A 24-week, Multicenter, proSpective stUdy to Evaluate the PASI 90 Clinical Response Rate and the Safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and Cw6-positive Patients With Moderate to Severe Chronic Plaque-type Psoriasis (SUPREME)
Phase: PHASE3
Conditions: Plaque Type Psorisis
Sponsor: Novartis Pharmaceuticals

Clinical Development 
Secukinumab (AIN457) 
Clinical Trial Protocol CAIN457AIT01 / NCT02394561
A 24-week, multicenter, proSpective stUdy to evaluate the 
PASI 90 clinical response rate and the safety PRofile of 
sEcukinuMab 300 mg in Cw6-negativE and Cw6-positive 
patients with moderate to severe chronic plaque-type 
psoriasis (SUPREME) – amended with an extension 
treatment period of up to 48 weeks 
Authors: 
 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2014-002865-31 
Version number: 
v03 (TC) 
Development phase: 
IIIb 
Release date: 
22 July 2016  
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
NCDS Template Version 03-Feb-2012 

Novartis 
Confidential 
Page 2 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Protocol synopsis ................................................................................................................. 9 
Amendment 1 .................................................................................................................... 19 
1 
Introduction ....................................................................................................................... 25 
1.1 
Background ............................................................................................................ 25 
2 
Study objectives ................................................................................................................. 27 
2.1 
Primary objective ................................................................................................... 27 
2.2 
Secondary objectives ............................................................................................. 28 
 
 28 
3 
Investigational plan ........................................................................................................... 28 
3.1 
Study design........................................................................................................... 28 
3.2 
Rationale of study design ....................................................................................... 29 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 30 
3.4 
Rationale for choice of comparator. ...................................................................... 30 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 30 
3.6 
Risks and benefits .................................................................................................. 30 
4 
Population .......................................................................................................................... 31 
4.1 
Inclusion criteria .................................................................................................... 31 
4.2 
Exclusion criteria ................................................................................................... 31 
4.3 
Eligibility criteria for entering the extension treatment period ............................. 33 
5 
Treatment ........................................................................................................................... 34 
5.1 
Protocol requested treatment ................................................................................. 34 
5.1.1 
Investigational treatment ....................................................................... 34 
5.1.2 
Additional study treatment .................................................................... 34 
5.2 
Treatment arms ...................................................................................................... 34 
5.3 
Treatment assignment ............................................................................................ 34 
5.4 
Treatment blinding ................................................................................................. 34 
5.5 
Treating the patient ................................................................................................ 34 
5.5.1 
Patient numbering ................................................................................. 34 
5.5.2 
Dispensing the investigational treatment .............................................. 34 
5.5.3 
Handling of study treatment .................................................................. 35 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 35 

Novartis 
Confidential 
Page 3 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 35 
5.5.6 
Rescue medication ................................................................................ 35 
5.5.7 
Concomitant treatment .......................................................................... 36 
5.5.8 
Prohibited Treatment ............................................................................. 36 
5.5.9 
Discontinuation of study treatment and premature patient 
withdrawal ............................................................................................. 37 
5.5.10 
Emergency breaking of treatment assignment ...................................... 37 
5.5.11 
Study completion and post-study treatment .......................................... 38 
5.5.12 
Early study termination ......................................................................... 38 
6 
Visit schedule and assessments ......................................................................................... 38 
6.1 
Information to be collected at screening ................................................................ 40 
6.2 
Patient demographics/other baseline characteristics ............................................. 40 
6.3 
Treatment exposure and compliance ..................................................................... 41 
6.4 
Efficacy .................................................................................................................. 41 
6.4.1 
Psoriasis Area and Severity Index (PASI) ............................................ 41 
6.4.2 
Investigator’s Global Assessment Scale (IGA) ..................................... 42 
6.4.3 
Appropriateness of efficacy assessments .............................................. 42 
6.5 
Safety ..................................................................................................................... 43 
6.5.1 
Physical examination ............................................................................ 43 
6.5.2 
Vital signs.............................................................................................. 43 
6.5.3 
Height, weight and waist ....................................................................... 43 
6.5.4 
Laboratory evaluations .......................................................................... 43 
6.5.5 
Electrocardiogram (ECG), chest X-ray ................................................. 44 
6.5.6 
Pregnancy and assessments of fertility ................................................. 44 
6.5.7 
Appropriateness of safety measurements .............................................. 44 
6.6 
Other assessments .................................................................................................. 44 
6.6.1 
Resource utilization ............................................................................... 44 
6.6.2 
Health-related Quality of Life ............................................................... 44 
6.6.3 
Hospital Anxiety and Depression Scale (HADS) ................................. 45 
 
 45 
7 
Safety monitoring .............................................................................................................. 46 
7.1 
Adverse events ....................................................................................................... 46 
7.2 
Serious adverse event reporting ............................................................................. 47 
7.3 
Liver safety monitoring ......................................................................................... 48 
7.4 
Pregnancy reporting ............................................................................................... 49 
8 
Data review and database management ............................................................................. 49 
8.1 
Site monitoring ...................................................................................................... 49 

Novartis 
Confidential 
Page 4 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
8.2 
Data collection ....................................................................................................... 50 
8.3 
Database management and quality control ............................................................ 50 
8.4 
Data Monitoring Committee .................................................................................. 51 
8.5 
Adjudication Committee ........................................................................................ 51 
9 
Data analysis ...................................................................................................................... 51 
9.1 
Analysis sets .......................................................................................................... 51 
9.2 
Patient demographics and other baseline characteristics ....................................... 51 
9.3 
Treatments ............................................................................................................. 52 
9.4 
Analysis of the primary variable ............................................................................ 52 
9.4.1 
Variable ................................................................................................. 52 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 53 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 53 
9.4.4 
Supportive analyses ............................................................................... 53 
9.5 
Analysis of secondary variables ............................................................................ 53 
9.5.1 
Efficacy variables .................................................................................. 53 
9.5.2 
Safety variables ..................................................................................... 54 
9.5.3 
Resource utilization ............................................................................... 55 
9.5.4 
Health-related Quality of Life ............................................................... 55 
9.5.5 
Pharmacokinetics .................................................................................. 56 
9.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 56 
 
 56 
9.5.8 
PK/PD ................................................................................................... 56 
9.6 
Interim analyses ..................................................................................................... 56 
9.7 
Sample size calculation .......................................................................................... 57 
10 Ethical considerations ........................................................................................................ 58 
10.1 
Regulatory and ethical compliance ........................................................................ 58 
10.2 
Informed consent procedures ................................................................................. 59 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 59 
10.4 
Publication of study protocol and results............................................................... 59 
11 Protocol adherence ............................................................................................................ 59 
11.1 
Protocol Amendments ........................................................................................... 60 
12 References ......................................................................................................................... 61 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 64 
14 Appendix 2: Liver event definitions and follow-up requirements .................................... 66 
15 Appendix 3: The PASI Scoring System ............................................................................ 69 
16 Appendix 4: The IGA mod 2011 rating scale ................................................................... 70 
 

Novartis 
Confidential 
Page 5 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
List of tables 
Table 5-1: Prohibited treatment ................................................................................................ 36 
Table 6-1: Assessment schedule (core study) ........................................................................... 39 
Table 6-2: Assessment schedule of extension treatment period ............................................... 40 
Table 9-1: Power analysis......................................................................................................... 57 
Table 14-1: Liver Event Definitions ......................................................................................... 66 
Table 14-2: Liver Event Follow Up Requirements .................................................................. 67 
 
List of figures 
Figure 3-1: Study design........................................................................................................... 29 
Figure 3-2: Extension Study design.......................................................................................... 29 
 

Novartis 
Confidential 
Page 6 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
List of abbreviations 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
AST  
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CASPAR 
Classification Criteria for Psoriatic Arthritis 
CRF 
Case Report Form 
DAR 
Dose Administration Record 
DLQI 
Dermatology Life Quality Index 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
GGT 
Gamma Glutamyl Transpeptidase 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
hs-CRP 
High Sensitivity C Reactive Protein 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 

Novartis 
Confidential 
Page 7 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function test 
LOCF 
Last Observation Carried Forward 
PASI 
Psoriasis Area Severity Index 
PP 
Per-Protocol 
PPD 
Purified Protein Derivative 
PUVA 
Psoralen combined with Ultraviolet A 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SNP 
Single Nucleotide Polymorphism 
SUSAR 
Suspected Unexpected Adverse Reaction 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
 
 

Novartis 
Confidential 
Page 8 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Glossary of terms 
 
Biological agents 
A substance that is made from a living organism or its products and is 
used in the prevention, diagnosis, or treatment of cancer and other 
diseases. Biological drugs include antibodies, interleukins, and vaccines. 
Cohort 
A group having one or more similar characteristics (such as habit of 
smoking or a particular disease) closely monitored over time. 
Human Leukocyte Antigen 
A collection of human genes on chromosome 6 that encode proteins that 
function in cells to transport antigens from within the cell to the cell 
surface. These proteins are sometimes referred to as the MHC, or major 
histocompatibility complex. 
Interleukin 
Any of a class of glycoproteins produced by leukocytes for regulating 
immune responses. 
Investigational treatment 
All investigational drugs whose properties are being tested in the study 
as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination.  
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage. 
Monoclonal Antibody 
An antibody produced by a single clone of cells. A monoclonal antibody 
is therefore a single pure type of antibody. Monoclonal antibodies can be 
made in large quantities in the laboratory and are a cornerstone of 
immunology. Monoclonal antibodies are increasingly coming into use as 
therapeutic agents. 
Phase IIIb study 
Clinical trials conducted after regulatory submission of a dossier, but 
prior to the medicine's approval and launch. These trials may 
supplement earlier trials, complete earlier trials, or may be directed 
toward new types of trials (e.g., quality of life, marketing) or Phase IV 
evaluations. This is the period between submission and approval of a 
regulatory dossier for marketing authorization. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all investigational/study treatment administration and all 
assessments (including follow-up). 
Study/investigational treatment 
discontinuation 
Point/time when patient permanently stops taking study/investigational 
treatment for any reason; may or may not also be the point/time of 
premature patient withdrawal. 
Variable 
Information used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points 
 
 
 

Novartis 
Confidential 
Page 9 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Protocol synopsis 
Protocol number 
CAIN457AIT01 
Title 
A 24-week, multicenter, proSpective stUdy to evaluate the PASI 90 
clinical response rate and the safety PRofile of sEcukinuMab 300 mg in 
Cw6-negativE and Cw6-positive patients with moderate to severe 
chronic plaque-type psoriasis (SUPREME) – amended with an extension 
treatment period of up to 48 weeks 
Brief title 
 
A study to evaluate the differences in the efficacy and safety of 
secukinumab between Cw6-negative and Cw6-positive patients with 
moderate to severe plaque-type psoriasis  
Sponsor and Clinical 
Phase 
Novartis  
IIIb 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Biological agents represent the most advanced type of treatment for 
psoriasis. Secukinumab is a human monoclonal anti IL-17A antibody 
that binds to human IL-17A and neutralizes its bioactivity by inhibiting 
IL17A produced by both Th17 cells and those of the innate immune 
system, thus providing complete anti IL17A blockage. Targeting IL-17A 
has the potential to reduce autoimmune inflammation while leaving other 
immune functions undisturbed. While targeting of Th1-promoting or 
Th17-promoting cytokines affects critical mediators such as IFN-γ, IL-22 
and IL-21, selective targeting of IL-17A leaves these Th1/17 activities, as 
well as certain protective functions of innate cells intact. Furthermore, as 
a fully human monoclonal antibody, secukinumab should reduce 
immunogenic risks compared to current or emerging antibody therapies 
that are not fully human.  
Many recent studies have shown that highly selective biologic drugs are 
not effective in every patient and that variations in the genome can be 
associated with different clinical responses or side effects to a given 
drug. The PSORS1 locus on chromosome 6p is generally understood to 
confer the most risk for psoriasis. A specific allele for this locus, HLA 
C*06, is present in about 60% of psoriatic patient cases. Data linking 
secukinumab efficacy to a particular genetic marker are lacking. 
Recent research has revealed a marked difference in the proportion of 
PASI 90 achievers at 12 weeks between Cw6-positive and Cw6-
negative patients (85.7% vs 56.5%) treated with ustekinumab (Talamonti 
M et al. 2013) and a greater efficacy of anti-TNFα drugs in CW6 
negative patients (Galli et al. 2013).Unlike anti-IL-12/23 agents, 
secukinumab inhibits IL-17 produced by both Th17 cells after 
presentation by antigen presenting cells (in this case Cw6) and cells of 
the innate immune system whose activation does not require antigen 
presentation. Providing a drug that is equally effective on both Cw6-
negative and Cw6-positive patients would be an important clinical 
accomplishment and would eliminate the need for costly HLA-Cw6 tests. 
The choice of a cohort study would therefore seem appropriate for this 
clinical context.  
The purpose of this study is to explore the different efficacy and safety 

Novartis 
Confidential 
Page 10 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
profiles of secukinumab 300 mg in patients with moderate to severe 
chronic plaque-type psoriasis, stratified for the presence of HLA-C*06, 
whose determination will be blinded for patients and investigators. The 
study will be conducted both on anti-TNFα-naïve and anti-TNFα failure 
patients and will also stratify for TNFα - 308 polymorphism, BMI, 
smoking and metabolic syndrome, among others. 
In addition, through amendment 2 of this protocol, a treatment extension 
of up to 48 weeks will be offered to willing patients reaching at least a 
PASI 75 response after 24 weeks of treatment during the core study. 
The purpose of the treatment extension is threefold; to explore response 
sustainability to secukinumab after 72 weeks of continuous treatment, to 
understand if HLA-CW6 can influence the kinetics of the response to 
secukinumab in the long term, and to generate long-term safety and 
tolerability data.  
Furthermore, as a consequence of the European Medicines Agency’s 
(EMA) approval of secukinumab in February 2015 “for the treatment of 
moderate to severe plaque psoriasis in adults who are candidates for 
systemic therapy,” inclusion criteria have been updated in order to 
guarantee treatment to systemically naïve patients, as per label. 
The study extension, for those patients who will enter, can be terminated 
for any reason by Novartis after a period of at least 12 weeks. 
Termination may occur only in selected regions where the drug is 
commercially available; this decision will be made on a region-by-region 
basis, as for some regions the study will continue as planned even 
though secukinumab may have become commercially available. 
Primary Objective(s) 
and Key Secondary 
Objective 
To evaluate the clinical response in Cw6-negative and Cw6-positive 
patients treated with secukinumab 300 mg with respect to the Psoriasis 
Area Severity Index (PASI) 90 response rate after 16 weeks, and 
thereafter for up to 72 weeks. 
Secondary Objectives 
 
- 
To compare the proportion of responders to PASI 50/75/90/100 
between cohorts at each time point. 
- 
To compare the mean changes vs baseline in IGA mod 2011 
between cohorts at each time point. 
- 
To compare time to reach PASI 90 between cohorts. 
- 
To compare time to reach PASI 75 between cohorts. 
- 
To evaluate the Quality of Life by means of the Dermatology Life 
Quality Index (DLQI) in all patients at each time point. 
- 
To evaluate anxiety and depression in all patients at each time point. 
- 
To evaluate the correlation between the Hospital Anxiety and 
Depression Scale (HADS) and PASI in all patients. 
- 
To evaluate changes from baseline in weight, BMI and waist in all 
patients at each time point. 
- 
To compare safety and tolerability between cohorts for 24 weeks, 
and thereafter for up to 72 weeks. 
- 
To evaluate the amount of resources used during the study in 
comparison with the 6 months prior to the beginning of the study. 
Study design 
This is a multicenter, prospective study involving Cw6-negative and 
Cw6-positive patients affected by moderate to severe chronic plaque 

Novartis 
Confidential 
Page 11 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
psoriasis. Patients will be centrally tested and stratified into two cohorts 
(Cw6-negative 
and 
Cw6-positive 
patients). 
Both 
patients 
and 
investigators will be blinded to the results with respect to Cw6. After a 
full screening visit, each eligible patient will be treated according to an 
induction regimen of two injections of secukinumab 150 mg a week for 
five weeks starting at baseline (week 0), followed by a maintenance 
period of one treatment (two injections) per month. At week 16, patients 
achieving a PASI 50 response will be eligible to continue on 
secukinumab for an additional 8 weeks. After a total of 24 weeks, willing 
patients reaching at least a PASI 75 response will enter an extension 
treatment period of up to 48 weeks. The total duration of the study, 
including the extension period, is therefore of 72 weeks. 
Population 
The study plans to enroll about 406 adult men or women, of which 365 
are evaluable patients, diagnosed with moderate to severe chronic 
plaque psoriasis for at least 6 months. The patients must be candidates 
for systemic therapy and may be treatment naïve or have failed to 
respond to other systemic therapy (including cyclosporine, methotrexate, 
psoralen combined with ultraviolet A (PUVA) or to an anti-TNFα (or is 
intolerant and/or has a contraindication to these).The study plans to 
involve approximately 50 centers. The extension phase will include 
approximately 306 of the patients initially enrolled in the core study. 
Inclusion criteria 
1. Subject 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. 
2. Men or women at least 18 years of age at time of screening. 
3. Diagnosis of moderate to severe chronic plaque-type psoriasis for at 
least 6 months (including concomitant psoriatic arthritis as per the 
Classification Criteria for Psoriatic Arthritis criteria [CASPAR]).  
4. Moderate to severe psoriasis as defined at enrollment by: 
 
PASI score ≥ 10  
or 
 
PASI score > 5 but < 10 and DLQI ≥10  
5. Patients that are candidates for systemic therapy, whether treatment 
naïve or after failed response to other systemic therapy (i.e. 
cyclosporine, methotrexate and PUVA) or to an anti-TNFα (or is 
intolerant and/or has a contraindication to these).  
Key Exclusion criteria 
1. Forms of psoriasis other than chronic plaque-type (e.g., pustular, 
erythrodermic and guttate psoriasis). 
2. Cyclosporine or methotrexate therapy within 4 weeks prior to Day 1.  
3. Anti-TNFα therapy within timelines depending on drug half-life.  
4. Previous exposure to secukinumab or any other biologic drug 
directly targeting IL-17 or the IL-17 receptor. 
5. Previous exposure to ustekinumab or any other biologic drug for the 
treatment of psoriasis that is not anti-TNFα therapy. 
6. Intravenous or intramuscular steroids within 2 weeks prior to 
screening and during screening.  
7. Ongoing use of corticosteroid topical treatments unless a washout 
period, as described in table 5-1, will be performed or UV 

Novartis 
Confidential 
Page 12 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
therapy. 
Inclusion criteria for 
extension treatment 
period 
1. Patients who have completed the CAIN457AIT01 core study.  
2. Written informed consent for protocol amendment 2 must be 
obtained before patients proceed to the extension treatment period. 
3. Patients must be deemed to be benefiting from the study drug based 
on at least a PASI 75 response rate after 24 weeks of treatment. 
Investigational therapy 
Secukinumab 300 mg (two s.c. injections of secukinumab 150 mg). 
Efficacy assessments 
– 
The Psoriasis Area and Severity Index (PASI) 
– 
The Investigator’s Global Assessment Scale (IGA mod 2011) 
Safety assessments 
– 
Physical examination, vital signs 
– 
Height, weight, waist 
– 
Laboratory assessments (hematology, blood chemistry, urinalysis) 
– 
hs-CRP 
– 
Electrocardiogram 
– 
Chest X-ray 
– 
Serum pregnancy test 
– 
Adverse event monitoring 
Other assessments 
– 
Health related quality of life 
 
The Dermatology Life Quality Index 
 
The Hospital Anxiety and Depression Scale 
– 
 
Data analysis 
The primary efficacy variable is the PASI 90 response after 16 weeks of 
treatment, defined as the achievement of ≥ 90% improvement 
(reduction) in PASI score after 16 weeks of treatment compared to 
baseline. The proportion of patients who reach PASI 90 at 16 weeks will 
be presented with the one-tailed 97.5% confidence interval of the Cw6 
positive – Cw6 negative difference. The primary objective as well as the 
secondary ones will be based on the ITT population. A supportive 
analysis will be done on the PP population. 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 response 
by visit will be presented with absolute, relative frequencies and 
confidence intervals. Summary statistics will be provided for absolute 
PASI scores and for percent changes from baseline by visit and cohort. 
Differences between cohorts in time to reach PASI 90, as well as PASI 
75, will be evaluated also by means of time to event analysis. 
Summary statistics for the IGA mod 2011 score over time will be 
presented by visit and cohort. Summary statistics for IGA 0 or 1 
response by visit and cohort will be presented with absolute and relative 
frequencies. 
Summary statistics will be provided for all the safety parameters: AEs, 
SAEs, laboratory data, height, weight, waist, BMI, vital signs and 
physical examination.  
Sample size calculation 
Phase III data on secukinumab show a PASI 90 response at 16 weeks 
of 71%. Under the assumption that 60% of all the enrolled patient 
population is represented by Cw6-positive patients, we can reasonably 
assume to observe a proportion of patients with PASI 90 of 80% in the 
Cw6-positive cohort. 

Novartis 
Confidential 
Page 13 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Under these assumptions, considering a one-side alpha level of 0.025 
and a power of 80%, 365 patients (219 Cw6-positive and 146 Cw6-
negative) are sufficient to evaluate if the response in terms of PASI 90 in 
the Cw6 negative cohort is not less than 12% respect to the Cw6 
positive cohort. 
Considering a dropout rate at 16 weeks of 10% equally divided in the 
two studied cohorts, a total of 406 patients should be enrolled.  
Although the sample size was calculated considering only Cw6 
haplotype, it will also be adequate for a regression model assessing 
differences from baseline of clinically relevant variables such as BMI, 
metabolic syndrome, smoking and TNFα-308 polymorphism, which, 
among the six existing polymorphisms, is the one most greatly affecting 
response to treatment with anti-TNFα drugs. 
Key words 
Chronic plaque psoriasis, PASI, HLA determination, IL-17A, Cw6, 
secukinumab. 

Novartis 
Confidential 
Page 14 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Amendment 3 
The purpose of this amendment is to correct some minor inconsistencies found in the 
inclusion and exclusion criteria detailed in the study protocol. The paragraph 6.4.2 has also 
been corrected. The informed consent form has been updated in order to correct minor 
discrepancies with the study protocol. 
Furthermore, we took advantage of this amendment in order to correct some typos present in 
the study protocol. 

Novartis 
Confidential 
Page 15 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Amendment 2 
The purpose of this amendment is to provide continued treatment of patients on secukinumab  
for an additional 48 weeks (overall up to 72 weeks), and thus allow for safety, tolerability, and 
efficacy data to be collected from the participating patients over a longer period of time. The 
extension period will allow meeting the following needs: 
1) Investigate response sustainability to secukinumab after 72 weeks of continuous 
treatment. 
2) Explore if HLA-CW6 can influence the kinetics of the response to secukinumab in the 
long term (ustekinumab data showed a faster response in CW6 positive patients 
compared with CW6 negative patients). 
Furthermore, as a consequence of the European Medicines Agency’s (EMA) approval in 
February 2015 of secukinumab “for the treatment of moderate severe plaque psoriasis in 
adults who are candidates for systemic therapy,” inclusion criterion number 5 has been 
changed in order to guarantee treatment to the population of systemically naïve patients, as 
per label. The study extension can be terminated by Novartis for any reason after a period of 
at least 12 weeks. Termination may occur only in selected regions where the drug is 
commercially available; this decision will be made on a region-by-region basis, as for some 
regions the study will continue as planned even though secukinumab may have become 
commercially available. 
Changes to the protocol (the protocol synopsis has also been modified accordingly) 
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 font for insertions. 
The major changes in this version of the protocol are as follows: 
 Title: “A 24-week, multicenter, proSpective stUdy to evaluate the PASI 90 clinical 
response rate and the safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and 
Cw6-positive patients with moderate to severe chronic plaque-type psoriasis 
(SUPREME) – amended with an extension treatment period of up to 48 weeks” 
 Section 1 – Introduction – has been updated to introduce the purpose of this 
amendment: 
Amendment 2 of the protocol has a threefold purpose; to explore response 
sustainability to secukinumab after 72 weeks of continuous treatment, to understand if 
HLA-CW6 can influence the kinetics of the response to secukinumab in the long 
term, and to generate long-term safety and tolerability data.  
Furthermore, as a consequence of the European Medicines Agency’s (EMA) approval 
of secukinumab in February 2015 “for the treatment of moderate to severe plaque 
psoriasis in adults who are candidates for systemic therapy,” inclusion criteria have 
been updated in order to guarantee treatment to systemically naïve patients, as per 
label. 
 Section 2.1 – Primary objective – now reads: “To evaluate the clinical response in 
Cw6-negative and Cw6-positive patients treated with secukinumab 300 mg with 

Novartis 
Confidential 
Page 16 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
respect to the Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks, 
and thereafter for up to 72 weeks.” 
 Section 2.2: A secondary objective has been modified: “To compare safety and 
tolerability between cohorts during the 24 weeks, and thereafter for up to 72 weeks.” 
 Section 3.1 – Study design – has been changed to reflect the addition of the extension 
period: 
The study has four periods: a screening period consisting of two visits (pre-screening 
and screening), an induction period of 4 weeks, a maintenance period of 20 weeks and 
an extension period of 48 weeks. Timelines of the study design are presented in 
Figure 3-1 and Figure 3-2. Detailed visit schedules can be found in Table 6-1 and 
Table 6.2. 
After the full screening visit (day -14 to -7), eligible patients will begin treatment at 
baseline (week 0) and will be followed for 24 weeks (core study), plus an additional 
48 weeks if participating in the extension treatment period. 
After a total of 24 weeks, willing patients reaching at least a PASI 75 response will 
enter an extension treatment period of an additional 48 weeks. The PASI score will be 
evaluated during the 72-week period. 
 Figure 3.2 has been added to illustrate the extension treatment period. 
 Section 3.6 – Risks and benefits – has been updated with recent efficacy and safety 
data. 
 Section 4 – Population – has been modified to guarantee treatment to systemically 
naïve patients and to indicate the number of patients to be enrolled in the extension 
period: 
The patients must be candidates for systemic therapy and may be treatment naïve or 
have failed to respond to other systemic therapy, including cyclosporine, 
methotrexate, psoralen combined with ultraviolet A (PUVA), or to an anti-TNFα (or 
is intolerant and/or has a contraindication to these). The study plans to involve about 
50 centers. 
The extension phase will include 306 of the patients taking part in the core study. 
 Section 4.1 – Inclusion criteria – Criterion no. 5 has been modified: 
5. Patients that are candidates for systemic therapy, whether treatment naïve or after 
failed response to other systemic therapy (i.e. cyclosporine, methotrexate and PUVA) 
or to an anti-TNFα (or is intolerant and/or has a contraindication to these). 
 Section 4.3 – Eligibility criteria for entering the extension treatment period – has been 
added: 
1. 
Patients who have completed the CAIN457AIT01 core study.  
2. 
Written informed consent for protocol amendment 2 must be obtained before 
patients proceed to the extension treatment period. 
3. 
Patients must be deemed to be benefiting from the study drug based on at least 
a PASI 75 response rate after 24 weeks of treatment. 

Novartis 
Confidential 
Page 17 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 Section 5.1.1 – Investigational treatment – has been modified to include instructions 
for the extension period: 
The study treatment will be administered by the site staff during the visit. Patients 
enrolled in the extension period will self-administer secukinumab and will be asked to 
keep a self-administration log during this period. 
 Section 5.5.4 – Instructions for prescribing and taking study treatment – has been 
modified to include instructions for the extension period: 
Patients proceeding to the extension period will self-administer treatment (two 150 
mg injections) once every 4 weeks for an additional 48 weeks. 
Willing patients reaching at least a PASI 75 response at the end of the 24-week core 
study will enter an extension treatment period of an additional 48 weeks. 
 Section 5.5.11 – Study completion and post-study treatment – has been modified to 
include information regarding the extension period: 
Willing patients reaching at least a PASI 75 response during the core study will be 
eligible to enter an extension treatment period of an additional 48 weeks. 
 Section 5.5.12 – Early study termination – now contains the following paragraph: 
The study extension can be terminated by Novartis for any reason after a period of at 
least 12 weeks. Termination may occur only in selected regions where the drug is 
commercially available; this decision will be made on a region-by-region basis, as for 
some regions the study will continue as planned even though secukinumab may have 
become commercially available. 
 Table 6-2 – Assessment schedule of extension treatment period – has been added. 
Table 6-2 lists all of the assessments of the extension phase and indicates with an “x” 
when the visits are performed. 
Patients should be seen for all visits on the designated day but a time window of ± 7 
days is allowed. 
 Section 6.4, Section 6.5 and Section 6.6 have been modified to include assessments in 
the extension-phase visits: 
6.4.1: The PASI will be assessed at each visit from V2 to V12 of the core study and at 
all four visits of the extension period. 
6.4.2: The IGA mod 2011 will be evaluated at each visit from V2 to V12 of the core 
study and at all four visits of the extension period. 
6.5.3: Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) 
and waist will be measured at visits 2, 3 and 12 of the core study and at all four visits 
of the extension period. 
6.5.4.1: Hemoglobin, hematocrit, red blood cells count, white blood cells count with 
differential (e.g. neutrophils, basophils, eosinophils, monocytes, lymphocytes), and 
platelets count will be measured at visits 2 and 3 and then at each visit starting from 

Novartis 
Confidential 
Page 18 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
visit 7 (including extension period). Appendix 1 shows the extended laboratory ranges 
that are considered clinically notable. 
6.5.4.2: Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, 
cholesterol, 
chloride, 
creatinine, 
creatine 
kinase 
(CK), 
gamma-glutamyl 
transpeptidase (GGT), glucose, lactate dehydrogenase (LDH), inorganic phosphorus, 
lipase, amylase, magnesium, potassium, total protein, AST, ALT, sodium, 
triglycerides, urea/blood urea nitrogen (BUN) and uric acid will be measured at visits 
2 and 3 and then at each visit of the core study starting from visit 7. 
The following clinical chemistry assessments will be run at all four visits of the 
extension period: albumin, alkaline phosphatase, total bilirubin, calcium, cholesterol, 
creatinine, CK, GGT, glucose, LDH, potassium, total protein, AST, ALT, sodium, 
triglycerides, uric acid. 
6.5.4.3: Dipstick measurements for specific gravity, protein, glucose and blood will 
be performed. WBC and RBC sediments will also be analyzed at visits 2, 10 and 12 
of the core study and at all four visits of the extension period. 
6.5.4.4: hsCRP will be assessed at visits 3, 10, and 12 of the core study and at all four 
visits of the extension period. 
6.6.2: Patients will be asked to complete the questionnaire at visits 3, 10 and 12 of the 
core study and at visits 2 and 4 of the extension period. 
6.6.3: Patients will be asked to complete the questionnaire at visits 3, 10 and 12 of the 
core study and at visits 2 and 4 of the extension period. 
 Section 7.2 – Serious adverse event reporting – has been modified: 
The investigator will complete the SAE Report Form in English, assess the 
relationship to the study treatment and send the completed and signed form by fax 
within 24 hours to the local Novartis Drug Safety and Epidemiology Department 
Novartis (DS&E). The original and the duplicate copies of the SAE Form, and the fax 
confirmation sheet will be kept with the case report forms at the study site. 
 Section 9.4 – Analysis of the primary variable – now reads: 
The primary objective of this study is to evaluate the clinical response in Cw6-
negative and Cw6-positive patients treated with secukinumab 300 mg with respect to 
the Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks, and 
thereafter for up to 72 weeks 
Additional minor changes have been made to the protocol to improve clarity and correct 
typographic errors.  
IRB/IEC 
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 must be approved by the IRB/IEC prior to implementation. The 
same applies to a revised Informed Consent that will take into account the changes described 
in this amended protocol. 
 

Novartis 
Confidential 
Page 19 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Amendment 1 
The aim of this amendment was to address concerns raised by the Italian Regulatory 
Authority (Agenzia Italiana del Farmaco – AIFA) following its evaluation of the original 
study protocol.  
1. The Agency pointed out a limit in the study’s methodological approach in that it adopts a 
measure of “non-inferiority,” a design used for randomized studies whose primary 
objective is to verify that one treatment is not less effective than another. Furthermore, the 
Agency questioned the study’s main objective; demonstrating a similar therapeutic 
response to secukinumab in a population stratified into Cw6 positive and Cw6 negative 
cohorts. This without having data available from trials comparing secukinumab and 
ustekinumab, a drug which has shown to be less effective in Cw6 negative patients.     
The robust efficacy of secukinumab has been demonstrated in various comparative 
studies. Two phase III, double-blind, 52-week trials, ERASURE and FIXTURE, randomly 
assigned 738 patients and 1306 patients, respectively, to subcutaneous secukinumab, 
placebo, or (in the FIXTURE study only) etanercept. The proportion of patients who met 
the criterion for PASI 75 at week 12 was significantly higher with secukinumab than with 
placebo or etanercept. The PASI 75 rate for secukinumab 300 mg was 81.6% in the 
ERASURE study and 76% in the FIXTURE study (Lang RG et al. 2014).  
The amount of efficacy and safety data related to secukinumab prompted, on 20 
November 2014, the Committee for Medicinal Products for Human Use (CHMP) to adopt 
a positive opinion, recommending the granting of marketing authorization for 
secukinumab intended for the treatment of moderate to severe plaque psoriasis in adults 
who are candidates for systemic therapy. 
Concerning data related to PASI 90 rates at week 12 for secukinumab and ustekinumab, 
they are substantially similar (59% vs. 51% respectively) (Langley RG et al. 2014, 
Leonardi CL et al. 2008, Papp KA et al. 2008) and a study comparing the two biologic 
drugs was to have data available by the end of 2014. 
In the last few years, a lot of attention has been given to associations of genome variations 
with different clinical responses to these highly selective biologic drugs (Costanzo et al. 
2011).  
Studies have demonstrated the influence of TNF-α-308 promoter polymorphism on the 
responsiveness to anti-TNF-α drugs in patients with psoriasis, rheumatoid arthritis and 
spondyloarthritis (Gallo E et al 2013, Cuchacovich M et al. 2006, Cuchacovich M et al. 
2004, Seitz M et al. 2007, O’Rielly DD et al. 2009).  
A recently published paper demonstrated an increased and faster response to ustekinumab 
in Cw6-positive compared to Cw6-negative patients (PASI 75 at week 12: 96.4% in Cw6-
positive vs. 65.2% in Cw6-negative patients; P = 0.008; PASI 50 at 4 weeks 89.3% in 
Cw6- positive vs 60.9% in Cw6-negative) (Talamonti M et al. 2013). 
Unlike anti-IL-12/23 agents, secukinumab inhibits IL-17 produced by both Th17 cells 
after presentation by antigen presenting cells (in this case Cw6) and cells of the innate 
immune system whose activation does not require antigen presentation. If secukinumab 
were equally effective on both Cw6 negative and Cw6 positive patients, as its mechanism 

Novartis 
Confidential 
Page 20 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
of action suggests, this would be a significant clinical accomplishment and would 
eliminate the need for costly HLA-Cw6 tests. The choice of a cohort study could therefore 
be appropriate for this clinical context.  
To better convey the purpose of the study, the title was changed to “A 24-week, 
multicenter, proSpective stUdy to evaluate the PASI 90 clinical response rate and the 
safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and Cw6-positive patients with 
moderate to severe chronic plaque-type psoriasis (SUPREME).” 
The primary objective of the study was reworded: “To evaluate the clinical response in 
Cw6-negative patients compared to Cw6-positive patients treated with secukinumab 300 
mg with respect to the Psoriasis Area Severity Index (PASI) 90 response rate after 16 
weeks.” 
Other parts of the protocol, as well as the description of the study rational, were also 
modified to suit the aim of the study.  
2. The Agency indicated the need to analyze a population stratified for different variables 
that could condition therapeutic response, and appropriately identified TNF-α 
polymorphism, smoking, BMI and metabolic syndrome as factors not considered in the 
original protocol. 
Although the sample size was calculated considering only Cw6 haplotype, it is also 
adequate for regression models assessing differences from baseline for clinically relevant 
variables. In fact, the expected number of patients who reach PASI 90 at week sixteen is at 
least 250 (roughly 71% of 365). Therefore, using a conservative criterion of a minimum of 
10 “events” for each predictor in the model, we can add up to 25 variables without loss of 
power (Vittinghoff E et al. 2007). As suggested, this model will take into account 
variables including BMI, smoking, metabolic syndrome and TNFα-308 polymorphism, 
which, among the six existing polymorphisms, is the one most greatly affecting response 
to treatment with anti-TNFα drugs. 
Section 9.7 of the protocol was updated to add these concepts. 
This amendment was also an opportunity to correct or clarify other items of the protocol: 
 Better define the inclusion criteria concerning the psoriasis diagnosis. 
Given the positive opinion of the CHMP previously mentioned, inclusion criteria were 
changed to include patients failing not two, but at least only one prior systemic therapy 
(even if CHMP opinion is related to first line systemic therapy, the decision was to be 
more conservative).  
Patients with a diagnosis of moderate to severe chronic plaque-type psoriasis for at 
least 6 months will be included in the study; localization of the disease on scalp and 
hands, and psoriatic arthritis are allowed disease manifestations and are not to be 
considered as mandatory for study inclusion (as previously stated by indicating them 
as a separate criterion). 
 Differentiate the wash-out periods to be used for biological immunomodulating agents 
before starting treatment with secukinumab, and add golimumab to the list of 
treatments requiring a wash-out period. 

Novartis 
Confidential 
Page 21 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 Specify the hepatitis B surface antigens and antibodies used for required hepatitis B 
testing. 
 Remove fasting plasma glucose (FPG) and lipid panel from the “fasting lab 
assessments” as they are already present among the “clinical chemistry” assessments. 
 Clarify the number of injections of secukinumab to be administered during the 
treatment period. 
 Clarify the period of Adverse Event reporting. 
 Update the introduction with current study results. 
 Clarify data collection procedures. 
Changes to the protocol (the protocol synopsis was also modified where applicable) 
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 font for insertions: 
The major changes in this version of the protocol were as follows: 
 Title: “A 24-week, multicenter, proSpective stUdy to evaluate the PASI 90 clinical 
response rate and the safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and 
Cw6-positive patients with moderate to severe chronic plaque-type psoriasis 
(SUPREME). 
 Section 1.1 was updated with current study results.  
 Section 2.1: The primary objective was changed: “To evaluate the clinical response in 
Cw6-negative andCw6-positive patients treated with secukinumab 300 mg with 
respect to the Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks.” 
 Section 2.3: 
 
 
 
 
 
 
 
 
 Section 3.1 – Study design, was revised by specifying that two injections of 
secukinumab 150 mg would be administered each week for five weeks during the 
induction phase, followed by a maintenance period of two injections per month. The 
section now also indicates that both Cw6 and 308-TNFα polymorphism will be 
centrally determined from samples taken during the pre-screening visit. 
 Section 3.2 – Rationale of study design, was revised to better convey the purpose of 
the study. 
 Section 4 – Population: “The patients must have failed to respond to at least one 
systemic therapy, including cyclosporine, methotrexate, psoralen combined with 
ultraviolet A (PUVA), or to an anti-TNFα (or is intolerant and/or has a 
contraindication to these).” 
 Section 4.1: Inclusion criteria No. 4 was deleted.  
 Section 4.1: Inclusion criteria No. 3 now reads: “Diagnosis of moderate to severe 
chronic plaque-type psoriasis for at least 6 months (including concomitant psoriatic 
arthritis as per the Classification Criteria for Psoriatic Arthritis criteria [CASPAR]).”  

Novartis 
Confidential 
Page 22 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 Section 4.1: Inclusion criteria No. 5 was changed: “Failed response to at least one 
systemic therapy (i.e. cyclosporine, methotrexate and PUVA) or to an anti-TNFα (or 
is intolerant and/or has a contraindication to these).” 
 Section 4.2: Exclusion criteria No. 12 now reads: “Subject tested positive for hepatitis 
B virus surface antigen (HBV) or virus B latent infection, hepatitis C virus antibody 
(HCV), or human immunodeficiency virus (HIV) at screening (an exam performed 
within the 6 months prior to inclusion and documented will be considered as valid).” 
 Table 5-1 Prohibited treatment, was revised by adding golimumab and specifying the 
washout periods for etarnecept, adalimumab and infliximab. 
 Section 5.5.4 – Instructions for prescribing and taking study treatment. 
Paragraph 1 was changed: All patients will receive Secukinumab 300 mg 
subcutaneously using the Phase III regimen: 300 mg (two 150 mg injections) a week 
for the first five weeks (visits 3-7), and once every 4 weeks thereafter (visits 8-12). 
 Table 6-1 Assessment schedule, was revised by substituting “fasting lab assessments” 
with “hsCRP”, by indicating the surface antigens and antibodies used for hepatitis B 
testing in the footnotes (HBsAg, HBsAb, HBcAb), by adding metabolic syndrome and 
testing for TNFα - 308 polymorphism and by extending the AE recording period to 
include screening. 
 Section 6.1 – Information to be collected on screening was revised and now reads 
“HLA-Cw6 determination will be performed at screening for patients who have 
provided written informed consent. A central laboratory will be used to determine 
Cw6. Patients will thereafter be stratified into the two cohorts. TNFα-308 
polymorphism will be centrally determined at the same time.” 
 Section 6.2 – Patient demographics/other baseline characteristics, was revised as 
follows: 
– A chest X-ray, an ECG and HCV, HBV (HBsAg, HBsAb, HBcAb), HIV tests will 
be required unless performed within the previous 6 months. Adequate 
documentation (assessment reports, tracking and imagines as applicable) must be 
available for previous evaluations to be considered valid at baseline. 
– High sensitivity C-reactive protein (hsCRP). 
– History (medical, smoking, psoriasis). 
 Section 6.5.1 – Physical examination: The following paragraph was added “Metabolic 
syndrome will require any 3 of the following 5 criteria: increased waist circumference 
(≥102 cm for men, ≥ 88 cm for women), elevated triglycerides (≥150 mg/dl), reduced 
high-density lipoprotein (HDL) cholesterol (≤ 40 mg/dl in men and ≤ 50 mg/dl in 
women), elevated blood pressure (≥ 130 mmHg systolic and ≥ 85 mmHg diastolic or 
ongoing treatment for hypertension) or elevated glucose (≥100 mg/dl or ongoing 
treatment for elevated glucose) (Expert Panel JAMA 2001).” 
 Section 6.5.3 – Height, waist and weight, was changed:  
Height in centimeters (cm) will be measured at visit 2 or 3 only.  

Novartis 
Confidential 
Page 23 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) and 
waist will be measured at visits 2, 3 and 12. Body Mass Index (BMI) will be derived 
from weight and height results. 
 Section 6.5.4.4 – Fasting laboratory assessments, was modified by substituting 
“fasting laboratory assessments” with “hsCRP.” 
 Section 8.2 – Data collection, presents the following change: “On-line validation 
programs check for data discrepancies and, by generating appropriate error messages, 
allow the data to be confirmed or corrected by the CRO working on behalf of 
Novartis.” 
 Section 9.2, paragraph 2, was changed and now reads: 
In order to interpret results adequately, the homogeneity of patients’ distribution 
between cohorts will be tested on selected baseline demographics and anamnestic 
variables (e.g. for gender, age, race, ethnicity, BMI, baseline PASI, baseline IGA, 
TNFα - 308 polymorphism, metabolic syndrome, smoking). Categorical variables will 
be analyzed by Cochran-Mantel-Haenszel test stratified by geographical region (i.e. 
north vs south/central) and BMI (< 25 vs ≥ 25). 
Paragraph 3 now reads: “Continuous variables will be analyzed by means of ANOVA 
model corrected by geographical region and BMI classes, as appropriate. Statistically 
significant variables will be included as covariates in the explanatory analysis model. 
Whenever necessary, normality will be assessed by means of Shapiro-Wilk test and 
with graphical methods. In case of non-normality, a non-parametric test will be used.”  
 Section 9.4 – Analysis of the primary variable was modified: “The primary objective 
of this study is to evaluate the clinical response in Cw6-negative and Cw6-positive 
patients treated with secukinumab 300 mg with respect to the Psoriasis Area Severity 
Index (PASI) 90 response rate after 16 weeks.” 
 Section 9.4.2 - Statistical model, hypothesis, and method of analysis 
Paragraph 1: “The proportion of patients who reach PASI 90 at 16 weeks will be 
presented with the one-tailed 97.5% confidence interval of the Cw6 positive (POS) – 
Cw6 negative (NEG) difference.” 
Paragraph 4: “A logistic regression analysis model will be also fitted, considering the 
geographical 
region, 
BMI, 
smoking, 
metabolic 
syndrome 
and 
TNFα-308 
polymorphism as well as the clinically relevant baseline variables as strata factors.” 
 Section 9.5.1 – Efficacy Variables 
PASI 
“The differences between cohorts in time to reach PASI 90, as well as PASI 75, will 
be evaluated by means of a log-rank test. The hazard ratios and their corresponding 
95% confidence intervals will be also computed using a stratified Cox proportional 
hazards regression model with Cw6 group and baseline PASI as explanatory variable 
and stratified by geographical region and BMI, as well as the clinically relevant 
baseline variables. The Kaplan-Meier estimates of the cumulative rate for each cohort 
will be plotted.” 

Novartis 
Confidential 
Page 24 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 Section 9.7 – Sample size calculation was expanded to further justify the 
appropriateness of the calculation. 
Paragraph 1 was changed to: The primary objective of this study is to evaluate the 
clinical response in PASI 90 at week 16 of Cw6-negative and Cw6-positive psoriatic 
patients. 
Paragraph 3 was changed to: From a previous study with ustekinumab (Talamonti et 
al. 2013) we can observe a difference in response to PASI 90 between Cw6-positive vs 
Cw6-negative patients of around 30%, in favor of Cw6-POS. Therefore, it is sensible 
to expect a response in the Cw6 negative cohort not less than 12 % respect to the Cw6 
positive group. 
The following paragraph was added at the end of the section: “Although the sample 
size was calculated considering only Cw6 haplotype, it is also adequate for regression 
models assessing differences from baseline for clinically relevant variables. In fact, the 
expected number of patients who reach PASI 90 at week sixteen is at least 250 
(roughly 71% of 365). Therefore, using a conservative criterion of a minimum of 10 
“events” for each predictor in the model, we can add up to 25 variables in the model 
without loss of power (Vittinghoff E et al. 2007). This model will take into account 
variables such as BMI, smoking metabolic syndrome and TNFα-308 polymorphism, 
which, among the six existing polymorphisms, is the one most greatly affecting 
response to treatment with anti-TNFα drugs.” 
IRB/IEC 
A copy of this amended protocol was sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol were approved by the IRB/IEC prior to implementation. The same 
applies to a revised Informed Consent that took into account the changes described in this 
amended protocol. 

Novartis 
Confidential 
Page 25 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
1 
Introduction 
1.1 
Background  
Psoriasis is a chronic, immune-mediated skin disease with a prevalence in Europe ranging 
between 0.73% (in Scotland) and 2.9% (in Italy) when considering individuals of all ages 
(Parisi R et al. 2012, Saraceno R et al. 2008, Simpson CR et al. 2002).  
Plaque-type psoriasis is characterized by increased proliferation of keratinocytes, and 
hyperplasia and marked dilation of vessels in the papillary dermal region, leading to the 
formation of red, scaly, raised plaques. Other histological features include the presence of 
neutrophils within small foci in the epidermis and prominent aggregates of mononuclear 
leukocytes in the dermis. These regions might function as organized lymphoid tissue that 
perpetuates immune inflammatory infiltrates (Lew W et al. 2004). Even normal skin contains 
abundant stores of T lymphocytes (Clark RA et al. 2006) and resident dendritic cells (Boyman 
O et al. 2005), suggesting that skin might be a potential site for the direct triggering of recall 
immune responses. It is also likely that keratinocytes are active participants in the recruitment 
and activation of leukocytes in psoriatic lesions. Thus in the skin of plaque-type psoriasis, 
there is the concomitant activation of innate and acquired immune cell types (Lowe MA et al. 
2007). 
The chronic colonization of T lymphocytes in the dermis and epidermis is thought to depend 
on environmental and genetic factors responsible for a dysregulation of the immune responses 
in the skin. Innate immune cells produce key cytokines (tumor necrosis factor α [TNF-α], 
interferon-α, interferon-γ, interleukin-1β, and interleukin-6) that activate myeloid dendritic 
cells. Activated dendritic cells present antigens and secrete mediators such as interleukin-12 
(IL12) and interleukin-23, leading to the differentiation of type 17 and type 1 helper T cells 
(Th17 and Th1). T cells, in turn, secrete mediators (e.g., interleukin-17A, interleukin-17F, and 
interleukin-22) that activate keratinocytes and induce the production of antimicrobial peptides 
(e.g., LL-37 cathelicidin and β-defensins), proinflammatory cytokines (TNF-α, interleukin-1β, 
and interleukin-6), chemokines (CXCL8 through CXCL11 and CCL20), and S100 proteins. 
These mediators feed back into the proinflammatory disease cycle and shape the 
inflammatory infiltrate (Nestle FO et al. 2009). 
Family and twin studies have clearly demonstrated that psoriasis has a strong genetic basis 
(Elder JT et al. 1994). Recent genome-wide association studies have expanded the group of 
genomic loci that are associated with the susceptibility to psoriasis (Chandran V et al. 2010, 
Liu H et al. 2008, Nair RP et al. 2009). In particular, the PSORS1 locus on chromosome 6p is 
generally understood to confer the most risk. A specific allele for this locus, human leukocyte 
antigen (HLA) C*06, is also the only genetic variance repeatedly observed to associate with 
the phenotypic features of psoriasis and is present in about 60% of psoriatic patient cases 
(Strange A et al. 2010, Stuart PE et al. 2010, Rahman P et al. 2005, Queiro R et al. 2013).  
The advent of biological drugs during the last decade has brought about radical changes in the 
management of various diseases, including psoriasis. Today, these agents represent the most 
advanced type of treatment for psoriasis.  

Novartis 
Confidential 
Page 26 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Etanercept, adalimumab, infliximab and golimumab are drugs that block tumor necrosis factor 
alpha (TNFα), a cytokine responsible for joint and skin inflammation and damage both in 
psoriasis and psoriatic arthritis. 
Ustekinumab is a human monoclonal antibody against interleukins 12 and 23 that has shown 
therapeutic potential for psoriasis. In a phase III, parallel, double-blind, placebo-controlled 
study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive 
ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or 
placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. 171 
(67.1%) patients receiving ustekinumab 45 mg, 170 (66.4%) receiving ustekinumab 90 mg, 
and eight (3.1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate 
vs placebo 63.9%, 95% CI 57.8-70.1, p<0.0001 for 45 mg and 63.3%, 57.1-69.4, p<0.0001 for 
90 mg). At week 40, long-term response was achieved by 150 patients in the 45 mg group and 
172 patients in the 90 mg group (Leonardi CL et al 2008). 
Two phase III, double-blind, 52-week trials, ERASURE and FIXTURE, randomly assigned 
738 patients and 1306 patients, respectively, to subcutaneous secukinumab at a dose of 300 
mg or 150 mg, placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg. The 
objective of each study was to show the superiority of secukinumab over placebo at week 12 
with respect to the proportion of patients that had a reduction of 75% or more from baseline in 
the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost 
clear) on a 5-point modified investigator's global assessment (co-primary endpoints). The 
proportion of patients who met the criterion for PASI 75 at week 12 was higher with each 
secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 
81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with 
placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% 
with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for 
each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 
on the modified investigator's global assessment at week 12 was higher with each 
secukinumab dose than with placebo or etanercept (Langley RG et al 2014). 
Many recent papers have shown that these highly selective drugs are not effective in every 
patient and that variations in the genome can be associated with different clinical response or 
side effects to a given drug (Costanzo A et al. 2011). 
The presence of the Single Nucleotide Polymorphisms (SNPs) in the TNF-α promoter and 
IL12B/IL23R genes seem to be associated with susceptibility to psoriasis and the response to 
anti-TNF-α drugs. In one study, SNPs for the TNF-α promoter and IL12B/IL23R genes, and 
the presence of the HLA-Cw6 haplotype were genotyped for 109 patients. The study 
identified a relationship between TNF-α and IL12B/IL23R polymorphisms and the short-term 
response to anti-TNF-α drugs in terms of Psoriasis Area and Severity Index (PASI) and 
involved body surface area (BSA)] (Gallo E et al 2013). Other studies demonstrated the 
influence of TNF-α-308 promoter polymorphism on the responsiveness to anti-TNF-α drugs 
in patients with rheumatoid arthritis and spondyloarthritis (Cuchacovich M et al. 2006, 
Cuchacovich M et al. 2004, Seitz M et al. 2007, O’Rielly DD et al. 2009). 
A recently published paper demonstrated an association between the presence of the HLA-
C*06 allele and the response to ustekinumab. The study showed an increased response to 
ustekinumab in Cw6-positive (Cw6POS) patients [PASI 75 at week 12: 96.4% in Cw6POS 
vs. 65·2% in Cw6-negative (Cw6NEG) patients; P = 0.008] and that HLA-Cw6POS patients 

Novartis 
Confidential 
Page 27 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
also responded faster to ustekinumab, 89.3% of them reaching PASI 50 at week 4, after a 
single injection (vs. 60.9% of HLA-Cw6NEG patients). The superior response of HLA-
Cw6POS patients was maintained throughout the study period and reached the highest 
statistical significance for PASI 75 at week 28 (96.35% Cw6POS vs. 72.7% Cw6NEG; odds 
ratio 9.8). Analysis of TNFAIP3 rs610604 polymorphism and LCE3B/3C gene deletions did 
not show any significant association with response to ustekinumab (Talamonti M et al. 2013).  
Secukinumab is a high-affinity human monoclonal anti-human IL-17A antibody of the IgG1/κ 
isotype that demonstrated a favorable safety and tolerability profile with robust clinical 
activity in a series of Phase II studies, and is undergoing an extensive Phase III program 
(Gisondi P et al 2014). Secukinumab binds to human IL-17A and neutralizes its bioactivity by 
inhibiting IL17A produced by both Th17 cells and cells of the innate immune system, thus 
providing complete anti IL17A blockage. Targeting IL-17A has the potential to reduce 
autoimmune inflammation while leaving other immune functions undisturbed. While targeting 
of Th1-promoting or Th17-promoting cytokines affects critical mediators such as IFN-γ, IL-
22 and IL-21, selective targeting of IL-17A leaves these Th1/17 activities, as well as certain 
protective functions of innate cells intact (Patel DD et al. 2013). Furthermore, as a fully 
human monoclonal antibody, secukinumab has low immunogenicity (i.e., antidrug antibodies) 
compared to current or emerging biologic therapies that are not fully human. Data linking 
secukinumab efficacy to a particular genetic biomarker are lacking. However, due to its 
mechanism of action, the efficacy of secukinumab should not be HLA restricted, and when 
considering the main haplotype associated with psoriasis, no difference between Cw6-
negative and positive patients is expected.  
The purpose of this study is to explore the different efficacy and safety profiles of 
secukinumab 300 mg in patients with moderate to severe chronic plaque-type psoriasis, 
stratified for the presence of HLA-C*06, whose determination will be blinded for patients and 
investigators. The study will be conducted both on anti-TNFα-naïve and anti-TNFα failure 
patients and will also stratify for various variables such as TNFα - 308 polymorphism, BMI, 
smoking and metabolic syndrome. 
Amendment 2 of the protocol has a threefold purpose; to explore response sustainability to 
secukinumab after 72 weeks of continuous treatment, to understand if HLA-CW6 can 
influence the kinetics of the response to secukinumab in the long term, to generate long-term 
safety and tolerability data.  
Furthermore, as a consequence of the European Medicines Agency’s (EMA) approval of 
secukinumab in February 2015 “for the treatment of moderate to severe plaque psoriasis in 
adults who are candidate for systemic therapy”, inclusion criteria have been updated in order 
to guarantee treatment to systemically naïve patients, as per label. 
2 
Study objectives 
2.1 
Primary objective 
To evaluate the clinical response in Cw6-negative and Cw6-positive patients treated with 
secukinumab 300 mg with respect to the Psoriasis Area Severity Index (PASI) 90 response 
rate after 16 weeks, and thereafter for up to 72 weeks. 

Novartis 
Confidential 
Page 28 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
2.2 
Secondary objectives 
• 
To compare the proportion of responders to PASI 50/75/90/100 between cohorts at each 
time point. 
• 
To compare the mean changes vs baseline in the Investigator’s Global assessment (IGA) 
mod 2011 between cohorts at each time point. 
• 
To compare time to reach PASI 90 between cohorts. 
• 
To compare time to reach PASI 75 between cohorts. 
• 
To evaluate the quality of life by means of the Dermatology Life Quality Index (DLQI) in 
all patients at each time point. 
• 
To evaluate anxiety and depression using the Hospital Anxiety and Depression Scale 
(HADS) in all patients at each time point. 
• 
To evaluate the correlation between HADS and PASI in all patients. 
• 
To evaluate changes from baseline in weight, BMI and waist in all patients at each time 
point. 
• 
To compare safety and tolerability between cohorts during the 24 weeks, and thereafter for 
up to 72 weeks. 
• 
To evaluate the amount of resources used during the study in comparison with the 6 
months prior to the beginning of the study. 
3 
Investigational plan 
3.1 
Study design 
This is a multicenter, prospective study involving Cw6-negative and Cw6-positive patients 
affected by moderate to severe chronic plaque psoriasis.  
The study has four periods: a screening period consisting of two visits (pre-screening and 
screening), an induction period of 4 weeks, a maintenance period of 20 weeks and an 
extension period of 48 weeks. Timelines of the study design are presented in Figure 3-1 and 
Figure 3-2. Detailed visit schedules can be found in Table 6-1 and Table 6.2. 
At pre-screening (day -28), patients will be centrally assessed for Cw6 positivity or negativity 
and stratified into two cohorts. Both patients and investigators will be blinded to the results. 
308-TNFα polymorphism will be centrally determined at the same time.  

Novartis 
Confidential 
Page 29 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
After the full screening visit (day -14 to -7), eligible patients will begin treatment at baseline 
(week 0) and will be followed for 24 weeks (core study), plus an additional 48 weeks if 
participating in the extension treatment period. 
The enrollment of patients into the two cohorts will be monitored during the study to prevent 
exceeding the number required by the sample size calculation (see Section 9.7 for details). 
All patients will be treated with Secukinumab 300 mg according to an induction regimen of 
two injections of secukinumab 150 mg a week for five weeks starting at baseline (week 0), 
followed by a maintenance period of two injections per month. Following the evaluation of 
psoriasis severity at week 16, patients achieving PASI 50 response will be eligible to continue 
on the study treatment for an additional 8 weeks. After a total of 24 weeks, willing patients 
reaching at least a PASI 75 response will enter an extension treatment period of an additional 
48 weeks. The PASI score will be evaluated during the 72-week period. Safety and 
tolerability data will be collected at every scheduled visit. 
Figure 3-1: Study design 
 
Figure 3-2: Extension Study design 
  
3.2 
Rationale of study design 
The efficacy of secukinumab, as well as the proposed dose/regimen, has already been 
clinically substantiated through extensive Phase II and III programs. Therefore, all patients 
will be treated with active drug using the same therapeutic regimen. 
Recent research has revealed a marked difference in the proportion of PASI 90 achievers 
between Cw6-positive and Cw6-negative patients (85.7% vs 56.5%) treated with ustekinumab 
(Talamonti M et al. 2013) and a greater efficacy of anti-TNFα drugs in CW6 negative patients 
(Galli E et al. 2013). Unlike anti-IL-12/23 agents, secukinumab inhibits IL-17 produced by 
both Th17 cells after presentation by antigen presenting cells (in this case Cw6) and cells of 
the innate immune system whose activation does not require antigen presentation. If 
secukinumab were equally effective on both Cw6 negative and Cw6 positive patients, as its 

Novartis 
Confidential 
Page 30 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
mechanism of action suggests, this would be an important clinical accomplishment and would 
eliminate the need for costly HLA-Cw6 tests. The choice of a cohort study would therefore 
seem appropriate for this clinical context.   
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
Extensive Phase II and Phase III programs have shown secukinumab to be very effective in 
treating plaque psoriasis. The protocol regimen and 300 mg dose delivered the most clinically 
meaningful benefit at 16 weeks to patients with respect to achievement of almost clear - clear 
skin, improved quality of life, speed of onset of action, and sustainability of symptoms relief. 
3.4 
Rationale for choice of comparator. 
Not applicable. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits  
As of 12 July 2014, over 10,900 subjects were enrolled in studies with secukinumab, with 
over 8,600 having received active drug at doses ranging from single and/or multiple doses of 
0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c. 
In total, 4,546 patients with moderate to severe plaque psoriasis were included in studies in 
the registration program. These included 3,430 patients treated with secukinumab in 10 phase 
II/III studies, 2,727 of whom were treated for at least 6 months and 2,029 for at least 48 
weeks. The Phase III program demonstrated secukinumab to be very effective in treating 
plaque psoriasis, with 300 mg being the dose that delivered the most clinically meaningful 
benefit to patients. The majority of patients treated with this dose achieved clear to almost 
clear skin, as shown by PASI 90 response and Investigator Global Assessment modified (IGA 
mod) 2011 0 or 1 response. 
The 3,430 psoriasis patients treated with secukinumab covered 2725 patient-years of exposure 
during the 10 Phase II/III clinical trials. The overall exposure-adjusted incidence of AEs per 
100 patient-years over the entire treatment period was lower in the 300 mg and 150 mg 
secukinumab groups (236.1 and 239.9, respectively) compared with the placebo and 
etanercept groups (351.8 and 243.4, respectively). Most AEs in all treatment groups were 
mild or moderate in severity. 
Secukinumab obtained EMA approval in February 2015 for the treatment of moderate to 
severe plaque psoriasis in adults who are candidates for systemic therapy. 
The Investigator’s Brochure (IB) provides a more detailed review of the pre-clinical and 
clinical information on secukinumab. 

Novartis 
Confidential 
Page 31 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
4 
Population 
The study plans to enroll 406 adult men or women, of which 365 are evaluable patients, 
diagnosed with moderate to severe chronic plaque psoriasis for at least 6 months. The patients 
must be candidates for systemic therapy and may be treatment naïve or have failed to respond 
to other systemic therapy, including cyclosporine, methotrexate, psoralen combined with 
ultraviolet A (PUVA), or to an anti-TNFα (or is intolerant and/or has a contraindication to 
these). The study plans to involve about 50 centers. 
The extension phase will include 306 of the patients taking part in the core study. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Subject must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give written, signed and dated informed 
consent before any study related activity is performed. 
2. Men or women at least 18 years of age at time of screening. 
3. Diagnosis of moderate to severe chronic plaque-type psoriasis for at least 6 months 
(including concomitant psoriatic arthritis as per the Classification Criteria for Psoriatic 
Arthritis criteria [CASPAR]).  
4. Moderate to severe psoriasis as defined at enrollment by: 
• 
PASI score ≥ 10  
or 
• 
PASI score > 5 but < 10 and DLQI ≥10  
5. Patients that are candidates for systemic therapy, whether treatment naïve or after failed 
response to other systemic therapy (i.e. cyclosporine, methotrexate and PUVA) or to an 
anti-TNFα (or is intolerant and/or has a contraindication to these).  
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator in order to ensure that the study 
population will be representative of all eligible patients. 
1. Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and 
guttate psoriasis). 
2. Cyclosporine or methotrexate administration within 4 weeks prior to Day 1.  
3. Anti-TNFα therapy within timelines depending on drug half-life.  
4. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or 
the IL-17 receptor. 
5. Previous exposure to ustekinumab or any other biologic drug for the treatment of 
psoriasis that is not anti-TNFα therapy. 

Novartis 
Confidential 
Page 32 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
6. Intravenous or intramuscular steroids within 2 weeks prior to screening and during 
screening. 
7. Ongoing use of corticosteroid topical treatments unless a washout period, as described in 
table 5-1, will be performed or UV therapy.  
8. Previous allogeneic bone marrow transplant or history of cell-based transplantation (e.g. 
islet cell transplantation or autologous stem cell transplantation). 
9. Treatment for infection with IV or oral antibiotics or antivirals within 14 days of Day 1. 
10. Subjects with known history of active TB. Accepted TB tests include:  
a. 
Negative purified protein derivative (PPD); < 5 mm of induration at 48 to 72 hours 
after test is placed).  
b. Negative Quantiferon –TB test (an exam performed within the 3 months prior to 
inclusion and documented will be considered as valid). 
11. Subject received any type of live attenuated vaccine < 6 weeks prior to Day 1 or is 
planning to receive any such vaccine over the course of the study. 
12. Subject tested positive for hepatitis B virus surface antigen (HBV) or virus B latent 
infection, hepatitis C virus antibody (HCV), or human immunodeficiency virus (HIV) at 
screening (an exam performed within the 6 months prior to inclusion and documented 
will be considered as valid). 
13. Subject has any underlying condition that predisposes to infections (history of 
splenectomy). 
14. History of cancer in the past three years. 
15. Underlying condition (including, but not limited to metabolic, hematologic, renal, 
hepatic, pulmonary, neurologic, endocrine, cardiovascular, infectious or gastrointestinal) 
that, in the opinion of the Investigator, would pose a risk to subject safety or interfere 
with study evaluation, procedures and completion. 
16. Abnormal laboratory results at screening: Liver tests: either aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) > 2.0 × upper 
limit of normal (ULN) or total bilirubin > 1.5 × ULN (except for subjects with Gilbert 
Syndrome). 
17. White blood cell count < 3,000 cells/mm3 (< 3 × 109/L in SI [international system] units). 
18. Hemoglobin < 10 g/dL. 
19. Subject is currently enrolled in another investigational study unless a washout period, as 
described in table 5-1, will be performed. 
20. Donation or transfusion of blood, plasma, or platelets within 90 days prior to inclusion. 
21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of female 
after conception until the termination of gestation, confirmed by a positive HCG 
laboratory test (> 10 mIU/mL). 

Novartis 
Confidential 
Page 33 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
22. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, must use effective contraception during the study and for 16 weeks 
after stopping treatment. Highly effective contraception methods include: 
 
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment. 
 
Male 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. 
 
Combination of any two of the following (a+b or a+c, or b+c): 
a. 
Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS). 
c. 
Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
In case of oral contraception, women should have been stable on the same pill for a minimum 
of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of childbearing potential.  
23. Known history of allergy to the investigational product formulation or to any other 
biologic therapy. 
4.3 
Eligibility criteria for entering the extension treatment period 
1. Patients who have completed the CAIN457AIT01 core study.  
2. Written informed consent for protocol amendment 2 must be obtained before patients 
proceed to the extension treatment period. 
3. Patients must be deemed to be benefiting from the study drug based on at least a PASI 75 
response rate after 24 weeks of treatment. 

Novartis 
Confidential 
Page 34 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Secukinumab 300 mg (two s.c. injections of secukinumab 150 mg). 
Secukinumab will be administered as solution for injection in a pre-filled syringe: clear to 
opalescent, colorless to slightly yellowish liquid (150 mg/1.0 mL) in a in a 1 mL long, single-
use, prefilled glass syringe with fluortec-coated bromobutyl rubber plunger stopper staked 
27G ½ inch needle and rigid needle sheet and needle safety device. The pre-filled syringe is 
incorporated into a triangular auto-injector/pen. 
The study treatment will be administered by the site staff during the visit. Patients enrolled in 
the extension period will self-administer secukinumab and will be asked to keep a self-
administration log during this period. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
Not applicable, all patients will receive secukinumab 300 mg. 
5.3 
Treatment assignment  
All patients will receive secukinumab 300 mg subcutaneously. 
5.4 
Treatment blinding  
Not applicable, this is an open label study. All patients will receive secukinumab 300 mg.  
5.5 
Treating the patient 
5.5.1 
Patient numbering  
Each patient is uniquely identified by a Subject Number which is composed of the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a patient, the Subject Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank Case Report Form (CRF) book available from 
the Electronic Data Capture (EDC) system.  
If an enrolled patient fails to be treated for any reason, the reason will be entered on the 
Screening Study Disposition CRF.  
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. This is an open label study. 

Novartis 
Confidential 
Page 35 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. 
Medication labels will be in the local language and comply with the legal requirements of 
each country.  
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits 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 investigational treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
Handling of other study treatment: not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
All patients will receive Secukinumab 300 mg subcutaneously using the Phase III regimen: 
300 mg (two 150 mg injections) a week for the first five weeks (visits 3-7), and once every 4 
weeks thereafter (visits 8-12). Patients proceeding to the extension period will self-administer 
treatment (two 150 mg injections) once every 4 weeks for an additional 48 weeks. 
The study treatment solution must be injected subcutaneously in non-affected areas of the 
skin. 
Following the evaluation of psoriasis severity at 16 weeks, patients achieving a PASI 50 
response will be eligible to continue on the study treatment for another 8 weeks. Their PASI 
score will be evaluated at 24 weeks. Willing patients reaching at least a PASI 75 response at 
the end of the 24-week core study will enter an extension treatment period of an additional 48 
weeks. 
All dates of injections given to the subject during the study must be recorded on the Dosage 
Administration Record e-CRF. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Investigational treatment dose adjustments and/or interruptions are not permitted. 
5.5.6 
Rescue medication 
The investigator may prescribe any medications and/or supportive care during the study based 
on clinical needs. Use of rescue medication must be recorded on the Concomitant 
medications/Significant non-drug therapies/Dose Administration Record in the Electronic 
Case Report Form (eCRF). 

Novartis 
Confidential 
Page 36 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after being 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. 
5.5.8 
Prohibited Treatment 
Use of the treatments displayed in Table 5-1 is NOT allowed after screening. 
If a prohibited treatment listed in Table 5-1 is used during the study, the patient must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. At the 
discretion of the investigator, if the patient’s use of a prohibited treatment presents undue 
safety risk for the patient, he/she should be discontinued from study treatment as per Section 
5.5.9. If the patient receives a live virus vaccination during the study, he/she must discontinue 
study treatment and enter the post-treatment follow up period. 
Table 5-1: Prohibited treatment 
Prohibited treatments 
Washout period (before day 1) 
Secukinumab or any other biologic drug directly 
targeting IL-17 or the IL-17 receptor 
No prior use allowed 
Ustekinumab  
No prior use allowed 
Alefacept, briakinumab, efalizumab 
6 months 
Biological immunomodulating agents other than 
the above: 
 
Etarnecept 
3 weeks 
Adalimumab 
6 weeks 
Infliximab 
12 weeks 
Golimumab 
8 weeks 
Other systemic immunomodulating treatments 
[e.g., MTX, cyclosporine A, corticosteroids 
(oral, i.v., intramuscular, s.c., intra-articular, 
transdermal), cyclophosphamide] 
4 weeks 
Other systemic psoriasis treatments (e.g. 
retinoid, fumarates) 
4 weeks 
Photo chemotherapy (e.g. PUVA) 
4 weeks 
Phototherapy (e.g., UVA, UVB) 
2 weeks 
Topical treatment that is likely to impact signs 
and symptoms of psoriasis (e.g. vitamin D 
analogues, 
pimecrolimus, 
retinoids, 
salicylvaseline, salicylic acid, lactic acid, 
tacrolimus, tar, urea alpha-hydroxy or fruit 
acids) 
2 weeks 

Novartis 
Confidential 
Page 37 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Live virus vaccinations 
6 weeks 
Any investigational treatment or participation in 
any interventional trial 
4 weeks or 5 half-lives (whichever is longer) 
Prohibited 
regimen 
of 
Topical 
Corticosteroids (TCS): 
 
TCS higher than moderate potency on any body 
location 
2 weeks 
TCS mild to moderate potency on any body 
location other than the face, scalp and or 
genitoanal area 
2 weeks 
TCS mild to moderate potency on the face, scalp 
and or genitoanal area 
1 day 
5.5.9 
Discontinuation of study treatment and premature patient withdrawal 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature withdrawal from the study and record 
this information.  
The investigator should discontinue the investigational treatment for a given patient and/or 
withdraw the patient from the study if, on balance, he/she believes that continuation would be 
detrimental to the patient’s well-being. 
The investigational treatment must be discontinued under the following circumstances:  
 
Withdrawal of informed consent 
 
Severe adverse events that, in the opinion of the Investigator, warrant discontinuation 
 
Pregnancy 
 
Use of prohibited treatment as per Table 5-1 
 
Any other protocol deviation that results in a significant risk to the patient’s safety 
Patients that do not achieve PASI 50 at week 16 will terminate treatment. For patients who are 
lost to follow-up (i.e. those patients whose status is unclear because they fail to appear for 
study visits without stating an intention to withdraw), the investigator should show "due 
diligence" by documenting the steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters in the source, etc. 
Patients who are prematurely withdrawn from the study will not be replaced by an equal 
number of newly enrolled patients. 
5.5.10 
Emergency breaking of treatment assignment 
Not applicable. 

Novartis 
Confidential 
Page 38 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
5.5.11 
Study completion and post-study treatment 
The core study will have a duration of 24 weeks. Following the evaluation of psoriasis 
severity at week 16, patients achieving PASI 50 response will be eligible to continue on the 
study treatment for an additional 8 weeks. Willing patients reaching at least a PASI 75 
response during the core study will be eligible to enter an extension treatment period of an 
additional 48 weeks. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care.  
5.5.12 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should 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 protect the patient’s interests. The investigator will be 
responsible for informing Ethics Committees (ECs) of the early termination of the trial. 
The study extension can be terminated by Novartis for any reason after a period of at least 12 
weeks. Termination may occur only in selected regions where the drug is commercially 
available; this decision will be made on a region-by-region basis, as for some regions the 
study will continue as planned even though secukinumab may have become commercially 
available. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. 
Patients should be seen for all visits on the designated day. A time window of ± 2 days for 
weekly visits and ± 7 days for the monthly visits is allowed. 
Patients who discontinue the investigational treatment should also return for the assessments 
in Table 6-1. If they refuse to return for these assessments or are unable to do so, every effort 
should be made to contact them or a knowledgeable informant by telephone, reporting it in the 
source documents. 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit, including a final contact at the 30-day point. Documentation of attempts to 
contact the patient should be recorded in the source documentation.  
 
 

Novartis 
Confidential 
Page 39 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 
Table 6-1: Assessment schedule (core study) 
∫Hematology: Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g. neutrophils, basophils, 
eosinophils, monocytes, lymphocytes) and platelet count; Chemistry: Albumin, alkaline phosphatase, total bilirubin, 
bicarbonate/CO2, calcium, cholesterol, chloride, creatinine, CK, GGT, glucose, LDH, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric acid. 
¥ Height will be assessed only at screening or at baseline 
* HBsAg, HBsAb, HBcAb 
^ End of Study visit for patients not proceeding to the extension treatment period.  
 
Table 6-2 lists all the assessments of the extension phase and indicates with an “x” when the 
visits are performed. 
Patients should be seen for all visits on the designated day but a time window of ± 7 days is 
allowed. 
 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12/EoS 
Week (relative to baseline) 
-4 
-2 
0 (± 2 
days) 
1 (± 2 
days) 
2 (± 2 
days) 
3 (± 2 
days) 
4 (± 2 
days) 
8 (± 7 
days) 
12 (± 7 
days) 
16 (± 7 
days) 
20 (± 7 
days) 
24 (± 7 
days) 
Day 
-28  -14 to -7 
1 
7 
14 
21 
28 
56 
84 
112 
140 
168 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
 
X 
 
 
 
 
 
 
 
 
 
 
TNFα - 308 polymorphism 
X 
 
 
 
 
 
 
 
 
 
 
 
Psoriasis: medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Previous Psoriasis therapies 
 
X 
 
 
 
 
 
 
 
 
 
 
Quantiferon TB-Gold (within 3 months) 
 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight, BMI and waist 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
Vital signs 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
PASI 
 
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 
Lab assessments: hematology and chemistry∫ 
 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
hsCRP 
 
 
X 
 
 
 
 
 
 
X 
 
X 
HCV, HBV* and HIV tests (within 6 months) 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Secukinumab administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DLQI 
 
 
X 
 
 
 
 
 
 
X 
 
X 
HADS 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Cw6 centralized determination  
X 
 
 
 
 
 
 
 
 
 
 
 
ECG (within 6 months) 
 
X 
 
 
 
 
 
 
 
 
 
 
Chest X-ray (within 6 months) 
 
X 
 
 
 
 
 
 
 
 
 
 
Study completion 
 
 
 
 
 
 
 
 
 
 
 
X^ 
Concomitant medication 
 
 
As needed 
Adverse events 
As needed 
Liver events 
 
 
As needed 

Novartis 
Confidential 
Page 40 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 
Table 6-2: Assessment schedule of extension treatment period 
* E0 corresponds to visit at week 24 of the core study (end of study) for patients proceeding to the extension treatment period. 
The assessments indicated here are in addition to those already scheduled for EOS visit (see table 6-1) 
∫ Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g. neutrophils, basophils, 
eosinophils, monocytes, lymphocytes) and platelet count. Chemistry: albumin, alkaline phosphatase, total bilirubin, calcium, 
cholesterol, creatinine, CK, GGT, glucose, LDH, potassium, total protein, AST, ALT, sodium, triglycerides, uric acid, hsCRP. 
6.1 
Information to be collected at screening 
HLA-Cw6 determination will be performed at screening for patients who have provided 
written informed consent. A central laboratory will be used to determine Cw6. Patients will 
thereafter be stratified into the two cohorts. TNFα-308 polymorphism will be centrally 
determined at the same time. 
6.2 
Patient demographics/other baseline characteristics 
The following data will be gathered/documented at visit 2 (day -14 to -7): 
– Demographic data [age, sex, race, ethnicity, and childbearing potential (for 
females only)]. 
– Verification of inclusion/exclusion criteria.  
– History (medical, smoking, psoriasis). 
– Previous psoriasis therapies in the 6 months prior to study entry. 
– A chest X-ray, an ECG and HCV, HBV (HBsAg, HBsAb, HBcAb), HIV tests will be 
required unless performed within the previous 6 months. Adequate documentation 
(assessment reports, tracking and imagines as applicable) must be available for previous 
evaluations to be considered valid at baseline. 
Visit 
E0* 
E1 
E2 
E3 
E4/ End of 
Extension or 
PPD 
Week (relative to baseline) 
24 
36 
48 
60 
72 
Recommended visit window (days) 
±7 
±7 
± 7 
±7 
±7 
Informed consent 
X 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
Weight and waist 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
PASI 
X 
X 
X 
X 
IGA mod 2011 
X 
X 
X 
X 
Lab assessments: hematology and chemistry∫ 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Secukinumab administration 
AS NEEDED 
DLQI 
 
 
X 
 
X 
HADS 
 
 
X 
 
X 
Check self-administration log 
X 
X 
X 
X 
Dispensing Secukinumab for self-administration at 
home 
X 
X 
X 
X 
 
Study extension completion 
 
 
 
 
X 
Concomitant medication 
AS NEEDED 
 
Adverse events 
AS NEEDED 
Liver events 
AS NEEDED 

Novartis 
Confidential 
Page 41 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
– A Quantiferon TB-Gold test or PPD test will be required unless performed within the 
previous 3 months. Adequate documentation (assessment report) must be available for 
previous evaluations to be considered valid at baseline. 
– Height, weight and waist. 
– Physical examination (only as source document). 
– Vital signs (heart rate, blood pressure). 
– PASI, IGA mod 2011. 
– Hematology, blood chemistry, urinalysis. 
– Serum pregnancy test. 
– 
 
Treatment with secukinumab will begin at visit 3 (day 1), during which the following data 
will be collected/documented: 
– Verification of inclusion/exclusion criteria. 
– Physical examination. 
– Vital signs. 
– Height (if not obtained at visit 2), weight and waist. 
– Hematology, blood chemistry. 
– High sensitivity C-reactive protein (hsCRP). 
– PASI, IGA mod 2011. 
– DLQI, HADS. 
6.3 
Treatment exposure and compliance 
Data on investigational drug will be reported on the Dosage Administration Record (DAR) of 
the eCRF in order to provide information about drug exposure. 
6.4 
Efficacy 
6.4.1 
Psoriasis Area and Severity Index (PASI) 
The primary efficacy variable is the measurement of the severity of psoriasis using the 
Psoriasis Area and Severity Index (PASI) (Richard GB et al. 2013), the most widely used tool 
for this purpose. PASI combines the assessment of the severity of lesions and the area affected 
into a single score with a range of 0 (no disease) to 72 (maximal disease). The PASI will be 
assessed at each visit from V2 to V12 of the core study and at all four visits of the extension 
period. 
A PASI score (Weisman et al. 2003) will be calculated as indicated in Appendix 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 

Novartis 
Confidential 
Page 42 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
on each body region is estimated as a percentage of the total area of that particular body 
region. In particular: 
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 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 
Usually, a PASI 75 improvement is used as a minimum threshold to evaluate the clinical 
efficacy of new psoriasis treatments (Callen JP et al. 2003). A PASI 90 improvement will be 
used as primary endpoint in this study. 
The following definitions of PASI will be used in this study: 
• 
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). 
6.4.2 
Investigator’s Global Assessment Scale (IGA) 
The IGA mod 2011 rating scale for overall psoriatic disease is shown in Appendix 4. The IGA 
mod 2011 scale has been developed based on a previous version of the scale used in 
secukinumab Phase II studies in collaboration with health authorities, in particular the FDA. 
The explanations/descriptions of the points on the scale have been improved to ensure their 
differentiation. The IGA mod 2011 will be evaluated at each visit from V2 to V12 of the core 
study and at all four visits of the extension period. It measures the severity of the disease on a 
five-point scale ranging from 0 (no disease, ‘clear’) to 4 (‘very severe’) (Richard GB et al 
2013). 
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. 
6.4.3 
Appropriateness of efficacy assessments 
The PASI is widely considered the gold standard for assessing psoriasis severity in a clinical 
trial setting (Richard GB et al. 2013). 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, 

Novartis 
Confidential 
Page 43 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
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). 
6.5 
Safety 
6.5.1 
Physical examination 
An overall physical examination will be performed by the investigational staff at visit 2 and 
include the examination of general appearance, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological. A short physical exam will include the examination of general appearance and 
vital signs (blood pressure and pulse) and will be performed at all visits starting from visit 3. 
Detailed information on each evaluated apparatus from all physical examinations must be 
included in the source documentation at the study site. 
Metabolic syndrome will require any 3 of the following 5 criteria: increased waist 
circumference (≥102 cm for men, ≥ 88 cm for women), elevated triglycerides (≥150 mg/dl), 
reduced high-density lipoprotein (HDL) cholesterol (≤ 40 mg/dl in men and ≤ 50 mg/dl in 
women), elevated blood pressure (≥ 130 mmHg systolic and ≥ 85 mmHg diastolic or ongoing 
treatment for hypertension) or elevated glucose (≥100 mg/dl or ongoing treatment for elevated 
glucose) (Expert Panel JAMA 2001). 
6.5.2 
Vital signs 
Sitting blood pressure and heart rate will be measured at visits 2 and 3 and then at each visit 
starting from visit 7. Clinically notable vital signs are defined in Appendix 1. 
6.5.3 
Height, weight and waist 
Height in centimeters (cm) will be measured at visit 2 or 3 only.  
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) and waist will 
be measured at visits 2, 3 and 12 of the core study and at all four visits of the extension 
period. BMI will be derived from weight and height results. 
6.5.4 
Laboratory evaluations 
6.5.4.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (e.g. 
neutrophils, basophils, eosinophils, monocytes, lymphocytes), and platelet count will be 
measured at visits 2 and 3 and then at each visit starting from visit 7 (including extension 
period). Appendix 1 shows the extended laboratory ranges that are considered clinically 
notable. 
6.5.4.2 
Clinical chemistry 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, creatine kinase (CK), gamma-glutamyl transpeptidase (GGT), glucose, 
lactate dehydrogenase (LDH), inorganic phosphorus, lipase, amylase, magnesium, potassium, 

Novartis 
Confidential 
Page 44 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
total protein, AST, ALT, sodium, triglycerides, urea/blood urea nitrogen (BUN) and uric acid 
will be measured at visits 2 and 3 and then at each visit of the core study starting from visit 7. 
The following clinical chemistry assessments will be run at all four visits of the extension 
period: albumin, alkaline phosphatase, total bilirubin, calcium, cholesterol, creatinine, CK, 
GGT, glucose, LDH, potassium, total protein, AST, ALT, sodium, triglycerides, uric acid. 
Appendix 1 shows the extended laboratory ranges that are considered clinically notable. 
6.5.4.3 
Urinalysis 
Dipstick measurements for specific gravity, protein, glucose and blood will be performed. 
WBC and RBC sediments will also be analyzed at visits 2, 10 and 12 of the core study and at 
all four visits of the extension period. 
6.5.4.4 
hsCRP 
hsCRP will be assessed at visits 3, 10, and 12 of the core study and at all four visits of the 
extension period. 
6.5.5 
Electrocardiogram (ECG), chest X-ray 
An ECG and chest X-ray will be required at visit 2 unless performed within the previous 6 
months. Adequate documentation (assessment reports, tracking and imagines as applicable) 
must be available for previous evaluations to be considered as baseline. 
6.5.6 
Pregnancy and assessments of fertility 
A serum pregnancy test will be performed at visit 2 in all fertile women. 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
6.6 
Other assessments 
6.6.1 
Resource utilization 
The amount of resources used during the study will be evaluated in comparison with the 6 
months prior to the beginning of the study. 
Resource utilization will be extrapolated from data collected from single items in the flow 
chart such as “medical history, psoriasis medical history, concomitant medications and 
adverse events.” 
6.6.2 
Health-related Quality of Life 
Quality of life will be assessed by means of the Dermatology Life Quality Index (DLQI), a 
validated, 10-item general dermatology disability index designed to assess health-related 
quality of life in adult subjects with skin diseases such as eczema, psoriasis, acne, and viral 
warts (Finlay AY et al. 1994). The measure is self-administered and includes domains of daily 
activities, leisure, personal relationships, symptoms and feelings, treatment, and work/school 
activities. The DLQI has well-established reliability and validity as determined in several 
studies (Shikiar et al 2003, Badia X et al. 1999, Lewis V et al. 2004, Shikiar et al. 2006). 

Novartis 
Confidential 
Page 45 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Moreover, it is frequently used in clinical psoriasis trials, has been tested across 32 different 
skin conditions and is available in 55 languages. The recall period is the previous week, and 
the instrument requires 1 to 2 minutes to complete. Each item has four response categories 
ranging from 0 (not at all) to 3 (very much). “Not relevant” is also a valid response and is 
scored as 0. The DLQI© total score is a sum of the 10 questions. Scores range from 0 to 30 
and higher scores indicate greater health-related quality of life impairment. Each subscale of 
the DLQI© may be analyzed separately. 
Patients will be asked to complete the questionnaire at visits 3, 10 and 12 of the core study 
and at visits 2 and 4 of the extension period. 
Completed questionnaires will be reviewed and examined by the investigator before the 
clinical examination for responses that may indicate potential AEs or SAEs. The investigator 
should review not only the responses to the questions in the questionnaires but also any 
unsolicited comments written by the patient. 
If the occurrence of AEs or SAEs is confirmed, the physician must record the events as per 
instructions given in Section 7.2 of the protocol. 
6.6.3 
Hospital Anxiety and Depression Scale (HADS) 
The Hospital Anxiety and Depression Scale (HADS) is a fourteen-item scale that generates 
ordinal data. Seven of the items relate to anxiety and seven relate to depression. This outcome 
measure was specifically developed to avoid reliance on aspects of these conditions that are 
also common somatic symptoms of illness, for example fatigue and insomnia or hypersomnia. 
Calculations of scores: each of the 14 items is rated on a 4-point scale (‘Yes, definitely’, ‘Yes, 
sometimes’, ‘No, not much’ and ‘No, not at all’). All items except 7 and 10 are scored as 
‘Yes, definitely’ = 3 to ‘No, not at all’ = 0. Items 7 and 10 are scored as ‘Yes, definitely’ = 0 
to ‘No, not at all’ = 3. The HADS consists of two sub-scores: the HAD‑A for anxiety and 
HAD‑D for depression; each sub-score ranges from 0 to 21 points; scores ≥11 indicate the 
presence of anxious or depressive disorders; scores between 8-10 points are borderline 
abnormal, and scores of ≤7 indicate that the disorder is not present. 
Patients will be asked to complete the questionnaire at visits 3, 10 and 12 of the core study 
and at visits 2 and 4 of the extension period. 
Completed questionnaires will be reviewed and examined by the investigator before the 
clinical examination for responses that may indicate potential AEs or SAEs. The investigator 
should review not only the responses to the questions in the questionnaires but also any 
unsolicited comments written by the patient. 
If the occurrence of AEs or SAEs is confirmed, the physician must record the events as per 
instructions given in Section 7.2 of the protocol. 

Novartis 
Confidential 
Page 46 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits, or through physical examination, laboratory tests, or 
other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
 they induce clinical signs or symptoms,  
 they are considered clinically significant,  
 they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values that are considered non-typical in a patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them accompanied by the following information. 
 the severity grade  
– mild: usually transient in nature and generally not interfering with normal activities 
– moderate: sufficiently discomforting to interfere with normal activities 
– severe: prevents normal activities 
 its relationship to the investigational treatment (no/yes)  
 its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported. 
 whether it constitutes a serious adverse event (SAE)  
 action taken regarding the investigational treatment  
 whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy) 
 its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
A serious adverse event (SAE) is any adverse event (appearance of or worsening of any pre-
existing) undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:  

Novartis 
Confidential 
Page 47 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 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 a routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
– for an 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  
– for treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE given above and not resulting in hospital admission  
– for social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
– medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: no action taken (i.e. further observation only); investigational treatment dosage 
adjusted/temporarily interrupted; investigational treatment permanently discontinued; 
concomitant medication given; and non-drug therapy given. The action taken to treat the 
adverse event should be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent. An assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the investigational 
treatment, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents. However, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse event reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 

Novartis 
Confidential 
Page 48 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Novartis within 24 hours of learning of its occurrence. Any SAEs experienced after the 30-
day period should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.  
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
The investigator will complete the SAE Report Form in English, assess the relationship to the 
study treatment and send the completed and signed form by fax within 24 hours to the local 
Novartis Drug Safety and Epidemiology Department Novartis (DS&E). The original and the 
duplicate copies of the SAE Form, and the fax confirmation sheet will be kept with the case 
report forms at the study site.  
Follow-up information will be sent to the same person to whom the original SAE Form was 
sent, re-stating the date of the original report. A new SAE Form will be used (stating that this 
is a “follow-up”). The follow-up report should describe whether the event is resolved or 
continues, if and how it was treated, and whether the patient continued or discontinued study 
participation. The form and fax confirmation sheet will be retained at the study site. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment, a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification to inform all investigators involved in any study with the same investigational 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
7.3 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
Liver events are divided into two categories: 
 Liver events of special interest, which consist of liver function test (LFT) elevations. 
 Medically significant liver events that are considered as serious adverse events and consist 
of marked elevations of LFTs and / or pre-specified adverse events. 
Please refer to Table 14-1 in Appendix 2 for complete definitions of liver events.  
Any liver event that meets the criteria for “medically significant” event, as outlined in Table 
14-1 of Appendix 2, should follow the standard procedures for SAE reporting as described 
in Section 7.2.  
Every liver event as defined in Table 14-1 of Appendix 2 should be followed up by the 
investigator or designated personal at the trial site as summarized below. 

Novartis 
Confidential 
Page 49 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
 Repeat the LFT to confirm elevation as appropriate. 
 Discontinue the investigational drug if appropriate. 
 Hospitalize the patient if appropriate. 
 Assess the causality of the liver event via exclusion of alternative causes (e.g., disease, co-
medications). 
 An investigation of the liver event needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatology consultancy, based on the investigator’s discretion. All follow-up information and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview CRF pages. 
7.4 
Pregnancy reporting 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy 
should be followed up to determine outcome, including spontaneous or voluntary termination, 
details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment. 
Any SAE experienced during pregnancy must be reported on the SAE Report 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, the field monitor will visit the site regularly to check the completeness of patient 
records, the accuracy of entries on the CRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that the investigational treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each 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 
of the presence of informed consent, adherence to the inclusion/exclusion criteria, 

Novartis 
Confidential 
Page 50 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Web based software will be used: no installation procedure will 
be needed. Each site will be authorized by the Administrator to access the eCRF. Each 
investigator site qualified personnel will be allowed to access the eCRF by means of a ‘login 
mask’ requiring User ID and Password and will be able to read, modify and update only the 
information he/she has previously reported. Each page should report site code and patient 
code. On-line validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected by the CRO working on behalf of 
Novartis. The Investigator must certify that the data entered into the Electronic Case Report 
Forms are complete and accurate. After database lock, the investigator will receive copies of 
the patient data or a CD-ROM for archiving at the investigational site.  
8.3 
Database management and quality control 
CRO working on behalf of Novartis will review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. The Data Manager of the CRO working on behalf of 
Novartis will perform the cleaning session reviewing the warning messages raised by on-line 
checks and running post-entry checks by means of validation programs. During this process, 
if clarifications are needed, the Data Manager will raise queries by means of data query forms 
through the WEB application. Designated investigator site staff is required to respond to the 
query and the Data Manager will make the correction to the database based on the query 
response. The data collection and the Queries flow as well as the on-line and off-line control 
checks will be detailed in the Data Management Plan and Data Validation documents. 
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. 
A central laboratory will analyze samples for Cw6 determination and enter the results in a 
dedicated section of the eCRF. Cohort status will be monitored to maintain the Cw6+/Cw6- 
ratio foreseen in the protocol. 
Data about study drug will be tracked using the eCRF. The system will be supplied by a CRO, 
who will also manage the database. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared completed and accurate, it will be locked and 
made available for data analysis. Any changes to the database after that time can only be made 

Novartis 
Confidential 
Page 51 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
after written agreement between the Clinical Trial Leader, the Trial Statistician and the Data 
Manager. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
9 
Data analysis 
All the data collected in this study will be listed and summarized as appropriate as described 
below. The data from all centers will be pooled and summarized. Continuous data will be 
summarized by mean, standard deviation (SD), median, first and third quartiles, minimum and 
maximum. Categorical data will be presented by absolute and relative frequencies (n and %). 
Unless stated otherwise, two-sided p-values will be presented. 
All statistical tables, listings and analyses will be produced using SAS® release 9.2 or later 
(SAS Institute Inc. Cary, NC, USA). 
More details about data analysis will be provided in the Statistical Analysis Plan.  
The data will be analyzed by the CRO working on behalf of Novartis. 
9.1 
Analysis sets 
The following analysis populations will be defined for statistical analysis. 
 Full Analysis Set (FAS): all enrolled patients. 
 Safety: all enrolled patients who were given at least one dose of study drug.  
 Intent-to-treat (ITT): all patients included in the safety population with at least one post-
baseline efficacy assessment. 
 Per-Protocol (PP): all patients included in the ITT population who completed the study 
without any major protocol violation. 
The primary and secondary objectives will be evaluated on the ITT population. A supportive 
analysis will be done on the PP population. 
All safety evaluations will be based on the safety population. 
9.2 
Patient demographics and other baseline characteristics 
All data about patient demographics and baseline characteristics, including derived variables, 
will be summarized overall and by cohort with summary descriptive statistics. Continuous 
data will be summarized by mean, standard deviation, median, first and third quartiles, 
minimum and maximum. Categorical data will be presented by absolute and relative 
frequencies (n and %). 

Novartis 
Confidential 
Page 52 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
In order to interpret results adequately, the homogeneity of patient distribution between 
cohorts will be tested on selected baseline demographics and anamnestic variables (e.g. for 
gender, age, race, ethnicity, BMI, baseline PASI, baseline IGA, TNFα - 308 polymorphism, 
metabolic syndrome, smoking). Categorical variables will be analyzed by Cochran-Mantel-
Haenszel test stratified by geographical region (i.e. north vs south/central) and BMI (< 25 vs ≥ 
25).  
Continuous variables will be analyzed by means of ANOVA model corrected by geographical 
region and BMI classes, as appropriate. Statistically significant variables will be included as 
covariates in the explanatory analysis model. Whenever necessary, normality will be assessed 
by means of Shapiro-Wilk test and with graphical methods. In case of non-normality, a non-
parametric test will be used.  
The number of the analysis populations will be described and the reasons for excluding a 
patient from any particular population will be provided with the number of protocol violators 
for each criterion. The difference between cohorts with respect to protocol deviations and 
reasons for dropout will be examined. 
Any condition entered as medical history or current medical conditions at baseline will be 
coded using the MedDRA dictionary. They will be summarized by system organ class and 
preferred term of the MedDRA dictionary.  
Summaries of psoriasis-specific medical history will be provided as well. 
9.3 
Treatments 
Study treatment administration details will be summarized overall and by cohort for the 
Safety population. The exposure to investigational drug (number of doses) and duration of 
exposure (days) will be summarized by means of usual descriptive statistics. Total actual dose 
will be compared with the total dose patients should take as per protocol and derived 
compliance will be summarized. The number of patients with permanent study drug 
interruptions will be described and the reasons that led to the interruption will be examined. 
The use of rescue medication, concomitant medications and significant non-drug therapies 
will be summarized by Anatomic Therapeutic Chemical (ATC) class, overall and by cohort 
for the Safety population. 
9.4 
Analysis of the primary variable 
The primary objective of this study is to evaluate the clinical response in Cw6-negative and 
Cw6-positive patients treated with secukinumab 300 mg with respect to the Psoriasis Area 
Severity Index (PASI) 90 response rate after 16 weeks, and thereafter for up to 72 weeks. 
9.4.1 
Variable 
The primary efficacy variable is the PASI 90 response after 16 weeks of treatment, defined as 
the achievement of ≥ 90% improvement (reduction) in PASI score after 16 weeks of treatment 
compared to baseline. 
The primary analysis will be based on the ITT population. A supportive analysis will be 
performed on the PP population. 

Novartis 
Confidential 
Page 53 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The proportion of patients who reach PASI 90 at 16 weeks will be presented with the one-
tailed 97.5% confidence interval of the Cw6 positive (POS) – Cw6 negative (NEG) 
difference. 
The null hypothesis: 
H0: Cw6 POS – Cw6 NEG ≥ 0.12: The difference in proportion of subjects achieving PASI 
90 response between the Cw6-positive cohort (Cw6 POS) and the Cw6-negative cohort (Cw6 
NEG) is at least 12%. 
The alternative hypothesis: 
HA: Cw6 POS – Cw6 NEG < 0.12: The difference in the proportion of subjects achieving 
PASI 90 response between the Cw6-positive cohort (Cw6 POS) and the Cw6-negative cohort 
(Cw6 NEG) is less than 12%. 
A logistic regression analysis model will be also fitted, considering geographical region, BMI, 
smoking, metabolic syndrome, TNFα-308 polymorphism, as well as the clinically relevant 
baseline variables as strata factors. 
9.4.3 
Handling of missing values/censoring/discontinuations 
All attempts will be made to ensure that the database contains full information for all data. For 
subjects who prematurely discontinue the study for any reason or subjects with missing visits 
(after baseline), PASI will be imputed using the Last Observation Carried Forward (LOCF) 
approach. If all PASI post-baseline efficacy values are missing, then these missing values will 
not be imputed and this subject will be removed from the analysis.  
9.4.4 
Supportive analyses 
A sensitivity analysis on the primary efficacy variable will be performed considering the 
subjects who prematurely discontinued the study without a 16-week PASI assessment as non-
responders.  
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
The primary analysis and the analyses of all secondary variables will be based on the ITT 
population.  
PASI 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 response by visit will be 
presented with absolute and relative frequencies.  
The following definitions of PASI response will be used: 
• 
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. 

Novartis 
Confidential 
Page 54 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
• 
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). 
Confidence intervals for response rates will be derived as well, based on the score method 
including continuity correction (Newcombe 1998). 
Summary statistics will be provided for absolute PASI scores and for percent changes from 
baseline by visit and cohort. A graphical representation will also be provided. 
The proportion of patients who reach PASI 75 after 16 weeks will be compared between 
cohorts with the same method presented for the primary endpoint. 
The differences between cohorts in time to reach PASI 90, as well as PASI 75, will be 
evaluated by means of a log-rank test. The hazard ratios and their corresponding 95% 
confidence intervals will be also computed using a stratified Cox proportional hazards 
regression model with Cw6 group and baseline PASI as explanatory variable and stratified by 
geographical region and BMI, as well as the clinically relevant baseline variables. The 
Kaplan-Meier estimates of the cumulative rate for each cohort will be plotted.  
IGA mod 2011 
Summary statistics for the IGA mod 2011 score over time, as well as percent changes from 
baseline, will be presented by visit and cohort. Summary statistics for IGA 0 or 1 response by 
visit and cohort will be presented with absolute and relative frequencies. Subjects achieving 
IGA score 0 or 1 are defined as IGA 0 or 1 responders. 
9.5.2 
Safety variables 
Vital signs 
Summary statistics of vital signs and changes from baseline will be provided by visit and 
cohort. Clinically notable vital signs will be listed and absolute and relative frequencies will 
be presented by visit and cohort. 
Height, weight and waist 
Summary statistics will be provided for height, weight, waist and derived BMI (calculated 
from body weight and height) by visit and cohort including changes from baseline.  
Hematology, clinical chemistry, urinalysis, hsCRP 
Summary statistics of raw data and absolute and changes from baseline will be provided 
for laboratory data by visit and cohort.  
Patients with values above (H) or below (L) notable criteria (see Appendix 1) will be listed 
and absolute and relative frequencies will be presented by visit and cohort. Laboratory values 
will be presented for each subject in a data listing with an indication of whether the value is 
above (H) or below (L) the normal reference range.  

Novartis 
Confidential 
Page 55 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Laboratory data will also be summarized by presenting shift tables for each laboratory 
parameter showing the number and percentage of subjects in each cohort with the most 
extreme post-baseline value that falls outside normal ranges by the classification of value at 
baseline (H/N/L).  
Adverse Events 
A summary table of AEs will be produced by cohort specifying the number of total events and 
the absolute and relative frequency of patients with AEs. The absolute and relative frequency 
of patients with study drug related AEs, severe AEs, SAEs, AEs with an outcome of death, 
AEs leading to discontinuation of treatment will be also reported.  
AEs will be tabulated also by System Organ Class, Preferred Term.  
SAEs will be summarized as well.  
All study drug related AEs, AEs with an outcome of death, AEs leading to discontinuation of 
treatment will be listed. 
The above reported analysis will focus on treatment emergent adverse events. A treatment-
emergent adverse event is defined as any adverse event that develops after initiation of the 
study treatments or any event already present that worsens following exposure to the study 
treatment. Non-treatment emergent adverse events will be listed separately. 
9.5.3 
Resource utilization 
Data relating to health resources use will be used for the purpose of economic evaluation, 
particularly, to compare the amount of health resources used in the 6 months prior to the 
beginning of the study and during the study. Health resources use will refer to all items of 
assistance provided to the patients in the 6 months prior to the beginning of the study and 
during the study. 
The analysis of health resources use will be conducted considering the patients’ demographic 
characteristics, anthropometric parameters (such as weight, BMI and waist circumference), 
co-morbidities (such as anxiety and depression), and scores provided by the Study (such as 
PASI, DLQI, HADS). 
The cost for all items of assistance provided to the patient and included into the economic 
evaluation will be calculated according to price (such as for drugs) or tariffs (such as for 
tests). 
Given the skewed distribution of costs, median value will also be presented (in addition to 
mean value). 
9.5.4 
Health-related Quality of Life 
Dermatology Life Quality Index  
Seven scores will be derived from the DLQI: the total score of each of the six dimensions as 
well as the total score over all items. The higher the score, the more quality of life is impaired.  
The percentage change from baseline will be derived for each of the seven scores. Summary 
statistics will be provided for absolute values as well as for the percentage change by visit. 
Change from baseline will be analyzed by means of a pairwise test for categorical data.  

Novartis 
Confidential 
Page 56 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
In addition, summary statistics will be provided for the number of subjects achieving DLQI 0 
or 1 at each time point. 
Hospital Anxiety and Depression Scale 
Descriptive statistics of HAD-A and HAD-D score at each time point with changes vs 
baseline will be provided.  
The sub-scores, HAD-A and HAD-D, will be displayed per class (i.e. scores ≥11 indicate the 
presence of anxious or depressive disorders; scores between 8-10 points are borderline 
abnormal, and scores of ≤7 indicate that the disorder is not present) at each time point by 
means of a shift table. 
In addition, the prevalence of anxiety and depression will be presented on the basis of the 
following three criteria: as per the score on the corresponding sub-scores of the HAD 
questionnaire, in terms of the treatment they are receiving for anxiety/depression, and 
according to both criteria. 
A correlation between HADS and PASI will be explored by means of a Spearman coefficient 
(or Pearson, according to the data distribution). A cross-table for PASI90 or PASI75 and 
HAD score ≥11 at baseline and at 16 weeks will also be provided.  
9.5.5 
Pharmacokinetics 
Not applicable. 
9.5.6 
Pharmacogenetics/pharmacogenomics 
Not applicable. 
9.5.8 
PK/PD 
Not applicable. 
9.6 
Interim analyses 
Not applicable. 

Novartis 
Confidential 
Page 57 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
9.7 
Sample size calculation 
The primary objective of this study is to evaluate the clinical response in PASI 90 at week 16 
of Cw6-negative and Cw6-positive psoriatic patients.  
According to literature data, Cw6-positive patients will be about 60% of the entire psoriatic 
patient population.  
From a previous study with ustekinumab (Talamonti et al. 2013) we can observe a difference 
in response to PASI 90 between Cw6-positive vs Cw6-negative patients of around 30%, in 
favor of Cw6-POS. Therefore, it is sensible to expect a response in the Cw6-negative cohort 
not less than 12 % respect to the Cw6-positive group. Further considerations are stated in the 
paragraph below. 
Phase III data on secukinumab show a PASI 90 response at 16 weeks of 71%. Under the 
assumption that 60% of all the enrolled patient population is represented by Cw6-POS 
patients, we can reasonably assume to observe a proportion of patients with PASI 90 of 80% 
in the Cw6-POS cohort. 
Under these assumptions, considering a one-side alpha level of 0.025 and a power of 80%, 
365 patients (219 Cw6-POS and 146 Cw6-NEG) are sufficient to evaluate if the response in 
terms of PASI 90 in the Cw6-negative cohort is not less than 12% respect to the Cw6-positive 
cohort. 
Considering a dropout rate at 16 weeks of 10% equally divided in the two studied cohorts, a 
total of 406 patients should be enrolled.  
All calculations were done with NQuery 7.0. 
A power analysis based on a different Cw6 patient distribution was made in order to facilitate 
patient enrollment without power-loss in the primary endpoint evaluation. Table 9-1 shows 
how the enrollment rate should be set free until the ratio between Cw6-POS and Cw6-NEG 
reaches the 1:1 rate-distribution, with a power of at least 80%.  
In particular, the number of Cw6-POS evaluable patients will range from 219 to 182, whereas 
those in the Cw6-NEG cohort will range from 146 to 182.  
Based on the table below, the enrollment in one of the two cohorts will be stopped when the 
target number is achieved (a maximum of 244 Cw6-POS patients will be allowed).   
Table 9-1: Power analysis 
  
  
  
  
  
  
  
Drop out 10% 
Power 
Ratio 
Cw6 
POS 
Cw6 
NEG 
Cw6 
POS 
Cw6 
NEG 
Overall 
Cw6 
POS 
Cw6 
NEG 
  
  
% 
% 
N 
N 
N 
N 
N 
80% 
0,66 
60% 
40% 
219 
146 
365 
244 
163 
80% 
0,70 
59% 
41% 
215 
150 
365 
239 
167 
80% 
0,72 
58% 
42% 
212 
153 
365 
236 
170 
80% 
0,75 
57% 
43% 
209 
156 
365 
233 
174 
81% 
0,79 
56% 
44% 
204 
161 
365 
227 
179 
81% 
0,82 
55% 
45% 
200 
165 
365 
223 
184 

Novartis 
Confidential 
Page 58 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
81% 
0,85 
54% 
46% 
197 
168 
365 
219 
187 
81% 
0,89 
53% 
47% 
193 
172 
365 
215 
192 
81% 
0,92 
52% 
48% 
190 
175 
365 
212 
195 
81% 
0,96 
51% 
49% 
186 
179 
365 
207 
199 
81% 
1,00 
50% 
50% 
182 
182 
364 
203 
203 
 
The choice of clinically relevant differences is based on the following considerations: 
• 
As the efficacy of secukinumab has already been clinically substantiated through 
extensive Phase II and III programs, all patients will be treated with active drug using the 
same therapeutic regimen (no placebo comparison will be done). 
• 
The primary variable is the proportion of patients who reach PASI 90 after 16 weeks. This 
endpoint is quite challenging and much more restrictive compared to PASI 75. Only the 
investigator is responsible for collecting the components or scoring signs and total 
regional areas in the PASI assessment. Therefore, it has great internal variability, which 
should be taken into account.  
• 
The paper on HLA-Cw6 ustekinumab data (Talamonti M et al. 20134) revealed a striking 
difference between Cw6-positive and Cw6-negative patients in the proportion of PASI 90 
achievements, 85.7% vs 56.5%. This difference in PASI 90 is very relevant in the daily 
clinical management of patients. 
Considering the above statements, it seems reasonable to claim that more than halving the 
difference observed with ustekinumab between Cw6-positive and Cw6-negative patients, 
secukinumab would be an advantage in terms of efficacy for Cw6-negative patients who do 
not respond properly to ustekinumab and other approved biologic drugs. 
Although the sample size was calculated considering only Cw6 haplotype, it is also adequate 
for regression models assessing differences from baseline for clinically relevant variables. In 
fact, the expected number of patients who reach PASI 90 at week sixteen is at least 250 
(roughly 71% of 365). Therefore, using a conservative criterion of a minimum of 10 “events” 
for each predictor in the model, we can add up to 25 variables in the model without loss of 
power (Vittinghoff E et al. 2007). This model will take into account variables such as BMI, 
smoking, metabolic syndrome and TNFα-308 polymorphism, which, among the six existing 
polymorphisms, is the one most greatly affecting response to treatment with anti-TNFα drugs. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with 
the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice (GCP), with applicable local regulations (including European 
Directive 2001/20/EC, US Code of Federal Regulations Title 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki. 

Novartis 
Confidential 
Page 59 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
10.2 
Informed consent procedures 
Eligible patients may be included in the study only after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. Informed consent must be obtained before 
conducting any study-specific procedures (i.e. all of the procedures described in the protocol). 
The process of obtaining informed consent should be documented in the patient’s source 
documents.  
Novartis will provide investigators a proposed informed consent form in a separate document 
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. 
10.3 
Responsibilities of the investigator and IRB/IEC 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC) before study start. A signed and dated statement that the protocol and 
informed consent have been approved by the IRB/IEC must be given to Novartis before study 
initiation. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Clinical Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
It is Novartis’ policy for multi-center clinical trials that the first publication is based on 
consolidated data from all centers, analyzed as stipulated in the protocol and agreed upon by 
investigators before trial initiation. 
11 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
trial to request approval of a protocol deviation, as requests to approve deviations will not be 
granted. 

Novartis 
Confidential 
Page 60 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
If the investigator feels a protocol deviation would improve the conduct of the study, this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC, it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such 
cases, Novartis should be notified of this action and the IRB/IEC at the study site should be 
informed within 10 working days or less, if required by local regulations. 
 
 

Novartis 
Confidential 
Page 61 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
12 
References 
- Badia X, Mascaro JM, Lozano R. (1999) Measuring health-related quality of life in 
patients with mild to moderate eczema and psoriasis: clinical validity, reliability and 
sensitivity to change of the DLQI. The Cavide Research Group. Br J Dermatol; 141: 698–
702. 
- Boyman, O. et al. (2005) Activation of dendritic antigen-presenting cells expressing 
common heat shock protein receptor CD91 during induction of psoriasis. Br. J. Dermatol; 
152, 1211–1218.  
- Callen JP, Krueger GG, Lebwohl M et al. (2003): AAD consensus statement on psoriasis 
therapies. J Am Acad Dermatol; 49: 897–899. 
- Chandran V, Raychaudhuri SP. (2010) Geoepidemiology and environmental factors of 
psoriasis and psoriatic arthritis. J Autoimmun; 34: J314-21.  
- Clark RA. et al. (2006) The vast majority of CLA+ T cells are resident in normal skin. J. 
Immunol; 176, 4431–4439. 
- Costanzo A, Spallone G, Talamonti M et al. (2011) New developments in the 
pharmacogenetics of psoriasis: HLACw6 as a marker for the treatment of psoriasis with 
biological therapies. Adv Psoriasis Inflam Skin Dis; 1:125-30. 
- Cuchacovich M, Ferreira L, Aliste M et al. (2004) TNF-α levels and influence of -308 
TNF-α promoter polymorphism on the responsiveness to infliximab in patients with 
rheumatoid arthritis. Scand J Rheumatol 2004; 33: 228-32. 
- Cuchacovich M, Soto L, Edwardes M et al. (2006) TNF-α -308 G/G promoter 
polymorphism and TNF-α levels correlate with a better response to adalimumab in 
patients with rheumatoid arthritis. Scand J Rheumatol; 35: 435-40. 
- Gallo E, Cabaleiro T, Roman M et al. (2013) The relationship between TNFα promoter 
and IL12B/IL23R genes polymorphism and the efficacy of anti-TNFα therapy in psoriasis: 
a case-control study. Br J Dermatol; 169:819-829. 
- Elder JT, Nair RP, Guo SW, et al. (1994). The genetics of psoriasis. Arch Dermatol.; 
130:216–24. 
- Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. 
Executive summary of the third report of the national cholesterol education program 
(NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in 
adults (Adult treatment Panel III). JAMA 2001; 285:2486-97.  
- Finlay AY, Khan GK. (1994) Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19: 210–216. 
- Gisondi P, Dalle Dedove C, Girolomoni G (2014) Efficacy and safety of secukinumab in 
chronic plaque psoriasis and psoriatic arthritis. Dermatol Ther; on line. 
- Langley RG, Boni MD, Elewski E et al. (2014) Secukinumab in plaque psoriasis – results 
of two phase three trials. NEJM; 371:326-338. 
- Leonardi CL, Kimball AB, Papp KA et al. (2008) Efficacy and safety of ustekinumab, a 
human interleukin-12/23 monoclonal antibody in patients with psoriasis: 76 weeks results 
from a randomised, double blind, placebo-controlled trial (PHOENIX 1). Lancet; 
37(9625):1665-74. 

Novartis 
Confidential 
Page 62 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
- Lew W, Bowcock AM., Krueger JG. (2004) Psoriasis vulgaris: cutaneous lymphoid tissue 
supports T-cell activation and ‘Type 1’ inflammatory gene expression. Trends Immunol; 
25, 295–305.  
- Lewis V, Finlay AY (2004) 10 years experience of the Dermatology Life Quality Index 
(DLQI). J Invest Dermatol Symp Proc; 9: 169– 180. 
- Liu Y, Helms C, Liao W et al. (2008) A genoma-wide association study of psoriasis and 
psoriatic arthritis identifies new diseases loci. PLoS Genet; 4:e1000041. 
- Lowes M., Bowcock AM., Krueger JG.1 (2007) Pathogenesis and therapy of psoriasis. 
NATURE; Vol 445|22 February. 
- Nair RP, Duffin KC, Helms C et al. (2009) Genoma-wide scan reveals association of 
psoriasis with IL23 and NF-kB pathways. Nat Genet; 41: 199-204. 
- Nestle F.O., Kaplan D.H., Barker J. (2009) Mechanisms of Disease Psoriasis. N Engl J 
Med;361:496-509. 
- Newcombe R.G. (1998) Interval estimation for the difference between independent 
proportions: comparison of eleven methods. Stat Med;17(8):857-72. 
- O’Rielly DD, Roslin NM, Beyene J et al. (2009) TNF-α -308 G/A polymorphism and 
responsiveness to TNF-α blockade therapy in moderate to severe rheumatoid arthritis:a 
sistematic review and meta-analysis. Pharmacogenomics J; 9:161-7. 
- Papp KA, Langley RG, Lebwohi M et al. (2008) Efficacy and safety of ustekinumab, a 
human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52 weeks results 
from a randomised, double blind, placebo-controlled trial (PHOENIX 2). Lancet; 371 
(9635):1675-84. 
- Parisi R, Symmons D, Griffiths C, et al. (2012) Global epidemiology of psoriasis: A 
systematic review of incidence and prevalence. J Inv Der;133:377-385. 
- Patel DD, Lee DM, Kalbinger F, Antoni C. (2013) Effect of IL17A blockade with 
Secukinumab in autoimmune diseases. Ann Rheum Dis; 72 Suppl 2: 116-23. 
- Queiro R, Tejou P, Alonso S, Coto P. (2013) Age at disease onset: a key factor for 
understanding psoriatic disease. Rheumatology; 22: online. 
- Rahman P, Elder JT. (2005) Genetic epidemiology of psoriasis and psoriatic arthritis. Ann 
Rheum Dis; 64 (Suppl 2):ii37-9 
- Richard G. B. Langley1, Steven R. et al. (2013) The 5-point Investigator’s Global 
Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in 
clinical trials J Dermatolog Treat. Dec 20. 
- Saraceno R, Mannheimer R, Chimenti S (2008) Regional distribution of psoriasis in Italy. 
J Eur Acad Dermatol Venereol 22:324–329. 
- Seitz M, Wirthmuller U, Moller B, Viliger PM. (2007) The -308 TNF-α gene 
polymorphism predicts therapeutic response to TNF-α blockers in rheumatoid arthritis and 
spondyloarthritis patients. Rheumatology; 46: 93-6. 
- Shikiar R, Bresnahan BW, Stone SP et al. (2003) Validity and reliability of patient 
reported outcomes used in psoriasis: results from two randomized clinical trials. Health 
Qual Life Outcomes; 1: 53. 

Novartis 
Confidential 
Page 63 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
- Shikiar R, Willian MK, Okun MM et al. (2006) The validity and responsiveness of three 
quality of life measures in the assessment of psoriasis patients: results of a phase II study. 
Health Qual Life Outcomes; 4: 71. 
- Simpson CR, Anderson WJA, Helms PJ et al. (2002) Coincidence of immune-mediated 
diseases driven by Th1 and Th2 subsets suggests a common aetiology. A population-based 
study using computerized general practice data. Clin Exp Allergy 32:37–42. 
- Strange A, Capon F, Spencer CC et al. (2010) A genoma wide association study identifies 
new psoriasis susceptibility loci and an interaction between HLA-C and ERAP-1. Nat 
Genet 0; 42: 985-90. 
- Stuart PE, Nair RP, Ellinghaus E et al. (2010) Genome-wide association analysis 
identifies three psoriasis susceptibility loci. Nat Genet; 42: 1000-4.  
- Talamonti M, Botti E, Galluzzo M et al. (2013) Pharmacogenetics of psoriasis: HLACw6 
but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response 
to interleukin 12/23 blocker ustekinumab. Br J Dermatol; 169: 458-463. 
- Vittinghoff E, Charles E. McCulloch. (2007) Relaxing the Rule of Ten Events per 
Variable in Logistic and Cox Regression; Am J Epidemiol;165:710–718. 
- Weisman S, Pollack CR, Gottschalk et al. (2003) Psoriasis disease severity measures. 
Comparing efficacy of treatments for severe psoriasis. Journ Dermatol Treat; 158-165. 
 
 
 
 

Novartis 
Confidential 
Page 64 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
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. No specific action is pre-defined within this protocol to respond to specific 
abnormal laboratory values, as it will be decided by the investigator/qualified site staff 
whether and 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 
ALT (SGPT): 
> 3 x Upper Limit of Normal (ULN) 
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) 
Blood Pressure and Heart Rate 
Normal blood pressure will be defined as a systolic pressure of 90 to <120 mmHg, and a 
diastolic blood pressure of 60 to <80 mmHg. Notable blood pressure will be hypertension 
(systolic blood pressure of ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg) or 
hypotension (systolic blood pressure of <90 mmHg and/or a diastolic blood pressure of <60 
mmHg). A blood pressure indicative of prehypertension (systolic blood pressure of 120 to 

Novartis 
Confidential 
Page 65 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
<140 mmHg and/or diastolic blood pressure of 80 to <90 mmHg) will not be regarded as 
notable. 
A normal pulse rate will be defined as a rate of 60 to 100 beats per minute (bpm). Notable 
pulse rates are a rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia). Whether 
action needs to be taken to address notable vital signs will be decided by the investigator, 
taking into account the overall status of the patient. No specific action is foreseen as part of 
the study protocol. 

Novartis 
Confidential 
Page 66 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
14 
Appendix 2: Liver event definitions and follow-up 
requirements 
Table 14-1: Liver Event Definitions 
 
Definition/ threshold 
Adverse event of special 
interest 
 
Laboratory values 
ALT or AST > 3 x ULN 
 
ALP > 2 x ULN 
 
TBL > 1.5 x ULN 
Medically significant event 
(SAE) 
 
Laboratory values 
ALT or AST > 5 x ULN (with or without TBL > 2 x ULN [mainly 
conjugated fraction]) 
 
ALP > 5 x ULN (with or without TBL > 2 x ULN [mainly conjugated 
fraction]) 
 
TBL > 3 x ULN 
 
Potential Hy’s Law cases (defined as ALT/AST > 3 x ULN and TBL 
> 2 x ULN [mainly conjugated fraction] without notable increase in 
ALP to > 2 x ULN) 
Adverse events 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 x ULN accompanied by general malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any event that links to a preferred term (PT) in the MedDRA 
dictionary falling under the SMQ sub-module “Drug-related hepatic 
disorders – severe events only”* or any “Hy’s law case” PT 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 
 
 

Novartis 
Confidential 
Page 67 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Table 14-2: Liver Event Follow Up Requirements 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
Potential Hy’s Law 
casea 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
 
ALT or AST 
> 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 5 to ≤ 8 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 x ULN 
accompanied by 
symptomsb 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
> 3 to ≤ 5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
week 
If elevation persists, establish 
causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 3 x ULN  
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
ALP (isolated) 
> 5 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, report to 
Novartis as an SAE 
Establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
> 2 to ≤5 x ULN  
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Investigator & Novartis 
Repeat LFT once or twice in the 
weekIf elevation persists, 
establish causality 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 2 x ULN  
(patient is 
N/A 
Repeat LFT at next visit 
 

Novartis 
Confidential 
Page 68 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
Criteria 
Event type 
Actions required 
Follow-up monitoring 
asymptomatic) 
TBL (isolated) 
> 3 x ULN 
Medically 
significant 
Repeat LFT within 48 hours 
If elevation persists, discontinue 
the study drug immediately 
Hospitalize if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 3 x ULN 
(patient is 
asymptomatic) 
AESI 
Central laboratory to report to 
Novartis 
Repeat LFT once or twice in the 
week. If elevation persists, 
establish causality 
investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
≤ 1.5 x ULN 
(patient is 
asymptomatic) 
N/A 
Repeat LFT at next visit 
 
Preferred terms 
Jaundice 
Medically 
significant 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Report to Novartis as an SAE 
Establish causality 
ALT, AST, TBL, Alb, PT, 
ALP and γGT until 
resolutionc (frequency at 
investigator discretion) 
“Drug-related 
hepatic 
disorders - severe 
events only” SMQ 
AE 
Medically 
significant 
Discontinue the study drug  
hospitalization if clinically 
appropriate 
Report to Novartis as an SAE 
Establish causality 
Investigator discretion 
a Elevated ALT/AST > 3 x ULN and TBL > 2 x ULN but with no notable increase in ALP to > 2 x ULN 
b General malaise, fatigue, abdominal pain, nausea, or vomiting, rash with eosinophilia 
c 
Resolution is defined as an outcome of one of the following: return to baseline values, stable 
values at three subsequent monitoring visits at least 2 weeks apart, remain at elevated level after a 
maximum of 6 months, liver transplantation, and death. 
 
 
 

Novartis 
Confidential 
Page 69 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
15 
Appendix 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 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Trunk 
(T)‡ 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Upper 
limbs (U) 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Lower 
limbs (L)§ 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
* Percentage (not score) of body region (not whole body) affected will be entered in the eCRF 
† Neck is assessed as part of the Head (H) body region. 
‡ Axillae and groin are assessed as part of the Trunk (T) body region. 
§ Buttocks are assessed as part of the Lower limbs (L) body region. 
 
 
 

Novartis 
Confidential 
Page 70 
Amended Clinical Trial Protocol Version No. 03 (TC) 
Protocol No. CAIN457AIT01 
16 
Appendix 4: 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 
Very 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.