................................................................................................... 43 
5.1.1 
Study drug ............................................................................................. 43 
5.1.2 
AE date imputation ............................................................................... 43 
5.1.3 
Concomitant medication date imputation ............................................. 44 
5.1.4 
First diagnosis date (Pso, PsA) imputation ........................................... 45 
5.1.5 
Other imputations .................................................................................. 45 
5.2 
AEs coding/grading ............................................................................................... 46 
5.3 
Laboratory parameters derivations ........................................................................ 46 
5.4 
Statistical models ................................................................................................... 46 
5.4.1 
Analysis of continuous data .................................................................. 46 
5.4.2 
Analysis of binary (and categorical) data .............................................. 46 
5.4.3 
Multiple imputations for response variables ......................................... 48 
5.4.4 
Analysis of time-to-event data .............................................................. 51 
5.4.5 
Crude incidence and related risk estimates ........................................... 52 
5.4.6 
Exposure adjusted incidence rate and related risk estimates ................ 53 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 54 
6 
Reference ........................................................................................................................... 55 


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List of abbreviations 
ACR 
American College of Rheumatology 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
BSA 
Body surface area 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
 
 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
Data will be analyzed by Novartis according to the data analysis section 9 of the study protocol 
which is available in Appendix 16.1.1 of the CSR. Important information is given in the 
following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 
This document covers statistical and analytical plans for CAIN457A2318 study with reference 
to the study protocol (version 01 - amended protocol) and the project standard analysis plans 
(AIN457A MAP ).  
1.1 
Study design 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in 
approximately 536 subjects with moderate to severe chronic plaque-type psoriasis with or 
without psoriatic arthritis comorbidity. The efficacy and safety data from this global study will 
primarily be used to support the registration of secukinumab in China. 
Randomization will be stratified by geographical region and presence of psoriatic arthritis at 
baseline. Subjects will be randomized using a 2:1:1 ratio into one of the treatment groups:  
• Secukinumab 300 mg regimen group: secukinumab 300 mg s.c. (two injections of 
secukinmab 150 mg) once weekly for four weeks (at Baseline, Weeks 1, 2, and 3), 
followed by dosing every four weeks, starting at Week 4 and until Week 48, except for 
weeks 13, 14, and 15 where they will receive a weekly dose of placebo to maintain the 
blind.  
• Secukinumab 150 mg regimen group: secukinumab 150 mg s.c. (one injection of 
secukinumab 150 mg and one injection of placebo matching secukinumab 150 mg) once 
weekly for four weeks (at Baseline, Weeks 1, 2, and 3), followed by dosing every four 
weeks, starting at Week 4 and until Week 48. Similar procedure as in the 300 mg group 
will be performed at week 13, 14, 15 to maintain the blind. 
• Placebo group: placebo secukinumab (two injections of placebo matching secukinumab 150 
mg) once per week for four weeks (at Baseline, Weeks 1, 2, and 3), followed by dosing 
every four weeks till week 8. Prior to receiving the Week 12 dose, PASI 75 responders in 
the placebo group will be assigned to the placebo group and receive placebo from Week 12 
till week 48; the PASI 75 non-responders will be reassigned to 300 mg secukinumab 
regimen group and receive their treatment from Week 12 till week 48.  
The study consists of four epochs: Screening (of at least 1 week and up to 4 weeks), Induction 
(of 12 weeks), Maintenance (of 40 weeks), and Follow-up epoch (of 8 weeks).The study design 
is presented in Figure 3-1. 
 


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Figure 3-1 Study design 
 
For ongoing review of safety information an internal Data Monitoring Committee (DMC) is 
established. 
In addition, a primary endpoint analysis is planned after all subjects have completed their Week 
16 visit. Full analysis of all data will be performed at the end of the study. 
1.2 
Study objectives and endpoints 
The primary objective of this study is to demonstrate the superiority of secukinumab in subjects 
with moderate to severe chronic plaque-type psoriasis in terms of both PASI 75 and IGA mod 
2011 0 or 1 response (co -primary endpoints) at Week 12 compared to placebo. 
The secondary objectives are : 
• To demonstrate the superiority of secukinumab in terms of PASI 90 response at Week 12 
compared to placebo. 
• To assess the efficacy of secukinumab in terms of: 
o maintaining PASI 75 response at Week 52 in subjects who were PASI 75 
responders at Week 12  
o maintaining IGA mod 2011 0 or 1 response at Week 52 in subjects who were IGA 
mod 2011 0 or 1 responders at Week 12. 
o PASI 50/75/90/100 response over time up to week 12 and week 52 
o IGA mod 2011 0 or 1 response over time up to week 12 and week 52 
o PASI score over time up to week 12 and week 52 
o IGA mod 2011 score over time up to week 12 and week 52 
o Time to PASI 75 response up to Week 12 


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In addition, the study will assess efficacy of secukinumab in treating subjects with psoriatic 
arthritis comorbidity in terms of ACR 20/50/70 response and ACR components at Week 12 
compared to placebo and over time until Week 52. The study will also assess the safety and 
tolerability of secukinumab with prefilled syringe in the patient population over the study 
period. 
The efficacy and safety data from this global study will primarily be used to support the 
registration of secukinumab in China, for the treatment of moderate to severe chronic plaque-
type psoriasis and psoriatic arthritis comorbidity. 
The efficacy variables are summarized as below: 
Table 1-1 Primary, secondary and exploratory variables 
Variable 
Type 
PASI 75 response @ Week 12 (compared to placebo) 
primary 
IGA 0/1  response @ Week 12 (compared to placebo) 
primary 
PASI 90 response @ Week 12 
key secondary 
PASI 75 response @ Week 52 for PASI 75 responders at Week 12 
secondary 
Loss of PASI 75 response for PASI 75 responders at Week 12 
secondary 
IGA 0/1 response @ Week 52 for IGA 0/1 responders at Week 12 
secondary 
Loss of IGA 0/1 response for IGA 0/1 responders at Week 12 
secondary 
PASI 50/75/90/100 response over time up to week 52 
secondary 
IGA 0/1 response over time up to week 52 
secondary 
PASI score over time up to week 52 
secondary 
IGA mod 2011 categories over time up to week 52 
secondary 
Time to PASI 75 response up to Week 12 
secondary 
ACR 20/50/70 response in subjects with psoriatic arthritis over time up to week 52 
secondary 
2 
Statistical methods 
2.1 
Data analysis general information 
Novartis will perform the week 16 and final analyses. Statistical software SAS verion 9.4 or 
later will be used. For week 16 analysis, data will be presented till week 16 visit. This analysis 
will include primary endpoint data analysis at Week 12 visit.  
Regarding the DMC analyses, a vendor - 
 will help with part of the work 
based on the internal resource and workload.  
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies. 


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If not otherwise specified, p-values will be presented for two-sided hypothesis testings and two-
sided confidence intervals will be displayed. Unless otherwise stated, the level of significance 
will be set to 5% (two-sided). 
All listings will be presented by treatment sequence. 
Footnotes on outputs will be kept to a minimum.  
Footnotes will generally be provided for 
• abbreviations used in the output; abbreviations used on several outputs, e.g. for listings in 
Appendix 16.2 can be presented on a separate page and do not have to be repeated as 
footnotes on each listing 
• sorting order of categories, e.g. for sorting within MedDRA (Medical Dictionary for 
Regulatory Activities) hierarchy levels 
• MedDRA version used for reporting of MedDRA coded data 
Footnotes will generally NOT be given for 
• units displayed on the output 
• interpretation of results (e.g. “odds ratio larger 1 favors active treatment”) 
• information that can be retrieved from the statistical section of the clinical study report (CSR) 
unless it is not identifiable from the output, e.g. 
• explanation of analysis model used unless results of more than one model are displayed 
on an output 
• derivations of variables (e.g. BMI will not be explained on a footnote) 
• information that will be provided in the clinical study protocol and/or methods section of 
the CSR (e.g. baseline definition if this is specified in the statistical section of the CSR)   
2.1.1 
General definitions  
2.1.1.1 
Study treatment 
The following study drugs will be used: 
• Investigational treatment 
o Secukinumab 150 mg: 1 ml liquid formulation in a pre-filled syringe 
o Secukinumab 300 mg: 2 pre-filled syringes each containing 150mg/ml liquid 
formulation 
• Control treatment 
o Placebo, 1 ml liquid formulation in a pre-filled syringe 
2.1.1.2 
Study Day 1 and other study days 
The first day of administration of randomized study treatment (first dose) is defined as Study 
Day 1 or Day 1.  
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first dose]+1, i.e., Day 
2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively. For the dates before 


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Day 1, study day for an event date is calculated as [Date of event] – [Date of first dose], i.e., 
Day -1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration of an 
event will be calculated as (Event end date – Event start date + 1). 
The descriptor “Day 0” will not be used. 
2.1.1.3 
Screening, baseline and post-baseline definitions 
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to the date of first dose of study treatment (for safety analysis) or prior to the randomization 
date (for efficacy analysis). Per protocol, subject informed consent must be obtained prior to 
performing any study related activity. The date of signing informed consent is the start date of 
screening period. Any assessment obtained during the screening period will be labeled 
screening assessment. Assessments made on Day 1 may occur before or after the randomization 
or the first dose. Further information will be found in [Programming Datasets Specifications 
(PDS)]. 
For efficacy analyses, baseline is the last assessment (including unscheduled visits) obtained 
before the randomization. All assessments obtained after randomization are considered as post-
baseline unless otherwise specified. 
For safety analyses, baseline is the last assessment (including unscheduled visits) obtained 
before the first dose of study treatment. All assessments obtained after the first dose of study 
treatment are considered as post-baseline unless otherwise specified. 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, for PROs, LAB assessments and ECG if no pre-
treatment value exists, values obtained after first dose of treatment can be used as baseline only 
if it was collected on the same day as first dose. 
2.1.1.4 
Day of last dose of randomized study treatment 
The date of last dose will be collected via the CRF. The subject’s exposure will be calculated 
considering the end of treatment period visit (e.g., treatment completion visit). The end of 
treatment period will be defined as the last dose plus 84 days or last visit whichever occurs 
earlier. i.e., for subjects who discontinued or have their last visit earlier than last dose plus 84 
days, the end of study treatment exposure will be the date of the last study visit in the 
corresponding treatment period.  
On-treatment is defined as assessments within last dose plus 84 days. 
2.1.1.5 
Visit window 
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. 
In this table, the days are counted since the first dose of study treatment (study days) for safety 
assessments, and the days are counted since the date of randomization for efficacy assessments. 


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These visit windows apply to measurements taken at every visit. For assessments collected less 
often different visit windows will be applied as detailed below. 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 60 instead 
of on Day 29, it will be re-aligned to visit window Week 12. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below. 
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 72-88 
Week 13 
13 
92 
89-95 
Week 14 
14 
99 
96-102 
Week 15 
15 
106 
103-109 
Week 16 
16 
113 
Day 110-127 
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 
Week 56 
56 
393 
Day 380-407 
Week 60 
60 
421 
Day 408-435 
* Baseline measurement before the first drug administration for safety assessments and before the randomization 
for efficacy assessments. 
For parameters which are not collected at every visit (e.g. 
 HAQ-DI), visit windows 
defined in Table 2-1 will be combined. For example, if a parameter is measured at Week 12 and 
Week 24 only, Week 12 visit window will extend from Day 2 to Day 88 (combining Week 1 to 
Week 12 visit windows), Week 24 will extend from Day 89 to Day 183 (combining Week 13 
to Week 24). If more than one assessment falls into the interval, the rules defined in Section 
2.1.1.6 below are applied. 


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For studies with re-randomization at the end of induction period or treatment epoch 1, 
assessments from maintenance period (or treatment epoch 2) will not be considered for 
induction period (or treatment epoch 1), e.g. if a Week 13 (scheduled visit) measurement would 
fall into the Week 12 visit window, this measurement would not be analyzed as induction period 
value. Of note, for subjects who discontinue in induction period, i.e. not moving into 
maintenance period, measurements taken in follow-up period would still be considered for 
induction period. 
Of note: subject’s height assessed during screening will not be remapped according to the 
analysis visit window. 
The analysis visit will be used for listing of visit and period for safety data. If a visit falls after 
the last visit window (after Day 435) it is not assigned an analysis visit and will be listed under 
label “After Week 60”. 
2.1.1.6 
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 2.1.1.3. 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 (e.g., for urine protein values “+” and “++”, 
the worst case is defined as “++”), 
• in case qualitative variables are based on quantitative variables, e.g. PASI 90 response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable.  
Table 2-2 
Rules for selecting values for analysis within a given visit window 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
See Section 2.1.1.3. 
Post-baseline efficacy 
All data except PRO, e.g., 
PASI, IGA 
The measurement closest to the target 
day will be used. In the event two 
measurements are taken equally apart 
(e.g., 1 day before target date and 1 day 
after), the earlier one will be used. 
If two measurement are taken on the 
same day then select the first one using 
eCRF visit number. 
If two measurement have been taken on 
the same day and same visit then select 
the worst. 


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Timing of measurement 
Type of data 
Rule 
Post-baseline efficacy 
PRO data 
The measurement closest to the target 
day will be used. In the event two 
measurements are taken equally apart 
(e.g., 1 day before target date and 1 day 
after), the earlier one will be used.  
If two measurement have been taken on 
the same day, select the worst. 
If two measurement have the same value, 
select the first one using eCRF visit 
number. 
Post-baseline safety 
Summary visit information 
(e.g. laboratory values, vital 
signs, etc.) 
The (non-missing) measurement closest 
to the target day will be used. In the event 
two measurements are taken equally 
apart (e.g., 1 day before target date and 1 
day after), the earlier one will be used. 
If two measurements are taken on the 
same day then select the first one (using 
the time). 
If two measurements are taken on the 
same date/time then use the first eCRF 
visit number (assuming this is the planned 
visit). 
If two measurements are taken on the 
same date/time/eCRF visit number then 
take the average value of these two 
results 
Post-baseline safety  
Notable abnormalities (e.g. 
vitals signs) and CTCAE 
grades for laboratory values 
The most extreme measurement in the 
window will be used. Note this means a 
subject can have a notably high and 
notably low measurement within an 
analysis period. 
2.2 
Analysis sets 
The following analysis sets will be used for the data analysis.  
Randomized set: The randomized set will be defined as all subjects who were randomized at 
baseline visit. Unless otherwise specified, misrandomized subjects will be excluded from the 
randomized set.  
Misrandomized subjects are subjects who are screen-failures, but have been randomized by the 
investigator before eligibility was finally assessed, however have not been treated. If subjects 
were re-screened and successfully randomized, they will be included in the randomized set 
according to the treatment assigned in the last randomization.  
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be analyzed according to the treatment assigned to at randomization. If the actual randomization 
stratum is different to the assigned stratum in IRT, the actual stratum will be used in analyses.  
Of note, subjects excluded from the randomized set will be excluded from the FAS. 


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Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. Subjects will be analyzed according to treatment received.  
The treatment received will be set to the treatment randomized. But if a subject has received the 
wrong treatment during the entire study, the treatment received will be set to this wrong 
treatment.  
For those subjects who received erroneously the wrong treatment at least once, an additional 
listing will be prepared displaying adverse events occurred after the treatment errors. 
The following study periods will be considered for analysis: 
• Screening period (before Randomization)  
• Induction period (Randomization to Week 12 pre-dose) 
• Maintenance period (Week 12 -dose to Week 52) 
• Entire treatment period = Induction period + Maintenance period (Randomization to 
Week 52) 
• Follow-up period (Week 52 to Week 60) 
• Entire study period = Induction period + Maintenance period (Randomization to Week 
52) + Follow-up period (Week 52 to Week 60) 
2.2.1 
Subgroup of interest 
The co-primary endpoints and important secondary endpoints will be evaluated using the 
subgroups defined in Table 2-3. Subgroup analyses for the study endpoints are represented in 
Table 2-4.  
If IRT mis-classify the stratrum, such as baseline psoriatic arthritis, the correct stratum will be 
derived based on baseline information and protocol deviation data. The correct stratum may be 
used for subgroup analysis.  
Table 2-3 
Subgroup definitions 
Subgroup 
variables 
Categories 
Description 
Label for 
outputs 
Suffix for 
outputs* 
Randomization 
region stratum 
China, Non-China 
All outputs will be 
repeated for Chinese 
patient 
Region 
stratum 
c 
Randomization 
stratum of psoriatic 
arthritis at baseline 
Yes, No 
 
Baseline PsA 
stratum 
a 
Weight category 
body weight category (< 70 kg,  
>=70 and <90 kg, >=90 kg) 
 
Weight 
category 
b 
Previous systemic 
therapy 
Yes, No 
 
 
Previous 
systemic 
therapy 
d 
 
 
 
 
 
 
 
 
 
 


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Subgroup 
variables 
Categories 
Description 
Label for 
outputs 
Suffix for 
outputs* 
* Suffixes will be used for the outputs numbering, see [TFL shell document] 
Table 2-4 
Subgroup analyses 
Endpoint/analysis 
Randomization 
stratas 
Weight 
category 
Previous psoriasis 
therapy* 
Co-primary endpoints: 
 
 
 
   PASI 75 response @ Week 12 
X 
X 
X 
   IGA 0/1 response @ Week 12 
X 
X 
X 
Secondary endpoints: 
 
 
 
   PASI 90 response @ Week 12 
X 
X 
X 
   PASI 50/75/90/100 response over time up to 
week 52 
X 
X 
X 
   IGA 0/1 response over time up to week 52 
X 
X 
X 
Note: presented are only those endpoints that need subgroup analyses. 
*: only for “Previous <biologic/systemic/non-biologic systemic> therapy” and embedded subgroup “failure” and 
non-biologic therapy failure “at least two failures”. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The summaries will be shown for the following treatment groups: 
• AIN457 300 mg, AIN457 150 mg, Placebo, Placebo - AIN 457 300mg, Placebo - 
Placebo, Total 
The following common background and demographic variables will be analyzed: 
Continuous variables: 
o Age (which is derived from year of birth and the Informed consent date) 
o Height 
o Weight 
o Body mass index (BMI) 
Categorical variables: 
o Region categories (China, non-China) 
o Age categories (<65 years, 65 years and older, 75 years and older) 
o Gender 
o Race 
o Ethnicity 
o Smoking status at baseline 
o Weight categories (<70 kg, >=70 and <90 kg, >= 90 kg) 
Body Mass Index (BMI) will be calculated using the following formula: 
                             BMI = (body weight in kilograms) / (height in meters)2 
For BMI, height and body weight the last value prior to randomization is used. If there is no 
weight recorded prior to taking of study treatment, BMI will be missing. 


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Of note: subject’s height will not be remapped according to the analysis visit window. 
Psoriasis specific baseline characteristics and history of disease will be summarized as well:  
Continuous variables: 
o Baseline PASI  
o Baseline total BSA 
o Baseline ACR (American College of Rheumatology) components 
o Baseline tender joint count  
o Baseline swollen joint count 
o Baseline CRP (hsCRP)  
o Baseline HAQ-DI score 
o Time since diagnosis of psoriasis 
o Time since diagnosis of psoriatic arthritis 
Categorical variables: 
o Baseline PASI categories (≤20, >20) 
o Baseline IGA mod 2011 score categories (at least mild, moderate, severe) 
o Severity of psoriasis categories (CHMP guidelines, mild (total BSA <10% and 
PASI < 10) , moderate ((PASI ≥10 or total BSA≥10%) and PASI ≤20 and total 
BSA ≤20%), severe (total BSA >20% or PASI > 20)) 
o Baseline psoriatic arthritis categories (yes, no) 
o Previous exposure to biologic systemic psoriasis therapy (yes, no) 
o Previous exposure to systemic psoriasis therapy (yes, no) 
o Previous exposure to non-biologic systemic psoriasis therapy (yes, no) 
o Previous failure to biologic systemic psoriasis therapy (yes, no) 
o Previous failure to systemic psoriasis therapy (yes, no)  
o Previous failure to non-biologic systemic psoriasis therapy (including 
phototherapy and photo- chemotherapy) (yes, no) 
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total) in the randomized set. 
Any condition entered on the Relevant medical history / current medical conditions CRF 
(including famility history) will be coded using the MedDRA dictionary. They will be 
summarized by System Organ Class (SOC) and Preferred Term (PT) of the MedDRA dictionary. 
Summaries for cardiovascular medical history will be summarized by categories.  
2.3.1 
Patient disposition 
The number of subjects screened will be presented. In addition, the reasons for screen failures 
will be provided. The number and percentage of subjects in the randomized set who completed 
study periods, the entire study and who discontinued the study prematurely (including the 
reason for discontinuation) will be presented for each treatment group and all subjects. 


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Of note, patients completed all the epochs planned in the protocol are defined as completers for 
the entire study. 
For each protocol deviation, the number and percentage of subjects for whom the deviation 
applies will be tabulated. 
2.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
2.4.1 
Study treatment / compliance 
The analysis of study treatment data will be based on the safety set. 
The number of secukinumab, secukinumab placebo injections will be summarized by treatment 
group by means of contingency tables. 
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of subjects with exposure of at least certain time thresholds will be displayed. The 
following categories will be presented: “any exposure”, “≥1 week” “≥4 weeks”, “≥8 weeks”,  
“≥12 weeks”, “≥16 weeks”, “≥20 weeks”, “≥24 weeks”, “≥28 weeks”, “≥32 weeks”, “≥36 
weeks”, “≥40 weeks” “≥44 weeks”, “≥48 weeks”, and “≥52 weeks”. 
Duration of exposure will be defined as the time from first dose of study medication to the last 
dose plus 84 days or last visit (including follow-up visits) whichever occurs earlier. i.e., for 
subjects who discontinued or have their last visit earlier than 84 days, the end of study treatment 
exposure will be the date of the last study visit in the follow-up period or in the corresponding 
treatment period. 
Duration of exposure (days) = min (‘end of treatment period’ date, last dose date +84) – first 
dose date +1 
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100 subject years) = duration of exposure (years) / 100 
2.4.2 
Prior, concomitant and post therapies 
Medications will be identified using Novartis Drug and Therapy Dictionary (NovDTD) 
including Anatomical Therapeutic Chemical (ATC) code. Prior and concomitant treatments will 
be summarized by treatment group for the safety set unless otherwise specified. Concomitant 
treatments will be displayed for the treatment period. 
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Medications will be presented in alphabetical order, by ATC codes and grouped by anatomical 
main group (the 1st level of the ATC codes). Tables will also show the overall number and 
percentage of subjects receiving at least one drug of a particular ATC code and at least one drug 
in a particular anatomical main group.  
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment, and last dose plus 84 days or last (including follow-up visits) whichever occurs 


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earlier will be a concomitant medication, including those which were started pre-baseline and 
continued into the treatment period.  
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized. 
Prior or concomitant medication will be identified based on recorded or imputed start and end 
dates of medication taken. Further rules will be given in Section 5. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary and key secondary endpoints 
The co-primary efficacy variables are PASI 75 response at Week 12 and IGA mod 2011 0 or 1 
response at Week 12. The key secondary endpoint is PASI 90 response at week 12. The analysis 
of the co-primary and key secondary variables will be based on the FAS. 
2.5.1.1 
Definition of PASI and related variables 
The investigator or trained qualified designee will complete the PASI assessments. Whenever 
possible, the same evaluator should perform this assessment at all visits. 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of areas 
affected, including head, trunk, upper limbs and lower limbs (see below for PASI assessment). 
The following calculations will be done: each reported percentage will be multiplied by its 
respective body region corresponding factor (head = 0.1, trunk = 0.3, upper limbs = 0.2, lower 
limbs = 0.4). The resulting 4 percentages will be added up to estimate the total BSA affected 
by plaque-type psoriasis. The PASI scoring system is further described in Table 2-8. 
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 2-6. 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: 
1. The neck is assessed as part of the head. 
2. The axillae and groin are assessed as part of the trunk. 
3. The buttocks are assessed as part of the lower limbs. 
4. When scoring the severity of erythema, scales should not be removed. 
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 will be 
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, I, D, and A denote erythema, induration, desquamation, and area, respectively, and h, 
u, t, and l denote head, upper extremities, trunk, and lower extremities, respectively (see Table 
2-5). 


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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 responsible for collecting the components or scoring signs and total 
surface area (BSA) for all visits. PASI will be done by investigator at randomization and week 
12 only; The PASI scores at other visits will be calculated by Novartis and will be used in the 
analysis and for derivation of PASI response values (see below). In addition, the investigator 
will determine PASI75 responder status at Week 12.


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Table 2-5 
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 = no involvement 
1 = >0-<10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
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 = no involvement 
1 = >0-<10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
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 = no involvement 
1 = >0-<10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
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 = no involvement 
1 = >0-<10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
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. 
 
The following definitions are possible efficacy evaluations that can be used in clinical trials in 
psoriasis (CHMP/EWP/2454/02, 2004):  
• PASI 50 response: subjects achieving ≥ 50% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 50 responders 
• PASI 75 response: subjects achieving ≥ 75% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 75 responders 
• PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 90 responders 
• PASI 100 response / remission: complete clearing of psoriasis (PASI=0) 


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2.5.1.2 
Definition of IGA mod 2011 score and IGA mod 2011 0 or 1 response 
The IGA mod 2011 rating scale for overall psoriatic disease (shown in Table 2-6) has been 
developed based on a previous version of the scale used in secukinumab phase II studies, and 
has been updated 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. It is recommended that the same evaluator conducts the 
assessments throughout the study whenever possible. 
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. 
Table 2-6 
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. 
Subjects require an IGA mod 2011 score at randomization of 3 or 4 in order to participate in 
the study. Based on this scale, subjects will be considered as IGA mod 2011 0 or 1 responder 
if they achieve a score of 0 or 1 and improve by at least 2 points on the IGA mod 2011 scale 
compared to baseline. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypotheses for PASI 75 response at Week 12 and IGA mod 2011 0 or 1 response 
at Week 12 being tested is that any of the secukinumab groups are not superior to placebo in 
the proportion of subjects with PASI 75 response and IGA mod 2011 0 or 1 response at Week 
12. 
Let pj denote the proportion of PASI 75 responders at Week 12 for treatment group j and rj 
denote the proportion of IGA mod 2011 0 or 1 responders at Week 12 for treatment group j, 
j=0, 1, 2, where 
0 corresponds to placebo, 
1 corresponds to secukinumab 150 mg, 


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2 corresponds to secukinumab 300 mg. 
The following hypotheses will be tested 
H1: p1 – p0 ≤ 0 versus HA1: p1 – p0 > 0, 
H2: p2 – p0 ≤ 0 versus HA2: p2 – p0 > 0, 
H3: r1 – r0 ≤ 0 versus HA3: r1 – r0 > 0, 
H4: r2 – r0 ≤ 0 versus HA4: r2 – r0 > 0. 
In other words: 
H1: secukinumab 150 mg is not superior to placebo with respect to PASI 75 response at Week 
12 
H2: secukinumab 300 mg is not superior to placebo with respect to PASI 75 response at Week 
12 
H3: secukinumab 150 mg is not superior to placebo with respect to IGA mod 2011 0 or 1 
response at Week 12 
H4: secukinumab 300 mg is not superior to placebo with respect to IGA mod 2011 0 or 1 
response at Week 12 
The primary endpoint (PASI 75 and IGA mod 2011 0 or 1 response at Week 12) will be 
evaluated using alogistic regression model with treatment group, baseline body weight 
category, geographical region, and baseline PASI score as explanatory variables. Odds ratios 
will be computed for comparisons of secukinumab dose regimens versus placebo. In case of the 
logistic regression does not converge due to low reponse rates in the placebo group, an exact 
logistic regression with be performed and the detailed analysis is described in Section 5.4.2.  In 
case of rates of 0% or 100% in one of the treatment groups,  confidence intervals and p-values 
from the t-test for the risk difference comparing to 0 will be provided for the analyses using 
multiple imputation; for the analyses using non-responder imputation, Fisher’s exact test will 
be performed and confidence intervals for risk difference will be provided. 
PASI 90 response at Week 12 will be evaluated analogously to PASI 75 and IGA mod 2011 0 
or 1 response at Week 12 (i.e., logistic regression analysis) and the following hypotheses will 
be tested: 
H5: secukinumab 150 mg is not superior to placebo with respect PASI 90 response at Week 12 
H6: secukinumab 300 mg is not superior to placebo with respect PASI 90 response at Week 
12 
The graphical approach of Bretz et al. 2009 for sequentially rejective testing procedures is used 
to illustrate the testing strategy: 
Figure 2-1 Testing strategy 


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One-sided p-values will be derived. The family-wise error will be set to α=2.5% (one-sided). 
The hypotheses are mapped into two sets (H1, H3, and H5) or (H2, H4, and H6) such that 
hypotheses within a set correspond to the same secukinumab dose regimen (150 mg or 300 mg). 
In essence, the type-I-error probability will be equally split for both sets of hypotheses and 
within each set the hypotheses are tested sequentially as follows: 
Within each pair of hypotheses (H1 or H3) and (H2 or H4) each hypothesis is tested at α/2. 
Only if both hypotheses of a pair are rejected, the testing sequence will continue and the PASI 
90 comparisons of secukinumab versus placebo are tested, H5 or H6 will be tested at α/2 (one-
sided). 
If all hypotheses within a set referring to a secukinumab dose regimen have been rejected, i.e., 
(H1, H3, and H5) or (H2, H4, and H6), the corresponding type-I-error probability can be passed 
on to the other group of hypotheses, and if needed, hypotheses can be retested at a new 
significance level. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Response variables based on PASI score and IGA mod 2011 categories will be imputed with 
multiple imputation (MI) as primary imputation method for the missing values. 
Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Within this analysis the PASI score or IGA mod 2011 
categories 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. 
Non-responder imputation will be used as a sensitivity method: Missing values with respect to 
response variables based on PASI score and IGA 2011 categories will be imputed with non-
response regardless to the reason for missing data (e.g. premature study discontinuation, missed 
visit, administrative issues), exceptions will apply to the following: 
• If a subject dropped out of the study prior to last scheduled visit and being responder 
consecutively at least for two preceding visits, the subject will be imputed as responder 
for the last scheduled visit. 
• If a subject who was responder at visit x-1 and visit x+1 but has missing data at visit x, 
then the subject will be imputed as responder for visit x, except for the missing data at 
last visit in the treatment period. 


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2.5.4 
Supportive analyses 
Sensitivity analyses will be performed as follows: 
Co-primary endpoints (PASI 90 and IGA 0 or 1 response at Week 12) and key secondary 
endpoints will be evaluated using the logistic regression as described in primary analysis 
method with non-responder imputations instead of multiple imputation for missing values.  
2.6 
Analysis of secondary efficacy objective(s) 
2.6.1 
Secondary endpoints  
2.6.1.1 
Maintenance of PASI 75 response after 52 weeks of treatment 
Summary statistics as well as 95% confidence intervals will be presented for maintenance of 
PASI 75 response at Week 52 for the subset of subjects with PASI 75 response at Week 12 in 
the secukinumab treatment groups. 
In addition, Kaplan-Meier estimates including 95% confidence intervals for cumulative rate of 
subjects losing PASI 75 response up to Week 52 will be calculated for the subset of subjects 
with PASI 75 response at Week 12 in the secukinumab treatment groups. 
2.6.1.2 
Maintenance of IGA 0 or 1 response after 52 weeks of treatment 
The same analyses as planned for maintenance of PASI 75 response will be performed for IGA 
0 or 1 response after 52 weeks of treatment, but analyses will be based on the subset of subjects 
with IGA 0 or 1 response at Week 12. 
2.6.1.3 
PASI 50/ 75/ 90/ 100 and IGA mod 2011 0 or 1 response over time 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 
response by visit will be presented in contingency tables and will include absolute and relative 
frequencies. Confidence intervals for response rates will be derived as well based on the score 
method including continuity correction (Newcombe 1998). 
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response at each visit up 
to Week 12, each secukinumab dose regimen will be compared to placebo using a logistic 
regression model with treatment group, baseline body weight, geographical region, and baseline 
PASI score as explanatory variables. 
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response the  placebo 
adjusted response rates including 95% confidence interval will be derived by visit up to Week 
12. In addition, Fisher’s exact test will be applied to pairwise treatment group comparisons to 
placebo. 
Figures will be provided as well displaying estimates for responder rates by treatment including 
confidence intervals. 
2.6.1.4 
PASI score over time 
Summary statistics will be provided for absolute PASI scores as well as for percent change from 
baseline by visit and treatment group. Figures will also be provided. 


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2.6.1.5 
IGA mod 2011 score over time 
Summary statistics for the IGA mod 2011 score over time will be presented by visit and 
treatment group in contingency tables. 
2.6.1.6 
Time to PASI 75 response 
Number and percentage of subjects with PASI 75 response based on the number of subjects in 
the FAS at risk as denominator will be provided by treatment group. 
Between-treatment differences will be evaluated using a log-rank test, stratified by geographical 
region, presence of psoriatic arthritis, to compare the cumulative rates between secukinumab 
treatment groups versus placebo. The hazard ratios for the comparisons and 95% confidence 
intervals will be computed using a stratified cox proportional hazards regression model with 
treatment and baseline PASI as explanatory variable and stratified by geographical region, and 
baseline body weight. 
Subjects without PASI 75 response will be considered as censored at Week 12. 
2.6.1.9 
Psoriatic arthritis 
Summary statistics will be 
 
 
provided for ACR 20 / 50 / 70 responses as well as for ACR component 
variables. 
2.6.1.9.1 Definition of ACR 20/50/70 response and ACR Components 
Evaluations to determine ACR response (ACR 20/50/70) include tender and swollen joint 
counts, HAQ-DI, PtGA Activity, PtGA Pain, PhGA PsA and acute phase reactant (ESR and 
hsCRP). The elements of the ACR scoring system are used in the same way as in standard trials 
of rheumatoid arthritis, with the exception of the number of joints tested, to include distal 


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interphalangeal joints of the feet and carpometacarpal joints of the hands, i.e., 78 joints for 
tenderness and 76 joints for swelling.  
ACR 20/50/70 
ACR 20, 50 or 70 responses correspond, respectively, to at least 20%, 50% or 70% 
improvement in comparison with baseline in the number of tender and swollen joint counts, in 
addition to similar improvements in at least three of five domains-HAQ-DI measure of 
disability, acute phase reactant (CRP or ESR) and the VAS scores of PtGA Activity, PtGA Pain 
and PhGA PsA. 
ACR20 is a binary response variable defined for each subject. A subject will be considered a 
responder according to ACR20 criteria if he/she has at least (i.e., ≥): 
• 20% improvement from baseline in tender 78-joint count 
• 20% improvement from baseline in swollen 76-joint count 
• 20% improvement from baseline in at least 3 of the following 5 measures: 
• Patient’s assessment of PsA pain (VAS 100 mm) 
• Patient’s global assessment of PsA disease activity (VAS 100 mm) 
• Physician’s global assessment of PsA disease activity (VAS 100 mm) 
• Patient self-assessed disability (Health Assessment Questionnaire [HAQ©] 
score) 
• Acute phase reactant (C-reactive protein [hsCRP]) or Erythrocyte 
sedimentation rate (ESR). 
In the definition above, the baseline value refers to the last measurement made prior to 
administration of the first dose of study treatment.  
Primarily, CRP will be used to calculate ACR response: ESR will only be used in the event 
CRP is missing. 
ACR50 and ACR70 are defined in the same way as ACR20 by replacing the 20% with 50% 
and 70% improvement from baseline, respectively.  
ACR Components 
Tender 78 joint count and swollen 76 joint count  
Joint counts will be performed at scheduled visits by the independent assessor(s) who must be 
well trained and part of the site personnel. Whenever possible, the same evaluator should 
perform these assessments at all visits. 
The 78 joints assessed for tenderness include the 8 distal interphalangeal, 10 proximal 
interphalangeal and 10 metacarpophalangeal joints of the hands, the 10 metatarsophalangeal 
and 10 proximal interphalangeal joints of the feet, the 2 wrists, 2 elbows , 2 shoulders , 2 
acromioclavicular, 2 sternoclavicular, 2 temporomandibular, 2 hip, 2 knee, 2 talo-tibial, and 2 
mid-tarsal joints plus 10 additional joints often involved in PsA (the first carpometcarpal and 
the DIP joints of the toes). All of these except for the hips are assessed for swelling. Joint 
tenderness and swelling to be graded present (1) or absent (0). Synovial fluid and/or soft tissue 


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swelling but not bony overgrowth represents a positive result for swollen joint count. 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. In addition, the total number of tender and swollen joints (right 
and left) will be automatically calculated. 
If the number of joints for which data were available (e.g., T) is less than 78/76 for the 
tender/swollen joint assessment, the number of tender/swollen joints (e.g., t) will be scaled up 
proportionately (i.e., 78*t/T or 76*t/T for tender or swollen joint count).   
For the change in tender joint counts and swollen joint counts will be summarized.  
Patient’s assessment of PsA Pain 
The patient’s assessment of pain will be performed using 100 mm visual analog scale (VAS) 
ranging from “no pain” to “unbearable pain” after the question “Please indicate with a vertical 
mark ( | ) through the horizontal line the most pain you had from your rheumatoid arthritis 
today”. 
For the change in PsA pain, the changes from baseline will be summarized. 
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 
rheumatoid arthritis affects you, please indicate with a vertical mark ( | ) through the horizontal 
line how well you are doing today”. 
The change in patient’s global assessment from baseline will be summarized. 
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. 
The change in physician’s global assessment from baseline will be summarized. 
Erythrocyte sedimentation rate (ESR) 
Blood for ESR, which is helpful in diagnosing inflammatory diseases and is used to monitor 
disease activity and response to therapy, will be obtained at scheduled visits. 
The change in ESR from baseline from baseline will be summarized. 
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 


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only. The hsCRP results from samples collected during the treatment period will be revealed 
following database lock only. 
The change of hsCRP from baseline will only be summarized. 
2.6.1.10 Relationship between response to secukinumab treatment and having 
failed to respond to previous biologic psoriasis therapy 
Response variables PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 by visit 
will be tabulated versus previous systemic psoriasis therapy, by treatment group. 
2.6.2 
Secondary statistical model, and method of analysis 
Not applicable. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing data for ACR response variables will be handled as below. 
1. Subjects who drop out of the trial for any reason will be considered non-responders from 
the time they drop out through week 52. 
2. Subjects who do not have the required data at baseline and at the specific time point to 
compute ACR response (i.e. tender and swollen joint counts and at least three of the five 
ACR core set variables) will be classified as non-responders. 
For subjects who switch treatment after induction period, values of induction period are not 
carried forward to maintenance period. 
Following the intent-to-treat principle for subjects who prematurely discontinue treatment, but 
who are observed in the follow-up period, efficacy data collected in follow-up periods will be 
linked to planned but missed study visits as well. 
2.6.4 
Overview of analysis methods of efficacy variables 
An overview of statistical analyses and methods applied to psoriasis efficacy variables is given 
in Table 2-7. 
Table 2-7 
Overview of analysis methods for efficacy variables 
Variable(s) 
Summary statistics 
for binary/ 
categorical data  
Logistic 
regression 
Summary 
statistics for 
continuous data 
Time-to-
event 
analysis 
Graphs 
PASI 75 response @ Week 12 
X 
X 
 
 
X* 
IGA 0/1 response @ Week 12 
X 
X 
 
 
X* 
PASI 90 response @ Week 12 
X 
X 
 
 
X* 
PASI 75 response @ Week 52 for PASI 75 
responders at Week 12 
X 
 
 
 
 
Loss of PASI 75 response for PASI 75 
responders at Week 12 
 
 
 
X 
 
IGA 0/1 response @ Week 52 for IGA 0/1 
responders at Week 12 
X 
 
 
 
 
Loss of IGA 0/1 response for IGA 0/1 
responders at Week 12 
 
 
 
X 
 
PASI 50/75/90/100 and IGA 0/1 response 
over time 
X 
X 
 
 
X** 


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Variable(s) 
Summary statistics 
for binary/ 
categorical data  
Logistic 
regression 
Summary 
statistics for 
continuous data 
Time-to-
event 
analysis 
Graphs 
Time to PASI 75 responders at Week 12 
 
 
 
X 
X 
PASI score over time 
 
 
X 
 
X** 
ACR 20/50/70 response in psoriatic arthritis 
subjects over time 
X 
 
 
 
X** 
IGA mod 2011 categories over time 
X 
 
 
 
 
* dot plot; ** time course plot 
2.7 
Safety analyses 
All safety analyses will be based on the safety set. Only those visits which were pre-planned in 
the protocol will be reported in tables and figures for safety variables.  
Treatment groups for evaluation 
The summaries of evaluation will be reported for both induction period and entire study period. 
The following groups will be used: 
• for induction period: 
• Secukinumab 150mg, Secukinumab 300mg, Placebo; 
• for entire study period: 
• Secukinumab 150mg, Secukinumab 300mg, Placebo,  
Any Secukinumab 300mg, Any Secukinumab dose. 
Safety analyses will be performed on treatment received or actual treatment (See Section 5.4.2, 
Safety Set). 
2.7.1 
Adverse events (AEs) 
For adverse events and other binary safety variables crude incidence and exposure time-
adjusted incidence will be derived as described below and summarized in Table 2-8.  
All adverse events are summarized based on treatment emergent only. The definition for 
“treatment emergent” is as below: 
• events started after the first dose of study medication or events present prior to the first 
dose of study medication but increased in severity based on preferred term  
• and started prior to the last dose plus 84 days (inclusive)  
All adverse events will be listed with “treatment emergent” flag displayed. 


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Table 2-8 
Overview of analyses on some safety endpoints 
Analysis period 
AEs & 
SPP/RMP 
risks 
(special AE 
interest) 
SAEs 
AEs-SMQ 
AEs by 
severity 
study 
treatment 
related AEs, 
death & other 
significant 
AEs 
notables 
(lab/vitals) 
treatment period 
(up to  
week 12) 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
treatment period 
(including all 
data) 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• exp.time 
adjusted 
incidence
* 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
*Note, Exposure adjusted incidence rates will be provided and follow the guideline as below: 
• Primary SOC level for AE and SAE 
• Level 1 for risks and SMQ 
• PT level for SAE 
• PT level for AE  ≥ 2% or incidence rate per 100 subject years ≥ 5.0 in AIN457 300 mg 
or AIN457 150 mg treatment group 
• Other selected AEs of special interest on lower levels (e.g. PT or SMQ level 2), if 
appropriate 
The crude incidence of treatment emergent adverse events will be summarized by primary 
System Organ Class (SOC) and Preferred Term (PT). Confidence intervals for the crude rate 
will be derived using the score method including continuity correction (Newcombe 1998) as 
described in Section 5.4.6. In addition, exposure time-adjusted incidence rates will be provided 
for the treatment period including all data (see Section 5.4.7). 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a 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.  
Adverse events will also be summarized by SMQ according to MedDRA, using a narrow search. 
The MedDRA version used for reporting the adverse events will be described in a footnote. 


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The most common adverse events reported ( z % in any group for each preferred term in the 
table by SOC and PT or  z % in any group for each SMQ table) will be presented in descending 
frequency according to its incidence in secukinumab group starting from the most common 
event. Here threshold value z is set to 2 (%) but it may be updated following review of the dry 
run outputs. 
A graphical display of the crude rates or exposure adjusted incidence rates within system organ 
classes will be presented as follows: For all AEs regardless of severity and seriousness, the 
point estimate within system organ classes will be presented graphically with system organ 
class on the y-axis. This figure will consist of two panels: i) point estimate of AEs, ii) point 
estimate of serious AEs. For the exposure adjusted incidences a linear-scale will be used on the 
x-axes. 
Separate summaries will be provided for deaths, serious adverse events, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment or 
interruption. 
Algorithms for date imputations will be provided in Section 5. 
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures. 
The adverse events occurred after the treatment errors in those subjects who received 
erroneously the wrong treatment at least once, will be listed. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
X% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.  
A listing of significant adverse event will be provided for China only per China Health 
Authority. The significant adverse event is defined as marked hematological and other 
laboratory abnormalities and any adverse events, apart from serious adverse events, that led to 
an intervention, including withdrawal of drug treatment ordose reduction.  
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Exposure adjusted incidence rates for adverse events of special interest will be provided as in 
Table 2-9. 


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Table 2-9 
Table of AEs of special interest 
Special AE interest: 
Notes (All levels are displayed) 
Inflammatory bowel disease (NMQ) (narrow) 
Include Crohns (PT) and Ulcerative 
colitis (PT) and others 
Opportunistic infections (NMQ) 
Candida infections (HLT) 
Herpes viral infections (HLT) 
Both Oral and other are included 
Staphylococcal infections (HLT) 
MACE (MI, Stroke, Cardiovascular death) (NMQ) 
Malignant or unspecified tumours (SMQ) 
Including BCC, SCC in SMQ 
Malignant or unspecified tumours (SMQ excl BCC and 
SCC) (NMQ) 
Upper respiratory tract infections (HLT) 
Other safety topics of interest, such as risks defined in the Safety Profiling Plan, Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are defined 
in the Program Case Retrieval Sheet that is stored in GPS at the path [/vob/util/sasviews/tms]. 
Crude rate of important identified and potential risks from Case Retrieval Sheet will be provided 
for all (non-serious and serious) cases and for all serious cases. Exposure-time adjusted rates 
will be provided for treatment period including all data for all (non-serious and serious) cases 
and for all serious cases. In addition, listings will be provided for the related AE risks. 
Risk measures and confidence intervals will be derived according to Section 5. 
The version of the Case Retrieval Sheet used for the analyses will be described in a footnote. 
This includes MedDRA version and Novartis MedDRA Query (NMQ) dictionary date.  
Important note: For the evaluation of risks primary and secondary system organ classes of the 
MedDRA dictionary will be considered. 
2.7.2 
Deaths 
Separate summary and listing will be provided for deaths. 
2.7.3 
Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry).  
Descriptive summary statistics for the change from baseline to each study visit will be presented 
by laboratory test 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 
Only “on-treatment” laboratory data will be summarized (i.e. assessments within last dose plus 
84 days). All laboratory data will be listed with “on-treatment” flag displayed. If two 
measurements are taken on the same date/time/CRF visit then use the average of two 
assessments. 


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For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. The numerical 
part of the reported result will be treated as the actual LLQ or ULQ. These laboratory values 
will be displayed in listings using the standard unit with the reported sign (“<” or “>”).” 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme laboratory test value within a treatment 
period. For the shift tables, the normal laboratory ranges will be used to evaluate whether a 
particular laboratory test value is normal, low, or high (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. Subjects with 
abnormal laboratory values will be listed and values outside the normal ranges will be flagged. 
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-10: 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). 
The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
baseline will be presented. These summaries will be split into hematology and chemistry. 


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Table 2-10 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.0 
Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L  
Life-threatening 
consequences; 
urgent intervention 
indicated 
Platelet count 
decreased 
<LLN – 75.0 
x10e9 /L 
<75.0 - 50.0 
x10e9 /L 
<50.0 – 25.0 
x10e9 /L 
<25.0 x 10e9 /L 
White blood cell 
decreased 
<LLN - 3.0 x 
10e9 /L 
<3.0 - 2.0 x 10e9 
/L 
<2.0 - 1.0 x 10e9 
/L 
 
<1.0 x 10e9 /L 
Neutrophil count 
decreased 
<LLN - 1.5 x 
10e9 /L 
<1.5 - 1.0 x 10e9 
/L 
<1.0 - 0.5 x 10e9 
/L 
<0.5 x 10e9 /L 
Lymphocyte 
count decreased 
<LLN - 0.8 x 
10e9/L 
<0.8 - 0.5 x 10e9 
/L 
<0.5 - 0.2 x 10e9 
/L 
<0.2 x 10e9 /L 
Creatinine 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x ULN 
>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 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase analyzed. Of note, 
baseline will be defined as last assessment prior to first dosing in initial treatment phase. If no 
pre-treatment value exists, also a value recorded after first dose can be used as baseline if it was 
collected on the same day as first dose, see Section 2.1.1.3. 
Exposure time adjusted incidence for subjects with newly occurring neutropenia of CTCAE 
grade >=2 will be summarized and listed in the listing. 
The number and percentage of subjects with newly occurring liver enzyme abnormalities will 
also be summarized based on the event criteria given in Table 2-11. 


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Table 2-11 
Liver-related events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
AST 
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN 
ALT or AST >3xULN & (nausea or vomiting or fatigue or general malaise or 
abdominal pain or (rash and eosinophilia)) 
TBL 
>1xULN;>1.5xULN; >2xULN; >3xULN, 
ALP 
>1.5xULN;>2xULN; >3xULN; >5xULN 
ALT or AST & 
TBL 
ALT or AST>3xULN & TBL >1.5xULN; 
ALT or AST>3xULN & TBL >2xULN; 
ALT or AST >5xULN & TBL >2xULN; 
ALT or AST >8xULN & TBL >2xULN; 
ALT or AST >10xULN & TBL >2xULN; 
ALT or AST >20xULN & 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  (Potential 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. 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN  (Potential Hy’s Law) 
or reported Hy’s Law case 
Note: “Hy’s Law case” is a lower level term in MedDRA (10070546) and may be 
reported as AE. 
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>5xULN. 
Individual subject data listings will be provided for subjects with newly occurring or worsening 
abnormal laboratory data. Data of subjects with newly occurring liver enzyme abnormalities 
will be listed in an additional listing. 
Fasting laboratory tests including fasting plasma glucose and fasting lipids will be evaluated 
only at screening. No analysis will be done for these measurements. 
For urinalysis, standard dipstick measurements for specific gravity, protein, glucose, pH, blood, 
urine blood (non-hemolyzed), urine blood (hemolyzed), bilirubin, ketones, WBC will be done 
at screening. For urinalysis, frequency tables will be presented. 


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2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Fridericia (QTcF) 
corrections will be presented for QTc. QTcF will be derived by the programmer using the 
formula: QTcF = QT/CubeRootRR(seconds). 
QTc will be summarized by computing the number and percentage of subjects with: 
• QTc > 500 msec  
• QTc > 480 msec 
• QTc > 450 msec 
• QTc changes from baseline > 30 msec 
• QTc changes from baseline > 60 msec 
• Sinus pause > 3 sec, if appropriate 
• PR > 250 msec 
Summary statistics will be presented for ECG variables by visit and treatment group. 
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters.   
 
2.7.4.2 
Vital signs 
Systolic and diastolic blood pressure are measured twice at each scheduled visits, and two 
mesurments are entered on the CRF page in this study. The average value of the two 
mesurments will be used in the vital sign analysis. 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed 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 
Only “on-treatment” vital signs will be summarized (i.e. assessments within last dose plus 84 
days). All vital signs will be listed with “on-treatment” flag displayed. 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-12 below. A 
listing of subjects with newly occurring notably abnormal vital signs will be provided. 
Table 2-12 
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 


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2.10 
Patient-reported outcomes 
Three tools will be used in this study: 


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2.10.2 
Health Assessment Questionnaire- Disability Index (HAQ-DI) (subjects 
with PsA only) 
The Health Assessment Questionnaire (HAQ©) was developed by Stanford University and is 
one of the most widely used measures to assess the long-term influence of chronic disease on a 
subject's level of functional ability and activity restriction. The disability assessment component 
of the HAQ (Health Assessment Questionnaire© – Disability Index), the HAQ-DI, assesses a 
subject's level of functional ability and includes questions of fine movements of the upper 
extremity, locomotor activities of the lower extremity, and activities that involve both upper 
and lower extremities. There are 20 items in eight categories of functioning including dressing 
& grooming, arising, 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 (without any difficulty [0]), with 
some difficulty (1), with much difficulty (2), and unable to do (3). The HAQ-DI also includes 
questions about the use of ‘aids or devices’ and aid from other people to supplement the answers 
given to the 20 items. 
Scoring for the eight functional categories and overall disability index scoring will be performed 
as follows:  
There are eight categories; first score within each category:  
▪ 
Dressing and Grooming, includes items 1 and 2  
▪ 
Arising, includes items 3 and 4  
▪ 
Eating, includes items 5, 6 and 7  


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▪ 
Walking, includes items 8 and 9  
▪ 
Hygiene, includes items 10, 11, and 12  
▪ 
Reach, includes items 13 and 14  
▪ 
Grip, includes items 15, 16 and 17  
▪ 
Activities, includes items 18, 19, and 20 
The score for each category will be the single response within the category with the highest 
score (greatest difficulty). For example, in the "Eating" category, there are two answers (one 
for each item). If "Cut your food with a knife or fork" is marked as "3" and "Lift a full cup or 
glass to your mouth" is marked as "0", then the score for the "Eating" category would be "3" 
(the response indicating the greatest difficulty within the category). If a component question is 
left blank or the response is too ambiguous to assign a score, then the score that that category 
will be determined by the remaining completed question(s). However, if any "aids or devices" 
and/or "help from another person" items at the bottom of each page are checked with the 
exception of “other”, the category to which they apply will be adjusted upward to "2". If the 
basic score is already "2" or "3", the score remains unchanged. "Aids or devices" and "help 
from another person" can only change a category's score to "2"; they do not change the score to 
a "1" or a "3". Companion aids/devices items for HAQ-DI categories are presented in Table 2-
13. No score will be adjusted for “other” ticked, regardless of the “other” specification. 
The score for the disability index will be the mean of the eight category scores. If more than 
two of the categories, or 25%, are missing, scale will not be scored. If fewer than 2 of the 
categories are missing, divide the sum of the categories by the number of answered categories. 
The higher score indicates greater disability. 
 
 
Table 2-1 
Companion aids/devices items for HAQ-DI categories 
HAQ-DI Category  
Companion Item  
Dressing & Grooming   
Devices used for dressing (button hook, zipper pull, long 
handled shoe horn etc.)   
Arising   
Built up or special chair   
Eating   
Built up or special utensils   
Walking   
Cane walker, crutches   
Hygiene   
Raised toilet seat, bathtub seat, bathtub bar   
Long handled appliances in bathroom   
Reach   
Long handled appliances for reach   
Grip   
Jar opener (for jars previously opened)  
The purpose of the HAQ-DI in this study is to assess the functional ability of subjects with PsA. 
 
  


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2.10.3 
Patient’s global assessments (subjects with PsA only) 
When a subject has PsA at randomization defined as at least 3 points of the CASPAR criteria 
and at least 3 tender and 3 swollen joints at randomization, the subject will be asked to complete 
the following non-validated instruments using using 100 mm VAS ranging from “very good” 
to “very poor” on the VAS: 
• Patient’s Global Assessment of disease activity (PtGA Activity) 
• Patient’s Global Assessment of psoriatic arthritis pain (PtGA Pain) 
Standard summary statistics will be shown for the PtGA activity and PtGA pain assessment.  
2.10.4 
Handling of missing values/censoring/discontinuations 
For 
 HAQ-DI scores, missing values will be replaced by LOCF. Baseline values will not 
be carried forward. If no pre-treatment value exists, values obtained after first dose of treatment 
can be used as baseline only if it was collected on the same day as first dose. In addition, missing 
baseline (PROs) values will be replaced by the means or modes of non-missing baseline values 
stratified by age group (<65 years, 65 years and older) and gender, for continuous scale or 
categorical/ordinal scale, respectively.  
2.11 
Biomarkers 
Not applicable. 
2.12 
Other Exploratory analyses 
Not applicable.  
2.13 
DMC 
Only safety data will be reviewed by the DMC, the detailed table/listing/figure (TFL) list will 
be provided in an excel file.  
There will be two sets of TLFs produced. The first set will be the Blinded Set which will use 
the dummy treatment group in the TFLs. However the study data are real. This set of TLFs will 
be made available to the Novartis Blinded team apart from the DMC members. The second set 
will be the unblinded set. This will include real study data which will be assigned to the 
treatment groups based on the randomization. This means that the treatment assignment in these 
TLFs will be real. This set of TLFs will only be handled by the Unblinded Team (Independent 
statistician, independent programmer) and will only be shared with DMC members.  
2.14 
Interim analysis 
After last patient completed the week 16, an analysis will be conducted 
 
. At Week 16 analysis, the primary endpoint analysis at Week 12 together with 
the Week 16 efficacy data analysis will be performed. For safety analysis, the data till week 16 
will be analyzed. 


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3 
Sample size calculation 
This global study aims at complementing the safety and efficacy knowledge on secukinumab 
with data obtained from patients in China and other countries. The planned cohort sizes address 
this objective, in particular with respect to safety data. 
At Baseline, subjects will be randomized to one of the two secukinumab treatment regimens or 
to placebo in a 2:1:1 ratio (300mg Secukinumab: 150mg Secukinumab: placebo). After the first 
12 weeks of treatment, non-responders under placebo will be re-assigned to 300 mg 
secukinumab treatment regimen. 
Reported PASI 75 response rate to placebo is generally in the range of 3% to 7% (Papp 2006; 
Menter 2008; Leonardi 2008; Papp 2008) whilst in a recent phase III trial, observed PASI 75 
response rate to placebo in Chinese subjects after twelve weeks of treatment was above 11% 
("Safety and effectiveness of ustekinumab/stelara in Chinese patients with psoriasis", 
ClinicalTrials.gov Identifier: NCT01008995). It is estimated that in the present study, up to 10% 
of the subjects under placebo will achieve a PASI 75 response during the first twelve weeks of 
treatment (induction period). 
According to CFDA requirement in use of biologic drug, it is planned to randomize 536 subjects 
at Baseline, i.e., using a 2:1:1 ratio, 268 patients for 300 mg secukinumab regimen and 134 
patients for 150 mg secukinumab regimen and placebo group, respectively.  
The PASI 75 and IGA mod 2011 0 or 1 response rates of secukinumab regimens at Week 12 
are assessed based on Phase III trials. PASI 75 response rates at Week 12 are approximately 
79.4% (95% C.I: [76.2, 82.4]) for the 300 mg secukinumab regimen and 69.2% (95% C.I: [65.6, 
72.6]) for the 150 mg secukinumab regimen. IGA mod 2011 0 or 1 response rates at Week 12 
are approximately 65.0% (95% C.I: [61.3, 68.6]) for the 300 mg secukinumab regimen and 51.4% 
(95% C.I: [47.7, 55.2]) for the 150 mg secukinumab regimen. Since two secukinumab dose 
regimens will be tested in parallel versus placebo with respect to the co-primary endpoints, 
PASI 75 response and IGA mod 2011 0 or 1 response after 12 weeks of treatment, the type-I-
error for each comparison will be split to α/2 (family-wise α=2.5%, one-sided). With 536 
(using a 2:1:1 ratio) subjects and assuming a response rate in the placebo group of 10% for 
PASI 75 response and IGA mod 2011 0 or 1 response, the power to demonstrate a response rate 
of 65.6% for PASI 75 and 47.7% for IGA mod 2011 0 or 1 in the secukinumab groups is above 
99%, based on Fisher’s exact test (nQuery Advisor 7.0, two group Fisher’s-exact test of equal 
proportions). 
The PASI 90 response rates of secukinumab regimens are approximately 56.6% (95% C.I: [52.8, 
60.3]) for the 300 mg secukinumab regimen and 41.1% (95% C.I: [37.4, 44.9]) for the 150 mg 
secukinumab regimen. 
With respect to the secondary endpoint of PASI 90 response at week 12 and with sample size 
of 536 (using a 2:1:1 ratio), the power to detect differences in response rates for each 
secukinumab dose regimen versus placebo is above 99%, based on Fisher’s exact test with type-
I-error of α/2 (family-wise α=2.5%, one-sided) for each comparison and placebo response 
rate of 5%. 


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4 
Change to protocol specified analyses 
Due to a very small number of subjects with relapse are expected, the Kaplan Meier analysis 
for time to relapse will not be provided.  
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Any partial dates will be imputed as follows: 
We take the earlier day of  
• The last day in the month and  
• The end day of the corresponding epoch 
5.1.2 
AE date imputation 
Impute AE end date: 
1. If the AE end date ‘month’ is missing, the imputed end date should be set to the earliest of 
the (min (last visit date, last dose date + 84 days), 31DECYYYY, date of death).  
2. If the AE end date ‘day’ is missing, the imputed end date should be set to the earliest of the 
(min (last visit date, last dose date + 84 days), last day of the month, date of death).  
3. If AE ‘year’ is missing or AE is ongoing, the end date will not be imputed.  
Impute AE start date:  
Before imputing AE start date, find the AE start reference date.  
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date).  
2. Else AE start reference date = treatment start date  
1. If the AE start date ‘year’ value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.  
2. If the AE start date ‘year’ value is less than the treatment start date year value, the AE 
started before treatment. Therefore:  
a. If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).  
b. Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).  
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore:  


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a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).  
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).  
4. If the AE start date year value is equal to the treatment start date year value:  
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.  
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).  
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day).  
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date.  
5.1.3 
Concomitant medication date imputation 
Impute CM end date:  
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month.  
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY).  
3. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date.  
Impute CM start date:  
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date.  
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY).  
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).  
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:  
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY).  


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b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY).  
4. If the CM start date year value is equal to the treatment start date year value:  
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date.  
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY).  
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY).  
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date.  
5.1.3.1 
Prior therapies date imputation 
See Section 5.1.3. 
5.1.3.2 
Post therapies date imputation 
See Section 5.1.3. 
5.1.4 
First diagnosis date (Pso, PsA) imputation 
1. If first diagnosis date is complete then imputed first diagnosis date = first diagnosis date.  
2. If only year is present in the first diagnosis date then do the following: 
a. If the year part of the first diagnosis date is equal to the year part of the inform consent 
date then imputed first diagnosis date = Jan 1 of the year of the first diagnosis date 
b. Otherwise imputed first diagnosis date = Jul 1 of the year of the first diagnosis date 
3. If only month and year part are present in the first diagnosis date then do the following: 
a. If the month and year part of the first diagnosis date is equal to the month and year 
part of the inform consent date then imputed first diagnosis date = 1st of the month of 
the year of the first diagnosis date 
b. Otherwise imputed first diagnosis date = 15th of the month of the year of the first 
diagnosis date 
5.1.5 
Other imputations 
Only PASI and IGA mod 2011 based response variables are imputed with multiple imputation 
or non-response, other response variables 
will be imputed with 
LOCF. 
For 
 HAQ-DI scores, missing values will be replaced by LOCF. Baseline values will not 
be carried forward. If no pre-treatment value exists, values obtained after first dose of treatment 
can be used as baseline only if it was collected on the same day as first dose. In addition, missing 


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baseline (PROs) values will be replaced by the means or modes of non-missing baseline values 
stratified by age group (<65 years, 65 years and older) and gender, for continuous scale or 
categorical/ordinal scale, respectively. 
For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. The numerical 
part of the reported result will be treated as the actual LLQ or ULQ. These laboratory values 
will be displayed in listings using the standard unit with the reported sign (“<” or “>”).” 
5.2 
AEs coding/grading 
Adverse events will also be coded according to MedDRA dictionary. The MedDRA version 
used for reporting the adverse events will be described in a footnote. 
Safety topics of interest, such as risks defined in the Safety Profiling Plan, Risk Management 
Plan or topics of interest regarding signal detection or routine analysis are defined in the 
Program Case Retrieval Sheet that is stored in GPS at the path [/vob/util/sasviews/tms]. 
5.3 
Laboratory parameters derivations 
See Section 2.7.3. 
5.4 
Statistical models 
5.4.1 
Analysis of continuous data 
5.4.1.1 
Summary statistics 
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group. 
For PASI score, DLQI total scores, summary statistics will be derived for absolute and 
percentage changes from baseline. 
5.4.2 
Analysis of binary (and categorical) data 
5.4.2.1 
Summary statistics 
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. If applicable, confidence intervals will be derived as 
well based on the score method including continuity correction [Newcombe (1998)]: 
With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), 
n as total number of subjects (i.e. number of subjects in the denominator), and pas estimated 
crude incidence (number of subjects with event / n) it is 
 
Then the lower limit is for 
 
p
q
−
=1
(
),
0
for
0
,0
=
=

p
L
p


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(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is for 
 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
For response variables (e.g. for IGA mod 2011 0 or 1, PASI 75, PASI 50, PASI 90 and PASI 
100 response) the placebo adjusted response rates (risk difference) including 95% confidence 
interval will be derived by visit. 
Figures will be provided for PASI 75 response (upper left) PASI 90 response (upper right), 
PASI 100 response (lower left) and IGA mod 2011 0 or 1 response (lower right) at Week 12 
and Week 16 as dot plots displaying treatments on the x-axis and point estimates including 95% 
confidence intervals on the y-axis.  
For time courses of response variables, the point estimate at each time point including 95% 
confidence interval will be plotted. 
5.4.2.2 
Logistic regression 
Binary outcome variables, including PASI 50 / 75 / 90 / 100 response and IGA mod 2011 0 or 
1 response, will be evaluated using a logistic regression model with treatment regimen, body 
weight category, geographical region and baseline PASI score. Odds ratios will be computed 
for comparisons of secukinumab versus placebo utilizing the logistic regression model fitted.  
If response rates are 0% or 100% in one of the treatment groups, fisher’s exact test will be used 
for the comparison, and odds ratio estimate will not be displayed in outputs, but “-” will be 
shown. 
The odds ratio will be calculated such that an odds ratio >1 is favorable for secukinumab. Using 
PROC GENMOD to calculate the confidence interval for the odds ratios assumes asymptotic 
normality of the Wald estimate for the regression coefficient. The 95% confidence interval for 
the regression parameter of the active treatment effect relative to control(s) will be calculated 
using an exponential transformation to create the confidence interval for the odds ratio. 
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests from Type III analyses. In the SAS procedure PROC GENMOD, a Type III analysis 
will be performed by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT. If 
logistic regression model does not converge, an exact logistic regression will be applied to 
response variables at each visit, and the following steps will be performed: 
1. Run the PROC GENMOD procedure with EXACT statement;  
2. If convergence not reached, remove the covariates from the model one by one until 
convergence is reached; start with removing continous variable (i.e., baseline PASI) and 
followed by categrical varable (geographical region, body weight category);  
(
),
1
for
1
,1
=
=

p
U
p


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3. If convergence not reached, perform Fisher’s exact test. 
It should be noted that this model might not converge if response rates are too low. 
For subgroup analyses of PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 
response, the logistic regression model will be fitted with treatment group, body weight 
category, geographical region and baseline PASI score as explanatory variables. Odds ratios 
will be computed for comparisons of secukinumab versus placebo utilizing the logistic 
regression model fitted. In case of non-convergence, Fisher’s exact test will be performed. 
Of note, for the subgroup analysis by body weight category (region), the weight category 
(region) variable will not be fitted in the logistic regression model. 
5.4.3 
Multiple imputations for response variables 
Primary and secondary endpoints will be evaluated by Logistic regression and odds ratio 
estimate as described in the primary analysis method with multiple imputations for missing 
values. In addition, logistic regression analysis for PASI 50, PASI 75, PASI 90, PASI 100 and 
IGA mod 2011 0 or 1 response by visits will be analyzed using multiple imputation method. 
In the multiple imputations analysis the response status will be imputed based on the individual 
treatment arm information. 
Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Rubin (1987) presented rules how to combine the multiple 
sets of estimates to produce overall estimates and confidence intervals that adequately 
incorporate missing data uncertainty.  
Missing values for the ‘change from baseline PASI score’ and ‘IGA mod 2011 score’ will be 
imputed simultaneously based on an underlying joint normal distribution and using a Markov 
Chain Monte Carlo (MCMC) method. The change from baseline in PASI score appears to 
follow closer to a normal distribution than the actual PASI score. Assuming normality for the 
‘IGA mod 2011 score’ is motivated by Schaefer (1997), where it was shown that the 
multivariate normal approximation for the imputation of incomplete categorical and binary data 
is robust.  
The imputations will be done separately for each treatment group including baseline weight, 
region (China/non-China), failure to at least one previous biologic (yes/no), and number of 
previous systemic therapies as additional covariates.  
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100, and IGA mod 2011 0 or 1 
response by visit will be presented in contingency tables with multiple imputations method. 
The number of imputations will be set to 100, the seed for the random function will be set to 
4572318 for this study. To generate the multiple imputed data sets, the SAS procedure MI can 
be used as follows: 
The input data set <pasi_iga> should have one record per subject with baseline PASI score and 
IGA mod 2011 score as well as all changes from baseline PASI and post-baseline IGA mod 
2011 score. 


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ODS LISTING CLOSE; 
ODS OUTPUT MissPattern=msgpat VarianceInfo=varinfo ParameterEstimates=param; 
PROC MI DATA=<pasi_iga> OUT=<impdata> SEED=457<studycode> NIMPUTE=100; 
 VAR <baseline weight>  <region> <failure to at least one biologic>  
     <number of previous systemic therapies>  
     <baseline PASI> <baseline IGA>  
     <change from baseline PASI week 1> - <change from baseline PASI week primary endpoint> 
     <IGA week1> - <IGA week primary endpoint>; 
  BY <treatment group>; 
RUN; 
ODS LISTING; 
 
Programming notes: 
• The SAS procedure MIANALYZE expects a variable called “_IMPUTATION_ which 
is generated by the MI procedure. It might be needed to set the SAS option 
“VALIDVARNAME=UPCASE” temporarily in the program before the MI call, this 
option should be reset after the MIANALYZE call to VALIDVARNAME=V6.  
• In case there are no missings in one treatment group, the MI procedure does not 
impute any values. In this case the corresponding data need to be imputed manually 
outside PROC MI and added to the dataset <impdata>. 
 
The imputed data are saved in data set <impdata>. The outcomes of interest, i.e. the PASI 
50/75/90/100 response and IGA mod 2011 0 or 1 response will be calculated, e.g. as follows: 
 
DATA <impdata2>; 
 SET <impdata>; 
IF <change from baseline PASI week primary endpoint>/<baseline PASI>=0.90 THEN <PASI 90 response> =1; 
ELSE <PASI 90 response>=0; 
<…repeat for all PASI response…> 
 
IF <baseline IGA> >=3 THEN DO; 
 
     IF <IGA week primary endpoint> < 1.5 THEN <IGA 0/1 response> =1; 
 
ELSE IF <IGA week primary endpoint> >=1.5 THEN <IGA 0/1 response> =0; 
 
ELSE PUT "E" "RROR:" stysid1a=; 
END; 
ELSE IF <baseline IGA>=2 THEN DO; 
 
     IF <IGA week primary endpoint> < 0.5 THEN <IGA 0/1 response> =1; 
 
ELSE IF <IGA week primary endpoint> >=0.5 THEN <IGA 0/1 response> =0; 
 
ELSE PUT "E" "RROR:" stysid1a=; 
END; 
ELSE <IGA 0/1 response> =0; 
RUN; 
 
The treatment differences for each imputed data set will then be evaluated by Logistic 
regression and ODDS ratio as described in Section 5.4.5.3. This analysis will be done by 
_IMPUTATION_ for the comparison to the placebo treatment group. The model should be 
estimating response probability = 1 by using DESECENDING option. Using the ESTIMATE 
option in the GENMOD procedure and the ODS OUTPUT data set “Estimates” provides the 
estimate for the odds ratio and confidence intervals. 


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PROC GENMOD <option>; 
CLASS <stratum> <treatment>; 
MODEL <response> = <explanatory variables> / link=logit dist=bin type3; 
BY <by-variables); 
ESTIMATE “OR. AIN 300 mg VS. Placebo” <treatment> 1 -1/exp;  
ODS OUTPUT Estimates=Estimates; 
RUN; 
The MIANALYZE procedure expects the parameter estimate in the variables ESTIMATE, and 
the corresponding standard error in the variable STDERR. Measurements can be obtained from 
“Estimates” dataset by selecting the row with ODDS ratio estimates.  
 
Data <modified dataset>; 
  set Estimates; 
  if substr(label,1,3)= “Exp”; 
  ESTIMATE=LBetaEstimate; 
  STDERR=StdErr; 
  effect= “OR”; 
  if missing(ESTIMATE) or missing(STDERR) then delete; 
RUN;  
 
The estimates and standard errors based on the 100 imputed data are then combined by applying 
Rubin’s rules for multiple imputed data sets, see Little and Rubin (2002).  
Programming notes:  
• The variables ESTIMATE and STDERR in the input data set for the MIANALYZE 
procedure may not be missing. Records with missing values need to be deleted and the 
variable _IMPUTATION_ needs to be renumbered and regenerated since for each by-
group the procedure expects consecutive numbers starting at 1. 
• The ESTIMATE and STDERR in terms of odds ratios from logistic regressions will be 
transformed to follow a normal distribution before MIANALYZE procedure. They will 
be transformed back to Odds Ratio to get the corrected ESTIMATE and corresponding 
CIs.   
The SAS procedure MIANALYZE will be applied as follows: 
Step 1: 
DATA <modified dataset_t>; 
 
SET <modified dataset>; 
 
estimate=log(ESTIMATE); 
 
stderr=(log(LBETAUPPERCL)-log(LBETALOWERCL))/(2*1.96); 
RUN ; 
 
ODS LISTING CLOSE; 
ODS OUTPUT ParameterEstimates=<results> VarianceInfo=<varinfo> ModelInfo=<modelinfo>; 
PROC MIANALYZE PARMS=<modified dataset>; 
  BY <by-variables>; 
  MODELEFFECTS OR; 
RUN; 
ODS LISTING; 
 
data <results_back>; 


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set <results>; 
 
estimate=exp(ESTIMATE); 
 
LCLMEAN=estimate*exp(-1.96*stderr); 
 
UCLMEAN=estimate*exp(+1.96*stderr); 
RUN ; 
5.4.4 
Analysis of time-to-event data 
Number and percentage of subjects with a clinical event based on the number of subjects in the 
analysis set at risk as denominator will be provided by treatment group.  
Median time to event (i.e., loss of PASI 75, IGA 0/1 response) and quartiles including 95% 
confidence intervals will be provided. The confidence intervals will be based on log-log 
transformation (PROC LIFETEST option conftype=log-log). In addition, for pre-specified time 
intervals the following will be presented in an output:  
• for each treatment group and time interval: subjects at risk, subjects with event, subjects 
with event divided by subjects at risk, cumulative subjects with event and cumulative 
event probability including 95% confidence interval 
The pre-specified time intervals for different treatment periods are as follows:  
Treatment period: “0 to ≤4 weeks”, “>4 weeks to <=8 weeks”, “>8 weeks to <=12 weeks”, “>12 
weeks to <=16 weeks”, “>16 weeks to <=20 weeks”, “>20 weeks to <=24 weeks”, “>24 weeks 
to <=28 weeks”, “>28 weeks to <=32 weeks”, “>32 weeks to <=36 weeks”, “>36 weeks to 
<=40 weeks”, and “>40 weeks”. 
For the statistical appendix, the subjects identifier, the time to event, the number of subjects 
with an event, number of subjects remaining at risk in the treatment group in the analysis set, 
estimate of the event rate and its estimated standard error, as estimable, will be provided for 
each treatment group using the SAS procedure LIFETEST.  
Subjects at risk, timepoint “0” and censoring will be defined as described in Table 5-1 below: 
Table 5-1 
Time to event: definition of risk set, timing and censoring by variable 
Variable: 
Time to 
Risk set 
Time = 0 
Time of 
event 
Censoring 
Psoriasis 
ConMed 
Informative  
censoring 
Loss of 
PASI 75 
All PASI 75 
responders at 
Week 12 per 
analysis visit 
AND at least 
have one PASI 
assessments 
after Week 12 
Week 12 
per 
analysis 
visit 
Date of 1st 
visit with  
loss of 
PASI 75 
observed 
End of 
treatment 
period as 
per CRF 
disposition 
page 
Censor (if 
ConMed 
taken 
before the 
event) 
Study 
phase 
discontinu-
ation with 
reason 
“lack of 
efficacy” 


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Variable: 
Time to 
Risk set 
Time = 0 
Time of 
event 
Censoring 
Psoriasis 
ConMed 
Informative  
censoring 
Loss of  
IGA 0/1 
All IGA 0/1 
responders at 
Week 12 per 
analysis visit 
AND at least 
have one IGA 
assessments 
after Week 12 
Week 12 
per 
analysis 
visit 
Date of 1st 
visit with  
loss of  
IGA 0/1  
observed 
End of 
treatment 
period as 
per CRF 
disposition 
page 
Censor (if 
ConMed 
taken 
before the 
event) 
Study 
phase 
discontinu-
ation with 
reason 
“lack of 
efficacy” 
Psoriasis ConMed is define in MAP appendix 
Time-to-event will be derived as:  
• date of event minus date of time=0 plus 1 day for subjects experiencing the event or 
• date of censoring minus date of time=0 plus 1 day for subjects not experiencing the 
event 
5.4.5 
Crude incidence and related risk estimates 
5.4.5.1 
Crude incidence and 100*(1-α)% confidence interval 
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event. 
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 1998).  
With z  as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), n 
as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n) it is 
. 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
Note: if p = 0 then L = 0 and if p = 1 then U = 1. 
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses. 
p
q
−
=1


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5.4.5.2 
Relative risk and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event with probability π1 and π0 respectively, the relative risk is estimated as p1/p0 with p1=x1/n1 
and p0=x0/n0. 
An asymptotic 100*(1-α)% confidence interval on the relative risk will be based on the back-
transformed large sample confidence limits on the log-transformed relative risk estimate which 
are obtained by application of the delta-method and Slutzky’s theorem (Lachin 2000). The SAS 
procedure PROC FREQ with option RELRISK in the TABLES statement will be used to 
provide the asymptotic 100*(1-α)% confidence interval on the relative risk. The estimate is not 
computed if either x1 or x0 equals 0. In this case, or if the crude incidences are low in both 
groups, the relative risk will be approximated by the odds ratio for which an exact confidence 
interval will be obtained as specified in Section 5.4.5.3. If the relative risk is not well 
approximated by the odds ratio but asymptotic normality is questionable, STATXACT will be 
used. 
5.4.5.3 
Odds ratio and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g. placebo) with n0 subjects at risk, of whom x1 and x0 experience a certain event with 
probability π1 and π0 respectively, the odds ratio is estimated as 
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p
−
−
 with p1= x1/n1 and p0=x0/n0. A conditional exact 100*(1-α)% confidence interval 
will be obtained by using the SAS procedure PROC FREQ with statement EXACT OR. 
5.4.5.4 
Risk difference and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0.  
Exact unconditional confidence limits for the risk difference will be obtained with SAS 
procedure PROC FREQ and option RISKDIFF in the TABLES statement, specifying the 
RISKDIFF option also in the EXACT statement.  
5.4.6 
Exposure adjusted incidence rate and related risk estimates 
5.4.6.1 
Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain treatment emergent event is observed, or if the event was not 
experienced, the (censored) time to the end of the observation period or last dose plus 84 days 
whichever occur earlier. The sequence of first occurrences of an event will be modeled to follow 
approximately a Poisson process with constant intensity θ. The rate parameter θ will be 
estimated as λ=D/T, where 

=
=
n
j
jt
T
1
and D is the number of subjects with at least one event. 


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Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson variable with 
parameter θT and observed value D can be obtained based on (Garwood, 1936), from which an 
exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai, 1993; Ulm, 
1990): 
Lower confidence limit   
 for D>0, 0 otherwise, 
Upper confidence limit 
 
where
k
c ,
 is the αth quantile of the Chi-square distribution with k degrees of freedom. 
5.4.6.2 
Exposure-adjusted event rate and 100*(1-α)% confidence interval 
For each of n subjects tj (j=1,...,n) specifies the exposure time. The number of occurrences of 
an treatment emergent event will be modeled to follow approximately a Poisson process with 
constant intensity θ. The rate parameter θ will be estimated as λ=D/T, where 

=
=
n
j
jt
T
1
 and D 
is the number of events (episodes). Conditionally on T, an exact 100*(1-α)% confidence interval 
for a Poisson variable with parameter θT and observed value D can be obtained based on 
(Garwood, 1936), from which an exact 100*(1-α)% confidence interval for D/T will be derived 
as follows (Sahai, 1993; Ulm, 1990): 
Lower confidence limit   
 for D>0, 0 otherwise, 
Upper confidence limit 
 
where
k
c ,
 is the α th quantile of the Chi-square distribution with k degrees of freedom. 
5.5 
Rule of exclusion criteria of analysis sets  
Protocol deviations for exclusion from analysis sets are defined in Table 5-2.  
Table 5-2 
Subject classification rules 
Analysis set 
PD Categories Codes that 
cause subject to be excluded 
Non-PD criteria that cause a 
subject to be excluded 
Randomization set 
NA 
Misrandomized subject 
FAS (Full Analysis Set)  
DVSPID: INCL02; OTH17 
Misrandomized subject 
Safety 
DVSPID: INCL02; OTH17 
Subjects who did not take any 
study treatment 
INCL02: ICF missing or not signed prior to initiating study procedure 
OTH17: Severe ICH-GCP non-compliance of study site 
 
T
c
L
D
2
,2
/
5.0

=
T
c
U
D 2
2
,
2
/
1
5.0
+
−
=

T
c
L
D
2
,2
/
5.0

=
T
c
U
D 2
2
,
2
/
1
5.0
+
−
=



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6 
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