Conditions: Moderate to Severe Plaque-type Psoriasis
Keywords: Psoriasis, inflammatory skin disease scaly patches secukinumab (AIN457) Psoriasis Area and Severity Index (PASI) Investigator Global Assessment (IGA) mod 2011
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1147
Healthy volunteers: no

Brief summary:
This was an extension study of secukinumab prefilled syringes in subjects with moderate to severe chronic plaque-type psoriasis completing preceding psoriasis phase III studies with secukinumab. Subjects on secukinumab at the end of treatment period in phase III studies (e.g., ongoing CAIN457A2302 and CAIN457A2303 and potentially other secukinumab phase III studies) were eligible to join this extension study. This extension study was planned to collect an additional 2 years of long-term efficacy, safety, and tolerability data of secukinumab in either continuous or interrupted therapy (randomized withdrawal period) in subjects showing at least partial response to secukinumab and completing treatment period on secukinumab in previous phase III studies. In this extension study, the prefilled syringe (PFS) liquid formulation of secukinumab were used.

Detailed description:

Arms:
arm 1: PASI 75 responders participated in "randomized withdrawal". Subjects who were PASI 75 responders at Week 52 visit of the core studies (e.g.CAIN457A2302 or CAIN457A2303) and have been on secukinumab s.c. 150 mg or 300 mg in core studies were randomized to continue same s.c. doses of secukinumab in PFS or receive placebo every 4 weeks up to Week 152 or until relapse. Participants on first full relapse received loading dose followed by routine dosing with secukinumab s.c. 150 mg or 300 mg regimen. arm 2: Partial responders were not randomized. Subjects who were partial responders at Week 52 visit in core studies (e.g.CAIN457A2302 or CAIN457A2303) and have been on secukinumab s.c. 150 mg or 300 mg in core studies did not participate in the randomized withdrawal. These subjects continued same treatment s.c. dose in PFS (secukinumab s.c. 150 mg or 300 mg) as they were receiving at the time of completing the maintenance period (Week 52) in the core studies.

Interventions: intervention 1: Secukinumab (AIN457) intervention 2: Placebo
Intervention descriptions: intervention 1: Secukinumab is a new type of psoriasis medication called a human monoclonal antibody. Monoclonal antibodies are proteins that recognize and bind to unique proteins that your body produces. Secukinumab binds and reduces the activity of a cytokine (a "messenger" protein in the body) called Interleukin 17 (IL-17). IL-17 is believed to be partly responsible for inflammation (pain, swelling, redness). Researchers believe that IL-17 causes symptoms of plaque-type psoriasis like plaques and scales. A product that targets IL-17 therefore may help to relieve these symptoms and conditions. intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Clinical Development 
Secukinumab (AIN457) 
Clinical Trial Protocol for Study CAIN457A2302E1 / NCT01544595
A multicenter, double-blind, randomized withdrawal 
extension study of subcutaneous secukinumab in prefilled 
syringes to demonstrate long-term efficacy, safety and 
tolerability up to 4 years in subjects with moderate to 
severe chronic plaque-type psoriasis completing preceding 
psoriasis phase III studies with secukinumab 
Authors: 
 
 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2012-000533-39 
Version number: 
v03 Clean 
Development phase: 
III 
Release date: 
29-Apr-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 3 ............................................................................................................................. 9 
Amendment 2, 09-Sep-2014 ..................................................................................................... 10 
Amendment 1, 08-April-2014 .................................................................................................. 11 
Protocol synopsis ............................................................................................................... 13 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.2 
Purpose .................................................................................................................. 21 
2 
Study objectives ................................................................................................................. 22 
2.1 
Primary objective ................................................................................................... 22 
2.2 
Secondary objectives ............................................................................................. 22 
2.3 
Exploratory objectives ........................................................................................... 24 
3 
Investigational plan ........................................................................................................... 25 
3.1 
Study design........................................................................................................... 25 
3.2 
Rationale of study design ....................................................................................... 31 
3.3 
Rationale of dose/regimen, duration of treatment ................................................. 33 
3.4 
Rationale for choice of comparator ....................................................................... 35 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 35 
3.6 
Risks and benefits .................................................................................................. 35 
4 
Population .......................................................................................................................... 36 
4.1 
Inclusion criteria .................................................................................................... 36 
4.2 
Exclusion criteria ................................................................................................... 36 
5 
Treatment ........................................................................................................................... 38 
5.1 
Protocol requested treatment ................................................................................. 38 
5.1.1 
Investigational treatment ....................................................................... 38 
5.1.2 
Additional study treatment .................................................................... 38 
5.2 
Treatment groups ................................................................................................... 38 
5.3 
Treatment assignment, randomization ................................................................... 39 
5.4 
Treatment blinding ................................................................................................. 41 
5.5 
Treating the subject ................................................................................................ 41 
5.5.1 
Subject numbering ................................................................................ 41 


Novartis 
Confidential 
Page 3 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
5.5.2 
Dispensing the investigational treatment .............................................. 42 
5.5.3 
Storage of investigational treatment ...................................................... 42 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 43 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 44 
5.5.6 
Rescue medication ................................................................................ 45 
5.5.7 
Concomitant treatment .......................................................................... 45 
5.5.8 
Prohibited Treatment ............................................................................. 45 
5.5.9 
Discontinuation of study treatment and premature subject 
withdrawal ............................................................................................. 46 
5.5.10 
Emergency unblinding of treatment assignment ................................... 48 
5.5.11 
Study completion and post-study treatment .......................................... 48 
5.5.12 
Early study termination ......................................................................... 49 
6 
Visit schedule and assessments ......................................................................................... 49 
6.1 
Information to be collected on screening failures .................................................. 58 
6.2 
Subject demographics/other baseline characteristics ............................................. 58 
6.2.1 
Subject demographics ........................................................................... 58 
6.2.2 
Other baseline characteristics ................................................................ 58 
6.3 
Treatment exposure and compliance ..................................................................... 58 
6.4 
Efficacy .................................................................................................................. 59 
6.4.1 
Investigator’s global assessment (IGA mod 2011) ............................... 59 
6.4.2 
Assessment of psoriasis area and severity index (PASI) ...................... 59 
6.4.3 
Assessment of rebound ......................................................................... 61 
6.4.4 
Appropriateness of efficacy assessments .............................................. 62 
6.5 
Safety ..................................................................................................................... 62 
6.5.1 
Physical examination ............................................................................ 62 
6.5.2 
Vital signs.............................................................................................. 63 
6.5.3 
Height and weight ................................................................................. 63 
6.5.4 
Laboratory evaluations .......................................................................... 63 
6.5.5 
Electrocardiogram (ECG) ..................................................................... 65 
6.5.6 
Pregnancy and assessments of fertility ................................................. 65 
6.5.7 
Appropriateness of safety measurements .............................................. 65 
6.6 
Other assessments .................................................................................................. 65 
6.6.1 
Waist circumference and hip circumference ......................................... 66 
6.6.2 
Fasting laboratory evaluations .............................................................. 66 
6.6.3 
Resource utilization ............................................................................... 67 
6.6.4 
Health-related Quality of Life (HRQoL) .............................................. 67 


Novartis 
Confidential 
Page 4 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.6.5 
Pharmacokinetics .................................................................................. 69 
 
 70 
6.6.7 
Other biomarkers ................................................................................... 70 
6.6.8 
Prospective suicidality assessment ........................................................ 70 
7 
Safety monitoring .............................................................................................................. 70 
7.1 
Adverse events ....................................................................................................... 70 
7.2 
Serious adverse events ........................................................................................... 72 
7.3 
Pregnancy reporting ............................................................................................... 73 
7.4 
Data Monitoring Committee .................................................................................. 74 
8 
Data review and database management ............................................................................. 74 
8.1 
Site monitoring ...................................................................................................... 74 
8.2 
Data collection ....................................................................................................... 74 
8.3 
Database management and quality control ............................................................ 74 
9 
Data analysis ...................................................................................................................... 75 
9.1 
Analysis sets .......................................................................................................... 76 
9.2 
Subject demographics and other baseline characteristics ...................................... 76 
9.3 
Treatments ............................................................................................................. 77 
9.4 
Analysis of the primary variable ............................................................................ 77 
9.4.1 
Variable ................................................................................................. 77 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 78 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 79 
9.4.4 
Supportive analyses ............................................................................... 80 
9.5 
Analysis of secondary variables ............................................................................ 80 
9.5.1 
Efficacy variables .................................................................................. 80 
9.5.2 
Safety variables ..................................................................................... 83 
9.5.3 
Health-related Quality of Life (HRQoL) .............................................. 85 
9.5.4 
Pharmacokinetics .................................................................................. 86 
 
 86 
9.5.6 
Biomarkers ............................................................................................ 86 
 
. 86 
9.6 
Interim analyses ..................................................................................................... 86 
9.7 
Sample size calculation .......................................................................................... 87 
10 Ethical considerations ........................................................................................................ 87 
10.1 
Regulatory and ethical compliance ........................................................................ 87 
10.2 
Informed consent procedures ................................................................................. 87 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 88 


Novartis 
Confidential 
Page 5 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
10.4 
Publication of study protocol and results............................................................... 88 
11 Protocol adherence ............................................................................................................ 88 
11.1 
Protocol Amendments ........................................................................................... 89 
12 References ......................................................................................................................... 89 
13 Appendices ........................................................................................................................ 91 
13.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 91 
13.2 
Appendix 2: Blood collection log for pharmacokinetics (PK) and 
immunogenicity (IG) ............................................................................................. 92 
13.3 
Appendix 3: Pharmacokinetics (PK) and immunogenicity (IG) sample 
labeling information ............................................................................................... 94 
13.3.1 
PK sample handling .............................................................................. 94 
13.3.2 
IG sample handling ............................................................................... 94 
 
List of tables 
Table 3-1 
Loading dose regimen at time of first full relapse* and treatment 
thereafter (treatment period) between Week 52 and Week 156 ............ 29 
Table 5-1 
Prohibited treatment .............................................................................. 45 
Table 6-1 
Assessment schedule ............................................................................. 51 
Table 6-2 
The IGA mod 2011 rating scale ............................................................ 59 
Table 6-3 
The PASI scoring system ...................................................................... 60 
Table 13-1 
Blood collection log for PK .................................................................. 92 
Table 13-2 
Blood collection log for IG ................................................................... 93 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 25 
Figure 3-2 
Model-based prediction of % PASI 75 responders and % of 
subjects relapsing during a period of 6 months after either 
continuous treatment or of withdrawal (based on responders at 
Week 52) ............................................................................................... 34 
Figure 3-3 
Observed loss of PASI 75 response during “fixed interval” 
maintenance treatment of study CAIN457A2211 ................................. 34 
Figure 9-1 
Testing strategy ..................................................................................... 79 
 


Novartis 
Confidential 
Page 6 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC  
anatomical therapeutic classification 
CHMP 
the European Union Committee for Medicinal Products for Human Use 
CPO 
country pharma organization 
CRF 
case report/record form (paper or electronic [e]) 
CRO 
contract research organization 
CS 
corticosteroid (s) 
CSR 
clinical study report 
DS&E 
Drug Safety & Epidemiology 
DLQI 
Dermatology Life Quality Index© 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
EDC 
electronic data capturing 
EQ-5D 
EuroQOL 5-Dimension© Health Questionnaire 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
HAQ 
Health Assessment Questionnaire© 
HAQ-DI 
Health Assessment Questionnaire© – Disability Index  
HDL 
high density lipoprotein 
HRQoL 
health-related quality of life 
IA&R 
Integrated Analytics & Reporting 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
ICF 
informed consent form 
IGA 
investigator’s global assessment 
IGA mod 2011 Novartis investigator’s global assessment modified 2011 
IIS 
Integrated Information Sciences 


Novartis 
Confidential 
Page 7 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
IG 
immunogenicity  
IL 
interleukin 
IRB 
institutional review board 
IRT 
interactive response technology 
IVRS 
interactive voice response system 
MedDRA  
Medical Dictionary for Regulatory Activities 
OC/RDC 
oracle clinical/remote data capturing 
PASI  
Psoriasis Area and Severity Index 
PD  
pharmacodynamic(s) 
PFS 
prefilled syringe 
PK 
pharmacokinetic (s) 
PMDA 
Pharmaceutical and Medical Devices Agency (Japan) 
PsA 
psoriatic arthritis 
PUVA 
psoralen + UVA treatment 
REB 
research ethics board 
s.c. 
subcutaneous 
SAE 
serious adverse event 
VAS 
visual analog scale 


Novartis 
Confidential 
Page 8 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Glossary of terms 
 
Term 
Definition 
Assessment 
A procedure used to generate data required by the study 
Control treatment 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug. 
Core studies 
Refers to the secukinumab phase III studies (e.g., CAIN457A2302 or 
CAIN457A2303 and other secukinumab phase III studies) from which 
subjects meeting the inclusion/exclusion criteria will potentially enter the 
extension study CAIN457A2302E1 
Enrollment 
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol). 
Epoch  
The planned stage of the subjects’ participation in the study. Each epoch 
serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after 
treatment has ended. 
Investigational treatment 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT system 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
Premature subject withdrawal 
Point/time when the subject exits from the study prior to the planned 
completion of all study treatment administration and assessments; at 
this time all study treatment administration is discontinued and no further 
assessments are planned 
Randomization number 
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment 
Stop study participation 
Point/time at which the subject came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Any treatment administered to the subject as part of the required study 
procedures; includes investigational treatment and any control 
treatments 
Study treatment discontinuation 
Point/time when subject permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature subject 
withdrawal 
Subject Number  
A number assigned to each subject who enrolls in the study. When 
combined with the site number, a unique identifier is created for each 
subject in the study. 
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 
Amendment Protocol v03 Clean 
Protocol No. CAIN457A2302E1 
Amendment 3 
Amendment rationale 
 
 
 
 
 
 
 
 
 
Subjects who complete treatment period and follow-up period are evaluated for 4 years 
regarding respective adverse events.  However, patient who prematurely discontinue treatment 
are evaluated for less than 4 years. 
Therefore, this amendment extends the evaluation of subjects who prematurely discontinue 
treatment regarding respective adverse events and concomitant medications in order to achieve 
a 4 year evaluation period. Evaluation of subjects should continue when achievable even if 
treatment is not continued for the duration. All subjects who prematurely discontinue treatment 
should complete all assessment of Week 260 (end of treatment visit) and of the follow-up period 
visits (Weeks 264 and 268). Subsequently, adverse events and use of concomitant medication 
will be evaluated by the investigator through telephone calls every 3 months for a duration of 4 
years from the time when subject has been enrolled into CAIN457A2302E1 study. If deemed 
necessary by the investigator unplanned assessments at site might be scheduled during this time. 
In addition, the study will NOT be terminated in selected countries where the drug is 
commercially available. 
Changes to the protocol 
The protocol introduces a follow-up 2 period to assess adverse events and concomitant 
mediations through telephone calls for all subjects who have prematurely discontinued 
treatment. 
Protocol Synopsis, Section 3.1, Figure 3-1, Section 6 and Table 6-1 were updated to introduce 
follow-up 2 period 
Section 3.5 was updated to specify the impact of follow-up 2 period on final database lock. 
Section 5.5.9 was updated to specify that subjects who prematurely discontinue treatment 
should enter follow-up 2 period  after completion of follow-up period assessments 
Section 5.5.10 was updated to reflect that subjects who are prematurely unblinded and 
discontinued from treatment should also enter follow-up 2 period 
Section 5.5.12 was updated to reflect that the study will NOT be terminated in selected countries 
where the drug is commercially available. 


Novartis 
Confidential 
Page 10 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Section 7.1 was updated to reflect that AE evaluation is done at each telephone call during 
follow-up 2 period as well. 
Section 7.2 was updated to reflect that SAE reporting is extended for subjects who enter follow-
up 2 period 
Section 6.5.4 and Table 6-1 were updated to add Amylase and Lipase to the Chemistry analysis 
panel to collect additional safety information 
 
Section 9.2 was updated to reflect that the test of baseline balance is not considered as 
appropriate use of significance test and may cause misinterpretation of the data. 
Section 9.5.2 was updated to specify data collection within the follow-up 2 period. Other minor 
corrections, clarifications, and editing changes of the protocol text were made in various 
sections 
 
All changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  The changes herein affect the Informed Consent, and sites are required to 
update and submit for approval a revised Informed Consent that takes into account the changes 
described in this amended protocol. 
Amendment 2, 09-Sep-2014 
Amendment rationale  
The purpose of this amendment is to clarify the wording for countries not selected for early trial 
termination when the drug is commercially available, this study will continue up to the end of 
additional 104 weeks of treatment. It also clarifies a discrepancy in the Assessment Schedule 
that PK samples at Week 140 are collected for all subjects and at Week 144 in case of relapse. 
This is consistent with Appendix 2. 
Changes to the protocol 
These changes were made to the protocol: 
• Section 5.5.12 was updated to reflect the clarification to early study termination. 
• Table 6-1 included a correction that PK samples are collected for all subjects at Week 
140 and at Week 144 in case of relapse.   
At the time of this amendment, recruitment is complete with 1146 patients randomized into the 
trial. It is not expected that this amendment will influence the study population or have a 
significant impact on the primary objective of the trial 


Novartis 
Confidential 
Page 11 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Amendment 1, 08-April-2014 
Amendment rationale  
The purpose of this amendment is to provide continued treatment for patients in the trial for an 
additional 104 weeks (or overall up to four years) or until the drug is commercially available in 
the market in the country of participation, whichever occurs first. This extension of treatment 
will allow for safety, tolerability, and efficacy data to be collected from the participating patients 
for a longer time period.  
All subjects will be unblinded and start open label at week 156.  Subjects on secukinumab 150 
mg may continue on 150 mg every 4 weeks or switch to 300 mg at Week 156 or any other 
regular site visit if the investigator feels the subject would benefit from the higher dose. Patients 
on 300 mg will continue on 300 mg. Patients who were on placebo during the randomized 
withdrawal period will start secukinumab 150 mg or 300 mg if the investigator decides the 
subject would benefit from the higher dose.   
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. The 
changes described in this amended protocol require IRB/IEC approval prior to implementation. 
In addition, if the changes herein affect the Informed Consent, sites are required to update and 
submit for approval a revised Informed Consent that takes into account the changes described 
in this amended protocol. 
Changes to the protocol included: 
• Synopsis was updated to reflect the changes in the main protocol text. 
• Added one study figure to describe the updated study design (Fig 3-1). 
• Section 1.1 was updated to reflect the purpose of extending the study for additional 2 
years to obtain safety data. 
• Study design (Section 3.1) was updated to include the open label period of the study and  
to allow the subjects to self-inject at home.  It will also allow the subjects receiving 150mg 
secukinumab to switch to a higher 300 mg dose of secukinumab during this period of the 
study. 
• Rationale of the study design (Section 3.2) was updated to clarify that the added open 
label period is primarily designed to collect additional safety data. 
• Section 3.5 was updated to allow possible Interim Analysis in the future if needed 
• Section 3.6 refers to Investigator Brochure for the most updated Risk/Benefit profile 
• Inclusion criteria (Section 4.1) were updated to specify the eligibility for the subjects to 
enter the extension maintenance period.  
• Treatment groups (Section 5.2) were updated to include the extension maintenance period. 
• Treatment blinding (Section 5.4) was updated to include the open label period, which is an 
unblinded study period.  
• Dispensing the investigational treatment (Section 5.5.2) describes that investigator will 
dispense via IRT, treatment packages for self-injection at home. 
• Section 5.5.4 was updated with the Home Administration instructions 


Novartis 
Confidential 
Page 12 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
• Prohibited treatment (Section 5.5.8) was updated to further clarify the use of prohibited 
concomitant medications to allow the use of antihistamines and topical corticosteroids 
• Section Discontinuation from  treatment period (Section 5.5.9) clarifies the procedures for 
patient who discontinue during the withdraw treatment /treatment period vs. the open label 
period 
• Section 5.5.12 clarifies  that the study treatment might be discontinued  in those countries  
when  the study drug becomes commercially available  
• Visit schedule (Section 6) was updated with assessments for the extension  maintenance 
period 
• PK sample stability  was clarified in Section 6.6.5 
• Section 9.6 clarifies  that additional interim analyses may be conducted  at various time 
points for publications or health authority request 


Novartis 
Confidential 
Page 13 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Protocol synopsis  
Title of study: A multicenter, double-blind, randomized withdrawal extension study of subcutaneous 
secukinumab in prefilled syringes to demonstrate long-term efficacy, safety, and tolerability up to 4 years 
in subjects with moderate to severe chronic plaque-type psoriasis completing preceding psoriasis phase 
III studies with secukinumab. 
Purpose and rationale: This extension study (CAIN457A2302E1) is planned to collect an additional  
four years of long-term efficacy, safety, and tolerability data of secukinumab in either continuous or 
interrupted therapy (randomized withdrawal period) in subjects completing either one of the two phase 
III studies CAIN457A2302 or CAIN457A2303 (and potentially other secukinumab phase III studies) and 
showing at least partial response to secukinumab at Week 52 of the core study . 
An interim analysis on safety data only at time of submission and a primary endpoint analysis (PEA) up 
to Week 68 will be conducted. The data collected in this study up to the time of the interim analysis may 
be part of the submission package. The data collected beyond the time of the interim analysis will deliver 
important long-term information on the effect of long-term treatment of chronic plaque-type psoriasis 
with secukinumab. Additional interim analyses may be conducted  at various time points for publications 
or health authority requests. 
The double-blind randomized withdrawal period will allow assessing whether continuation of treatment 
with secukinumab is of benefit to subjects after having been treated with secukinumab for up to 52 weeks 
in the preceding phase III studies, compared to stopping treatment with secukinumab. In addition, this 
treatment period will deliver important information on the effect of stopping treatment with secukinumab, 
including time to relapse (i.e., loss of ≥50% of previous gain in PASI reduction) and frequency of 
rebounds, and therefore addresses the needs brought forward by Health Authorities. 
Objectives:  
Primary objective 
To demonstrate the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to severe 
chronic plaque-type psoriasis, who were PASI 75 responders at Week 52 of the core study, with respect 
to loss of PASI 75 up to Week 68, compared to placebo. 
Secondary objectives  
• 
To assess the efficacy of secukinumab 150 mg or 300 mg with respect to PASI 50/75/90/100 
response and IGA 0 or 1 response, compared to placebo over time in subjects who were 
PASI 75 responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg with respect to PASI score and 
IGA mod 2011 score, compared to placebo over time in subjects who were PASI 75 
responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
• 
To assess time to PASI 75 response for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to loss of IGA 0 or 1 response, compared to 
placebo in subjects who were PASI 75 responders and IGA 0 or 1 responders at Week 
52. 
• 
To assess time to IGA 0 or 1 response for subjects who were IGA 0 or 1 responders at re-
randomization, and who lost IGA 0 or 1 response during randomized withdrawal, and who 
were re-treated after relapse with secukinumab 150 mg or 300 mg. 
• 
To assess the clinical safety of secukinumab 150 mg or 300 mg as assessed by vital signs, 
clinical laboratory values, electrocardiograms (ECGs), and adverse events (AEs) monitoring, 


Novartis 
Confidential 
Page 14 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
compared to placebo in subjects who were PASI 75 responders at Week 52, in subjects who 
were re-treated after relapse with secukinumab 150 mg or 300 mg, and in subjects who were 
partial responders at Week 52. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to changes in Dermatology Life Quality 
Index© (DLQI©), compared to placebo over time in subjects who were PASI 75 responders at 
Week 52, over time for subjects who were re-treated after relapse with secukinumab 150 mg 
or 300 mg, and over time in subjects who were partial responders at Week 52. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to DLQI 0 or 1 achievement, compared to 
placebo over time in subjects who were PASI 75 responders at Week 52, over time for 
subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg, and over 
time in subjects who were partial responders at Week 52. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to EuroQOL 5-Dimension© Health 
Questionnaire (EQ-5D©) score, compared to placebo over time in subjects who were PASI 75 
responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
• 
To investigate the effects of treatment with secukinumab 150 mg or 300 mg on the 
occurrence of rebound following cessation of therapy, in subjects who were PASI 75 
responders at Week 52, for subjects who were re-treated after relapse with secukinumab 150 
mg or 300 mg, and in subjects who were partial responders at Week 52. 
• 
To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to relapse, compared to placebo in 
subjects who were PASI 75 responders at Week 52.  
• 
To investigate the development of immunogenicity (IG) against secukinumab over time. 
Exploratory objectives 
• 
 
  
• 
 
 
  
• 
To explore the effects of treatment with secukinumab with respect to the Health Assessment 
Questionnaire©– Disability Index (HAQ©-DI) in subjects with psoriatic arthritis (PsA) at 
baseline of core study over time.  
Study design: 
CAIN457A2302E1 is a four year multicenter, double-blind, randomized withdrawal extension study of 
two ongoing phase III studies CAIN457A2302 and CAIN457A2303 and will potentially include subjects 
rolling over from other secukinumab phase III studies (preceding studies collectively referred as core 
studies). About 1,220 subjects from approximately 300 sites in studies CAIN457A2302 and 
CAIN457A2303 are rolling over to this extension study.  
In this extension study, the prefilled syringe (PFS) liquid formulation of secukinumab will be used. In 
order to maintain double-blind in this study, matching placebo is used. 
This 4 year extension study will include a 2-year double blind period (between Week 52 and Week 156), 
during which randomized withdrawal analysis will be performed, followed by an additional 2-year open 
label period (between Week 156 to Week 260). The subjects will receive the last blinded treatment at 
Week 152.  At Week 156, after performing the scheduled study assessments, the site will contact IRT 


Novartis 
Confidential 
Page 15 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
to unblind the study treatment. Therefore Week 156 is the end of blinded withdrawal treatment/treatment 
period (EoT) and the beginning of the open label period. Week 156 will be the first open label treatment. 
Subject will receive the last dose of the study drug at Week 256. Week 260 will be the end of open label 
treatment period (OL-EoT).Subjects completing the maintenance period (52 weeks) in the core studies 
(e.g., CAIN457A2302 and CAIN457A2303) will be classified based on Week 52 PASI response as PASI 
75 responders (achieving at least PASI 75) or partial responders (achieving at least PASI 50, but not 
PASI 75) or non-responders (not achieving at least a PASI 50 response). This Week 52 visit in the 
core studies is the randomization visit for CAIN457A2302E1 (extension study).  
For the subjects classified as PASI 75 responders at Week 52 the study consists of 5 or 6 
periods  
(i) screening period: is the duration between signing the informed consent form (ICF) and randomization 
registered with Interactive Response Technology (IRT). 
(ii) randomized withdrawal period: the duration of randomized withdrawal period for each subject is 
different i.e., starting from Week 52 until the subject experiences the relapse or up to Week 156.  
(iii) treatment period: A placebo subject experiencing a relapse during the withdrawal period will receive 
four doses of secukinumab s.c. at weekly intervals followed by secukinumab s.c. every four weeks. 
Subjects on secukinumab in the randomized withdrawal period who have a relapse, will be given four 
weekly doses of placebo s.c. Following the loading doses, subjects will continue on secukinumab 
treatment at 4 week intervals. Any subject, whether randomized to placebo or active treatment, will only 
be treated once with the weekly loading dose regimen. For subsequent relapses, patients will continue 
on secukinumab at 4 week intervals. Week 152 will be the last dose of the blinded treatment period. At 
Week 156 subjects will enter the open label period. The site must call IRT in order to unblind the subject 
to enter the open label period prior to performing the dosing.  
(iv) open label period: The treatment will be unblinded at Week 156 and the subjects will enter the open 
label period. During this period, the subjects will be given pre-filled syringes and instructed to perform 
self-injection at home every 4 weeks and return to the site every 12 or 16 weeks (please see Table 6-1 
Assessment schedule).  The first open label dose will be given at the site at Week 156.  Subjects 
previously randomized to receive 150 mg secukinumab may continue with 150 mg secukinumab open 
label or may switch to 300 mg s.c. at the discretion of the investigator. Subjects previously randomized 
to 300 mg secukinumab will continue with 300 mg secukinumab open label. Subjects receiving placebo 
during randomized withdrawal period will start secukinumab 150 mg or 300 mg at the discretion of the 
investigator. Any subject on 150 mg s.c. may be switched to 300 mg s.c. at the discretion of the 
investigator at a regularly scheduled visit. Note: the Week 244 visit will be the last scheduled visit at 
which the subjects will be allowed to switch to 300 mg dose. Decreasing the dose from 300 mg to 150 
mg is not allowed.  
Placebo patients who enter the open label period will be given once weekly s.c. injections of 
secukinumab for 4 consecutive weeks and then s.c. injections every 4 weeks. Patients who choose not 
to switch from placebo to secukinumab will be allowed to exit the study. For subjects, who will not enter 
the open label period, Week 156 will be the EoT visit at which no treatment will be administered. After 
completing the Week 156 EoT visit, these subjects will enter the follow up period. For all the subjects 
who enter the open label period, the last dose of the study medication will be administered at Week 256. 
Week 260 is the end of the open label treatment period (OL- EoT). 
(v) follow-up period (for all subjects): treatment free period (Week 264 to Week 268). 
(vi) follow-up 2 period: treatment free period only for patients who prematurely discontinued treatment 
All subjects who prematurely discontinue treatment should complete all assessment of Week 260 (end 
of treatment visit) and of the follow-up period visits (Weeks 264 and 268). Subsequently, adverse events 
and use of concomitant medication will be evaluated by the investigator through telephone calls every 3 
months for a duration of 4 years from the time when subject has been enrolled into CAIN457A2302E1 
study  


Novartis 
Confidential 
Page 16 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
For the subjects classified as partial responders at Week 52 the study consists of 4 or 5 
periods 
(i) screening period: is the duration between signing the informed consent form (ICF) and randomization 
registered with IRT. 
(ii) treatment period: starting from the randomization visit at Week 52 continuing through Week 156. The 
patients will receive secukinumab s.c. every 4 weeks at the dose which they were originally assigned in 
the core study. At Week 156 they will enter the open label period. For subjects who don’t enter the open 
label period, Week 156 visit is the EoT. 
 (iii) open label period: At Week 156, the subjects will be given pre-filled syringes and starting Week 160 
the subjects will be asked to perform self-injection at home every 4 weeks and return to the site every 
12 or 16 weeks (please see Table 6-1 Assessment schedule). Also, at Week 156 subjects receiving 150 
s.c. may be switched to 300 mg s.c. if the subject and the PI agree that the subject would benefit from 
the higher dosage at a regularly scheduled visit. The subjects will receive the last dose of the study 
medication at Week 256.  
(iv) follow-up period (for all subjects): treatment free period (Week 264 to Week  268). 
(v) follow-up 2 period: treatment free period only for patients who prematurely discontinued treatment 
All subjects who prematurely discontinue treatment should complete all assessment of Week 260 (end 
of treatment visit) and of the follow-up period visits (Weeks 264 and 268). Subsequently, adverse events 
and use of concomitant medication will be evaluated by the investigator through telephone calls every 3 
months for a duration of 4 years from the time when subject has been enrolled into CAIN457A2302E1 
study.  
 
 
NOTE: Partial responders DO NOT participate in the randomized withdrawal and DO NOT receive any 
loading dose even if they experience a full relapse (a loss of >50% of the maximum PASI gain compared 
to baseline of the core study). 
Subjects classified as partial responders at Week 52 of the core studies will continue the same 
treatment dose in PFS (secukinumab s.c. 150 mg or 300 mg) that they were receiving at the time of 
completing the maintenance period (Week 52) in the core study.  
In the follow-up period (Week 264 to Week 268) all subjects will visit the study site for safety and 
efficacy assessments while being off-treatment.  
In the follow-up 2 period safety will be evaluated by the investigator through telephone calls every 3 
months for a duration of 4 years from the time when subject has been enrolled into CAIN457A2302E1 
study for patients who have prematurely discontinued treatment only.  
Population: All subjects from study CAIN457A2302 or CAIN457A2303 (and potentially rolling over from 
other secukinumab phase III studies) who were randomized to and have been receiving secukinumab 
treatment during the maintenance period of the core studies (e.g., CAIN457A2302 or CAIN457A2303), 
and who completed the full study treatment period (52 weeks) in the core studies, and who have at least 
a partial response at Week 52 of the core studies, and who comply with the inclusion and exclusion 
criteria of this study, are eligible to enter into this extension study. 
Inclusion/Exclusion criteria:  
Inclusion criteria 
Subjects eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Subjects who completed the full study treatment period (52 weeks) in the core studies (e.g., 
CAIN457A2302 or CAIN457A2303), and after randomization have been receiving 


Novartis 
Confidential 
Page 17 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
secukinumab treatment during the maintenance phase of the core studies, and show at least 
a partial response (PASI 50 or better)  at Week 52 of the core studies. 
2. Written informed consent must be obtained before any assessment is performed. 
3. For inclusion in the open label period, written informed consent for protocol amendment 1 
must be obtained.  
4. For inclusion in the open label period, the subject must be deemed to benefit from the study 
drug based on the investigator's clinical judgment. 
Exclusion criteria 
Subjects fulfilling any of the following criteria are NOT eligible for inclusion in this study: 
1. A protocol deviation in the core studies which according to the investigator will prevent the 
meaningful analysis of the extension study for the individual subject 
2. Ongoing use of prohibited psoriasis or non-psoriasis treatments. Time period to use of 
prohibited treatments in the core study detailed in the Table below have to be adhered. 
 
Prohibited treatments†,‡  
Time period before randomization visit at 
Week 52 
Alefacept, briakinumab, efalizumab, ustekinumab 
6 months 
Biological immunomodulating agents other than 
above (e.g., adalimumab, etanercept, infliximab) 
12 weeks 
Other systemic immunomodulating treatments§ (e.g., 
MTX, cyclosporine A, corticosteroids§, 
cyclophosphamide) 
4 weeks 
Other systemic psoriasis treatments* (e.g., retinoids, 
fumarates) 
4 weeks 
Photochemotherapy (e.g., PUVA) 
4 weeks 
Phototherapy (e.g., UVA, UVB) 
2 weeks 
Use of topical treatment ** that is likely to impact signs 
and symptoms of  psoriasis for >14 days* (e.g., 
corticosteroids [CS], vitamin D analogues,  
pimecrolimus, retinoids, salicylvaseline, salicylic acid, 
lactic acid,  tacrolimus, tar, urea, α-hydroxy or fruit 
acids) 
2 weeks 
Live virus vaccinations during extension study 
6 weeks 
Any investigational treatment or participation in any 
interventional clinical trial during extension trial 
4 weeks or 5 half-lives (whichever Is longer) 
†If a subject inadvertently used the prohibited treatment in core study (e.g., CAIN457A2302 or 
CAIN457A2303) without undue safety risk till completion of Week 52, he/she must have completed the 
time period as defined in the table above. Subjects who have not completed an adequate time period 
(table above) will not be eligible for the current extension study.  
‡In case of undue safety risk for the subject, the subject should discontinue study treatment at the 
discretion of the investigator. If the subject received a live virus vaccination during the study, the 
subject must discontinue study treatment. 
§Inhalative CS with only a topical effect (e.g., to treat asthma) are not considered “systemic 
immunomodulating treatments” and are therefore acceptable as co-treatment. 
*There is no restriction on the use of anti-histamines or the use of corticosteroids in the eye or ear   
**Topical corticosteroid (CS) treatment, or use of other topical treatment that is likely to impact signs 
and symptoms of psoriasis, is not allowed for treatment of psoriasis, except when applied to the face, 
scalp, and/or genitoanal area for ≤14 consecutive days. Topical corticosteroid use for indications other 
than psoriasis not on an area affected with psoriasis is allowed for ≤14 consecutive days 


Novartis 
Confidential 
Page 18 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
3. Subjects not expected to benefit from participation in the extension study, as assessed by the 
subject and investigator 
4. Subjects expected to be exposed to an undue safety risk if participating in the study 
5. Current severe progressive or uncontrolled disease which in the judgment of the investigator 
renders the subject unsuitable for the study 
6. Plans for administration of live vaccines during the study period 
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test (>10 mIU/mL) 
8. Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, unwilling to use effective contraception during the study and for 16 weeks after 
stopping treatment. Effective contraception is defined as either: 
• 
Barrier method: Condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicide (where available). Spermicides alone are not a barrier method of 
contraception and should not be used alone  
The following methods are considered more effective than the barrier method and are also acceptable: 
• 
Total abstinence: When this is in line with the preferred and usual lifestyle of the subject 
(Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception) 
• 
Female sterilization: have had a surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow-up hormone level assessment  
• 
Male partner sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject  
• 
Use of established oral, injected or implanted hormonal methods of contraception, intrauterine 
device (IUD) or intrauterine system (IUS) 
NOTE: Women are considered post-menopausal and not of child bearing potential if they have had: 
• 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or  
• 
six months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL [for US only: and 
estradiol <20 pg/mL] or 
• 
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 is she considered not of child bearing potential. 
No additional exclusion criteria may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects. 
Investigational and reference therapy:  
Novartis will provide the following study treatments 
1. Investigational treatment: Secukinumab 150 mg/1 mL solution for injection is provided in PFS 
for s.c. administration. The 150 mg/1 mL solution in PFS is used for both s.c.150 mg dose (1 
syringe) and s.c. 300 mg dose (2 syringes). For blinding purpose the subject in 150 mg 
treatment group will also receive one syringe of placebo secukinumab 150 mg. 
2. Reference therapy: Placebo secukinumab 150 mg/1 mL solution for injection is provided in 
PFS for s.c. administration. It contains a mixture of inactive excipients, matching the 
composition of secukinumab 150 mg. 


Novartis 
Confidential 
Page 19 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Secukinumab 150 mg/1 mL and placebo secukinumab 150 mg/1 mL is labeled as AIN457 150 mg/1 mL/ 
Placebo. 
Efficacy assessments: All efficacy assessments should be performed prior to administration of study 
treatment. The following order should be applied when performing the efficacy assessments during study 
visits: 
• 
Investigator’s Global Assessment (IGA mod 2011; scale from 0 – 4) 
• 
Psoriasis Area and Severity Index (PASI; score from 0 – 72) 
• 
Rebound assessment  
Other assessments:  
• 
Safety assessments: 
• 
Evaluation of all AEs and SAEs including injection site reactions, physical examination; 
vital signs; weight and height, laboratory assessments including hematology, clinical 
chemistry, local urinalysis, immunogenicity (IG) (assessment of anti-secukinumab 
antibody development), ECG ,pregnancy and assessments of fertility 
• 
 
• 
Fasting laboratory evaluations; plasma glucose, lipid panel 
• 
PK 
• 
Health-related Quality of life (HRQoL): The impact of psoriasis on various aspects of subject’s 
health-related quality of life will be assessed by the following validated instruments: 
• 
Dermatology Life Quality Index (DLQI©) 
• 
EuroQOL 5-Dimension© Health Status Questionnaire (EQ-5D©) 
• 
Health Assessment Questionnaire- Disability Index (HAQ©-DI) (subjects with psoriatic 
arthritis [PsA] at baseline of the core study) 
Data analysis:  
Treatment groups for analysis will include: 
• 
Subjects who were PASI 75 responders at Week 52 
• 
Secukinumab 150 mg 
• 
Secukinumab 300 mg 
• 
Placebo (secukinumab 150 mg in core studies) 
• 
Placebo (secukinumab 300 mg in core studies) 
• 
Subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg 
• 
Secukinumab 150 mg 
• 
Secukinumab 300 mg 
• 
Subjects who were partial responders at Week 52 
• 
Secukinumab 150 mg 
• 
Secukinumab 300 mg 
The following hypotheses will be tested for 52 weeks≤ t ≤68 weeks 
• 
H1: Secukinumab 150 mg is not different from placebo with respect to the cumulative rate for 
subjects who lost PASI 75 response up to Week 68 
• 
H2: Secukinumab 300 mg is not different from placebo with respect to the cumulative rate for 
subjects who lost PASI 75 response up to Week 68 
The familywise error will be set to α=2.5% (one-sided). The two hypotheses H1 (referring to 150 mg) 
and H2 (referring to 300 mg) will be tested at α/2=1.25% one-sided. In case, a null hypothesis has been 


Novartis 
Confidential 
Page 20 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
rejected for one dose, but not for the other dose, the alpha can be shifted to the other dose and the null 
hypotheses can be retested at level α=2.5% (one-sided). 
For loss of PASI 75 response, between-treatment differences will be evaluated using a log-rank test, 
stratified by geographical region and body weight stratum, to compare the survival functions between 
secukinumab treatment groups versus placebo. The hazard ratios for these comparisons for loss of 
PASI 75 response and their corresponding 95% confidence intervals will be computed using a stratified 
Cox proportional hazards regression model with treatment group, core study and baseline PASI of core 
study and baseline (at Week 52) PASI of extension study as explanatory variable and stratified by 
geographical region and body weight stratum. The primary analysis will be the log-rank test. Subjects 
who have not lost PASI 75 response up to Week 68 will be considered as censored observations. 
Separate analyses will be performed for comparison of 150 mg secukinumab with placebo and 300 mg 
secukinumab with placebo. The two placebo groups will not be pooled for this analysis. 


Novartis 
Confidential 
Page 21 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
1 
Introduction 
1.1 
Background 
CAIN457A2302E1 is an extension study to two ongoing phase III studies CAIN457A2302 and 
CAIN457A2303, and will potentially include subjects from other secukinumab phase III studies 
(preceding studies collectively referred as core studies). Study CAIN457A2302 and study 
CAIN457A2303, each, is multicenter, randomized, controlled trial to investigate the efficacy 
of secukinumab after twelve weeks of treatment, and safety, tolerability and long-term efficacy 
up to one year in subjects with moderate to severe chronic plaque-type psoriasis. Both the 
studies are planned to demonstrate superiority of secukinumab compared with placebo. In 
addition, the study CAIN457A2303 aims also to show the non-inferiority versus etanercept. 
Please refer to the protocols of the respective studies for full details. 
At the end-of-phase-II meetings with several Health Authorities (FDA, EMA, and PMDA) in 
the first quarter of 2011, it was agreed to submit data from core studies along with interim data 
from at least one extension study to show long-term efficacy, safety, and tolerability of 
secukinumab in subjects with psoriasis. This study will also provide information from a 
randomized withdrawal period for subjects who have shown a PASI 75 response to 
secukinumab at Week 52 of the core studies (e.g., CAIN457A2302 or CAIN457A2303) for 2 
years until Week 156. The long-term efficacy, safety, and tolerability data (open label) will be 
collected for an additional 2 years. The overall treatment period (core study [52 weeks] plus 
extension [268 weeks]) is 320 weeks. 
Subjects (PASI 75 responders and partial responders) randomized to and completing Week 52 
of the core studies (e.g., CAIN457A2302 or CAIN457A2303) on secukinumab treatment will 
be eligible to join this extension study, which is planned to collect up to- four  years of long-
term efficacy, safety, and tolerability data of secukinumab in either continuous or interrupted 
therapy (randomized withdrawal period). Subjects on placebo treatment or etanercept in the 
maintenance phase of the core studies, as well as subjects on secukinumab, but not showing at 
least a partial response, will not be eligible to enter this extension study.  
The study design, objectives, and other procedures of this extension study are applicable to 
other secukinumab phase III studies from which subjects meeting the inclusion/exclusion 
criteria will potentially enter the extension study CAIN457A2302E1.  
In this extension study, the prefilled syringe (PFS) liquid formulation of secukinumab will be 
used. 
1.2 
Purpose  
This extension study (CAIN457A2302E1) is planned to collect an additional four years of long-
term efficacy, safety, and tolerability data of secukinumab in either continuous or interrupted 
therapy (randomized withdrawal period) in subjects completing either one of the two phase III 
studies CAIN457A2302 or CAIN457A2303 (and potentially other secukinumab phase III 
studies) and showing at least partial response to secukinumab at Week 52 of the core study. An 
interim analysis on safety data only and a primary endpoint analysis (PEA) up to Week 68 will 
be conducted.  


Novartis 
Confidential 
Page 22 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
The data collected in this study up to the time of the interim analysis will be part of the 
submission package. The data collected beyond the time of the Week 68 interim analysis will 
deliver important  information on the effect of long-term treatment of chronic plaque-type 
psoriasis with secukinumab. Additional interim analyses may be conducted at various time 
points for publications or health authority requests. 
The two year double-blind randomized withdrawal period will allow assessing whether 
continuation of treatment with secukinumab is of benefit to subjects after having been treated 
with secukinumab for up to 52 weeks in the preceding phase III studies, compared to stopping 
treatment with secukinumab. In addition, this treatment period will deliver important 
information on the effect of stopping treatment with secukinumab, including time to relapse 
(i.e., loss of ≥50% of previous gain in PASI reduction) and frequency of rebounds, and therefore 
addresses needs brought forward by Health Authorities. The two year double–blind period of 
the study will be followed by a two year open label period. During the open label treatment 
period, subjects initially on the lower dose (150 mg) will be offered to switch to the higher dose 
(300 mg), at the discretion of the investigator. This allows all subjects in the study to receive 
the most efficacious dose of secukinumab.  
2 
Study objectives 
For study treatments and description of treatment subgroups refer Section 3.1. 
2.1 
Primary objective 
To demonstrate the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis, who were PASI 75 responders at Week 52 of the core 
study, with respect to loss of PASI 75 up to Week 68, compared to placebo.  
2.2 
Secondary objectives 
• To assess the efficacy of secukinumab 150 mg or 300 mg with respect to PASI 
50/75/90/100 response and IGA 0 or 1 response, compared to placebo over time in 
subjects who were PASI 75 responders at Week 52, over time for subjects who were re-
treated after relapse with secukinumab 150 mg or 300 mg, and over time in subjects who 
were partial responders at Week 52   
• To assess the efficacy of secukinumab 150 mg or 300 mg with respect to PASI score and 
IGA mod 2011 score, compared to placebo over time in subjects who were PASI 75 
responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52   
• To assess time to PASI 75 response for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg. 
• To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to loss of IGA 0 or 1 response, compared 


Novartis 
Confidential 
Page 23 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
to placebo in subjects who were PASI 75 responders and IGA 0 or 1 responders at 
Week 52.   
• To assess time to IGA 0 or 1 response for subjects who were IGA 0 or 1 responders at re-
randomization, and who lost IGA 0 or 1 response during randomized withdrawal, and who 
were re-treated after relapse with secukinumab 150 mg or 300 mg. 
• To assess the clinical safety of secukinumab 150 mg or 300 mg as assessed by vital signs, 
clinical laboratory values, electrocardiograms (ECGs), and adverse events (AEs) 
monitoring, compared to placebo in subjects who were PASI 75 responders at Week 52, in 
subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg, and in 
subjects who were partial responders at Week 52.   
• To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to changes in Dermatology Life Quality 
Index© (DLQI©), compared to placebo over time in subjects who were PASI 75 
responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
• To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to DLQI 0 or 1 achievement, compared 
to placebo over time in subjects who were PASI 75 responders at Week 52, over time for 
subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg, and over 
time in subjects who were partial responders at Week 52. 
• To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to EuroQOL 5-Dimension© Health 
Questionnaire (EQ-5D©) score, compared to placebo over time in subjects who were PASI 
75 responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
• To investigate the effects of treatment with secukinumab 150 mg or 300 mg on the 
occurrence of rebound following cessation of therapy, in subjects who were PASI 75 
responders at Week 52, for subjects who were re-treated after relapse with secukinumab 
150 mg or 300 mg, and in subjects who were partial responders at Week 52. 
• To assess the efficacy of secukinumab 150 mg or 300 mg in subjects with moderate to 
severe chronic plaque-type psoriasis with respect to relapse, compared to placebo in 
subjects who were PASI 75 responders at Week 52. 
• To investigate the development of immunogenicity (IG) against secukinumab over time. 


Novartis 
Confidential 
Page 24 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
2.3 
Exploratory objectives  
• 
 
  
• 
 
 
 
• To explore the effects of treatment with secukinumab with respect to the Health 
Assessment Questionnaire© – Disability Index (HAQ©-DI) in subjects with psoriatic 
arthritis (PsA) at baseline of core study over time.  


Novartis 
Confidential 
Page 25 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
3 
Investigational plan 
3.1 
Study design 
Figure 3-1 Study design 
 
 
 
PFS: prefilled syringe; Week 52 – end of maintenance period in core studies (e.g., CAIN457A2302 or 
CAIN457A2303) which is randomization (Rand*) visit for CAIN457A2302E1 (extension study); The 
screening period will be the duration between signing the informed consent form and randomization 
registered with Interactive Response Technology (IRT); s.c.: subcutaneous; Week 156 end of 
treatment period (EoT); Week 260 – open label end of treatment (OL-EoT) period; q4wk – every four 
weeks; end of follow up (EOF) 
Primary endpoint analysis (PEA) at Week 68;  PASI 75 Responders: subjects with PASI 75 at 
Week 52 of core study;  
 Partial responders: subjects with PASI 50, but not PASI 75 response at 
Week 52 of core study; first full relapse – a loss of > 50% of the maximum PASI gain compared to the 
baseline of core study  
(A) PASI 75 Responders entering randomized withdrawal period 
Subjects who were PASI 75 responders at Week 52 visit of the core studies (e.g.,CAIN457A2302 or 
CAIN457A2303) and have been on secukinumab s.c. 150 mg or 300 mg in the core studies will be 
randomized to continue same s.c. doses of secukinumab in PFS or receive placebo every 4 weeks up 
to Week 152. Randomization in each group will be 2:1 (refer protocol text for details) 
R
PR


Novartis 
Confidential 
Page 26 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
a. Secukinumab 150 mg PFS group: One s.c. injection of secukinumab 150 mg in PFS plus s.c. 
injection of placebo secukinumab 150 mg in PFS at randomization (Week 52) and thereafter every 4 
weeks up to Week 152 (or until first relapse). Subjects with first full relapse will be treated with two 
s.c. injections of placebo secukinumab 150 mg in PFS once weekly for three weeks (1 week, 2 weeks 
and 3 weeks later). After 4 weeks following relapse the routine dosing with secukinumab 150 mg 
regimen every 4 weeks dosing is continued thereafter. Subjects who enter the open label period to 
continue beyond Week 152 will receive one injection of 150 s.c. every 4 weeks. Starting Week 156, 
subjects on 150 mg s.c. will have the option to switch to 300 mg s.c.at regularly scheduled visits. 
b. Placebo secukinumab 150 mg PFS: Two s.c. injections of placebo secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks up to Week 152 (or until first relapse). Subjects 
with first full relapse will be treated with one s.c. injection of secukinumab 150 mg in PFS plus one 
s.c. injection of placebo secukinumab 150 mg in PFS once weekly for four weeks (at the visit where 
the relapse was diagnosed, 1 week, 2 weeks and 3 weeks later). After 4 weeks following relapse the 
routine dosing with secukinumab 150 mg regimen every 4 weeks dosing is continued thereafter. 
Subjects on placebo who enter the open label period to continue beyond Week 152 will be treated with 
one  injection of secukinumab 150 mg s.c. in PFS once weekly for four weeks and then one injection  
s.c. every 4 weeks. Starting Week 156, subjects on 150 mg s.c. will have the option to switch to 
300mg s.c.( two injections of 150 s.c.) at regularly scheduled visits.  
c. Secukinumab 300 mg PFS group: Two s.c. injections of secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks up to Week 152 (or until first relapse). Subjects 
with first full relapse will be treated with two s.c. injections of placebo secukinumab 150 mg in PFS 
once weekly for three weeks (1 week, 2 weeks and 3 weeks later). After 4 weeks following relapse the 
routine dosing with secukinumab 300 mg regimen every 4 weeks dosing is continued thereafter. 
Subjects who enter the open label period to continue beyond Week 152 will receive two injections of 
150 s.c. every 4 weeks. 
d. Placebo secukinumab 300 mg PFS : Two s.c. injections of placebo secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks up to Week152 (or until first relapse). Subjects 
with first full relapse will be treated with two s.c. injection of secukinumab 150 mg in PFS plus once 
weekly for four weeks (at the visit where the relapse was diagnosed, 1 week, 2 weeks and 3 weeks 
later). After 4 weeks following relapse the routine dosing with secukinumab 300 mg regimen every 4 
weeks dosing is continued thereafter. Subjects on placebo who enter the open label period to continue 
beyond Week 152  will be treated with two s.c. injections of secukinumab 150 mg in PFS once weekly 
for four weeks and then two s.c. injections of secukinumab 150 mg s.c. every 4 weeks. 
● Refer protocol text for details and for treatment at relapse.  
(B) Partial responders not entering the randomized withdrawal period 
● Subjects who were partial responders at Week 52 visit in core studies (e.g., CAIN457A2302 or 
CAIN457A2303) and have been on secukinumab s.c. 150 mg or 300 mg in core studies do not 
participate in the randomized withdrawal. These subjects will continue same treatment s.c. dose in 
PFS (secukinumab s.c. 150 mg or 300 mg) as they were receiving at the time of completing the 
maintenance period (Week 52) in the core studies. Subjects continuing beyond week 152 will be given 
open label secukinumab.  Starting Week 156, subjects on 150 mg s.c. will have the option to switch to 
300 mg s.c.at regularly scheduled visits.  
● NOTE: Subjects who are non-responders at Week 52 of the core studies (e.g., CAIN457A2302 or 
CAIN457A2303) are not eligible to enter this extension study, and will complete follow-up visits in the 
core studies. 
Follow-up 2 period: treatment free period only for patients who prematurely discontinued treatment 
 
An outline of the study design is presented in Figure 3-1, while a detailed visit and assessment 
schedule can be found in Table 6-1. The study design is applicable to other secukinumab phase 
III studies from which subjects meeting the inclusion/exclusion criteria will potentially enter 
the extension study CAIN457A2302E1. 


Novartis 
Confidential 
Page 27 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
This 4 year extension study will include a 2-year double blind period (between Week 52 and 
Week 156) during which randomized withdrawal analysis will be performed, followed by an 
additional 2-year open label period (between Week 156 to Week 260). The subjects will receive 
the last blinded treatment at Week 152. At Week 156, after performing the scheduled study 
assessments and prior to receiving the first unblinded dose of the study drug, the site will be 
asked to contact IRT to unblind the study treatment.  For subjects who will continue into the 
open label period, Week 156 will be the beginning of the open label period. The subjects who 
will not continue into the open label period Week 156 will be the end of blinded withdrawal 
treatment/treatment period (EoT) at which no study drug will be administered. During the open 
label period, subjects will receive the last dose of the study drug at Week 256. Week 260 will 
be the end of open label treatment period (OL-EoT).  
Subjects completing the maintenance period (52 weeks) in the core studies (e.g., 
CAIN457A2302 or CAIN457A2303) will be classified based on Week 52 PASI response as 
“PASI 75 responders” or “partial responders” or “non-responders”. This Week 52 visit in the 
core studies is the randomization visit for CAIN457A2302E1 (extension study).  
• PASI 75 Responders:  subjects with a PASI 75 response (subjects achieving ≥ 75% 
improvement [reduction] in PASI score compared to baseline of the core study) at Week 
52 of core study 
• Partial responders: subjects with a PASI 50 response (subjects achieving ≥ 50% 
improvement [reduction] in PASI score compared to baseline of the core study, but not 
PASI 75 response) at Week 52 of core study  
• Non-responders: not achieving at least a PASI 50 response at Week 52 of core study  
For the subjects classified as PASI 75 responders at Week 52 the study 
consists of 5 or 6 periods  
At Week 52 of the core studies subjects enrolling in the extension trial will go through a 
screening period, a randomized withdrawal period, a treatment period, a two year 
secukinumab open label period and a follow up period. 
(i) screening period: is the duration between signing the informed consent form (ICF) and 
randomization registered with interactive response technology (IRT). 
(ii) randomized withdrawal period (double blind): Subjects will be randomized to either 
secukinumab or placebo. The subjects will continue on either secukinumab or placebo until 
there is a relapse or up to Week 156.  If there is a relapse the patient will enter the treatment 
period.  
 In randomized withdrawal period (between Week 52 and Week 156), subjects in the group of 
PASI 75 responders who have been receiving secukinumab s.c. 150 mg dose during the 
maintenance period of core studies will be randomized 2:1 to continue same s.c. doses of 
secukinumab in PFS from the core studies or receive s.c. placebo secukinumab in PFS. 
Similarly, those subjects who were receiving secukinumab s.c. 300 mg dose during the 
maintenance period of core studies will be randomized 2:1 to continue same s.c. doses of 
secukinumab in PFS from the core studies or receive s.c. placebo secukinumab in PFS. 
Randomization will be stratified by geographical region and by body weight (< 90 kg or ≥90 
kg) collected at Week 52. In order to maintain double-blind in this study, matching placebo is 


Novartis 
Confidential 
Page 28 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
used. Therefore subjects classified as PASI 75 responders and entering the randomized 
withdrawal period will be randomized (as explained above) at Week 52 in either of four 
treatment groups (Figure 3-1). Subjects who were on s.c. secukinumab 150 mg in the core study 
will be randomized to (a) or (b) treatments and subjects who were on s.c. secukinumab 300 mg 
in the core study will be randomized to (c) or (d) treatments, as explained below: 
a. Secukinumab 150 mg PFS group: One s.c. injection of secukinumab 150 mg in PFS plus 
s.c. injection of placebo secukinumab 150 mg in PFS at randomization (Week 52) and 
thereafter every 4 weeks up to Week 152 (or until first full relapse). 
b. Placebo secukinumab 150 mg PFS: Two s.c. injections of placebo secukinumab 150 mg in 
PFS at randomization (Week 52) and thereafter every 4 weeks up to Week 152 (or until 
first full relapse).  
c. Secukinumab 300 mg PFS group: Two s.c. injections of secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks up to Week 152 (or until first full 
relapse).  
d. Placebo secukinumab 300 mg PFS: Two s.c. injections of placebo secukinumab 150 mg in 
PFS at randomization (Week 52) and thereafter every 4 weeks up to Week 152 (or until 
first full relapse). 
Subjects in the randomized withdrawal period experiencing a first full relapse (a loss of >50% 
of the maximum PASI gain compared to baseline of the core study) at any scheduled visit after 
Week 52 during the randomized withdrawal period, will enter the treatment period. The dose 
regimen in treatment period (loading dose and treatment thereafter) is described in Table 3-
1. 


Novartis 
Confidential 
Page 29 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Table 3-1 
Loading dose regimen at time of first full relapse* and treatment 
thereafter (treatment period) between Week 52 and Week 156 
Groups at time of randomization 
(Week 52) 
Treatment period 
Loading dose regimen at time of first full relapse* 
and treatment thereafter 
Secukinumab 150 mg PFS  
Two s.c. injections of placebo secukinumab 150 mg in 
PFS once weekly for three weeks (1 week, 2 weeks and 
3 weeks later). After 4 weeks following relapse the 
routine dosing with secukinumab 150 mg regimen every 
4 weeks dosing is continued thereafter. 
Placebo secukinumab 150 mg PFS  
One s.c. injection of secukinumab 150 mg in PFS plus 
one s.c. injection of placebo secukinumab 150 mg in PFS 
once weekly for four weeks (at the visit where the relapse 
was diagnosed, 1 week, 2 weeks and 3 weeks later). 
After 4 weeks following relapse the routine dosing with 
secukinumab 150 mg regimen every 4 weeks dosing is 
continued thereafter. 
Secukinumab 300 mg PFS  
Two s.c. injections of placebo secukinumab 150 mg in 
PFS once weekly for three weeks (1 week, 2 weeks and 
3 weeks later). After 4 weeks following relapse the 
routine dosing with secukinumab 300 mg regimen every 
4 weeks dosing is continued thereafter. 
Placebo secukinumab 300 mg PFS  
Two s.c. injection of secukinumab 150 mg in PFS plus 
once weekly for four weeks (at the visit where the relapse 
was diagnosed, 1 week, 2 weeks and 3 weeks later). 
After 4 weeks following relapse the routine dosing with 
secukinumab 300 mg regimen every 4 weeks dosing is 
continued thereafter. 
*first full relapse: (a loss of >50% of the maximum PASI gain compared to baseline of the core study)  
Those subjects experiencing a second relapse will NOT receive any loading dose regimen, 
regardless of the group they are randomized at Week 52 of the core studies. However, they 
will continue secukinumab s.c. 150 mg (one s.c. injection of secukinumab 150 mg in PFS 
with matching placebo) or 300 mg (two s.c. injections of secukinumab 150 mg) dose given 
every four weeks through Week 152 and at Week 156 they will enter the open label period.  
Subjects who do not experience first full relapse will continue the treatment to which they 
were randomized at Week 52 through Week 152 at Week 156 they will enter the open label 
period.  
(iii) treatment period (double blind):  A placebo subject experiencing a relapse during the 
withdrawal period will receive four doses of secukinumab s.c. at weekly intervals followed by 
secukinumab s.c. every four weeks.  Subjects on secukinumab in the randomized withdrawal 
period who have a relapse, will be given four weekly doses of placebo s.c.  Following the 
loading doses subjects will continue on secukinumab treatment at 4 week intervals. Any subject, 
whether randomized to placebo or active treatment, will only be treated once with the weekly 
loading dose regimen. For subsequent relapses patients will continue on secukinumab at 4 week 
intervals. At Week 152 subjects will receive the last treatment of the blinded treatment period. 
Week 156 will be the end of the treatment period (EoT). 


Novartis 
Confidential 
Page 30 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
(iv)  open label period:  The treatment will be unblinded at Week 156 and the subjects will  enter 
the open label period. During this period, the subjects will be given pre-filled syringes and 
instructed to perform self-injection at home every 4 weeks and return to the site every 12 or 16 
weeks (see Table 6-1 Assessment schedule). The first open label dose will be given at the site 
at Week 156. Subjects on 150mg s.c may continue on 150mg s.c. and subjects on 300 mg s.c. 
will continue on 300 mg s.c secukinumab. Subjects who were on placebo during the randomized 
withdrawal period will start on secukinumab 150 mg s.c. or 300 mg s.c. if the investigator 
decides the subject would benefit from the higher dose. Placebo subjects who enter the open 
label period will be given once weekly s.c. injections of secukinumab for 4 consecutive weeks 
and then s.c. injections every 4 weeks. Any subject starting on secukinumab 150 mg may 
continue on 150 mg every 4 weeks or switch to 300 mg at Week 156 or any other regular site 
visit if the investigator decides the subject would benefit from the higher dose. Note: the Week 
244 visit will be the last scheduled visit at which the subjects will be allowed to switch to 300mg 
dose. Decreasing the dose from 300 mg to 150 mg is not allowed. For all subjects, who will not 
enter the open label period, Week 156 will be the EoT visit at which no treatment will be 
administered. After completing the Week 156 EoT visit, these subjects will enter the follow up 
period. For all subjects who enter the open label period, the last dose of the study medication 
will be given at Week 256. Week 260 is the end open label treatment period. 
(v) follow-up period (for all subjects): treatment free period (Week 264 to Week 268). 
(vi) follow-up 2 period: treatment free period for patients who prematurely discontinued 
treatment. All subjects who prematurely discontinue treatment should complete all assessment 
of Week 260 (end of treatment visit) and of the follow-up period visits (Weeks 264 and 268). 
Subsequently, adverse events and use of concomitant medication will be evaluated by the 
investigator through telephone calls every 3 months for a duration of 4 years from the time 
when subject has been enrolled into CAIN457A2302E1 study  
 
For the subjects classified as partial responders at Week 52 the study consists 
of 4 or 5 periods 
(i) screening period: is the duration between signing the informed consent form (ICF) and 
randomization registered with IRT. 
(ii) treatment period (double blind): starting from the randomization visit at Week 52 continuing 
through Week 156 ,   subjects in the group of partial responders who have been receiving s.c. 
secukinumab150 mg or 300 mg dose during the maintenance period of core studies will 
continue the same treatment dose in PFS (secukinumab s.c. 150 mg or 300 mg) that they were 
receiving at the time of completing the maintenance period (Week 52) in the core study (Figure 
3-1), i.e., a subject continuing secukinumab s.c. 150 mg will use one s.c. injection of 
secukinumab 150 mg in PFS plus s.c. injection of placebo secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks until Week 152; and a subject continuing 
secukinumab s.c. 300 mg will use two s.c. injections of secukinumab 150 mg in PFS at 
randomization (Week 52) and thereafter every 4 weeks until Week 152. At Week 152 subjects 
will receive the last treatment of the blinded treatment period. Week 156 will be the end of the 
treatment period (EoT). 


Novartis 
Confidential 
Page 31 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
(iii) open label period: The first open label dose will be given at the site at Week 156. At Week 
156, the subjects will be given pre-filled syringes and starting Week 160, the subjects will be 
asked to perform self-injection at home every 4 weeks and return to the site every 12 or 16 
weeks (see Table 6-1 Assessment schedule). Also, at regularly scheduled visits at the site, the 
subject receiving 150 mg s.c. may be switched to 300 mg s.c. if the subject and the PI agree that 
there would be a benefit from a higher dosage. The last visit at which the subjects may be 
switched to the higher dosage is Week 244. For all subjects, who will not enter the open label 
period, Week 156 will be the EoT visit at which no treatment will be administered. After 
completing the Week 156 EoT visit, these subjects will enter the treatment-free follow up 
period. For all subjects who enter the open label period, the last dose of the study medication 
will be given at Week 256. Week 260 is the end open label treatment period.  
(iv) follow-up period: treatment free period (Week 264 to Week 268). 
(v) follow-up 2 period: treatment free period for patients who prematurely discontinued 
treatment 
NOTE: Partial responders DO NOT participate in the randomized withdrawal and DO NOT 
receive any loading dose even if they experience a full relapse (a loss of >50% of the maximum 
PASI gain compared to baseline of the core study) 
Subjects on placebo treatment or etanercept in the maintenance phase of the core studies will 
not be eligible to enter this extension study, and will complete follow-up visits in the core 
studies. 
Follow-up period (Week 264 to Week 268) 
The treatment-free follow-up period (no study treatment administered during follow-up period) 
includes visits at Week 264 (Follow-up visit F4, which is 4 weeks after the EoT/OL-EoT visit, 
and 8 weeks after last study treatment administration) and Week 268 (follow-up visit F8 [or 
End of follow-up {EOF}]), which is 8 weeks after the EoT/OL-EoT visit, and 12 weeks after 
the last study treatment administration. 
Follow-up 2 period 
Subjects who have prematurely discontinued treatment prior to the end of treatment phase 
(Week 260), and completed the subsequent follow-up period visits (Weeks 264 and 268) should 
enter the treatment free follow-up 2 period. Follow-up 2 period consists of telephone calls every 
3 months and unplanned assessments e.g. physical examinations, vital signs and laboratory 
assessments at the site if investigator considers this necessary. The end of Follow-up 2 period 
(EOF2) for an individual subject will be after 4 years from the time when subject has been 
enrolled into the CAIN457A2302E1 study (Figure 3-1).  
 
3.2 
Rationale of study design 
The first two years (104 weeks), of this multicenter, double-blind, randomized withdrawal 
extension study is set up to collect the long-term efficacy, safety and tolerability of secukinumab 


Novartis 
Confidential 
Page 32 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
in either continuous or interrupted therapy (randomized withdrawal/treatment period). The 
second two years of the study is open label and primarily designed to collect additional safety 
data. 
Since interruptions of treatment for various reasons are common in chronic diseases such as 
psoriasis, the first two years of this extension study will investigate the effect of treatment 
interruption as well as re-treatment following treatment interruption in a “randomized 
withdrawal” design. 
In addition, the “randomized withdrawal” period will allow assessing whether continuation of 
treatment with secukinumab is of benefit to subjects after having been treated with secukinumab 
for up to 52 weeks, compared to stopping treatment with secukinumab. 
The concept of “randomized withdrawal” is in line with recommendations from the EMA as 
outlined 
in 
the 
guidelines 
for 
the 
development 
of 
drugs 
to 
treat 
psoriasis 
(CHMP/EWP/2454/02), and with feedback received at the end-of-phase-II meetings with the 
FDA, the EMA, and the PMDA. 
Because a relapse can only reasonably be assessed if a subject has a response to start with, only 
subjects that have a PASI 75 at Week 52 of one of the core studies will be re-randomized into 
the randomized withdrawal period of this extension study. 
The “randomized withdrawal” period does not have a defined end. Instead, retreatment 
(including loading dose) will be initiated for each subject individually if at any scheduled visit 
a relapse is experienced. This is considered appropriate, since a subject not suffering from a 
relapse is not considered in need of active treatment at that time, and hence should not be 
exposed to treatment until the worsening of the disease (relapse). After two years any subjects 
on placebo in the randomized withdrawal arm will either be discontinued or started on 
secukinumab.  
Partial responders (i.e., subjects having a PASI 50 response, but not a PASI 75 response) are 
also allowed to enter the extension study; they will continue the treatment they received during 
the maintenance of the core study. This is based on the rationale that a subject could have been 
a responder during most of the core study, but suffered from a minor loss of response at Week 
52 (e.g., because of seasonal variation), and could still be regarded to benefit from continuous 
treatment with secukinumab. In addition, even for a subject responding to secukinumab only 
with a partial response, continuous treatment with secukinumab might still be the best available 
treatment option for this subject (e.g., due to intolerance or non-availability of other options). 
Therefore, at Week 52 of the core study, investigator and subject will perform an assessment of 
whether the subject is expected to benefit from inclusion in the extension study; if that 
assessment is positive, the subject is eligible to enter the extension study. 
In the last two years of the study during the open label period subjects on 150 mg s.c. will be 
allowed to switch to 300 mg s.c. at the discretion of the investigator. The switch will be allowed 
starting Week 156 and only during the scheduled visit. Once subjects switch into the higher 
dose, they will not be allowed to switch back to the lower dose. Also, subjects initially 
randomized to 300 mg s.c. will not be allowed to switch to 150 mg sc at any time during the 
study.Non-responders to secukinumab (i.e., subjects not having at least a PASI 50 response) at 


Novartis 
Confidential 
Page 33 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Week 52 of the core studies are not eligible to enter the extension study, since they do not show 
a meaningful response to the active treatment. 
Subjects on placebo in the core studies until Week 52 are not eligible to enter the extension 
study because they have shown that their disease status is not in need of active treatment. Hence, 
there is no benefit expected for these subjects from entering the extension study. 
Subjects on etanercept in the core study (CAIN457A2303) until Week 52 are not eligible to 
enter the extension study because the extension study has no objective that would justify 
comparison of secukinumab against an active comparator; instead, the main focus of the study 
objectives is to compare different secukinumab regimens against each other. Since etanercept 
is an approved treatment in the countries where the study CAIN457A2303 is performed in, 
subjects can receive etanercept by prescription. 
3.3 
Rationale of dose/regimen, duration of treatment 
The doses and regimens selected for secukinumab are projected to deliver high efficacy while 
at the same time ensuring subject safety. The proposal to continue treatment with s.c. doses of 
150 mg and 300 mg administered every four weeks, as well as the additional treatment duration 
of 208 weeks (leading to an overall treatment period [core plus extension] of 260 weeks) is 
based on the need for efficacy and safety information during chronic treatment in subjects 
suffering from chronic plaque-type psoriasis. 
The rationale of the dose/regimen for re-treatment after full relapse is supported by model-based 
considerations. These model-based predictions are subject to caveats and assumptions, but 
appear to provide plausible guidance. The predictions are considered as extrapolations, as they 
are made for regimens, time points, subject subsets and withdrawal/re-treatment patterns for 
which limited or no data is available, as they have not (or not in exactly this way) been studied 
so far (which is the nature of the current status of development of secukinumab in psoriasis). 
The inclusion of a randomized withdrawal treatment period will allow assessing time to relapse 
and frequency of rebound after cessation of treatment, compared to continuous treatment. This 
is in line with guidelines for the development of drugs to treat psoriasis (CHMP/EWP/2454/02). 
The switch from the lyophilisate to the more convenient prefilled syringe is supported by the 
results of clinical study CAIN457A2106, which has shown that the exposure profiles of both 
formulations are virtually identical. This will also remove the need to have unblinded 
pharmacists involved in the study; these were necessary in the core studies to ensure the double-
blind. 
Model-based predictions in Figure 3-2 suggest: 
• Subjects lose PASI 75 response after withdrawal at an approximate rate of 10% per month 
(see Figure 3-2 left). 


Novartis 
Confidential 
Page 34 
Amendment Protocol v03 Clean 
Protocol No. CAIN457A2302E1 
•
Substantially less subjects show a full relapse, the predictions reaching 10% after four
months (see Figure 3-2 right).
Figure 3-2 
Model-based prediction of % PASI 75 responders and % of subjects 
relapsing during a period of 6 months after either continuous 
treatment or of withdrawal (based on responders at Week 52) 
Model base exploration with high and unquantifiable uncertainty, thus no intervals are provided 
The use of loss of PASI 75 as primary objective is supported by results from study 
CAIN457A2211 wherein a loss of PASI 75 was observed during treatment-free maintenance 
periods in an increasing number of subjects over time (see Figure 3-3).  
Figure 3-3 
Observed loss of PASI 75 response during “fixed interval” 
maintenance treatment of study CAIN457A2211 
AIN457: Secukinumab 
AIN457 150 mg 
AIN457 150 mg 


Novartis 
Confidential 
Page 35 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
During each 4-week interval, an additional approximately 10% of subjects lost PASI 75 
response; twelve weeks after last administration of secukinumab, 33.3% of the subjects had lost 
PASI 75 response. While data from Week 16 is not available from that study, since subjects 
were retreated after 12 weeks, it can reasonably be expected that around 40% of subjects will 
have lost PASI 75 response 16 weeks after last administration of secukinumab. This percentage 
is large enough to allow for a meaningful comparison as outlined in the primary endpoint of 
extension study CAIN457A2302E1. 
It is understood that the trough level of secukinumab after 12 weeks of treatment in study 
CAIN457A2211 might be somewhat different than at Week 52 of studies CAIN457A2302 and 
CAIN457A2303, but this is expected to have no major impact on the time to loss of PASI 75. 
3.4 
Rationale for choice of comparator 
Use of placebo (i.e. withdrawal of active therapy) in a randomized withdrawal study design 
until retreatment is necessary (in the case of psoriasis a “relapse”, i.e., loss of >50% of the 
previous gain in PASI reduction) is in accordance with Health Authority Guidelines on Choice 
of Control Group in Clinical Trials (e.g., CPMP/ICH/364/96 2001). This is also be supported 
by the fact that all subjects will have the opportunity to receive active treatment after 
experiencing a relapse. All patients in the last two years of the trial will be on active treatment. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
A PEA will be conducted when all subjects have completed Week 68 of treatment. Data from 
this PEA will be provided for the Day 120 update during the process of market authorization. 
Of note, the study procedures will not be modified as a result of this PEA. 
Additional interim analyses may be conducted at various time points for publications or health 
authority requests. The study procedures will not be modified as a result of these interim 
analyses. 
When each subject of the study has either completed treatment period and follow-up period or  
discontinued treatment and completed follow-up and follow-up 2 periods (last telephone 
contact) or withdrawn from study the final database lock occurs.  
3.6 
Risks and benefits 
Non-clinical studies have not shown any impediment to using secukinumab either intravenously 
(i.v.) or s.c. in man. Study CAIN457A2302E1 will use secukinumab drug substance solution in 
PFS; this formulation has already been used in a biocomparability study, CAIN457A2106, and 
has shown almost identical properties compared to the lyophilisate. 
Secukinumab is expected to show good to excellent efficacy in the treatment of psoriasis, as 
outlined in Section 1.1. 
At the time of Amendment 1, over 6200 subjects with a variety of autoimmune diseases have 
received secukinumab. Details of the risk and benefits are outlined in the current version of the 
Investigator Brochure. 


Novartis 
Confidential 
Page 36 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
The risk to subjects in this trial will be minimized by compliance with the inclusion/exclusion 
criteria, proper study design and close clinical monitoring. 
In the extension study CAIN457A2302E1, all subjects will receive active treatment, either from 
the start of the study, or after they have experienced a relapse. To ensure a double-blind design, 
some subjects will receive  placebo up to 156 weeks or until the first relapse, according to the 
group to which they were randomized. 
All quality, non-clinical pharmacology and toxicology data, as well as the available clinical  
efficacy and safety data, are considered sufficient to expect a positive benefit / risk ratio for the 
treatment of psoriasis with secukinumab, and therefore to initiate extension study 
CAIN457A2302E1. 
4 
Population 
All subjects from study CAIN457A2302 and CAIN457A2303 (and potentially rolling over 
from other secukinumab phase III studies) who were randomized to and have been receiving 
secukinumab treatment during the maintenance period of the core studies (e.g., CAIN457A2302 
or CAIN457A2303), and who completed the full study treatment period (52 weeks) in core 
studies and who have at least a partial response at Week 52 of the core studies, and who comply 
with the inclusion and exclusion criteria of this study, are eligible to enter into this extension 
study. 
Assuming drop-outs rates of 5% for secukinumab and 15% for placebo in the induction phases 
of the core studies, 15% drop-out rate in the maintenance phases of the core studies, and a PASI 
50 response rate of about 95%, it is aimed that a total of about 1,220 subjects will be eligible to 
enter this extension study across approximately 300 sites worldwide.  
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Subjects who completed the full study treatment period (52 weeks) in the core studies 
(e.g., CAIN457A2302 or CAIN457A2303), and after randomization have been receiving 
secukinumab treatment during the maintenance phase of the core studies, and show at 
least a partial response (PASI 50 or better) at Week 52 of the core studies. 
2. Written informed consent must be obtained before any assessment is performed. 
3. For inclusion in the open label period, written informed consent for protocol amendment1 
must be obtained.  
4. For inclusion in the open label period, the subject must be deemed to benefit from the 
study drug based on the investigator's clinical judgment.  
4.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are NOT eligible for inclusion in this study: 
1. A protocol deviation in the core studies which according to the investigator will prevent 
the meaningful analysis of the extension study for the individual subject 


Novartis 
Confidential 
Page 37 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
2. Ongoing use of prohibited psoriasis or non-psoriasis treatments. Time period to use of 
prohibited treatments in the core study detailed in the protocol have to be adhered to Table 
5-1. 
3. Subjects not expected to benefit from participation in the extension study, as assessed by 
the subject and investigator 
4. Subjects expected to be exposed to an undue safety risk if participating in the study 
5. Current severe progressive or uncontrolled disease which in the judgment of the 
investigator renders the subject unsuitable for the study 
6. Plans for administration of live vaccines during the study period 
7. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (>10 mIU/mL) 
8. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unwilling to use effective contraception during the study and for 16 
weeks after stopping treatment. Effective contraception is defined as either: 
• Barrier method: Condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicide (where available). Spermicides alone are not a barrier method of 
contraception and should not be used alone  
The following methods are considered more effective than the barrier method and are also 
acceptable: 
• Total abstinence: When this is in line with the preferred and usual lifestyle of the 
subject (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception) 
• Female sterilization: have had a surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment  
• Male partner sterilization (at least 6 months prior to screening). For female subjects on 
the study, the vasectomized male partner should be the sole partner for that subject  
• Use of established oral, injected or implanted hormonal methods of contraception, 
intrauterine device (IUD) or intrauterine system (IUS) 
NOTE: Women are considered post-menopausal and not of child bearing potential if they have 
had: 
• 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or  
• six months of spontaneous amenorrhea with serum FSH levels >40 mIU/mL [for US 
only: and estradiol <20 pg/mL] or 
• 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 is she considered not of child bearing potential. 


Novartis 
Confidential 
Page 38 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
No additional exclusion criteria may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible subjects. 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Novartis will provide the following study treatments 
1. Investigational treatment: Secukinumab 150 mg/1 mL solution for injection is provided in 
PFS for s.c. administration. The 150 mg/1 mL solution in PFS is used for both s.c.150 mg 
dose (1 syringe) and s.c. 300 mg dose (2 syringes). For blinding purpose the subject in 150 
mg treatment group will also receive one syringe of placebo 150 mg during the blinded 
period of the study 
2. Reference therapy: Placebo secukinumab 150 mg/1 mL solution for injection is provided 
in PFS for s.c. administration. It contains a mixture of inactive excipients, matching the 
composition of secukinumab 150 mg. 
Secukinumab 150 mg/1 mL and placebo secukinumab 150 mg/1 mL is labeled as AIN457 150 
mg/1 mL/Placebo. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this study. 
5.2 
Treatment groups 
The study treatment will be provided in individual boxes that contain secukinumab or placebo 
PFS sealed in a plastic wrapper. Each study treatment box consists of actual PFS and a safety 
device type X100L 
. The safety syringe is aided with a needle guard 
system that will aid protection from accidental needle sticks. 
For the subjects classified as PASI 75 responders at Week 52 the study 
consists of 5 or 6 periods  
(i) screening period: is the duration between signing the informed consent form (ICF) and 
randomization registered with IRT. 
(ii) randomized withdrawal period: the duration of randomized withdrawal period for each 
subject is different i.e., starting from Week 52 until the subject experiences the relapse or up to 
Week 156 (see Section 3.1 on Study Design  for additional details) 
(iii) treatment period: starting from the visit in randomized withdrawal period at which a subject 
experiences relapse and continuing through Week 156. During the Week 152 visit subject will 
receive the last blinded dose of the study treatment. At Week 156 the subjects will enter the 
open label period. For subject who will not move to the open label period, the Week 156 visit 
is the EoT. For subjects who will move to the open label period, the Week 156 visit will be the 
first open label treatment. 


Novartis 
Confidential 
Page 39 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
(iv) open label period: starting from Week 156 to Week 260 all subjects will be on open label 
secukinumab. The subjects will receive the last dose of the study medication at Week 256.  The 
Week 260 visit is the OL –EoT. 
(v) follow-up period (for all subjects): treatment free period (Week 264 to Week 268) 
(vi) follow-up 2 period: treatment free period only for patients who prematurely discontinued 
treatment. All subjects who prematurely discontinue treatment should complete all assessment 
of Week 260 (end of treatment visit) and of the follow-up period visits (Weeks 264 and 268). 
Subsequently, adverse events and use of concomitant medication will be evaluated by the 
investigator through telephone calls every 3 months for a duration of 4 years from the time 
when subject has been enrolled into CAIN457A2302E1 study. 
  
For the subjects classified as partial responders at Week 52 the study consists 
of 4 or 5 periods 
(i) screening period: is the duration between signing the informed consent form (ICF) and 
randomization registered with IRT. 
(ii) treatment period: starting from the randomization visit at Week 52 continuing through Week 
156 the subjects will receive secukinumab s.c. every 4 weeks  at the dose which they were 
originally assigned  in the core study.  During the Week 152 visit subject will receive the 
last blinded dose of the study treatment. At Week 156 the subjects will enter the open label 
period. For subject who will not move to the open label period, the Week 156 visit is the 
EoT. For subjects who will move to the open label period, the Week 156 visit will be the 
first open label treatment. 
(iii) open label period:  starting from Week 156 to Week 260 all subjects will be on open label 
secukinumab. The subjects will receive the last dose of the study medication at Week 256.  
The Week 260 visit is the OL –EoT. 
(iv) follow-up period (for all subjects): treatment free period (Week 264 to Week 268). 
(v) follow-up 2 period: treatment free period only for patients who prematurely discontinued 
treatment. All subjects who prematurely discontinue treatment should complete all 
assessment of Week 260 (end of treatment visit) and of the follow-up period visits (Weeks 
264 and 268). Subsequently, adverse events and use of concomitant medication will be 
evaluated by the investigator through telephone calls every 3 months for a duration of 4 
years from the time when subject has been enrolled into CAIN457A2302E1 study. 
 NOTE: Partial responders DO NOT participate in the randomized withdrawal and DO NOT 
receive any loading dose even if they experience a full relapse (a loss of >50% of the maximum 
PASI gain compared to baseline of the core study) 
5.3 
Treatment assignment, randomization 
At the end of Week 52 visit in the core study (e.g., Visit 21 of study CAIN457A2302 or 
CAIN457A2303) the investigator will complete Week 52 assessments, enter the PASI response 
into the eCRF and register the completion of Week 52 visit in the IRT.  


Novartis 
Confidential 
Page 40 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
The IRT system will search (after the PASI response status has been updated by investigator or 
designee in IRT) the databases of core studies at Week 52 to identify whether or not the subject 
has been on secukinumab (s.c. 150 mg or 300 mg) at the time of completion of Week 52 visit 
in the core study. 
For the subjects classified as PASI 75 responders at Week 52 
Once investigator or designee has entered Week 52 PASI response status in the IRT and also 
registered with IRT the completion of Week 52 visit of the core studies on secukinumab 
treatment, a subject will be eligible for randomization in the extension study. 
The Week 52 visit in the core study is the randomization visit for CAIN457A2302E1 (extension 
study). 
Based on the fulfillment of inclusion/exclusion criteria by the subject and IRT notification from 
the database of core studies at Week 52 (explained above), the investigator (or designee) will 
call the IRT set up of extension study (CAIN457A2302E1).The IRT can be contacted via the 
Interactive Voice Response System (IVRS) or Interactive Web Response System (IWRS). The 
IRT will assign a randomization number to the subject, which will be used to link the subject 
to a treatment groups (secukinumab 150 mg or placebo secukinumab 150 mg or secukinumab 
300 mg or placebo secukinumab 300 mg) and will specify a unique medication number for the 
first package of investigational treatment to be dispensed to the subject. The randomization 
number will not be communicated to the caller or any of the site staff members. 
The randomization numbers at Week 52 will be generated using the following procedure to 
ensure that treatment assignment is unbiased and concealed from subjects and investigator staff. 
A subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment groups, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s).  
Randomization will be stratified by geographical region and by body weight (< 90 kg or ≥90 
kg) collected at Week 52. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Audit Readiness, Validation & Randomization Group within IIS IA&R (Integrated Information 
Science Integrated Analytics and Reporting). 
For the subjects classified as partial responders at Week 52 
The same randomization process used for PASI 75 responders at Week 52 will be followed for 
partial responders at Week 52. 
A randomization numbers will be assigned to partial responders. These randomization numbers 
will be linked to the two different treatment groups (secukinumab 150 mg, secukinumab 300 
mg) which correspond to the treatment received in the core studies. Partial responders at Week 
52 will then continue to receive the treatment they were assigned in the core studies. 


Novartis 
Confidential 
Page 41 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
5.4 
Treatment blinding  
Subjects, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the study treatment from the time of randomization until final database 
lock, using the following methods: 
1. Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study. 
2. The identity of the treatments will be concealed by the use of investigational treatment 
that are all identical in packaging, schedule of administration and appearance.  
In order to maintain blind in this study, placebo is used.  
During the double blinded period of the study,  unblinding will only occur in the case of subject 
emergencies (see Section 5.5.10), at the time of the primary endpoint at Week 68, and when the 
patients enter the open label part of the study at Week 156After all subjects complete Week 68, 
designated sponsor team members will be unblinded, whereas the subjects, investigator staff, 
and persons performing the assessments will remain blinded until Week 156  to ensure reliable 
efficacy and safety measures. At Week 156 all subjects will enter the open label period and 
subjects, investigator staff, and persons performing the visit assessments will become 
unblinded.  
In case the results of the core study are published while the extension study is ongoing, the data 
will be published in groups only, with limited ability to unblind individual subjects (The 
exception to this might be rare safety events that, if occurring in only one treatment group, 
would allow unblinding of the affected subjects). However, since this would be relevant to only 
a very small group of subjects, if any, no impact on the overall validity of the extension study 
is expected. Nevertheless, the integrity of the primary endpoint is not affected since no 
unblinding with respect to placebo in the randomized withdrawal is performed. 
5.5 
Treating the subject 
5.5.1 
Subject numbering 
Subjects in the extension study CAIN457A2302E1 will be assigned a uniquely identified 
subject number for the extension study. The uniquely identified subject number is composed by 
the study identifier (CAIN457A2302E1), 4-digit study site identifier assigned by Novartis for 
the site in the core study and a 3-digit sequential number assigned by the investigator in the core 
study (e.g.,CAIN457A2302E1_1234001). The last 7 digits of the unique subject identifier will 
remain the same for the subject in the core study and the extension study. 
Subjects will be given the ICF during one of the scheduled visits of the core study (e.g., Week 
48 [Visit 20] or at earlier visit in study CAIN457A2302 or CAIN457A2303) to read and 
understand for their participation in this extension study. Subjects will NOT be signing the 
ICF before completing the assessments on Week 52 visit of the core study (e.g., Visit 21 of the 
study CAIN457A2302 or CAIN457A2303) and unless the investigator has entered the Week 
52 PASI response in the IRT, and registered the completion of the core study Week 52 visit in 
the IRT, and the IRT confirms that the subject was on secukinumab in the core study. 


Novartis 
Confidential 
Page 42 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Subjects who are eligible (as decided by the investigator or designee) based on the 
inclusion/exclusion criteria and IRT notification (see Section 5.3) will be asked to sign the ICF. 
In order to enter data for extension study CAIN457A2302E1, the site is to select a CRF book, 
add the subject’s number from the core study (e.g., CAIN457A2302 or CAIN457A2303) and 
update the electronic data capturing (EDC) system with this number. 
If the subject fails to be treated for any reason, the IRT must be notified immediately and the 
reason for not being treated will be entered on the Screening Epoch Disposition electronic Case 
Repot Form (eCRF). The data or information regarding demography for the subjects not 
randomized will be available as a listing from the core study databases. The Inclusion/Exclusion 
eCRF for the extension study CAIN457A2302E1 is to be completed for the subjects not 
randomized (after signing the ICF), along with Adverse Events eCRF (for study 
CAIN457A2302E1) for any SAE that occurred after signing the ICF. If a subject fails to be 
treated in the extension study, the subject completes the follow-up visits in the respective core 
study. 
5.5.2 
 Dispensing the investigational treatment 
Each study site will be supplied by Novartis with study treatment in packaging of identical 
appearance. 
The boxes containing single prefilled syringes with study treatment solution (secukinumab or 
placebo secukinumab) has a 2-part label. A unique medication number is printed on each part 
of this label. The blinded qualified study site staff personal will identify the study treatment box 
to dispense to the subject by contacting the IRT and obtaining the medication number(s). 
Immediately before dispensing the box containing PFS with study treatment, blinded qualified 
study site staff personal will detach the outer part of the label from the boxes and affix it to the 
source document (Drug Label Form) for that subject’s unique subject number.  
At Week 160, and once the home administration is operationally set up, subjects will be 
expected to perform home administrations at the protocol specified time points. For these cases 
the investigator will dispense, via IRT, an appropriate number of investigational treatment 
packages for home administrations and detach outer part of the label from the packaging. The 
subjects will record the date(s) of administration at home and will return the used medication 
and packaging at their next visit to the site. Subjects will be asked to return all unused 
medication and packaging the latest at the completion of the study or at the time of 
discontinuation of the investigational treatment. Site staff will record in the appropriate 
documents the dates of the administration.  Detailed instructions will be provided separately. 
5.5.3 
Storage of investigational treatment  
Single PFS with study treatment solution (secukinumab or placebo) will be packed in individual 
boxes. The boxes 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, PFS should be stored according to the instructions specified on the 
treatment labels. PFS and/or clinical supplies are to be dispensed and administered only in 
accordance with the protocol. 


Novartis 
Confidential 
Page 43 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
The boxes containing the PFS with study treatment solution should be kept at 2 to 8°C (36°F 
and 46°F). PFS should be protected from direct exposure to light. Therefore the PFS must be 
stored protected from light. 
The medication label will be in the local language and will comply with the legal requirements 
of each country. The label will include storage conditions for the investigational treatment but 
no information about the subject except for the medication number. 
The investigator (or designee) must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Monitoring of drug accountability will be 
performed by 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 
(or designee) will return all used and unused study treatment, packaging, drug labels, and a copy 
of the completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site. 
5.5.4 
Instructions for prescribing and taking study treatment 
Each subject will require two boxes of syringe set (PFS) per dose throughout the study. 
• One secukinumab 150 mg PFS and one placebo secukinumab PFS (150 mg group) 
OR  
• Two secukinumab 150 mg PFS (300 mg group) OR  
• Two placebo secukinumab 150 mg PFS (Placebo group)  
All study treatment kits assigned to the subject during the study will be recorded/databased in 
the IRT. 
The syringes with the ready-to-use study treatment solution (PFS) will be provided by the site 
staff during the study visit. 
All doses of study treatment (secukinumab and/or placebo secukinumab) will be injected at the 
study site after Week 52 assessments for study CAIN457A2302 or CAIN457A2303 have been 
completed. It is preferred that subject should self-inject, however, if a subject is not able or not 
willing to self-administer, administration will be performed by study site staff. 
The first study treatment administration (self or by study site staff) will occur at randomization 
visit (Week 52) after inclusion/exclusion criteria have been confirmed, the core study scheduled 
assessments at Week 52 have been performed, and the scheduled blood samples have been 
drawn, and only after the investigator has registered the completion of the core study with IRT. 
For subjects willing to self-inject, the first use at randomization visit (Week 52) will take place 
under guidance and the supervision of one site staff member. At the randomization visit (Week 
52) the subjects will be instructed through the site staff by walking them through the 
“Instructions For Use” on how to self-inject via PFS. At the following visits, subjects will 
receive the PFS at the study site. 
NOTE: The needle cover of the syringe contains dry rubber (latex), which should not be handled 
by persons sensitive to this substance. 


Novartis 
Confidential 
Page 44 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
At study visits when pre-dose blood samples have to be drawn (Table 6-1), the study treatment 
will be injected only after the blood samples have been taken. 
At each visit, all study assessments, including the completion of health-related quality of life 
(HRQoL) tools (as reported by subjects), should be completed prior to the injection of study 
treatment.  
After Week 256, no further study treatment will be administered. In addition, no study treatment 
is administered during the follow-up period and follow-up 2 period. 
All dates, times of injections, mode of injection (self or by study site staff) during the study 
must be recorded on the Dosage Administration Record eCRF. Immediately before dispensing 
the package for injection, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that subject’s unique 
subject number.  
Administration 
Secukinumab solution for s.c. injection or placebo secukinumab solution (active or placebo, 
respectively) will be provided in PFS. 
The study treatment solution must be injected in non-affected areas of the skin. If possible, 
throughout the trial administer the study treatment to one of the following body regions, 
changing the injection site from visit to visit: right thigh, left thigh, right stomach, left stomach, 
upper outer arm (when assisted by attendant). 
Prior to administration the boxes containing the PFS with study treatment solution should be 
allowed to come to room temperature unopened for about 20 minutes before administration. 
Used PFS should be disposed immediately after use in a sharps container OR according to the 
regulatory needs of the respective countries. 
Home administration 
During the open label period, after approximately two years of study of self-administered 
treatment under the supervision of site staff during the double blinded period, subjects will be 
expected to self-administer the PFS at home when they are not visiting the site for any other 
trial related procedures. 
The subjects will be allowed to self-administer treatment at home (starting Week 160) only if 
they have exhibited correct use for self-administering the PFS at the site. 
It is important that during the self-administration period at home, subjects contact the 
investigator / site staff in case they are experiencing any AE/SAEs or have any concerns.  
If the subject is not able / not confident to self-administer the PFS, he/she should visit the site 
every 4 weeks during the open label treatment period, according to the visit schedule, and either 
the staff or the subject will administer the study drug. However, during those visits no other 
assessments will be performed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment   
No dose adjustments or interruptions are permitted. 


Novartis 
Confidential 
Page 45 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
5.5.6 
Rescue medication  
Rescue medication is not permitted in this study. 
5.5.7 
Concomitant treatment  
The investigator must consider the baseline and ongoing concomitant treatment in core study 
(e.g., CAIN457A2302 or CAIN457A2303) Concomitant medications eCRF, Surgeries and 
Medical Procedures eCRF, and Prior Psoriasis Therapy eCRF page at Week 52 randomization 
visit before a subject enters the extension study (CAIN457A2302E1). The Week 52 
concomitant medication data for the extension study will be the same as the baseline 
concomitant medication data of the core study for all three eCRFs. All concomitant medications 
that were ongoing from the core study at the Week 52 randomization visit will be followed in 
the extension on the applicable Concomitant medications eCRF or Surgeries and Medical 
Procedures eCRF. 
The investigator should instruct the subject to notify the study site about any new treatments 
he/she takes after the start of the extension study treatment. All medications and significant non-
drug therapies (including physical therapy and blood transfusions) administered after the 
subject starts study treatment must be listed on the Concomitant medications eCRF or the 
Surgeries and Medical Procedures eCRF. Start date, end date, dose, unit, frequency, route and 
reason for administration or change are to be recorded. 
5.5.8 
Prohibited Treatment  
 Use of any treatments displayed in Table 5-1 that could confound the efficacy is NOT allowed 
for any indication during the study excluding the treatment-free follow-up 2 period. 
The investigator should instruct the subject to notify the study site about any new treatments 
he/she takes after the start of the study treatment. All prohibited medications and significant 
non-drug therapies administered after the subject starts treatment with study treatment must be 
listed on the Concomitant medications eCRF or the Surgeries and Medical Procedures eCRF. 
Table 5-1 
Prohibited treatment  
Prohibited treatments†,‡  
Time period before randomization visit at 
Week 52 
Alefacept, briakinumab, efalizumab, ustekinumab 
6 months 
Biological immunomodulating agents other than 
above (e.g., adalimumab, etanercept, infliximab) 
12 weeks 
Other systemic immunomodulating treatments§ (e.g., 
MTX, cyclosporine A, corticosteroids§, 
cyclophosphamide) 
4 weeks 
Other systemic psoriasis treatments* (e.g., retinoids, 
fumarates) 
4 weeks 
Photochemotherapy (e.g., PUVA) 
4 weeks 
Phototherapy (e.g., UVA, UVB) 
2 weeks 


Novartis 
Confidential 
Page 46 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Prohibited treatments†,‡  
Time period before randomization visit at 
Week 52 
Use of opical treatment ** that is likely to impact signs 
and symptoms of  psoriasis for >14 days* (e.g., 
corticosteroids [CS], vitamin D analogues,  
pimecrolimus, retinoids, salicylvaseline, salicylic acid, 
lactic acid,  tacrolimus, tar, urea, α-hydroxy or fruit 
acids) 
2 weeks 
Live virus vaccinations during extension study 
6 weeks 
Any investigational treatment or participation in any 
interventional clinical trial during extension trial 
4 weeks or 5 half-lives (whichever Is longer) 
†If a subject inadvertently used the prohibited treatment in core study (e.g., CAIN457A2302 or CAIN457A2303) without undue 
safety risk till completion of Week 52, he/she must have completed the time period as defined in the table above. Subjects who 
have not completed an adequate time period (table above) will not be eligible for the current extension study.  
‡In case of undue safety risk for the subject, the subject should discontinue study treatment at the discretion of the investigator. If 
the subject received a live virus vaccination during the study, the subject must discontinue study treatment. 
§Inhalative CS with only a topical effect (e.g., to treat asthma) are not considered “systemic immunomodulating treatments” and 
are therefore acceptable as co-treatment. 
*There is no restriction on the use of anti-histamines or the use of corticosteroids in the eye or ear 
** Topical corticosteroid (CS) treatment, or use of other topical treatment that is likely to impact signs and symptoms of psoriasis, 
is not allowed for treatment of psoriasis, except when applied to the face, scalp, and/or genitoanal area for ≤14 consecutive days. 
Topical corticosteroid use for indications other than psoriasis not on an area affected with psoriasis is allowed for ≤14 consecutive 
days. 
5.5.9 
Discontinuation of study treatment and premature subject withdrawal 
Subjects may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
Discontinuation from a treatment period  
If premature withdrawal occurs for any reason, the investigator must make every effort to 
determine the primary reason for a subject’s premature withdrawal from the study and record 
this information on the end of randomized withdrawal /treatment  EoT eCRF (Week 156) or if 
the subject is discontinued during the open label period on the OL-EoT eCRF (Week 260). 
Study treatment must be discontinued under the following circumstances: 
• Withdrawal of informed consent 
• Emergence of the following AEs: the AEs that in the judgment of the investigator, taking 
into account the subject’s overall status, prevent the subject from continuing participation 
in the study (for example, sepsis or serious infection).  
• Any laboratory abnormalities that in the judgment of the investigator, taking into  
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study. 
• Pregnancy (see sections 6.5.6 and 7.3) 
• Use of prohibited treatment as per recommendations in Table 5-1. 
• Any other protocol deviation that results in a significant risk to the subject’s safety 


Novartis 
Confidential 
Page 47 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
In addition to the requirements mentioned above for study treatment discontinuation, the 
investigator should discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being. 
Subjects discontinued from study treatment should NOT be considered withdrawn from the 
study. If the subject discontinues treatment during the randomized withdrawal/double blinded 
treatment or open label period then  the site staff must record the date and primary reason for 
stopping study treatment on the appropriate EoT eCRF  
When subject discontinues the study treatment, then assessments described at Week 260 should 
be performed approximately four weeks after their last dose of secukinumab and the subject 
should then return per appropriate schedule for assessments described at Week 264 and Week 
268 (follow-up period). Subsequently, these subjects should enter the follow-up 2 period.  
The investigator must contact the IRT when the subject completes the assessments on Week 
156 and/or Week 260 due to study treatment discontinuation. 
Study treatment must be discontinued after emergency unblinding. 
The appropriate personnel from the study site and Novartis will assess whether study treatment 
should be discontinued for any subject whose treatment code has been broken inadvertently for 
any reason. 
See Section 6 for the required assessments of these subjects after study treatment 
discontinuation. 
Withdrawal from a treatment-free period 
If premature withdrawal occurs for any reason in the treatment-free follow-up period, or follow-
up 2 period, the investigator must make every effort to determine the primary reason for a 
subject’s premature withdrawal from the study and record this information on the applicable 
end of study period eCRF (follow-up period completion eCRF [Week 268]) or Follow-up 2 
period completion eCRF, respectively).  
Subjects who withdraw from follow-up 2 period should perform the Week 268 assessments (see 
Table 6-1). 
Premature subject withdrawal 
Subjects who state an intention to withdraw prematurely from the study will be asked to return 
for follow-up visits to assess safety after cessation of therapy and, if willing, to assess duration 
of effect (e.g., rebound assessments). If the subject returns to the study site to have his/her 
follow-up visits (Week 264 and Week 268), the investigator will follow the study treatment 
discontinuation procedures. 
The investigator must contact the IRT when the subject completes the assessments of  the EoT/ 
OL-EoT visit to register the subject’s early completion of the study due to subject withdrawal. 


Novartis 
Confidential 
Page 48 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Lost to follow-up 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show “due diligence” by documenting in the source documents steps taken to contact the 
subject, e.g., dates of telephone calls, registered letters, etc. 
5.5.10 
Emergency unblinding of treatment assignment  
Emergency breaking of the assigned treatment code should only be undertaken when it is 
essential to treat the subject safely and efficaciously. Most often, study treatment 
discontinuation and knowledge of the possible treatment assignments are sufficient to treat a 
study subject who presents with an emergency condition. Emergency code breaks are performed 
using the IRT. When the investigator or his/her blinded designee contacts the system to unblind 
a subject, he/she must provide the requested subject identifying information and the date, time, 
and reason for unblinding. The investigator will then receive details of the treatment for the 
specified subject and a fax confirming this information. The system will automatically inform 
the Novartis monitor for the study site and the Clinical Trial Head that the code has been broken.  
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT access codes in case of emergency. The investigator (or designee) will inform the 
subject how to contact his/her backup in cases of emergency when he/she is unavailable. The 
protocol number, study treatment name if available, subject number, and instructions for 
contacting the local Novartis CPO (or any entity to which it has delegated responsibility for 
emergency code breaks) to the subject in case an emergency treatment code break is required 
at a time when the investigator and backup are unavailable. 
Study treatment for the study subject must be discontinued after emergency unblinding. 
Subjects who are prematurely unblinded will be discontinued from the study treatment and 
requested to return for the applicable end of period visit (end of randomized withdrawal period 
visit or the end of the treatment period visit [Week 260], two follow-up visits at Week 264 and 
Week 268 and follow-up 2 period. 
5.5.11 
Study completion and post-study treatment  
A subject entering into the extension study CAIN457A2302E1 will be said to have completed 
the extension study after he/she has completed all visits and assessments as defined in Table 6-
1 and received all doses of the study treatment in accordance with the protocol. 
The extension study as a whole will be considered complete when eligible subjects rolled over 
from the core study (e.g., CAIN457A2302 or CAIN457A2303) have completed as per protocol 
the visits and assessments defined in Table 6-1 for the extension study CAIN457A2302E1. 
The investigator also must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
Subjects who complete the extension study CAIN457A2302E1 may be eligible to enter another 
planned extension trial. 


Novartis 
Confidential 
Page 49 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
5.5.12 
Early study termination  
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and properly managed as described in Section 6 
for a prematurely withdrawn subject. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the subject’s interests. The investigator will be responsible for informing 
Institutional Review Boards (IRBs) and/or Independent Ethics Committees (IECs) of the early 
termination of the trial. 
6 
Visit schedule and assessments  
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Subjects should be seen for all visits on the designated day within the allowed “visit window” 
specified below or as close to it as possible. 
During the treatment periods, subjects may be seen at an unscheduled visit, e.g., if they 
experience deterioration of psoriasis, or AEs that in the opinion of the investigator need 
intervention or repeated laboratory testing. During these unscheduled visits, study treatment 
will NOT be administered.  
A visit window of “±5” will be allowed for Week 52 to Week 256 during randomized 
withdrawal and/or treatment period, the open label period or the follow-up period. Patients are 
expected to adhere as close as possible to the visit schedule. 
Relapse visits (R1, R2, and R3) will have visit window of “±2” days. Time schedule of relapse 
visits cannot be anticipated and will be different for each subject experiencing first full relapse 
(a loss of >50% of the maximum PASI gain compared to baseline of the core study). 
Subjects who discontinue study treatment will continue to be followed for safety assessments. 
They are not considered withdrawn from the study. 
Subjects who discontinue study treatment before completing the study, and those who 
prematurely withdraw from the study for any reason should be scheduled for a study visit 4 
weeks after their last study treatment administration, at which time all the assessments listed 
for EoT (Week 260) will be performed (see Section 5.5.10). Subjects will return to the study 
site for further assessments as indicated under the follow-up visits (Week 264 and 268). 
Only subjects who prematurely discontinued study treatment should enter follow-up 2 period 
after completion of follow-up visits (Weeks 264 and 268). Follow-up 2 period includes 
telephone calls every 3 months until 4 years from the time subjects have been enrolled into 
CAIN457A2302E1 as well as potential unplanned assessments e.g physical examinations, vital 
signs and laboratory assessments during this time.  
If they refuse to return for the needed assessments in the follow-up period or are unable to do 
so, every effort should be made to contact them or a knowledgeable informant by telephone or 
by sending appropriate correspondence (i.e. certified letter) immediately. At this contact, the 
safety (e.g., potential occurrence of AE or SAE) and the primary reason for a subject’s 
premature withdrawal should be determined. 


Novartis 
Confidential 
Page 50 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
At a minimum, subjects will be contacted for safety evaluations during the 12 weeks following 
the last dose of study treatment, including final contact at the 12 week point. Documentation of 
attempts to contact the subject should be recorded in the subject record. 
Order of assessments: 
• Subject to complete HRQoL tools prior to any investigator assessments. Order of HRQoL 
tools is: DLQI©, EQ-5D©, HAQ©-DI (subjects with history of PsA at baseline of core 
study). Note: EQ-5D© will not be performed during the open label period. 
• Investigator to complete investigator assessments. Order is: 
1. IGA 
2. PASI  
• All remaining study visit procedures (e.g., laboratory sample collection, vital signs 
measurements) must be completed prior to study treatment dosing. 
• Enter PASI and IGA assessments into eCRFs BEFORE contacting IRT at any scheduled 
visit during the double blind period 
• Contact IRT to register the subject visit. 
• Syringe set boxes of study treatment (secukinumab or placebo secukinumab) are made 
available to the subjects for self-injection or administration by study site staff  


Novartis 
Confidential 
Page 51 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Table 6-1 
Assessment schedule 
 
*Randomized withdrawal and/or treatment period  (Year 1 and 2) 
Unscheduled 
visit
Relapse 1 (R1)b 
Relapse 2 (R2) b 
Relapse 3 (R3) b 
Week (Relative to Baseline 
of core studies) 
52a 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 104 108 112 
116 120 124 128 132 136 140 
144 
148 
152 
156 
Visit window (in days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Day 
365 
393 421 
449 477 505 533 561 589 
617 645 673 701 729 757 785 
813 841 869 897 925 953 981 1009 1037 1065 
1093 
Visit at the site 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Obtain informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x18  
 
 
 
Inclusion/exclusion criteria1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
Demography and other 
characteristics2 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Height4 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
x3 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
Vital signs 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Urinalysis (local) 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Lab analysis:  
chemistry and 
hematology5 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Fasting Labs:  
lipid panel5 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Fasting Labs:  
plasma glucose4,5 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Serum pregnancy test5  
x6 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x7 
 
 
 
Urine pregnancy test 
(local)6 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
ECG (standard 12 lead) 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Blood sample for IG8 
x3 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
x 
x9 
 
 
 


Novartis 
Confidential 
Page 52 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
*Randomized withdrawal and/or treatment period  (Year 1 and 2) 
Unscheduled 
visit
Relapse 1 (R1)b 
Relapse 2 (R2) b 
Relapse 3 (R3) b 
Week (Relative to Baseline 
of core studies) 
52a 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 104 108 112 
116 120 124 128 132 136 140 
144 
148 
152 
156 
Visit window (in days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
Day 
365 
393 421 
449 477 505 533 561 589 
617 645 673 701 729 757 785 
813 841 869 897 925 953 981 1009 1037 1065 
1093 
Blood sample for PK8 
x3,10 x 
x x10 x 
x x10 x 
x x10 x 
x 
x x10 x 
x x10 x 
x x10 x 
x x10 
x 
x 
x 
x10 
x9 
 
 
 
PASI 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x11 x11 x11 
Assessment of rebound 
symptoms12 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
IGA mod 2011 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x11 x11 x11 
EQ-5D© 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
DLQI© 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
HAQ-DI©14 
x3 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Adverse event (AE) assessment 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x11 x11 x11 
Serious AE assessment 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x11 x11 x11 
Concomitant medications 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x x11 x11 x11 
Randomization via IRT15 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of  study 
treatment  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 20 
 
x 
x 
x 
Complete PASI and IGA eCRF 
and call IRT  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
End of screening phase 
completion eCRF 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
End of blinded randomized 
withdrawal/ treatment period 
(EoT): submit  EoT period 
completion  eCRF and call IRT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
End of follow-up period: submit 
follow-up period completion  
eCRF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call to subjects from study-
coordinator reminding the visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
 
 


Novartis 
Confidential 
Page 53 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
Open Label  treatment period (Year 3 and 4) 
Unscheduled  visits 21 
Follow-up 
period 
Follow-
up 2 
period 
Week (Relative to 
Baseline of core 
studies) 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
216 
220 
224 
228 
232 
236 
240 
244 
248 
252 
256 
260 
264 
/F4 
268  
/F8 
Phone 
call every 
three 
months 
Visit window (in days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Day 
1121 
1149 1177 1205 1233 1261 1289 1317 1345 1373 1401 1429 1457 1485 1513 1541 1569 1597 1625 1653 1681 1709 1737 1765 1793 1821 
1849 1877 
 
Visit at the sites19 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
x 
 
Home administration17 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
 
x 
x 
x 
 
 
 
 
 
Physical examination 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
x 
 
Height4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
Vital signs 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
 
Urinalysis (local) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
Lab analysis:  
chemistry including 
amylase and lipase 
and hematology5 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
x 
 
Fasting Labs:  
lipid panel5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
 
Fasting Labs:  
plasma glucose 4,5 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
Serum pregnancy test5  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x7 
 
 
 
Urine pregnancy test 
(local)6 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 


Novartis 
Confidential 
Page 54 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
Open Label  treatment period (Year 3 and 4) 
Unscheduled  visits 21 
Follow-up 
period 
Follow-
up 2 
period 
Week (Relative to 
Baseline of core 
studies) 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
216 
220 
224 
228 
232 
236 
240 
244 
248 
252 
256 
260 
264 
/F4 
268  
/F8 
Phone 
call every 
three 
months 
Visit window (in days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Day 
1121 
1149 1177 1205 1233 1261 1289 1317 1345 1373 1401 1429 1457 1485 1513 1541 1569 1597 1625 1653 1681 1709 1737 1765 1793 1821 
1849 1877 
 
ECG (standard 12 
lead) 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
x 
 
Blood sample for IG8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x9 
 
x 
 
Blood sample for PK8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x10 x9 
 
x10 
 
PASI 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
 
Assessment of 
rebound symptoms12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x13 
x 
 
IGA mod 2011 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
 
DLQI© 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
HAQ-DI©14 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Adverse event (AE) 
assessment 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
Serious AE 
assessment 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
Concomitant 
medications 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
x 
x 
x 
x 
Complete PASI and 
IGA eCRF and call IRT  
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
Administration of study 
treatment 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 


Novartis 
Confidential 
Page 55 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
 
Open Label  treatment period (Year 3 and 4) 
Unscheduled  visits 21 
Follow-up 
period 
Follow-
up 2 
period 
Week (Relative to 
Baseline of core 
studies) 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
212 
216 
220 
224 
228 
232 
236 
240 
244 
248 
252 
256 
260 
264 
/F4 
268  
/F8 
Phone 
call every 
three 
months 
Visit window (in days) 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Day 
1121 
1149 1177 1205 1233 1261 1289 1317 1345 1373 1401 1429 1457 1485 1513 1541 1569 1597 1625 1653 1681 1709 1737 1765 1793 1821 
1849 1877 
 
End of open label 
treatment period (OL-
EoT): submit  EoT 
period completion  
eCRF and call IRT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
End of follow-up 
period: submit follow-
up period completion  
eCRF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
End of follow-up 2 
period: submit follow-
up 2 period completion  
eCRF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Call to subjects from 
study-coordinator 
reminding about the 
visit 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
x 
x 
 
 
eCRF:electronic case report form; PK:pharmacokinetics; IG:immunogenicity 
*For subjects classified as PASI 75 responders at Week 52 of the core study (e.g., CAIN457A2302 or CAIN457A2303), the study consists of 5 or 6  
periods – screening period, randomized withdrawal period, treatment period, open label period (OL) ,follow-up period and follow-up 2 period; For 
subjects classified as partial responders at Week 52 of the core study (e.g., CAIN457A2302 or CAIN457A2303), the study consists of 4 or 5 periods – 
screening period, treatment period, open label period ,follow-up period and follow-up 2 period; The screening period will be the duration between signing 
the informed consent form and randomization registered with Interactive Response Technology (IRT). 


Novartis 
Confidential 
Page 56 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
aSubjects would be randomized on the same day (Week 52) which is end of maintenance period of the core study (e.g.,CAIN457A2302 or 
CAIN457A2303). 
bRelapse visits (R1, R2 and R3) will have visit window of ±2 days. 
1These assessments are supported by and are stored with the source documentation. However, data regarding to which inclusion/exclusion criteria are 
not met are captured on the Inclusion/Exclusion Screen eCRF.  
2 Investigator must consider the baseline data of core study (e.g., CAIN457A2302 or CAIN457A2303) Demography eCRF, Smoking History eCRF, 
Cardiovascular History eCRF, Medical History eCRF, Psoriasis History eCRF, Psoriatic Arthritis History eCRF, and Prior Psoriasis Therapy eCRF at 
Week 52 before a subject enters the extension study. The data for these assessments at Week 52 visit for extension study will be same as the baseline 
data of the core study. 
3 Data for these assessments already have been collected at end of maintenance visit (Week 52) of the core study (e.g. CAIN457A2302 or 
CAIN457A2303). The data on the eCRFs for these assessments in extension study at Week 52 will be same as end of maintenance visit (Week 52) of 
the core study. AE and SAE data will be again collected after completion of core study Week 52 visit assessments. PASI response status from Week 52 
records of the core study to be entered in the IRT by the unblinded site personal from core study for randomization in the extension study. 
4 The data for this assessment to be collected freshly at Week 52 (randomization). 
5 Samples will be shipped to and analyzed by the central laboratory.  
6To be done for female subjects for whom local urine pregnancy test at end of maintenance period (Week 52) of core study is positive. The study drug 
treatment should not be given until the results confirm that subject is not pregnant. 
7If there is a positive urine pregnancy test, study treatment must be withheld and a serum pregnancy test must be done at the same visit. 
8Samples will be shipped by the sites and stored by the central laboratory. Samples will be shipped to reference laboratories for analysis. Each PK and 
IG sample is to be collected pre-dose.  
9An unscheduled IG and or PK sample is collected only to replace an IG or PK sample not taken at a regular scheduled visit. 
10 The PK blood sampling at these scheduled visits must be collected for all subjects. PK blood collections at other time points are “event driven” i.e., PK 
blood samples will only be collected in case of relapse.    
11Relapse visits (R1 to R3) are the visits in the treatment period. The time schedule for these 3 relapse visits will be different for each subject. A subject 
will make these relapse visits after a full relapse (a loss of >50% of the maximum PASI gain compared to baseline of the core study) occurred on the 
previous scheduled visit. PASI and IGA mod 2011 assessments, and data on AEs, SAEs and concomitant medications will be collected during these 3 
relapse visits. 12Rebound assessments to be done during the randomized withdrawal period as well as during the treatment period.  Note, the duration of 
randomized withdrawal period until the subject experiences the relapse is different for each subject and does not have definite end.  
13Unscheduled rebound assessment only to be done for an unscheduled visit that occurs during the follow-up period. 
14 Only for subjects with psoriatic arthritis (PsA) recorded on the Psoriatic Arthritis History eCRF during screening in core study.  


Novartis 
Confidential 
Page 57 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
15 The investigator must complete the core study Week 52 assessments, enter the PASI response on the eCRF and register the completion of Week 52 
visit in the IRT system of core study. Based on the fulfillment of inclusion/exclusion criteria by the subject and IRT notification from the database of core 
studies at Week 52, the investigator must call the IRT set up of extension study (CAIN457A2302E1). 
16 PASI and other assessments must be completed, entered into the eCRFs before calling the IRT at each site visit from Week 56 to Week 256. For 
Week 52 refer to footnote 14. 
17Patients who cannot self-administer medication at home may come to the site for administration of the medication. 
18 Informed consent for the extension amendment may  be obtained any time prior to the first open label study exposure. 
19 The visits at the sites are scheduled every 12 weeks, except for the visits between Week 192 - Week 208 and between Week 244 – Week 260, which 
are scheduled every 16 weeks. 
20  Dosing only to be performed if the subject  enters the open label treatment period. First treatment of the open label period will be administered at 
Week 156 once all assessments of Visit Week156 are performed, the call to IRT is done and the subject  has signed the revised informed consent for 
amendment 1. Placebo subjects who enter the open label period will be given once weekly s.c. injections of secukinumab for 4 consecutive weeks and 
then s.c. injections every 4 weeks. Any subject starting on secukinumab 150 mg may continue on 150 mg every 4 weeks or switch to 300 mg at Week 
156 or any other regular site visit if the investigator decides the subject would benefit from the higher dose.21 During follow-up 2 period unscheduled 
visits may include unplanned assessments like physical examinations, vital signs and laboratory assessments if investigator considers this necessary.


Novartis 
Confidential 
Page 58 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.1 
Information to be collected on screening failures  
All subjects who have signed an informed consent but who cannot or chose not to enter the 
randomized withdrawal or treatment period will be considered screen failures. The IRT must 
be called within 2 days and the reason for not being randomized will be entered on the Screening 
Phase Disposition electronic Case Report Form (eCRF). The Screening visit date, the 
Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion Criteria eCRF must be 
completed. If the subject has any SAE in the screening period (between signing the ICF and 
being randomized), the Adverse Event eCRF and a paper SAE form must be completed.  
If a subject fails to be treated in the extension study, the subject completes the follow-up visits 
in the respective core study. 
The Withdrawal of Consent eCRF should be completed if consent was withdrawn during the 
screening period before the subject was randomized. The Death eCRF should be completed in 
the case of a death. 
6.2 
Subject demographics/other baseline characteristics 
6.2.1 
Subject demographics 
The investigator must consider the baseline data of the core study (e.g., CAIN457A2302 or 
CAIN457A2303) Demography eCRF at Week 52 randomization visit before a subject enters 
the extension study.  
Subject demographic and baseline characteristics data to be collected on all subjects include: 
date of birth, age, sex, race, ethnicity, source of subject referral, prior and concomitant 
medications (relative to core studies), and relevant medical history/current medical condition 
present before signing informed consent. The demographic data of the extension study will be 
the same as the demographic data of the core study. 
6.2.2 
Other baseline characteristics 
The investigator must consider the baseline data of the core study (e.g., CAIN457A2302 or 
CAIN457A2303) Smoking History eCRF, Cardiovascular History eCRF, Medical History 
eCRF, Psoriasis History eCRF, Psoriatic Arthritis History eCRF, and Prior Psoriasis Therapy 
eCRF at Week 52 randomization visit before a subject enters the extension study. The data on 
these eCRFs in the extension study will be same as the data entered for these eCRFs in the core 
study. 
6.3 
Treatment exposure and compliance 
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record eCRF page. 
Compliance will be assessed by Novartis study personnel at each visit using box counts and 
information provided by the investigator and/or site staff. 


Novartis 
Confidential 
Page 59 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.4 
Efficacy 
All efficacy assessments should be performed prior to administration of study treatment. 
It is important to perform the IGA before the PASI, as the knowledge of PASI scoring can 
potentially influence how the evaluator scores the IGA. Therefore, the following order should 
be applied when performing the efficacy assessments during study visits: 
• Investigator’s Global Assessment (IGA mod 2011; scale from 0 – 4) 
• Psoriasis Area and Severity Index (PASI; score from 0 – 72) 
• Rebound assessment 
6.4.1 
Investigator’s global assessment (IGA mod 2011) 
IGA mod 2011 will be conducted for overall psoriatic disease as indicated in Table 6-1. It is 
recommended that the same evaluator conducts the assessment throughout the study whenever 
possible. 
The IGA mod 2011 rating scale for overall psoriatic disease is shown in Table 6-2. 
The IGA mod 2011 scale has been used in the core studies (e.g., CAIN457A2302 and 
CAIN457A2303), and in secukinumab phase II studies in collaboration with Health Authorities, 
in particular the FDA. 
The IGA mod 2011 used in this study is static, i.e., it refers exclusively to the subject’s disease 
state at the time of the assessments, and does not attempt a comparison with any of the subject’s 
previous disease states, whether at baseline of core study or at a previous visit. 
The IGA mod 2011 score will be recorded in the eCRF. 
Table 6-2 
The IGA mod 2011 rating scale 
Score 
Short 
description 
Detailed description 
0 
Clear 
No signs of psoriasis. Post-inflammatory hyperpigmentation may be 
present. 
1 
Almost clear 
Normal to pink coloration of lesions; no thickening; no to minimal 
focal scaling 
2 
Mild 
Pink to light red coloration; just detectable to mild thickening; 
predominantly fine scaling 
3 
Moderate 
Dull bright red, clearly distinguishable erythema; clearly 
distinguishable to moderate thickening; moderate scaling 
4 
Severe 
Bright to deep dark red coloration; severe thickening with hard edges; 
severe / coarse scaling covering almost all or all lesions 
Note: Involvement of nails is not part of the assessment. 
Based on this scale, a subject will be considered as IGA 0 or 1 responder if the subject achieves 
a score of 0 or 1 and improved by at least 2 points on the IGA scale compared to baseline. 
6.4.2 
Assessment of psoriasis area and severity index (PASI) 
The investigator or qualified designee will complete the PASI assessment as indicated in Table 
6-1. Whenever possible, the same evaluator should perform this assessment at all visits. 


Novartis 
Confidential 
Page 60 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 6-3. The head, trunk, upper limbs and lower limbs are assessed 
separately for erythema, thickening (plaque elevation, induration), and scaling (desquamation). 
The average degree of severity of each sign in each of the four body regions is assigned a score 
of 0-4. The area covered by lesions on each body region is estimated as a percentage of the total 
area of that particular body region. Further practical details help the assessment: 
1. The neck is assessed as part of the head. 
2. The axillae and groin are assessed as part of the trunk. 
3. The buttocks are assessed as part of the lower limbs. 
4. When scoring the severity of erythema, scales should not be removed. 
Table 6-3 
The PASI scoring system 
Body region 
Erythema  (E) 
Thickening (plaque 
elevation, induration, I) 
Scaling(desquamation) 
(D) 
Area score 
(based on 
true 
area %, A)* 
Head (H) †  
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Trunk (T) ‡ 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Upper limbs 
(U) 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Lower limbs 
(L) § 
 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
*Percentage (not score) of body region (not whole body) affected will be entered in the eCRF 
†Neck is assessed as part of the Head (H) body region. 
‡Axillae and groin are assessed as part of the Trunk (T) body region. 
§Buttocks are assessed as part of the Lower limbs (L) body region. 
Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 
10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated 
using the formula: 


Novartis 
Confidential 
Page 61 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
The keys for the letters are provided in Table 6-3. 
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0. 
The investigator is only responsible for collecting the components or scoring signs and total 
regional area. PASI calculations, including changes over time will be done by Novartis via the 
PASI Score eCRF. At Week 52, the investigator or qualified designee should ensure that all the 
information required for the PASI calculation was entered into the PASI Score eCRF at Week 
52 and that a PASI score is available prior to contacting IRT. The Investigator or qualified 
designee will enter the Week 52 PASI score into the IRT system at Week 52 before subject 
receives the study treatment. 
Based on PASI at Week 52, a subject to be eligible must be either a PASI 75 responder or partial 
responder according to the definitions stated below:  
• PASI 75 responders: subjects with PASI 75 response (subjects achieving ≥ 75% 
improvement [reduction] in PASI score compared to baseline of the core study) at Week 
52  
• Partial responders: subjects with PASI 50 response (subjects achieving ≥ 50% 
improvement [reduction] in PASI score compared to baseline of the core study, but not 
achieving a PASI 75 response) at Week 52  
During the study, at each visit, the PASI score will be calculated and response will be classified 
according to the definitions from CHMP guidelines for psoriasis CHMP/EWP/2454/ 02 2004  
• PASI 75 response: subjects achieving ≥ 75% improvement (reduction) in PASI score 
compared to baseline of the core study are defined as PASI 75 responders 
• PASI 50 response: subjects achieving ≥ 50% improvement (reduction) in PASI score 
compared to baseline of the core study are defined as PASI 50 responders 
• PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
compared to baseline of the core study are defined as PASI 90 responders 
• PASI 100 response/remission: complete clearing of psoriasis (PASI=0) 
• Relapse: when the achieved maximal PASI improvement from baseline of core study is 
reduced by >50% 
For subjects in PASI 75 responder group and entering the randomized withdrawal period, PASI 
response status at each visit (after Week 52 visit) will be calculated to determine if subject will 
enter the treatment period. PASI at the visit will be compared to the PASI baseline of the core 
study to assess if subject meets criteria for "first full relapse" (loss of >50% of maximum PASI 
gain compared to PASI baseline of the core study). Sites will have to enter relapse assessment 
into eCRFs and update the IRT at each visit in randomized withdrawal period. Subjects with 
first full relapse then stop randomized withdrawal period and enter treatment period.  
6.4.3 
Assessment of rebound 
Rebound of disease will be assessed as indicated in Table 6-1.  


Novartis 
Confidential 
Page 62 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
In addition to the assessment of PASI, the investigator will assess whether new pustular 
psoriasis, or new erythrodermic psoriasis, or more inflammatory psoriasis occurred (yes/no). 
Definitions related to rebound 
• Rebound: A Subject experiences a rebound, if PASI increases to > 125% of baseline 
(where baseline is the PASI at the randomization of the core study) PASI, or if new 
pustular psoriasis, or new erythrodermic psoriasis, or more inflammatory psoriasis occurs 
within 8 weeks after the last dose of study treatment has been administered. 
6.4.4 
Appropriateness of efficacy assessments  
The PASI score, the assessment of the severity of the psoriasis symptoms and the extent to 
which the subject’s body area is affected by the disease, is considered acceptable by Health 
Authorities (CHMP/EWP/2454/02 2004) to assess efficacy in conjunction with IGA mod 2011. 
6.5 
Safety 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered. 
• Evaluation of all AEs and SAEs including injection site reactions  
• Physical examination 
• Vital signs 
• Laboratory assessments 
• Hematology 
• Clinical chemistry 
• Urinalysis 
• Immunogenicity (IG; assessment of anti-secukinumab antibody development) 
• ECG  
• Pregnancy and assessments of fertility 
See Table 6-1  
6.5.1 
Physical examination  
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems will 
be performed as indicated in Table 6-1. 
 If possible, assessments for an individual subject should be performed by the same member of 
the study site staff throughout the study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the signing of the informed consent form 
will have been already entered during core study in the Medical History screen on the subject’s 
eCRF. Significant findings made after signing informed consent which meet the definition of 
an AE must be recorded on the Adverse Event screen of the subject’s eCRF (see Section 7). 


Novartis 
Confidential 
Page 63 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.5.2 
Vital signs  
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 6-1.  
After the subject has been sitting for five minutes, with back supported and both feet placed on 
the floor, systolic and diastolic blood pressure will be measured twice (measurements separated 
by 1 to 2 minutes) using a validated device, with an appropriately sized cuff. In case the cuff 
sizes available are not large enough for the subject's arm circumference, a sphygmomanometer 
with an appropriately sized cuff may be used (Mancia et al 2007). On the Vital Signs eCRF, the 
average of the two measurements will be entered. If possible, assessments should be performed 
by the same study site staff member throughout the study. 
Normal blood pressure will be defined as a systolic pressure of 90 to <120 mmHg, and a 
diastolic blood pressure of 60 to <80 mmHg under the measurement conditions outlined above. 
Notable blood pressure will be hypertension (systolic ≥140 mmHg and/or diastolic ≥ 90 mmHg) 
or hypotension (systolic <90 mmHg and/or diastolic <60 mmHg). A blood pressure indicative 
of prehypertension (systolic 120 to < 140 mmHg and/or diastolic 80 to < 90 mmHg) will not be 
regarded as notable (Chobanian et al 2003). A normal pulse rate will be defined as a rate of 60 
to 100 beats per minute under the measurement conditions outlined above. Notable pulse rates 
are a rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia). 
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 subject. No specific action is foreseen 
as part of the study protocol. 
6.5.3 
Height and weight  
Height and body weight will be measured as listed in Table 6-1. Height and body weight will 
be measured in indoor clothing, but without shoes. If possible, body weight assessments should 
be performed by the same study site staff member and using the same scale throughout the 
study. The body weight recorded at Week 52 will be used to stratify the subject population for 
randomization at Week 52. 
6.5.4 
Laboratory evaluations  
Subjects should avoid smoking within the hour preceding the blood draws. A central laboratory 
will be used for analysis of all specimens listed below, unless noted otherwise. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. Refer the Laboratory Manual for identification of 
laboratory reference range values and the schema for notification of site staff and Novartis for 
out of range values. 
Appendix 1 shows the extended laboratory ranges that are considered clinically notable. 
Whether action needs to be taken to address notable laboratory values will be decided by the 
investigator, taking into account the overall status of the subject. No specific action is foreseen 
as part of the study protocol. 


Novartis 
Confidential 
Page 64 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured at all scheduled study visits, within the visit window specified in Table 
6-1. 
Clinical chemistry 
Serum chemistries will include urea, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), 
GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, total 
protein, albumin, uric acid, amylase and lipase.  Serum chemistries will be measured at all 
scheduled study visits within the visit window specified in Table 6-1. 
Local urinalysis 
Dipsticks will be provided by the central laboratory to the study sites for local urinalysis 
assessments. The sites will record the results in the appropriate eCRF page for each subject. 
Standard dipstick measurements for specific gravity, protein, glucose, pH, blood, urine blood 
dipstick (non-hemolyzed), urine blood dipstick (hemolyzed), bilirubin, ketones and WBC will 
be done at scheduled visits as indicated in Table 6-1. 
Immunogenecity (IG) 
Blood samples for IG (anti-secukinumab antibodies) will be taken pre-dose at the scheduled 
timepoints as indicated in Table 6-1 and Appendix 2, Table 13-2. Blood samples (approximately 
2 mL) will be collected into serum separator tubes (SST). The blood sample will be allowed to 
clot over a minimum of 30 minutes at room temperature prior to harvesting of the serum. The 
serum will be obtained by centrifugation at approximately 2500 revolutions per minute (rpm) 
for 10 minutes. 
Serum samples will be placed on ice, split into 2 aliquots (labeled plain barrier polypropylene 
tubes) and then stored (within 30 minutes of collection) at approximately -70°C to -20°C prior 
to shipment on dry ice to the central laboratory. Shipment of stored aliquots from the site to the 
central lab should be on a monthly basis. To the extent possible, the site should send each aliquot 
to the central laboratory separately. If a study site does not have the facility to store aliquots at 
the conditions specified, then they will maintain the sample on dry ice at the site and ship on 
dry ice on the day of collection. The central lab will ship one aliquot of the samples on dry ice 
to the analytical laboratory. The remaining aliquots must be kept at the central lab as a backup 
sample. Remaining samples will only be disposed of after approval by the Clinical Trial Head 
(typically 6 to 12 months after the clinical study report [CSR] is published). 
All blood samples will be taken by direct venipuncture. The actual sample collection date and 
exact time of collection will be entered on the Blood collection for IG eCRF or the Unscheduled 
blood collection for IG eCRF, as appropriate. Sampling problems will be noted in the ‘Reason 
sample not taken’ section of the eCRF. 
A laboratory manual will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment. 


Novartis 
Confidential 
Page 65 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Tubes and labels will be provided by the central laboratory with study/sample type and sample 
number preprinted on the label. 
Further details on labeling of the IG samples can be found in Appendix 3, Section 13.3.2. 
6.5.5 
Electrocardiogram (ECG)  
A standard 12-lead ECG will be performed as indicated in Table 6-1. At each visit when an 
ECG is done, the investigator must review and initial the tracing. The tracing must then be 
stored with the subject's source documents. 
All ECGs must be performed on the ECG machines provided to the study site. All ECGs will 
be independently reviewed by a central reader. Instructions for the collection and transmission 
of the ECGs to the independent reviewer will be provided in the ECG investigator manual. 
Even though there is no exclusion criterion specifically based on the ECG, clinically significant 
findings from the ECG assessment made at Week 52 of the core study must be discussed with 
the Novartis Medical Monitor prior to enrolling the subject in the extension study. 
If the ECG findings are clinically relevant and would prevent the subject from participating in 
the study (taking into account the subject's overall status as well as the medication profile), the 
subject should not receive study treatment. 
6.5.6 
Pregnancy and assessments of fertility  
Before entering the extension study, the investigator must consider the results of serum β-hCG 
test already performed on all women of child-bearing potential at the time of entering the core 
studies (e.g., CAIN457A2302 and CAIN457A2303). 
All women of child-bearing potential who are eligible to participate in this extension study will 
have a local urine pregnancy test as indicated in Table 6-1. If positive, they will undergo a 
serum pregnancy evaluation conducted at the central laboratory 
Any woman whose resulting pregnancy test is positive (based on serum β-hCG as defined by 
the central laboratory) at the randomization visit Week 52 will have to discontinue from this 
extension study and return to the follow-up assessments in the core study. 
A positive urine pregnancy test during the treatment periods of the study requires immediate 
interruption of study treatment until serum β-hCG is performed and found to be negative. If the 
serum β-hCG test is positive, the subject must be discontinued from the trial (see Section 5.5.10) 
6.5.7 
Appropriateness of safety measurements  
The safety measures used in this study are reliable and relevant standard measures for a biologic 
immunomodulating agent in psoriasis.  
6.6 
Other assessments 
These includes (as indicated in Table 6-1) 
• Waist circumference and hip circumference  
• Fasting laboratory evaluations,  
• HRQoL assessments such as 


Novartis 
Confidential 
Page 66 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
1. DLQI© 
2. EQ-5D© 
3. HAQ©-DI (subjects with PsA at baseline of the core study) 
• PK assessments will be done as indicated in Table 6-1.  
  
Note: EQ-5D assessments will not be performed during the open label period. 
6.6.1 
Waist circumference and hip circumference 
Waist and hip circumference (cm or inches) will be measured twice and recorded in the source 
documentation by the investigator (or designee) at scheduled visits as indicated in Table 6-1. 
The average of the two measurements will be recorded in the eCRF. Waist/hip circumference 
ratio will be calculated from the waist and hip circumference measurements. Waist and hip 
circumference will be measured as follows (WHO Document, 1988, Lohman TG, 1988). 
The subject should stand with weight evenly balanced on both feet 25-30 cm apart. Mark the 
level of the lowest rib margin with a marker pen, palpate the iliac crest in the mid-axillary line 
and mark this level on the skin as well. Apply an elastic tape (e.g., a narrow string of silk covered 
elastic rubber band) horizontally midway between the lowest rib margin and the iliac crest (this 
is to assist in defining the levels of the waist circumference). The tape should be tied firmly 
enough to stay in position around the abdomen about the level of the umbilicus. 
The subject should be asked to breathe normally and at the time of making the measurements, 
the subject should be asked to breathe out gently to prevent from contracting their muscles or 
holding their breath. Measure the circumference of the tape using a plastic tape measure (not 
elastic or metal). 
Repeat the above with the elastic tape around the point yielding the maximum circumference 
over the buttocks. 
It is recommended that the observer sits in front of the subject and that the same study site staff 
member carries out the assessment throughout the study wherever possible 
Note: waist and hip  circumference will not be performed during the open label period. 
6.6.2 
Fasting laboratory evaluations 
Fasting (8 hour duration with water ad libitum) laboratory tests will be assessed as indicated in 
Table 6-1. 
Subjects should avoid smoking within the hour preceding the blood draws. 
A central laboratory will be used for analysis of all fasting laboratory specimens. Details of the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to the investigators in the Laboratory Manual. 
6.6.2.1 
Plasma glucose 
Fasting plasma glucose will be taken as a fasting blood sample at scheduled visits as indicated 
in Table 6-1. 


Novartis 
Confidential 
Page 67 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.6.2.2 
Lipid panel 
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol, triglycerides, lipoprotein (a), apolipoprotein B, apolipoprotein A-1, and adiponectin 
will be measured from a fasting blood sample at scheduled visits as indicated in Table 6-1. 
6.6.3 
Resource utilization  
Not applicable. 
6.6.4 
Health-related Quality of Life (HRQoL) 
The impact of psoriasis on various aspects of subject’s HRQoL will be assessed by the 
following validated instruments: 
• Dermatology Life Quality Index© (DLQI©) 
• EuroQOL 5-Dimension© Health Status Questionnaire (EQ-5D©) 
• Health Assessment Questionnaire©- Disability Index (HAQ©-DI) (subjects with PsA at 
baseline of core study) 
At the appropriate scheduled visits (see Table 6-1), questionnaires are to be completed by each 
subject in the language with which she/he is most facile, and before she/he sees the investigator 
for clinical assessments. Responses will be collected using digitized paper with a digital pen. 
The digitized paper will serve as source documentation; the pen will be transferred to its 
docking station for transmittal of the subject’s responses to the vendor’s database. Subjects are 
to initial and date the white box (and not the shaded area of the form) at the bottom left hand 
portion of the last page of the questionnaire. In those countries not permitting subjects to initial 
documents, the date and 3-letter initials of the country in which the subject participates is to be 
used. By ensuring that the initials are placed in the white box, the subject’s initials will not be 
copied when the digital pen activates its camera to record a digitized copy of the completed 
questionnaires. The digitized pen writes in green ink. Only this pen may be used for making 
corrections and only the subject may make corrections. Corrections must be “single-lined” 
through, and should be dated and where permitted, initialed by the subject. 
The subject is to be given sufficient space and time to complete the questionnaires. The study 
coordinator is to check the questionnaires for completeness and encourage the subject to 
complete any missing responses. The original questionnaires will be kept with the subject’s file 
as source documentation.  
Completed questionnaires will be reviewed and examined by a blinded staff member at the site 
(not the investigator or evaluator of the subject for the physician assessments), before the 
clinical examination, for responses that may indicate potential AEs or SAEs. The investigator 
is to review not only the responses to the questions in the questionnaires but also to look for 
unsolicited comments written by the subject. If AEs or SAEs are confirmed by the investigator, 
then she/he must record the events as per instructions given in Section 7 of the protocol. 
Investigators and study coordinators are not to encourage subjects to change the responses 
reported in the completed questionnaires. Study coordinators are to complete the header 
information at the top of the questionnaire prior to distributing it to the subjects. 


Novartis 
Confidential 
Page 68 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
6.6.4.1 
Dermatology Life Quality Index© (DLQI©) 
The DLQI© is a 10-item general dermatology disability index designed to assess HRQoL in 
adult subjects with skin diseases such as eczema, psoriasis, acne, and viral warts (Finlay and 
Khan, 1994). The measure is self-administered and includes domains of daily activities, leisure, 
personal relationships, symptoms and feelings, treatment, and work/school. The measure is 
widely used: it has been tested across 32 different skin conditions and is available in 55 
languages. The recall period is the last week, and the instrument requires 1 to 2 minutes for 
completion. 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 HRQoL impairment. 
Additionally, each subscale of the DLQI© may be analyzed separately.  
The DLQI© questionnaire (date of publication 1994) will be completed by the subject as 
indicated in Table 6-1. 
6.6.4.2 
EuroQOL 5-Dimension© (EQ-5D©) Health Status Questionnaire 
The EQ-5D© is a generic instrument to assess each subject’s health status. It provides a simple 
descriptive profile and a single index value for health status. The instrument essentially consists 
of 2 pages – the EQ-5D© descriptive system and the EQ visual analog scale (VAS). The EQ-
5D© descriptive system comprises the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. 
Each dimension has 3 response levels: no problems, some problems, severe problems. The 
subject is asked to indicate her/his health state by ticking (or placing a cross) in the box against 
the most appropriate statement in each of the 5 dimensions. 
The VAS records the respondent’s self-rated health on a vertical scale where the endpoints are 
labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’. This information 
can be used as a quantitative measure of health outcome as judged by the individual 
respondents. 
The EQ-5D© questionnaire (date of publication 1990) is to be completed by the subject at the 
visits indicated in Table 6-1. 
6.6.4.3 
Health Assessment Questionnaire©- Disability Index (HAQ©-DI) 
(subjects with PsA only) 
The HAQ© was developed by Stanford University and is one of the most widely used measures 
to assess the long-term influence of chronic disease on a subject's level of functional ability and 
activity restriction. Although originally developed for use in subjects with rheumatic disease, 
the HAQ© has been employed across a large variety of disease areas. The disability assessment 
component of the HAQ©-DI, assesses a subject's level of functional ability and includes 
questions of fine movements of the upper extremity, locomotor activities of the lower extremity, 
and activities that involve both upper and lower extremities. There are 20 items in eight 
categories of functioning including dressing & grooming, arising, eating, walking, hygiene, 
reach, grip, and usual activities. The stem of each item asks over the past week "Are you able 
to …" perform a particular task. Each item is scored on a 4-point scale from 0 to 3, representing 
normal (without any difficulty [0]), with some difficulty (1), with much difficulty (2), and 


Novartis 
Confidential 
Page 69 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
unable to do (3). The HAQ©-DI also includes questions about the use of ‘aids or devices’ and 
aid from other people to supplement the answers given to the 20 items.  
The purpose of the HAQ©-DI in this study is to assess the functional ability of subjects with 
PsA at baseline of the core study. 
The HAQ©-DI questionnaire will be completed by the subject as indicated in Table 6-1 by all 
subjects with a medical history of PsA recorded on the Psoriatic Arthritis History eCRF during 
the screening period of the core study. 
6.6.5 
Pharmacokinetics  
At all study sites, blood samples will be collected for PK at the scheduled visits as indicated in 
Table 6-1. 
For a detailed description of the blood sampling schema, including time points, refer to the 
Blood Log in Appendix 2, Table 13-1.  
All blood samples will be taken by direct venipuncture. Blood samples (approximately 2 mL, 
not less than 1.5 mL) will be collected into SST. The blood sample will be allowed to clot over 
a minimum of 30 minutes at room temperature prior to harvesting of the serum. The serum will 
be obtained by centrifugation at approximately 2,500 rpm for 10 minutes. 
Serum samples will be placed on ice, split into 2 aliquots (polypropylene tubes) and then stored 
(within 30 minutes of collection) at -70°C to -20°C (approximately) prior to shipment to the 
central laboratory. Shipment of stored aliquots from the site to the central lab should be on a 
monthly basis. To the extent possible, the site should send each aliquot to the central laboratory 
separately. If a study site does not have the facility to store aliquots at the conditions specified, 
then samples must be stored on dry ice at the site and shipped on dry ice on the day of collection. 
The central lab will ship one aliquot of the samples on dry ice to the analytical laboratory. The 
remaining aliquots must be kept at the central lab as a backup sample. Remaining samples will 
only be disposed of after approval by the Clinical Trial Head (typically 6 to 12 months after the 
Clinical study report (CSR) is published). 
The actual sample collection date and exact time of collection will be entered on the Blood 
collection for PK eCRF or the Unscheduled blood collection for PK eCRF, as appropriate. 
Sampling problems will be noted in the ‘Reason sample not taken’ section of the eCRF. 
PK sample handling, labeling and shipment instructions 
A laboratory manual will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment. Tubes and labels will be provided by the 
central laboratory with study/sample type and sample number preprinted on the label. 
Further details on labeling of the PK samples can be found in Appendix 3, Section 13.3.1. 
PK sample stability 
Secukinumab is stable in serum samples for at least 20 months at -20°C or at -80°C.   


Novartis 
Confidential 
Page 70 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
PK analytical methods 
An Enzyme-Linked Immunosorbent Assay (ELISA) method will be used for bioanalytical 
analysis of secukinumab in serum, with an anticipated lower limit of quantification (LLOQ) of 
80 ng/mL. The detailed method description to assess secukinumab concentration will be 
described in the bioanalytical raw data of the study and in the respective BDR. 
6.6.7 
Other biomarkers  
Not applicable. 
6.6.8 
Prospective suicidality assessment 
Not applicable. 
7 
Safety monitoring  
7.1 
Adverse events 
An 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 study 
treatment. Medical conditions/diseases present before starting study treatment are only 
considered AEs if they worsen after starting study treatment. Abnormal laboratory values or 
test results constitute AEs only if they induce clinical signs or symptoms, are considered 
clinically significant, or require therapy. 
The occurrence of AEs should be sought by non-directive questioning of the subject at each 
visit or each telephone call during the study. AEs also may be detected when they are 
volunteered by the subject during or between visits or through physical examination, laboratory 
test, or other assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  


Novartis 
Confidential 
Page 71 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
• they require therapy.  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease.  
The investigator must consider the AEs still ongoing at Week 52 of the core study (e.g., 
CAIN457A2302 or CAIN457A2303) at the time a subject enters the extension study. The 
ongoing AEs from the core study will be followed to final outcome in the extension study 
clinical trial database. New AEs with onset while subject is in the extension study will be 
entered in the Adverse Event eCRF of the extension study. 
Investigators have the responsibility for managing the safety of individual subject and 
identifying adverse events. Alert ranges for labs and other test abnormalities are included in 
Appendix 1. 
AEs should be recorded in the Adverse Events eCRF under the signs, symptoms or diagnosis 
associated with them accompanied by the following information. 
• The severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study treatment (suspected: Yes or No) 
• its duration (start and end dates) or if continuing at final examination)  
• whether it constitutes a SAE  
• action taken with study treatment 
• concomitant medications taken 
• outcome and  
• whether the AE led to study discontinuation 
An SAE is any AE (appearance of [or worsening of any pre-existing] undesirable sign[s], 
symptom[s] or medical conditions[s]) which meets any one of the following criteria  
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• 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  


Novartis 
Confidential 
Page 72 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, i.e., defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see Section 7.2. 
All AEs should be treated appropriately. The action taken to treat the AE should be recorded 
on the Adverse Event eCRF.  
AEs that occur after informed consent has been obtained must be captured on the Adverse event 
eCRF. Once an AE is detected, it should be followed until its resolution or until it is judged to 
be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study 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 IB or will be communicated between IB updates in the form of Investigator 
Notifications (IN). This information will be included in the informed consent given to the 
subject and should be discussed with the subject during the study as needed. 
The investigator should also instruct each subject to report any new AE (beyond the protocol 
observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events 
To ensure patient safety, every SAE, regardless of causality, occurring during  following time 
periods must be reported to Novartis within 24 hours of learning of its occurrence:  
• after the subject has provided informed consent and until 12 weeks after the last 
administration of study treatment or 30 days after the subject has stopped the study 
participation (defined as last visit of the study at Week 268)  for subjects who don’t 
enter follow-up 2 period  
• after the subject has provided informed consent and until the last telephone contact for 
patients who enter follow-up 2 period  
Any SAEs experienced after these periods 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. 


Novartis 
Confidential 
Page 73 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Information about all SAEs (either initial or follow-up information) is collected and recorded 
on the paper Serious Adverse Event Report Form (SAE report form) or where available the 
Serious Adverse Event Form within the remote data capturing (RDC) system. The investigator 
must assess the relationship to each specific study treatment and complete the paper or 
electronic SAE report form in its entirety in English.  
When SAEs are recorded on the paper SAE form, these should be faxed within 24 hours of 
awareness of the SAE to the local Novartis Drug Safety and Epidemiology (DS&E) 
Department. The telephone and fax number of the contact persons in the local department of 
DS&E, specific to the site, are listed in the investigator folder provided to each site. The original 
copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. 
When SAEs are recorded electronically in the Oracle Clinical/ Remote Data Capture (OC/RDC) 
system, these should be entered, saved and e-signed within 24 hours of awareness of the SAE. 
These data will automatically be submitted to Novartis DS&E immediately after investigator 
signature or 24 hours after entry, whichever occurs first. 
The Investigator must assess the relationship to the study treatment.  
Note that any follow-up information provided should describe whether the event has resolved 
or continues, if and how it was treated, whether the blind was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a DS&E Department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN) to inform all investigators involved in any study with the 
same investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. 
7.3 
Pregnancy reporting  
To ensure subject safety, each pregnancy occurring while the subject is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the local Novartis DS&E Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
treatment 
Any SAE experienced during pregnancy must be reported on the SAE Report Form. 


Novartis 
Confidential 
Page 74 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
7.4 
Data Monitoring Committee 
A data monitoring committee (DMC) will review the safety data of this trial at selected time 
intervals at least until the Week 68 PEA. Details regarding the DMC process will be available 
in relevant secukinumab DMC charter. 
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 eCRFs with the investigators and their staff. During 
the study, the field monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the eCRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original ICF signed by the subject and a 
signed copy is given to the subject. 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and of data that will be used for all primary and safety variables. Additional checks 
of the consistency of the source data with the eCRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the subjects 
will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The investigator must certify that 
the data entered into the eCRFs are complete and accurate. After database lock, the investigator 
will receive copies of the subject data for archiving at the investigational site.  
8.3 
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the eCRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 


Novartis 
Confidential 
Page 75 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
any required corrections or additions. Novartis personal will not make any corrections or 
additions to the data. Queries are sent to the investigational site using an electronic data query. 
Designated investigator site staff is required to respond to the query and confirm or correct the 
data. If the electronic query system is not used, a paper Data Query Form will be faxed to the 
site. Site personnel will complete and sign the faxed copy and fax it back to Novartis staff that 
will make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site. 
Concomitant medications entered into the database will be coded using the World Health 
organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and AEs will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
Subjects will use electronic pens to enter data on HRQoL tools. This data will be processed 
centrally and the results will be sent electronically to Novartis (or a designated CRO). 
Randomization codes and data about all study treatment dispensed to the subject and all IVR 
recorded dosage changes will be tracked using an IRT. The system will be supplied by a vendor, 
who will also manage the database. The database will be sent electronically to Novartis (or a 
designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
9 
Data analysis 
Treatment groups for analysis will include: 
• Subjects who were PASI 75 responders at Week 52 
• Secukinumab 150 mg 
• Secukinumab 300 mg 
• Placebo (secukinumab 150 mg in core studies) 
• Placebo (secukinumab 300 mg in core studies) 
• Subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg 
• Secukinumab 150 mg 
• Secukinumab 300 mg 


Novartis 
Confidential 
Page 76 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
• Subjects who were partial responders at Week 52 
• Secukinumab 150 mg 
• Secukinumab 300 mg 
For open-label period analyses subjects being switched from 150 mg to 300 mg will be 
summarized as well. 
NOTE: Week 52 assessments refer to Baseline extension assessments 
9.1 
Analysis sets  
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set. Mis-randomized subjects will be defined as those subjects where IRT 
contact is made by the site either prematurely or inappropriately prior to confirmation of the 
subject’s final randomization eligibility and double-blind study treatment was not administered 
to the subject. 
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be analyzed according to the treatment assigned to at randomization, but actual stratum, if 
stratified randomization is used. 
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. Subjects will be analyzed according to treatment received. 
9.2 
Subject demographics and other baseline characteristics  
Demographics and baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects. 
Medical history 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. 
To establish a baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether or not a subject currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not occur for 
that subject. 


Novartis 
Confidential 
Page 77 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Psoriasis specific medical history will be summarized by treatment group. Previous treatments 
for psoriasis and whether or not response was achieved will be summarized by treatment group. 
All the medical history information will be retrieved from the core studies. 
9.3 
Treatments 
Study treatment 
The analysis of study treatment data will be based on the safety set. 
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of subjects with cumulative exposure levels (e.g., any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented. 
Prior and concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term. 
The number and percentage of subjects receiving different classes of prior psoriasis therapy 
(biologic systemic therapy, non-biologic systemic therapy, topical, phototherapy, 
photochemotherapy) will be presented by treatment group as well as the reasons for stopping 
their previous prior psoriasis therapies (primary lack of efficacy, secondary lack of efficacy, 
lack of tolerability, other) and the total duration of exposure to psoriasis therapies previously. 
Prior concomitant medications will be retrieved from the core studies. 
9.4 
Analysis of the primary variable 
9.4.1 
Variable 
The primary variable is the cumulative rate of subjects who lost PASI 75 response up to Week 
68 (time=0 being defined as Week 52). 


Novartis 
Confidential 
Page 78 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypotheses are that the cumulative rate for subjects who lost PASI 75 response 
up to Week 68 are not different between secukinumab 150 mg and corresponding placebo as 
well as between secukinumab 300 mg and corresponding placebo. 
Let pj(t) denote the proportion of PASI 75 responders at time t for treatment group j, and let 
p0,j(t) denote the proportion of PASI 75 responders at time t for placebo group j, j=1, 2, where  
• 0,j corresponds to placebo (secukinumab 150 mg in core studies) for j=1 and to placebo 
(secukinumab 300 mg in core studies) for j=2, 
• 1 corresponds to secukinumab 150 mg, 
• 2 corresponds to secukinumab 300 mg. 
The following hypotheses will be tested for 52 weeks≤ t ≤68 weeks 
• H1: p1(t) – p0,1(t) = 0 versus HA1: p1(t)– p0,1(t) ≥ 0, 
• H2: p2(t) – p0,2(t) = 0 versus HA2: p2(t) – p0,2(t) ≥ 0, 
In other words 
• H1: Secukinumab 150 mg is not different from placebo with respect to the cumulative rate 
for subjects who lost PASI 75 response up to Week 68 
• H2: Secukinumab 300 mg is not different from placebo with respect to the cumulative rate 
for subjects who lost PASI 75 response up to Week 68 
Number and percentage of subjects with loss of PASI 75 response based on the number of 
subjects in the full analysis set at risk as denominator will be provided by treatment group.  
For loss of PASI 75 response, between-treatment differences will be evaluated using a log-rank 
test, stratified by geographical region and body weight stratum, to compare the survival 
functions between secukinumab treatment groups versus placebo. The hazard ratios for these 
comparisons for loss of PASI 75 response and their corresponding 95% confidence intervals 
will be computed using a stratified Cox proportional hazards regression model with treatment 
group, core study and baseline PASI of core study and baseline PASI of extension study as 
explanatory variable and stratified by geographical region and body weight stratum. The 
primary analysis will be the log-rank test. Subjects who have not lost PASI 75 response up to 
Week 68 will be considered as censored observations. 
The Kaplan-Meier estimates of the (1 minus cumulative rate loss of PASI 75 response) for each 
treatment will be plotted. The plot will include the number of subjects at risk for each treatment 
group at pre-specified time points (e.g., visits). 
The number of subjects with loss of PASI 75 response, number of subjects in the analysis set, 
estimate of cumulative rate up to Week 68, median event time, and its estimated standard error, 
as estimable will be provided for each treatment group. In addition, for pre-specified time 
intervals (e.g., 4-week intervals) the following will be presented: 
• for each treatment group and time interval: subjects at risk, subjects with loss of PASI 75 
response, subjects with loss of PASI 75 response divided by subjects at risk, cumulative 
subjects with event and cumulative event probability including 95% confidence interval. 


Novartis 
Confidential 
Page 79 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
• for treatment comparisons the hazard ratio derived via Cox regression as well as log-rank 
test and Wilcoxon test. 
Separate analyses will be performed for comparison of 150 mg secukinumab with placebo and 
300 mg secukinumab with placebo. The two placebo groups will not be pooled for this analysis. 
Testing strategy 
The familywise error will be set to α=2.5% (one-sided). The two hypotheses H1 (referring to 
150 mg) and H2 (referring to 300 mg) will be tested at α/2=1.25% one-sided. In case, a null 
hypothesis has been rejected for one dose, but not for the other dose, the alpha can be shifted to 
the other dose and the null hypotheses can be retested at level α=2.5% (one-sided). The 
graphical approach of [Bretz et al (2009)] for sequentially rejective testing procedures is used 
to illustrate the testing strategy (Figure 9-1): 
Figure 9-1 
Testing strategy 
 
Other secondary endpoints will not be included in the testing strategy. 
9.4.3 
Handling of missing values/censoring/discontinuations 
For the primary analysis subjects who did not lose PASI 75 response before Week 68 but with 
missing values at Week 68 will be considered as censored. Other time-to-event analyses will be 
handled analogously. 
For other analyses (not time to event) missing values with respect to response variables based 
on PASI score and IGA mod 2011 score will be imputed with non-response regardless of the 
reason for missing data (e.g., premature study discontinuation, missed visit, administrative 
issues).  
Following the intent-to-treat principle for subjects who prematurely discontinue treatment, but 
who are observed in the follow-up period, efficacy data collected in follow-up periods will be 
linked to planned but missed study visits as well, following imputation schemes described in 
the analysis plan (e.g., if a subject discontinues treatment at Week 56, but has follow-up visit 
F4, the PASI score observed at Visit F4 might be used for Week 60 assessments). 
The last observation carried forward method will be applied to PASI score and IGA mod 2011 
score. Note, that responses based on PASI score or IGA mode will be imputed differently as 
described above. 
If all post Randomization Visit efficacy values are missing for one efficacy parameter then these 
missing values will not be imputed and this subject will be removed from the analysis of the 
corresponding variable, i.e., it might be that the number of subjects providing data to an analysis 


Novartis 
Confidential 
Page 80 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
is smaller than the number of subjects in the FAS. In addition, missing baseline values will not 
be imputed. 
9.4.4 
Supportive analyses 
Sensitivity analyses will be performed as follows: 
• Subjects fulfilling at least one of the following criteria will be classified as non-responders 
with respect to PASI 75 and IGA 0 or 1 response at Week 68 and the Cox proportional 
hazards regression analysis of the primary analysis will be repeated: 
• subjects with missing injection (s) up to Week 68,  
• dropouts due to AEs, unsatisfactory therapeutic effect up to Week 68, and 
• subjects with missing data at Week 68.  
• PASI 75 will be evaluated using Cox proportional hazards regression as described above 
with multiple imputations instead of non-responder imputation for missing values. Within 
this analysis the PASI score will be imputed and response variables will be derived based 
on the imputed scores. For each treatment group values will be imputed separately. 
Further details will be given in the analysis plan. 
In addition, the secukinumab treatment groups will also be compared, i.e. a Cox proportional 
hazards regression will be fitted as described above including all four treatment groups. Placebo 
(secukinumab 150 mg in core studies) and Placebo (secukinumab 300 mg in core studies) will 
be compared as well as secukinumab 150 mg and secukinumab 300 mg. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
Subjects who were PASI 75 responders at Week 52 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit 
will be presented in contingency tables and will include absolute and relative frequencies. 
Confidence intervals for response rates will be derived as well based on the score method 
including continuity correction (Newcombe, 1998). 
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response at each visit, each 
secukinumab dose regimen will be compared to placebo (up to last visit with more than 5% of 
subjects in placebo group) by means of the stratified Cochran-Mantel-Haenszel-test as well as 
by means of a logistic regression model with treatment group, geographical region, body weight 
stratum, and baseline PASI as effects. 
For PASI 50, PASI 75, PASI 90 and IGA 0 or 1 response the placebo-adjusted response rates 
including 95% confidence interval (based on normal approximation) will be derived by visit. 
Figures will be provided as well displaying estimates for responder rates by treatment including 
confidence intervals. 


Novartis 
Confidential 
Page 81 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Subjects that were re-randomized at Week 52, hence who PASI 75 responder will be split into 
two subgroups based on the IGA 0 or 1 response at Week 52. For each of these subgroups 
summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit 
will be presented in contingency tables and will include absolute and relative frequencies. 
Loss of PASI 75 response over time 
The loss of PASI 75 response will be repeated, but not truncated at Week 68 and subjects who 
did not lose PASI 75 response up to Week 68 will not be considered as censored. In addition, 
the secukinumab treatment groups will also be compared, i.e. a Cox proportional hazards 
regression will be fitted as described above including all four treatment groups. Placebo 
(secukinumab 150 mg in core studies) and Placebo (secukinumab 300 mg in core studies) will 
be compared as well as secukinumab 150 mg and secukinumab 300 mg. 
Loss of IGA 0 or 1 response over time 
Loss of IGA 0 or 1 response over time will be analyzed analogously to the loss of PASI 75 
response, but it will be restricted to the subset of subjects who have been IGA 0 or 1 responder 
at Week 52. 
PASI score over time 
Summary statistics will be provided for absolute PASI scores as well as for percent change from 
baseline by visit and treatment group. Figures will also be provided. 
IGA mod 2011 score over time 
Summary statistics for the IGA mod 2011 score over time will be presented by visit and 
treatment group in contingency tables. 
Relapse 
Relapse will be analyzed analogously to loss of PASI 75 response. Additional analyses will be 
performed for relapses observed in the follow-up period. 
Rebound 
Rebound is defined as a worsening of PASI of > 125% of the value at baseline (core study), or 
new pustular, erythrodermic or more inflammatory psoriasis occurring within 8 weeks of 
stopping therapy (i.e., if this definition is fulfilled at more than 8 weeks after last study treatment 
administration, this is not defined as rebound). The number and percentage of subjects 
experiencing rebound will be presented by visit and treatment group. 


Novartis 
Confidential 
Page 82 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg 
Time to PASI 75 response 
Kaplan-Meier estimates including 95% confidence intervals for cumulative rate of subjects 
gaining PASI 75 response after relapse will be calculated (time point of re-initiation of 
secukinumab therapy will be defined as time zero).  
Time to IGA 0 or 1 response 
Time to IGA 0 or 1 response will be analyzed analogously to time to PASI 75 response but 
limited to the subset of subjects who were not IGA 0 or 1 responder at time of relapse. 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit 
after relapse will be presented in contingency tables and will include absolute and relative 
frequencies. Confidence intervals for response rates will be derived as well based on the score 
method including continuity correction (Newcombe, 1998). 
PASI score over time 
Summary statistics will be provided for absolute PASI scores as well as for percent change from 
baseline by visit and treatment group. Figures will also be provided. 
IGA mod 2011 score over time 
Summary statistics for the IGA mod 2011 score over time will be presented by visit and 
treatment group in contingency tables. 
Relapse 
This analysis will be the same as for “subjects who were PASI 75 responders at Week 52”  
Rebound 
This analysis will be the same as for the “subjects who were PASI 75 responders at Week 52”  
Subjects who were partial responders at Week 52 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit 
will be presented in contingency tables and will include absolute and relative frequencies. 
Confidence intervals for response rates will be derived as well based on the score method 
including continuity correction (Newcombe, 1998). 


Novartis 
Confidential 
Page 83 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
PASI score over time 
Summary statistics will be provided for absolute PASI scores as well as for percent change from 
baseline by visit and treatment group. Figures will also be provided. 
IGA mod 2011 score over time 
Summary statistics for the IGA mod 2011 score over time will be presented by visit and 
treatment group in contingency tables. 
Relapse 
This analysis will be the same as for the “subjects who were PASI 75 responders at Week 52”  
Rebound 
This analysis will be the same as for the “subjects who were PASI 75 responders at Week 52” 
9.5.2 
Safety variables 
All safety evaluations will be performed on the Safety set. For adverse events an analysis based 
on pooled treatment groups “any secukinumab 150 mg” and “any secukinumab 300 mg” will 
also be done. In the analysis of the subjects who were re-treated after relapse with secukinumab 
150 mg or 300 mg only safety data after re-treatment after relapse will be reported. With the 
exception of adverse events that qualify as "treatment emergent" (see definition below), data 
collected from telephone visits and unscheduled visits in follow-up period 2 will only be 
included in individual patient listings, but not in summary tables.  
Adverse events 
Treatment emergent adverse events are defined as any events started after the first dose of 
 study treatment and within 84 days after the last study treatment, or events present prior to the 
first dose of study treatment, but increased in severity based on preferred term within 84 days 
after the last study treatment. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one adverse events with the same 
preferred term, the adverse event with the greatest severity will be presented. If a subject 
reported more than one adverse events within the same primary system organ class, the subject 
will be counted only once with the greatest severity at the system organ class level, where 
applicable.  
Confidence intervals for relative frequencies will be derived as well according to the score 
method including continuity correction by Newcombe, 1998. 
Separate summaries will be provided for death, serious adverse event, other significant adverse 
events leading to discontinuation and adverse events leading to dose adjustment (including 
study treatment discontinuation). 


Novartis 
Confidential 
Page 84 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
A graphical display of relative frequencies within system organ classes and relative risks, if 
appropriate, will be presented. 
For infections, time-to-event analysis will be done. Results will be tabulated and the Kaplan-
Meier estimates for the cumulative rate will be plotted.  
Additional analyses will be provided for adjudicated adverse events. 
In supplementary analyses, exposure (or observation)-time adjusted analyses in terms of 
incidence rate and event rate will be provided. 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post baseline. 
For each parameter, the maximum change from baseline within each study period will be 
analyzed analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented  for most extreme values post-baseline. 
Immunogenicity 
Summary statistics for baseline, each post-baseline visit and change from baseline to each visit 
will be provided. Summary statistics will be provided for the percent of subjects with 
immunogenicity. If appropriate, shift tables will also be presented. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. 
ECG 
Summary statistics will be presented for ECG variables by visit and treatment group. 


Novartis 
Confidential 
Page 85 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
9.5.3 
Health-related Quality of Life (HRQoL)  
EQ-5D© 
The EQ-5D© is a questionnaire with 5 questions (regarding mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) each with three categories (no problem, moderate 
problem, severe problems) and a health state assessment from 0 (worst possible health state) to 
100 (best possible health state). The number and percentage of subjects in each of the three 
categories for each question will be presented by visit and treatment group. Summary statistics 
will be shown for the health state assessment by visit and treatment group. 
DLQI©  
The DLQI© measures functional disability of subjects with dermatological disorders that are 
greater than 18 years of age and had been utilized as a relevant clinical measure in atopic 
dermatitis, as well as other dermatitis clinical trials. The DLQI© is a simple, validated, self-
administered 10-item questionnaire.  The instrument contains six functional scales (i.e., 
symptoms and feeling, daily activities, leisure, work and school, personal relationships, 
treatment). For the DLQI©, each question will be answered with the following response: “not 
at all,” “a little,” “a lot,” or “very much”. 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.  
For each of the seven scores the percentage change from baseline will be derived. Summary 
statistics will be provided for absolute values as well as for the percentage change by visit and 
treatment group. 
For the “subjects who were PASI 75 responders at Week 52” the following analysis will be 
performed as well: 
The absolute value and the percentage change from baseline of DLQI© total score will be 
analyzed with the Van-Elteren test using type-II weights, for all pairwise comparisons between 
secukinumab treatment groups versus placebo. The Van-Elteren test will be performed at each 
visit. Language of the questionnaire and body weight stratum will be the strata adjusted for in 
the Van-Elteren test. In addition, stratified Hodges-Lehmann estimates for the median as well 
as confidence intervals will be derived for the absolute values and percentage change to baseline 
for each treatment group as well as for all pairwise comparisons between secukinumab 
treatment groups versus placebo. 
It is understood that conclusions obtained from the confidence intervals of these estimates 
(mean or Hodges-Lehmann estimates for the median) will not be completely consistent with the 
testing results (Van-Elteren test) which constitute the key analysis for drawing conclusions. 


Novartis 
Confidential 
Page 86 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
In addition, summary statistics will be provided for number of subjects achieving DLQI 0 or 
1. For the “subjects who were PASI 75 responders at Week 52” the secukinumab treatment 
groups will be compared to placebo by means of Fisher’s exact test. 
HAQ©-DI (for subjects with PSA at baseline of the core study) 
Summary statistics will be derived for HAQ©-DI score over time for all subjects with psoriatic 
arthritis recorded on the Psoriatic Arthritis History eCRF at screening visit of the core study. 
Absolute and relative frequencies for HAQ©-DI response will also be presented. HAQ©-DI 
response is defined by an improvement of 0.3 score points compared to baseline. 
9.5.4 
Pharmacokinetics  
All completed subjects with quantifiable PK measurements of secukinumab will be included in 
the PK data analysis. Serum concentrations will be expressed in mass per volume units. All 
concentrations below the limit of quantification or missing data will be labeled as such in the 
concentration data listings. PK concentrations will be summarized by visit and treatment group. 
In addition to mean, standard deviation, coefficient of variation, median and quartiles, the 
geometric mean and geometric coefficient of variation and n(log) will be presented. 
9.5.6 
Biomarkers 
Not applicable. 
 
 
 
   
9.6 
Interim analyses 
One interim analysis is planned for this study. At time of marketing authorization submission 
of the AIN457A project blinded safety data of this study will be reported. 
A PEA is planned to be performed when all subjects have completed the visit at which the 
primary endpoint is assessed (Week 68). At this time point, the Sponsor will be unblinded, 
whereas investigators and study participants will remain blinded. 


Novartis 
Confidential 
Page 87 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
All data collected up to Week 68 will be analyzed. 
Additional interim analyses may be conducted at various time points for publications or health 
authority requests. The study procedures will not be modified as a result of these interim 
analyses 
9.7 
Sample size calculation 
Assumptions for the number of subjects eligible for randomized withdrawal (i.e for the 
analysis of primary endpoint): 
• Drop-out rate on secukinumab at Week 12 in core studies: 5% (estimate from 
CAIN457A2211) 
• Drop-out rate on placebo at Week 12 in core studies: 15% (from CAIN457A2211) 
• Placebo PASI 75 response rate at Week 12: 5% (conservative assumption) 
• Drop-out rate on secukinumab up to Week 52 in core studies: 15% (common for 
secukinumab induction and placebo induction regimens, as in Leonardi et al, 2008) 
• PASI 75 response rate at Week 52 on secukinumab 150 mg in core studies: 65% (from 
dosing rationale in protocols of core studies) (power would be larger for 300 mg if we 
would assume similar loss of PASI75 rates) 
• Type-I-error rate is defined to one-sided 2.5%  
With these assumptions it is estimated to have 414 subjects eligible per dose to enter the 
randomized withdrawal, with a randomization ratio of 2:1 this would be 276 subjects on 150 
mg and 138 subjects on placebo. With about 400 subjects the study would have more than 90% 
power to detect differences in the cumulative rates if 10% of subjects on secukinumab lost PASI 
75 response versus 23% on placebo, PASS 2008 software (Log Rank Survival Power Analysis 
- Simple). 
 
 
10 
Ethical considerations  
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative of the subject. 
In cases where the subject’s representative gives consent, the subject should be informed about 
the study to the extent possible given his/her understanding. If the subject is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 


Novartis 
Confidential 
Page 88 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
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 subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC  
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted 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/REBs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made. 
10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence  
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the trial 
to request approval of a protocol deviation, as requests to approve deviations will not be granted. 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants.  Under no circumstances should an investigator collect additional data or 
conduct any additional procedures for any research related purpose involving any 
investigational drugs.  
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 


Novartis 
Confidential 
Page 89 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
and approved by the IRB/IEC it cannot be implemented. All significant protocol deviations will 
be recorded and reported in the CSR. 
11.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC. Only 
amendments that are required for subject safety may be implemented prior to IRB/IEC approval. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed within 10 
working days. 
12 
References 
References are available upon request 
Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially 
rejective multiple test procedures. Statistics in Medicine; 28: 586-604. 
Chobanian AV, Bakris GL, Black HR (2003) Seventh report of the joint national committee 
on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension; 
42:1206–1252. 
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use (2001) Guideline for choice of control group in 
clinical Trials. CPMP/ICH/364/96 corr document. London, UK. 
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr 
document. London, UK.  
Finlay AY, Khan GK (1994) Dermatology Life Quality Index (DLQI): A simple practical 
measure for routine clinical use. Clin Exp Dermatol; 19:210–216. 
Lohman TG, Roche AF (1988) Anthropometric standardization reference manual. Martoral 
R(eds) Champaign, IL: Human Kinetics. 
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-week results 
from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 371:1665–
1674.  
Mancia G, De Backer G, Dominiczak A, et al. (2007) Guidelines for the Management of 
Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the 
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J 
Hypertens; 25:1105–1187. 


Novartis 
Confidential 
Page 90 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872. 


Novartis 
Confidential 
Page 91 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
13 
 Appendices  
13.1 
Appendix 1: Clinically notable laboratory values and vital signs 
The following criteria will be used to define expanded limits and notable abnormalities of 
keylaboratory tests. Notable values for blood pressure and pulse are presented in Section 6.5.2 
Whether action needs to be taken to address notable laboratory or vital signs values will be 
decided by the investigator, taking into account the overall status of the subject. No specific 
action is foreseen as part of the study protocol. 
Liver Function and Related Variables 
Alanine transaminase (ALT) (SGPT):  
> 3 x Upper Limit of Normal (ULN) 
Aspartate transaminase (AST) (SGOT):  
> 3 x ULN 
Total bilirubin:  
 
 
 
> 2 x ULN 
Alkaline phosphatase:  
 
 
> 2.5 x ULN 
Renal Function and Electrolyte Variables 
Creatinine (serum):   
 
 
> 1.5 x ULN 
Potassium:  
 
 
 
 
> 6 mmol/L or < 3 mmol/L 
Sodium:  
 
 
 
 
> 160 mmol/L or < 115 mmol/L 
Hematology Variables 
Hemoglobin:   
 
 
 
≥ 20 g/dL decrease from baseline 
Platelet count:  
 
 
 
< Lower Limit of Normal (LLN) 
White blood cell count:  
 
 
< 0.8 x LLN 
Neutrophils   
 
 
 
< 0.9 x LLN 
Eosinophils   
 
 
 
> 1.1 x ULN 
Lymphocytes   
 
 
 
> 1.1 x ULN 
Urinalysis Variable 
Protein urine dipstick:  
 
 
++* 
 
* ++ is ≥ 100 mg/dL 


Novartis 
Confidential 
Page 92 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
13.2 
Appendix 2: Blood collection log for pharmacokinetics (PK) and 
immunogenicity (IG) 
Table 13-1 
Blood collection log for PK 
Visit Name 
Time point 
Volume 
(approx.) 
Analyte 
Sample number 
PK collection number** 
Week 521 
Pre-dose 
(2 mL) 
AIN457 for PK 
(5) 
(5) 
Week 56 
Pre-dose 
2 mL 
AIN457 for PK 
6 
5 
Week 60 
Pre-dose 
2 mL 
AIN457 for PK 
7 
5 
Week 642 
Pre-dose 
2 mL 
AIN457 for PK 
8 
5 
Week 68 
Pre-dose 
2 mL 
AIN457 for PK 
9 
5 
Week 72 
Pre-dose 
2 mL 
AIN457 for PK 
10 
5 
Week 762 
Pre-dose 
2 mL 
AIN457 for PK 
11 
5 
Week 80 
Pre-dose 
2 mL 
AIN457 for PK 
12 
5 
Week 84 
Pre-dose 
2 mL 
AIN457 for PK 
13 
5 
 
Week 882 
Pre-dose 
2 mL 
AIN457 for PK 
14 
5 
Week 92 
Pre-dose 
2 mL 
AIN457 for PK 
15 
5 
Week 96 
Pre-dose 
2 mL 
AIN457 for PK 
16 
5 
Week 100 
Pre-dose 
2 mL 
AIN457 for PK 
17 
5 
Week 1042 
Pre-dose 
2 mL 
AIN457 for PK 
18 
5 
Week 108 
Pre-dose 
2 mL 
AIN457 for PK 
19 
5 
Week112 
Pre-dose 
2 mL 
AIN457 for PK 
20 
5 
Week 1162 
Pre-dose 
2 mL 
AIN457 for PK 
21 
5 
Week 120  
Pre-dose 
2 mL 
AIN457 for PK 
22 
5 
Week 124 
Pre-dose 
2 mL 
AIN457 for PK 
23 
5 
Week 1282 
Pre-dose 
2 mL 
AIN457 for PK 
24 
5 
Week 132 
Pre-dose 
2 mL 
AIN457 for PK 
25 
5 
Week 136 
Pre-dose 
2 mL 
AIN457 for PK 
26 
5 
Week 1402 
Pre-dose 
2 mL 
AIN457 for PK 
27 
5 
Week 144 
Pre-dose 
2 mL 
AIN457 for PK 
28 
5 
Week 148 
Pre-dose 
2 mL 
AIN457 for PK 
29 
5 
Week 152 
Pre-dose 
2 mL 
AIN457 for PK 
30 
5 
Week 1562  
Pre-dose 
2 mL 
AIN457 for PK 
31 
5 
Week  2602 
672 hours* 
2 mL 
AIN457 for PK 
32 
5 
Week 2682(F8) 
2016 hours* 
2 mL 
AIN457 for PK 
33 
5 
1The data and sample numbering for Week 52 visit (randomization) will have been collected as part of 
the end of maintenance visit (Week 52) from core study (e.g., CAIN457A2302 or CAIN457A2303) 
2The PK blood sampling at these time point must be collected for all subjects. PK blood collections at 
the other time points are “event driven” i.e., PK blood samples will only be collected in case of relapse. 
*Scheduled post-dose time points for sample numbers 32 and 33 (672 hours and 2016 hours post-
dose, respectively) refer to the last dose given at Week 256 as time 0. 
**If a PK sample is collected at an unscheduled visit, the sample numbers will follow the pattern 1001, 
1002 etc. 


Novartis 
Confidential 
Page 93 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
Table 13-2 
Blood collection log for IG 
Visit Name 
Time point 
Volume 
(approx.) 
Analyte 
IG collection 
number** 
Week 521 
Pre-dose 
(2 mL) 
anti-AIN457 for IG 
(503a) 
Week 76 
Pre-dose 
2 mL 
anti-AIN457 for IG 
504 
Week 104 
Pre-dose 
2 mL 
anti-AIN457 for IG 
505 
Week 128 
Pre-dose 
2 mL 
anti-AIN457 for IG 
506 
Week 140 
Pre-dose 
2 mL 
anti-AIN457 for IG 
507 
Week 156 
Pre-dose 
2 mL 
anti-AIN457 for IG 
508 
Week 260 
672 hours* 
2 mL 
anti-AIN457 for IG 
509 
Week 268 (F8) 
2016 hours* 
2 mL 
anti-AIN457 for IG 
510 
1The data and sample numbering for Week 52 visit (randomization) will have been collected as part of 
the end of maintenance visit (Week 52) from core study (e.g., CAIN457A2302 or CAIN457A2303) 
* Scheduled post-dose time points for sample numbers 509 and 510 (672 hours and 2016 hours post-
dose, respectively) refer to the last dose given at Week 256 as time 0. 
** If a IG sample is collected at an unscheduled visit, the sample numbers will follow the pattern, 3001, 
3002, etc. 
 


Novartis 
Confidential 
Page 94 
Amendment Protocol v03 Clean 
 
Protocol No. CAIN457A2302E1 
 
13.3 
Appendix 3: Pharmacokinetics (PK) and immunogenicity (IG) 
sample labeling information 
13.3.1 
PK sample handling  
The samples must be labeled as in the following example and as provided by the central 
laboratory  
Study code: 
 
CAIN457A2302E1 
Site: 
 
cccc (4 digits for the current site number) 
Subject:  
Ccccrrr (4 digits for the site number where the subject was randomized 
concatenated with 3 digits for the assigned subject number. Add ‘0’ ahead of the numbers if 
needed to obtain the correct number of total digits) 
Sample number: 
As indicated in Table 13-1 
Analyte: 
 
AIN457 for PK 
Labels will be provided by the central laboratory with all information preprinted. 
As PK samples are managed by a central laboratory, no added label should cover the original 
label. 
 
13.3.2 
IG sample handling  
The samples must be labeled as in the following example and as provided by the central 
laboratory  
Study code: 
 
CAIN457A2302E1 
Site: 
 
 
cccc (4 digits for the current site number) 
Subject: 
 
Ccccrrr 
(4 digits for the site number where the subject was randomized 
concatenated with 3 digits for the assigned subject number. Add ‘0’ 
ahead of the numbers if needed to obtain the correct number of total 
digits) 
Sample number: 
As indicated in Table 13-2 
Analyte: 
 
anti-AIN457 for IG 
Labels will be provided by the central laboratory with all information preprinted. 
As IG samples are managed by a central laboratory, no added label should cover the original 
label. 

SAP_001.pdf: 
Clinical Development 
Secukinumab (AIN457) 
Clinical Trial Protocol CAIN457A2302E1 / NCT01544595
A multicenter, double-blind, randomized withdrawal 
extension study of subcutaneous secukinumab in prefilled 
syringes to demonstrate long-term efficacy, safety and 
tolerability up to 4 years in subjects with moderate to 
severe chronic plaque-type psoriasis completing preceding 
psoriasis phase III studies with secukinumab 
RAP Module 3 – Detailed Statistical Methodology for final 
analysis 
Author: 
 
Document type: 
RAP Documentation 
Document status: 
Amendment 1.0 
Release date: 
02-Nov-2017
Number of pages: 
62 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Document History – Major Changes compared to previous version of RAP module 3. 
Version 
Date 
Changes 
1.0 
26-Jun-2017 
First draft 
2.0 
31-Aug-2017 
Second draft 
1.0 
15-Sep-2017 
Final 
Amendment 
1.0 
25-Oct-2017 
Amylase and Lipase related criateria added in table 1-18  
 
 
 
 


Novartis 
Confidential 
Page 3 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
1 
Statistical methods planned in the protocol and determination of sample size ................... 8 
1.1 
Statistical and analytical plans ................................................................................. 9 
1.1.1 
Changes to statistical methods planned in the protocol .......................... 9 
1.1.2 
Footnotes ................................................................................................. 9 
1.2 
Subjects and treatments ......................................................................................... 10 
1.3 
Treatment group definitions .................................................................................. 11 
1.4 
Subgroup definitions .............................................................................................. 16 
1.5 
Assessment windows, baseline and post baseline definitions, missing data 
handling ................................................................................................................. 16 
1.5.1 
Assessment windows ............................................................................ 16 
1.5.2 
Study Day 1 and other study days ......................................................... 16 
1.5.3 
Screening (extension), baseline and post-baseline definitions .............. 17 
1.5.4 
Visits windows ...................................................................................... 18 
1.5.4.1 
Visits windows for subjects with relapse .............................................. 21 
1.5.5 
Multiple assessments within visit windows .......................................... 23 
1.5.6 
Day of last dose of randomized study treatment ................................... 24 
1.6 
Subject disposition, background and demographic characteristics ....................... 24 
1.6.1 
Subject disposition ................................................................................ 24 
1.6.2 
Background and demographic characteristics ....................................... 25 
1.6.3 
Medical history ...................................................................................... 26 
1.7 
Study medication ................................................................................................... 26 
1.8 
Concomitant medication ........................................................................................ 27 
1.9 
Efficacy evaluation ................................................................................................ 28 
1.9.1 
Variables ............................................................................................... 28 
1.9.1.1 
Definition of PASI and related variables .............................................. 29 
1.9.1.2 
Health Assessment Questionnaire - Disability Index (HAQ-DI) .......... 33 
1.9.1.3 
Overview of analysis methods of efficacy variables ............................. 34 
1.9.2 
Statistical hypothesis, model, and method of analysis .......................... 35 
1.9.3 
Testing strategy ..................................................................................... 37 
1.9.4 
Handling of missing values/censoring/discontinuations in RW 
period ..................................................................................................... 38 


Novartis 
Confidential 
Page 4 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
1.9.4.1 
Details for imputations (non- responder and LOCF) and visit 
windowing 
40 
1.9.4.2 
Multiple imputations for loss of PASI 75 response .............................. 40 
1.9.5 
Supportive analyses ............................... Error! Bookmark not defined. 
1.9.6 
Secondary variables .............................................................................. 45 
1.9.7 
Methods of analysis............................................................................... 46 
1.9.8 
Risk set, timing and censoring for time to event analysis ..................... 48 
 
 49 
1.9.10 
Biomarkers ............................................................................................ 50 
1.9.11 
Health-related Quality of Life (HRQoL) ........................................... 50 
1.10 
Standard safety evaluation ..................................................................................... 51 
1.10.1 
Adverse events ................................................................................... 51 
1.10.2 
Laboratory data ..................................................................................... 53 
1.10.3 
Vital signs.............................................................................................. 57 
1.10.4 
Electrocardiogram (ECG) ..................................................................... 58 
1.10.5 
Immunogenicity .................................................................................... 59 
1.11 
Sample size calculation .......................................................................................... 59 
2 
Clinical Study Report -  Appendix 16.1.9 Documentation of statistical methods ............ 60 
3 
References ......................................................................................................................... 61 
 


Novartis 
Confidential 
Page 5 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
List of tables 
Table 1-1 
Subject classification rules .................................................................... 11 
Table 1-2 
Treatment groups by subjects group for efficacy analysis .................... 11 
Table 1-3 
Treatment groups by subjects group for safety analysis ....................... 13 
Table 1-4 
Analysis by period................................................................................. 15 
Table 1-5 
Visit windows for scheduled visits relative to Week 52 ....................... 19 
Table 1-6 
Visit windows for subjects re-treated after relapse ............................... 22 
Table 1-7 
Rules for selecting values for analysis .................................................. 23 
Table 1-8 
Subgroups based on the previous psoriasis therapy .............................. 28 
Table 1-9 
Primary, secondary and exploratory variables ...................................... 28 
Table 1-10 
The PASI scoring system ...................................................................... 31 
Table 1-11 
The IGA mod 2011 rating scale ............................................................ 33 
Table 1-12 
Companion aids/devices items for HAQ-DI categories ........................ 34 
Table 1-13 
Overview of analysis methods for efficacy variables ........................... 35 
Table 1-14 
Time to event: definition of risk set, timing and censoring by 
variable .................................................................................................. 48 
Table 1-15 
Overview of analyses on some safety endpoints ................................... 52 
Table 1-16 
Overview of analyses on some safety endpoints ................................... 52 
Table 1-17 
CTCAE grades for laboratory parameters to be analyzed .................... 55 
Table 1-18 
Liver-related events ............................................................................... 57 
Table 1-19 
Criteria for notable vital sign abnormalities .......................................... 58 
 
List of figures 
Figure 1-1 
Testing strategy ..................................................................................... 38 
 


Novartis 
Confidential 
Page 6 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
List of abbreviations 
 
AE 
adverse event 
ALQ 
above level of quantification 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
below level of quantification 
BMI 
Body Mass Index 
BSA 
body surface area 
CHMP  
Committee for medicinal products for human use  
CMH 
Cochran-Mantel-Haenszel 
CRP 
C-reactive protein 
CSA 
cyclosporine A 
CSR 
clinical study report 
CT 
computerized tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
DHP  
Data Handling Plan 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribo Nucleic Acid 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
eCRF 
electronic case report/record form 
EQ-5D 
EuroQOL 5-Dimension Health Questionnaire© 
FAS 
full analysis set 
FDA 
United States Food and Drug Administration 
GGT 
gamma-glutamyl transferase 
HAQ 
Health Assessment Questionnaire© 
HAQ-DI 
Health Assessment Questionnaire© – Disability Index 
HDL 
high density lipoprotein 


Novartis 
Confidential 
Page 7 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Hgb 
Hemoglobin 
HRQoL 
health-related quality of life 
hsCRP 
high sensitivity C-reactive protein 
IA&R 
Integrated Analytics & Reporting  
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IDF 
International Diabetes Federation 
IEC 
independent ethics committee 
IGA 
investigator’s global assessment 
IGA mod 2011 
Novartis Investigator’s Global Assessment modified 2011 
IIS 
Integrated Information Sciences   
IRT 
interactive response technology 
i.v. 
intravenous(ly) 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LDL 
low density lipoprotein 
LLN 
Lower Limit of Normal 
MACE 
Major Adverse Cardiovascular Event 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMQ 
Novartis MedDRA Query 
NovDTD 
Novartis Drug and Therapy Dictionary 
PASI 
Psoriasis Area and Severity Index 
PBO 
Placebo 
PD 
pharmacodynamic(s) 
PD 
protocol deviation 
PEA 
Primary end point analysis 
PG 
pharmacogenetic(s) 
PGIC 
Patient Global Impression of Change 
PhGA  
physician global assessment 
PtGA  
patient’s global assessment 
PK 
pharmacokinetic(s) 


Novartis 
Confidential 
Page 8 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
PsA 
psoriatic arthritis 
PT 
Preferred Term 
PUVA 
psoralen + UVA treatment 
QFT 
QuantiFERON TB-Gold test 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
REB 
research ethics board 
RMP 
Risk Management Plan 
RW 
Randomized withdrawal period 
SAE 
serious adverse event 
SDI 
Standard Disability Index 
SPP 
Safety Profiling Plan 
s.c. 
subcutaneous(ly) 
SOC 
System Organ Class 
TB 
Tuberculosis 
TBL 
total bilirubin 
TG 
Triglycerides 
ULN 
Upper Limit of Normal 
VAS 
visual analog scale 
WBC 
white blood cell 
 
 
 
 
 
 
1 
Statistical methods planned in the protocol and 
determination of sample size 
Data will be analyzed by Novartis using SAS according to the data analysis section 9 of the 
study protocol which is available in Appendix 16.1.1 of the CSR. Important information is given 
in the following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR. 


Novartis 
Confidential 
Page 9 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
1.1 
Statistical and analytical plans 
The planned analysis is described in Section 9 (Data Analysis) of the study protocol which is 
available in Appendix 16.1.1 of the CSR.   
This document mainly covers statistical and analytical plans for the final analysis after database 
lock. The key analyses which conducted previously might be re-run using the final data.  
The key secondary analyses during RW period using the final data will be re-run for PASI 75 
responders at week 52. The re-run analyses are including summary and analysis of PASI 
50/75/90/100 response and IGA 0 or 1 response, loss of PASI 75/IGA 0 or 1 response, time to 
relapse, and DLQI. Since loss of PASI 75 during randomized withdrawal period will be re-run, 
the primary endpoint – loss of PASI 75 up to week 68 will not be performed in the final analysis. 
In addition, a summary of PASI 50/75/90/100 response and IGA 0 or 1 response till week 156 
will also be provided using retreatment patients after relapse. 
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies. 
If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed. 
Unless otherwise stated, the level of significance will be set to 5% (two-sided, family-wise type-
I-error). 
All listings will be presented by treatment sequence. 
1.1.1 
Changes to statistical methods planned in the protocol 
Shift tables will be provided for all parameters to compare a subject’s baseline laboratory 
evaluation relative to the most extreme laboratory test value within a treatment period (either 
RW or treatment period) rather than relative to the visit’s observed value. 
A listing of immunogenicity data will be provided. 
A definition of “rebound-like events” was introduced to capture rebound events that occur at 
any point after stopping therapy; whereas, the definition of rebound includes only rebound 
events that occur within 8 weeks of stopping therapy. 
For rebound and relapse no imputed data will be used and analyses will be based on observed 
data only. 
Full analysis set included subjects having at least one post baseline efficacy assessment. 
1.1.2 
Footnotes 
Footnotes on outputs will be kept to a minimum also for outputs not covered in [Efficacy MAP 
M7.1] or [Safety MAP M7.1].  
Footnotes will generally be provided for 
• abbreviations used in the output; abbreviations used on several outputs, e.g. for listings in 
Appendix 16.2 can be presented on a separate page and do not have to be repeated as 
footnotes on each listing 


Novartis 
Confidential 
Page 10 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
• sorting order of categories, e.g. for sorting within MedDRA (Medical Dictionary for 
Regulatory Activities) hierarchy levels 
• MedDRA version used for reporting of MedDRA coded data 
Footnotes will generally NOT be given for 
• units displayed on the output 
• interpretation of results (e.g. “odds ratio larger 1 favors active treatment”) 
• information that can be retrieved from the statistical section of the clinical study report 
(CSR) unless it is not identifiable from the output, e.g. 
• explanation of analysis model used unless results of more than one model are 
displayed on an output 
• derivations of variables (e.g. BMI will not be explained on a footnote) 
• information that will be provided in the clinical study protocol and/or methods section of 
the CSR (e.g. baseline definition if this is specified in the statistical section of the CSR) 
1.2 
Subjects and treatments  
The following analysis sets will be used for the data analysis. 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set. Mis-randomized subjects will be defined as those subjects where IRT 
contact is made by the site either prematurely or inappropriately prior to confirmation of the 
subject’s final randomization eligibility and double-blind study treatment was not administered 
to the subject.  
PASI 75 non- responders being incorrectly randomized as PASI 75 responders will be 
analyzed as PASI 75 responders in randomized withdrawal period 
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatments has been assigned and have at least one post baseline efficacy 
assessment and on secukinumab at week 52 of core. Following the intent-to-treat principle, 
subjects will be analyzed according to the treatment assigned to at randomization. If the actual 
stratum is different to the assigned stratum in IRT, the actual stratum will be used in analyses.  
PASI 75 non- responders being incorrectly randomized as PASI 75 responders will be analyzed 
as PASI 75 responders in randomized withdrawal period. 
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during RW period for PASI 75 responders and treatment period for partial responders as well 
as subjects re-treated after relapse. Subjects will be analyzed according to treatment received. 
The treatment received will be set to the treatment randomized. But if a subject has received the 
wrong treatment during the entire study, the treatment received will be set to this wrong 
treatment. For those subjects who received erroneously the wrong treatment at least once, an 
additional listing will be prepared displaying adverse events occurred after the treatment errors. 


Novartis 
Confidential 
Page 11 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-1 
Subject classification rules 
Analysis set 
PD Population Codes that 
cause subject to be excluded 
Non-PD criteria that cause a 
subject to be excluded 
Randomization set 
NA 
Mis-randomized subject 
FAS (Full Analysis Set)  
1, 3 
No post baseline efficacy 
assessment 
Safety 
2, 3, 6 
Not treated in the extension 
1.3 
Treatment group definitions 
The following treatment labels (Table 1-2, Table 1-3) will be used for re-run tables and final 
analysis in the order provided below.  
Table 1-2 
Treatment groups by subjects group for efficacy analysis 
 
Evaluation of 
Analysis 
Period 
Treatment group label (order 
as listed) 
Analysis 
Subjects who 
were PASI 75 
responders 
at 
Week 52 
 
RW 
AIN457 150 mg1  
AIN457 300 mg2  
AIN457 150 mg – Placebo3 
AIN457 300 mg – Placebo4  
PASI 50/75/90/100 response and IGA 0 or 
1 response  
Loss of PASI 75/IGA 0 or 1 response 
Time to relapse 
DLQI 
Subjects who 
were re-treated 
after 
relapse 
with 
AIN457 
150 mg or 300 
mg 
Treatment AIN457 150 mg  
Placebo - AIN457 150 mg5 
AIN457 300 mg 
Placebo - AIN457 300 mg6 
PASI 50/75/90/100 response and IGA 0 or 
1 response 
All subjects 
On 
Treatment 
Period 
 
AIN457 150 mg stay7 
AIN457 300 mg stay8 
All AIN457 150 mg9 
All AIN457 300 mg10 
AIN457 150 mg only11 
AIN457 150 mg - 300 mg12 
AIN457 300 mg only13 
Final analysis 
1 AIN457 150mg group includes the PASI 75 responders at week 52 who were randomized to AIN150mg at week 
52; and the partial responders at week 52 were continued received AIN 150mg from week 52. 
2 AIN457 300mg group includes the PASI 75 responders who were randomized to AIN300mg at week 52; and the 
partial responders at week 52 were continued received AIN 300mg from week 52. 


Novartis 
Confidential 
Page 12 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
3 AIN457 150mg – Placebo group includes the PASI 75 responders who were assigned AIN 457 150mg during 
core study, and randomized to placebo at week 52. 
4 AIN457 300mg – Placebo group includes the PASI 75 responders who were assigned AIN 457 300mg during 
core study, and randomized to placebo at week 52. 
5 Placebo – AIN457 150mg group includes the subjects who were randomized to placebo at week 52, and relapsed 
then treated by AIN457 150mg during RW period. 
6 Placebo – AIN457 300mg group includes the subjects who were randomized to placebo at week 52, and relapsed 
then treated by AIN457 300mg during RW period. 
7 AIN457 150 mg stay group includes the subjects who were PASI 75 responders at Week 52 and staying strictly 
in 150mg AIN457 treatment from Week 52. The subjects received placebo at Week 52 and switched to AIN457 
150 mg will not be included in this treatment group. Subjects up-titrated from AIN457 150mg to 300mg during 
open label period will not be included in this group. 
8 AIN457 300 mg stay group includes the subjects who were PASI 75 responders at Week 52 staying strictly in 
300mg AIN457 treatment from Week 52. The subjects received placebo at Week 52 and switched to AIN457 300 
mg will not be included in this treatment group. 
9 All AIN457 150 mg group includes all the subjects who were assigned to AIN457 150 mg at Week 52, regardless 
whether they are initial PASI 75 responder or partial responder at Week 52, or who were assigned to placebo at 
week 52 but relapsed and retreated by AIN457 150 mg during randomized withdrawal period. The subjects who 
up titrated to 300 mg during the open label period will be included in the efficacy analysis for this treatment group. 
For the subjects assigned to placebo group at Week 52 and switched to AIN457 150 mg after relapse, the efficacy 
data after 16 weeks (including 16 weeks) post AIN457 treatment will be included in this group. In addition, the 
subgroup analysis will be performed for the following two subgroup groups: 1) Subjects who stayed on AIN457 
150mg and never were up-titrated; 2) Subjects up-titrated from AIN457 150mg to 300mg during open label period. 
10All AIN457 300 mg group includes all the subjects who were assigned to AIN457 300 mg at Week 52, regardless 
whether they are initial PASI 75 responder or partial responder at Week 52, or who were assigned to placebo at 
week 52 but relapsed and retreated by AIN457 300 mg during randomized withdrawal period. For the subjects 
assigned to placebo group at Week 52 and switched to AIN457 300 mg after relapse, the efficacy data after 16 
weeks post AIN457 treatment will be included in this group. The subjects up titrated during the open label period 
will not be included in this group. 
11AIN457 150 mg only group is from ‘ALL AIN457 150 mg’ group and includes the subjects who were PASI 75 
responders or partial responder at Week 52 and staying strictly in 150mg AIN457 treatment from Week 52. The 
subjects received placebo at Week 52 and switched to AIN457 150 mg will not be included in this treatment group. 
Subjects up-titrated from AIN457 150mg to 300mg during open label period will not be included in this group. 
12 AIN457 150 mg - 300 mg group is from ‘ALL AIN457 150 mg’ group and includes the subjects who started 
AIN457 150 mg from Week 52 and up-titrated from AIN457 150mg to 300mg during open label period.  
13 AIN457 300 mg only group is from ‘ALL AIN457 300 mg’ group and includes the subjects who were PASI 75 
responders or partial responder at Week 52 and staying strictly in 300mg AIN457 treatment from Week 52. The 
subjects received placebo at Week 52 and switched to AIN457 300 mg will not be included in this treatment group. 


Novartis 
Confidential 
Page 13 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-3 
Treatment groups by subjects group for safety analysis 
Evaluation of 
Analysis Period 
Treatment group label  
(order as listed) 
Comment on treatment 
group definition 
Table/Figure 
 
Entire 
study 
Period,  
 
Any AIN 457 150 mg1 
Any AIN 457 300 mg2 
Any AIN 457 dose 
AIN 457 150 mg – Placebo3 
AIN 457 300 mg – Placebo4 
 
 
 
Same as in Table 1-1 
Same as in Table 1-1 
Follow-up 
2 
Period 
 
Any AIN 457 150 mg 
Any AIN 457 300 mg 
Any AIN 457 dose 
 
1 Any AIN457 150 mg group includes all the subjects who have ever received at least one dose of AIN457 150 mg 
from Week 52 to Week 256 (Week 260 EOT no dose), regardless whether they are initial PASI 75 responder or 
partial responder at Week 52. For the subjects assigned to placebo group at Week 52 and switched to AIN457 150 
mg after relapse or started AIN457 150 mg during open label period, the safety data during and after 1st AIN457 
dose will be included in this group. For subjects starting with 150 mg AIN457 dose and switched to 300 mg 
AIN457, the period used the low dose will be counted for the ‘Any AIN457 150mg’ group.  
2 Any AIN457 300 mg group includes all the subjects who have ever received at least one dose of AIN457 300 mg 
from Week 52 to Week256 (Week 260 EOT no dose), regardless whether they are initial PASI 75 responder or 
partial responder at Week 52. For the subjects assigned to placebo group at Week 52 and switched to AIN457 300 
mg after relapse or started AIN457 300 mg during open label period, the safety data during and after 1st AIN457 
dose will be included in this group. For subjects starting with 150 mg AIN457 dose and switched to 300 mg 
AIN457 at any time, the period after switching to the high dose will be included in the ‘Any AIN457 300 mg’ 
group.  
3 AIN457 150mg – Placebo group includes the PASI 75 responders who were assigned AIN 457 150mg during 
core study, and randomized to placebo at week 52. Only data for subjects received placebo period were included 
in safety analysis. 
4 AIN457 300mg – Placebo group includes the PASI 75 responders who were assigned AIN 457 300mg during 
core study, and randomized to placebo at week 52. Only data for subjects received placebo period were included 
in safety analysis.  
 
So, for re-run efficacy analysis the data will be analyzed for RW period. Regarding retreatment 
patients after relapse, the data till week 156 will be presented. For data analysis till week 156, 
the following treatment groups will be reported 
• Subjects who were PASI 75 responders at Week 52  
AIN457 150 mg 
AIN457 300 mg 
AIN457 150mg - Placebo  
AIN457300mg - Placebo  
 
• Subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg 


Novartis 
Confidential 
Page 14 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
AIN457 150 mg 
AIN457 300 mg 
Placebo - AIN457 150 mg 
Placebo – AIN457 300 mg 
 
For final analysis, the following treatment groups will be reported for the on treatment period. 
AIN457 150 mg stay 
AIN457 300 mg stay 
All AIN457 150 mg 
All AIN457 300 mg 
AIN457 150 mg only 
AIN457 150 mg - 300 mg 
AIN457 300 mg only 
The following study periods will be considered for analysis: 
• 
Screening period (before Randomization in extension)  
• 
Randomized withdrawal (RW) period for subjects who were PASI 75 responders at Week 
52- the duration of RW period for each subject is different i.e., starting from Week 52 until 
the subject experiences the first full relapse for efficacy analyses and until the subjects 
reinitiating the secukinumab after first full relapse for safety analyses. RW period is not 
fixed for all the subjects but varies for subject to subject based on occurrence of relapse. 
Subjects not experiencing the relapse will end their RW period at Week 156. 
• 
Treatment period for subjects with relapse (for efficacy analyses it is starting from the visit 
in RW period at which a subject experiences first full relapse to Week 156. Safety analysis 
will not be re-run for subjects with relapse). 
• 
Treatment period for subjects with partial response (Week 52 to Week 156)  
• 
Open label period for subjects who were continued in the study and were unblinded at 
Week 156. The first open label dose were given at the site at Week 156. Subjects previously 
randomized to receive 150 mg secukinumab may continue with 150 mg secukinumab open 
label or may switch to 300 mg s.c. at the discretion of the investigator. Subjects previously 
randomized to 300 mg secukinumab continued with 300 mg secukinumab open label. 
Placebo subjects who entered the open label period were given once weekly s.c. injections 
of secukinumab for 4 consecutive weeks and then s.c. injections every 4 weeks. Any subject 
starting on secukinumab 150 mg may continue on 150 mg every 4 weeks or switch to 300 
mg at Week 156 or any other regular site visit if the investigator decided the subject would 
benefit from the higher dose. The Week 244 visit was the last scheduled visit at which the 
subjects were allowed to switch to 300 mg dose. Decreasing the dose from 300 mg to 150 
mg was not allowed. 
• 
Follow-up (FU) period (for all subjects)*: treatment free period (Week 264 to Week 268). 


Novartis 
Confidential 
Page 15 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
• 
Follow-up 2 （FU 2） period: treatment free period only for subjects who prematurely 
discontinued treatment. All subjects who prematurely discontinued treatment should 
complete all assessment of Week 260 (end of treatment visit) and of the follow-up period 
visits (Weeks 264 and 268). Subsequently, adverse events and use of concomitant 
medication were evaluated by the investigator through telephone calls every 3 months for 
duration of 4 years from the time when subject has been enrolled into CAIN457A2302E1 
study. 
• 
Entire study period = Combination of RW period + treatment period for subjects with 
relapse and treatment period for subjects with partial response + open label period (Week 
156 – Week 260) + follow-up period ( Week 264 – Week 268). 
• 
On treatment period = Combination of RW period + treatment period for subjects with 
relapse and treatment period for subjects with partial response + open label period (Week 
156 – Week 260). 
The number of subjects in the analysis sets may differ between the study periods listed above.   
The primary and secondary efficacy variables for final analysis are described as in table 1-4. 
Table 1-4 
Analysis by period 
Endpoint/analysis 
Period 
RW  
treatment 
(re-treated 
after 
relapse) 
treatment 
(partial 
responders) 
On 
treatment 
period  
Follow-up 
Entire 
study 
period 
 
 
 
 
 
 
 
Demography & 
baseline 
characteristics 
X 
 
 
 
 
X 
Previous & 
concomitant 
medication 
 
 
 
 
 
X 
Medical history 
 
 
 
 
 
X 
Study medication: 
duration of 
exposure 
 
 
 
 
 
X 
Loss of PASI 75 
response over time 
after 52 weeks of 
treatment 
X 
 
 
 
 
 
PASI 50/75/90/100 
and IGA mod 2011 
0 or 1 response 
over time 
X 
X2 
 
X 
 
 
Loss of IGA 0 or 1 
response over time 
after 52 weeks of 
treatment 
X1 
 
 
 
 
 


Novartis 
Confidential 
Page 16 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Endpoint/analysis 
Period 
RW  
treatment 
(re-treated 
after 
relapse) 
treatment 
(partial 
responders) 
On 
treatment 
period  
Follow-up 
Entire 
study 
period 
PASI score over 
time 
 
 
 
X 
 
 
IGA mod 2011 
score over time 
 
 
 
X 
 
 
Relapse  
 
 
 
 
X 
 
Rebound 
 
 
 
 
X 
 
EQ-5D 
 
 
 
X 
 
 
DLQI 
X 
 
 
X 
 
 
HAQ©-DI 
 
 
 
X3 
 
 
DLQI 0 or 1 
achievement 
X 
 
 
X 
 
 
Note: 
X1: restricted to the subset of subjects who have been IGA 0 or 1 responder at Week 52 
X2: for subjects  who re-treated with secukinumab 
X3 :for subjects with PSA at baseline of the core study 
 
1.4 
Subgroup definitions  
No subgroup analyses will be conducted for final analysis.  
1.5 
Assessment windows, baseline and post baseline definitions, 
missing data handling 
1.5.1 
Assessment windows 
No assessment windows have been defined for this study. Visit windows are described below. 
If not otherwise specified, ‘first dose’, ‘randomization’ and ‘baseline’ are with respect to 
extension. 
1.5.2 
Study Day 1 and other study days 
Study day is defined with respect to extension. The first day of administration of randomized 
study treatment (first dose) in extension is defined as Study Day 1 or Day 1.  
All other study days will be labeled relative to Day 1.  For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first dose]+1, i.e., Day 
2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively. For the dates before 
Day 1, study day for an event date is calculated as [Date of event] – [Date of first dose], i.e., 
Day -1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration of an 
event will be calculated as (Event end date – Event start date + 1). 


Novartis 
Confidential 
Page 17 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
The descriptor “Day 0” will not be used. 
1.5.3 
Screening (extension), baseline and post-baseline definitions 
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to the date of first dose of study treatment (for safety analysis) or prior to the randomization 
date in extension (for efficacy analysis).  Per protocol, subject informed consent must be 
obtained prior to performing any study related activity.  The date of signing informed consent 
is the start date of screening period.  Any assessment obtained during the screening period will 
be labeled screening assessment.  Assessments made on Day 1 may occur before or after the 
randomization or the first dose in extension. Further information will be found in [RAP Module 
8]. 
Baseline is defined with respect to core and extension as follows: 
Core baseline:  
For efficacy analyses, core baseline is the last assessment (including unscheduled visits) 
obtained before the randomization in core. All assessments obtained after randomization in core 
are considered as post-baseline unless otherwise specified. 
For safety analyses, core baseline is the last assessment (including unscheduled visits) obtained 
before the first dose of study treatment in core. All assessments obtained after the first dose of 
study treatment in core are considered as post-baseline unless otherwise specified. 
Of note, as core baseline measurements are already identified in the core studies, they can be 
readily used for the purpose of extension study. 
Extension baseline:  
For efficacy analyses, extension baseline is the last assessment (including unscheduled visits) 
obtained on or after Week 52 and before the randomization in extension. All assessments 
obtained after randomization in extension are considered as post-baseline unless otherwise 
specified. 
For safety analyses, extension baseline is the last assessment (including unscheduled visits) 
obtained on or after Week 52 and before the first dose of study treatment in extension. All 
assessments obtained after the first dose of study treatment in extension are considered as post-
baseline unless otherwise specified. 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, for patient reported outcomes (e.g. patient’s assessment 
of PSA pain), lab, ECG, if no pre-treatment value exists a value recorded after first dose can 
also be used as baseline if it was collected on the same day as first dose.  
For efficacy analyses, core baseline will be used for PASI and IGA related variables, such as 
PASI response, PASI score, et al. Extension baseline will be used for PRO variables. 
For safety analyses, extension baseline will be used for all safety variables if not specified. 


Novartis 
Confidential 
Page 18 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
1.5.4 
Visits windows 
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are protocol defined scheduled visits around which visit windows were created to cover 
the complete range of days within the study. The visit windows are shown in Table 1-5. In this 
table, the days are counted since the first dose of study treatment in extension (study days in 
extension) for safety assessments and the days are counted since the date of randomization in 
extension for efficacy assessments. These visit windows apply to measurements taken at every 
visit. For assessments collected less often different visit windows will be applied as detailed 
below. 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 56 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 60. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below in section 1.5.5. 
Of note, subjects are allowed to have gaps in visits. 
The analysis visit will be used for listing of visit and period.  If a visit falls after the last visit 
window (after Day 1527 in the example below) it is not assigned to analysis visit and will be 
listed under label “After Week 268”. 
For the open label period, only the scheduled site visits are included in the table below. 


Novartis 
Confidential 
Page 19 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-5 
Visit windows for scheduled visits relative to Week 52 


Novartis 
Confidential 
Page 20 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Analysis Visit 
Week 
(relative to 
baseline of 
core) 
Scheduled 
Day  
Visit Window 
Week 52/baseline 
52 
1 
Up to Day 1* 
Week 56 
56 
29 
Day 2-43 
Week 60 
60 
57 
Day 44-71 
Week 64 
64 
85 
Day 72-99 
Week 68 
68 
113 
Day 100-127 
Week 72 
72 
141 
Day 128-155 
Week 76 
76 
169 
Day 156-183 
Week 80 
80 
197 
Day 184-211 
Week 84 
84 
225 
Day 212-239 
Week 88 
88 
253 
Day 240-267 
Week 92 
92 
281 
Day 268-295 
Week 96 
96 
309 
Day 296-323 
Week 100 
100 
337 
Day 324-351 
Week 104 
104 
365 
Day 352-379 
Week 108 
108 
393 
Day 380-407 
Week 112 
112 
421 
Day 408-435 
Week 116 
116 
449 
Day 436-463 
Week 120 
120 
477 
Day 464-491 
Week 124 
124 
505 
Day 492-519 
Week 128 
128 
533 
Day 520-547 
Week 132 
132 
561 
Day 548-575 
Week 136 
136 
589 
Day 576-603 
Week 140 
140 
617 
Day 604-631 
Week 144 
144 
645 
Day 632-659 
Week 148 
148 
673 
Day 660-687 
Week 152 
152 
701 
Day 688-715 
Week 156 
156 
729 
Day 716-743 
Week 168 
168 
813 
Day 744-855 
Week 180 
180 
897 
Day 856-939 
Week 192 
192 
981 
Day 940-1023 
Week 208 
208 
1093 
Day 1024-1149 
Week 220 
220 
1177 
Day 1150-1219 
Week 232 
232 
1261 
Day 1220-1303 
Week 244 
244 
1345 
Day 1304-1387 
Week 260 
260 
1457 
Day 1388-1471 
Week 264  
264 
1485 
Day 1472-1499 
Week 268  
268 
1513 
Day 1500-1527 
8 WK after last study 
drug admin.** 
 
 
Week 264 visit 


Novartis 
Confidential 
Page 21 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
12 WK after last study 
drug admin.** 
 
 
Week 268 visit 
* Baseline measurement before the first drug administration for safety assessments and before 
the randomization for efficacy assessments. The days are counted since the first dose of study 
treatment in extension for safety assessments, and the days are counted since the date of 
randomization in extension for efficacy assessments. 
** 8/12 WK after last study drug administration will be used for re-bound analysis. 
For parameters which are not collected at every visit (e.g. DLQI, EQ-5D, HAQ-DI), visit 
windows defined in Table 1-5 will be combined. For example, if a parameter is measured at 
Week 64 and Week 76 only, Week 64 visit window will extend from Day 2 to Day 99 
(combining Week 56 to Week 64 visit windows), Week 76 will extend from Day 100 to Day 
183 (combining Week 68 to Week 76). If more than one assessment falls into the interval, the 
rules defined in section 1.5.5 below are applied. 
Assessments from treatment period will not be considered for RW period. Assessments from 
RW period will not be considered for treatment period. Assessments from RW and treatment 
period may be considered for follow-up period.  
Assessments from RW/treatment period will not be considered for open label period. 
Assessments from open label period will not be considered for RW/treatment period.  
The ‘by visit’ safety summaries for the ‘whole treatment period’ will be reported as per the 
analysis visits relative to Week 52 as defined in Table 1-5. 
Of note, for subjects who discontinue in RW period, i.e. not moving into treatment period, 
efficacy measurements taken in follow-up period would still be considered for RW period as 
specified in Section 1.9.4.1.  
1.5.4.1 
Visits windows for subjects with relapse 
Visit windows for subjects who relapsed (either in PASI 75 responders or partial responders) 
will be defined analogously to general visit windows as defined in section 1.5.4, but the days 
are counted since the date of relapse for efficacy assessments including PASI response and IGA 
0/1 response. The visit windows are shown in Table 1-6. 


Novartis 
Confidential 
Page 22 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-6 
Visit windows for subjects re-treated after relapse  
 
Analysis Visit 
Week after 
relapse 
Day  
Visit Window 
Week 0 
0 
1 
Up to Day1 
Week 1 after relapse1 
1 
8 
day 2-11 
Week 2 after relapse1 
2 
15 
day 12-18 
Week 3 after relapse1 
3 
22 
day 19-25 
Week 4 after relapse 
4 
29 
day 26-43 
Week 8 after relapse 
8 
57 
day 44-71 
Week 12 after relapse 
12 
85 
day 72-99 
Week 16 after relapse 
16 
113 
day 100-127 
Week 20 after relapse 
20 
141 
day 128-155 
Week 24 after relapse 
24 
169 
day 156-183 
Week 28 after relapse 
28 
197 
day 184-211 
Week 32 after relapse 
32 
225 
day 212-239 
Week 36 after relapse 
36 
253 
day 240-267 
Week 40 after relapse 
40 
281 
day 268-295 
Week 44 after relapse 
44 
309 
day 296-323 
Week 48 after relapse 
48 
337 
day 324-351 
Week 52 after relapse 
52 
365 
day 352-379 
Week 56 after relapse 
56 
393 
day 380-407 
Week 60 after relapse 
60 
421 
day 408-435 
Week 64 after relapse 
64 
449 
day 436-463 
Week 68 after relapse 
68 
477 
day 464-491 
Week 72 after relapse 
72 
505 
day 492-519 
Week 76 after relapse 
76 
533 
day 520-547 
Week 80 after relapse 
80 
561 
day 548-575 
Week 84 after relapse 
84 
589 
day 576-603 
Week 88 after relapse 
88 
617 
day 604-631 
Week 92 after relapse 
92 
645 
day 632-659 
Week 96 after relapse 
96 
673 
day 660-687 
Week 100 after relapse 
100 
701 
day 688-715 
Week 104 after relapse 
104 
729 
day 716-743 
Week 108 after relapse  
108 
757 
day 744-771 
1 = Applicable for subjects with relapse in RW period only. 
 


Novartis 
Confidential 
Page 23 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
1.5.5 
Multiple assessments within visit windows 
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (See Table 
1-5 & Table 1-6). 
For subjects with relapse switching from PBO to AIN XX, the assessments taken while subject 
receiving placebo will be considered in RW period and the assessments taken while 
secukinumab will be considered in treatment period. 
For baseline assessment definition see Section 1.5.3. For post-baseline visit windows the 
following applies (unless otherwise specified): 
• for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen);  
• for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined (e.g., for urine protein values “+” and “++”, 
the worst case is defined as “++”), 
• in case qualitative variables are based on quantitative variables, e.g. PASI 75 response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable.  
Table 1-7 
Rules for selecting values for analysis 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
See Section 1.5.3 
Post-baseline efficacy 
All data except DLQI, EQ-5D 
and health assessment 
The measurement closest to the 
target day will be used.  In the 
event two measurements are 
taken equally apart (e.g., 1 day 
before target date and 1 day 
after), the earlier one will be 
used 
 
Post-baseline efficacy 
DLQI, EQ-5D and health 
assessment 
The measurement closest to the 
target day will be used.  In the 
event two measurements are 
taken equally apart the earlier 
one will be used. 
If two measurements have been 
taken on the same day, select 
the worst. 


Novartis 
Confidential 
Page 24 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Timing of measurement 
Type of data 
Rule 
Post-baseline safety 
Summary visit information (e.g. 
lab, ECG, etc.) 
The non-missing measurement 
closest to the target day will be 
used.  In the event two 
measurements are taken 
equally apart (e.g., 1 day before 
target date and 1 day after), the 
earlier one will be used. If two 
measurements are taken on the 
same day then select the first 
one (using the time). 
If two measurements are taken 
on the same date/time then use 
the first visit number (assuming 
this is the planned visit). 
Post-baseline safety  
Notable abnormalities (e.g., vital 
signs, ECG), CTCAE grades 
The most extreme 
measurement in the window will 
be used. Note this means a 
subject can have a notably high 
and notably low measurement 
within a window (analysis 
period). 
1.5.6 
Day of last dose of randomized study treatment 
The date of last dose will be collected in the CRF.  The subject’s exposure will not be calculated 
using last dose. It will be calculated considering the last visit in RW period for PASI 75 
responders and last visit in treatment period for partial responders as well as subjects re-treated 
after relapse. If a subject in RW period discontinued early, then the last visit during the RW 
period is considered. If a subject in treatment period discontinued early, then the last visit during 
the treatment period is considered. 
1.6 
Subject disposition, background and demographic 
characteristics 
1.6.1 
Subject disposition 
The number and percentage of subjects in the randomized set who completed study periods), 
and who discontinued the study prematurely (including the reason for discontinuation) will be 
presented by study period for each treatment group and all subjects.  
Since the study design is very complicated, the disposition will be provided based on below 
flow chart. 


Novartis 
Confidential 
Page 25 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
 
For each protocol deviation, the number and percentage of subjects for whom the deviation 
applies will be tabulated. 
1.6.2 
Background and demographic characteristics 
The following common background and demographic variables will be analyzed for assessing 
the baseline comparability: 
Continuous variables: 
o Age at extension baseline (which is derived from date of birth and the 
screening assessment date) 
o Height (at core study baseline and extension baseline) 
o Weight (at core study baseline and extension baseline) 
o Body mass index (BMI) (at core study baseline and extension baseline) 
Categorical variables: 
o Age categories (<65 years, 65 years and older, 75 years and older) at extension 
baseline 
o Gender 
o Race 
o Ethnicity 
o Smoking status at core baseline 
Psoriasis specific baseline characteristics and history of disease will be summarized as well: 
baseline PASI(at core study baseline and extension baseline), extension baseline PASI 75 
responders, extension  baseline PASI partial responders, baseline IGA mod 2011 score (at least 
mild, moderate, severe) (at core study baseline and extension baseline), types of previous 
psoriasis therapies at core study baseline  , previous exposure to biologic systemic psoriasis 


Novartis 
Confidential 
Page 26 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
therapy, previous exposure to systemic psoriasis therapy, previous exposure to non-biologic 
systemic psoriasis therapy, previous failure to biologic systemic psoriasis therapy, previous 
failure to systemic psoriasis therapy, previous failure to non-biologic systemic psoriasis therapy. 
Body Mass Index (BMI) will be calculated using the following formula: 
BMI = (body weight in kilograms) / (height in meters)2 
For BMI, height and body weight used is the last value prior to randomization at core study 
baseline and extension baseline. If there is no weight recorded prior to taking of study treatment, 
BMI will be missing.  
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total) in the randomized set.  
1.6.3 
Medical history 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. Concurrent or medical history of disease of 
interest will be summarized by categories and treatment group. 
All the medical history information will be retrieved from the core studies. 
1.7 
Study medication 
The analysis of study treatment data will be based on the safety set. 
In case it cannot be identified from the data collected or assumed from the planned treatment 
whether an injection contained placebo or secukinumab, it will be assumed that the syringe 
contained secukinumab. This applies for example to the 150 mg secukinumab treatment group 
(in which subjects should receive both an active and a placebo injection) if only one injection 
is given. If the medication pack number is not available, it will be assumed that the secukinumab 
injection was applied. If this scenario occurs for subjects in the 300 mg treatment group or in 
the placebo treatment group, respectively, when subjects should receive two identical injections, 
it will be assumed that they received secukinumab or placebo, respectively, as planned. 
The duration of exposure to study treatment in the extension will be summarized by treatment 
group. In addition, the number of subjects with exposure of at least certain time thresholds will 
be displayed. The following categories will be presented: “any exposure”, “≥4 weeks”, “≥8 
weeks”, “≥12 weeks”, and so on with an increase of time threshold by 4 weeks until there are 
some subjects in the category or the last category “≥256 weeks” is presented. 
Duration of exposure will be defined and summarized as follows: 
Duration of exposure is defined as the time from first dose of study medication in the extension 
to the last dose plus 84 days or last visit whichever occurs earlier. i.e., for subjects who 
discontinued or have their last visit earlier than 84 days, the end of study treatment exposure 
will be the date of the last study visit.  


Novartis 
Confidential 
Page 27 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Duration of exposure (days) = min (‘last study visit’ date, last dose date +84) – first dose date 
+1 
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100-patient years) = duration of exposure (years) / 100 
The analyses of duration of exposure described above will be done for the entire study treatment 
period. 
1.8 
Concomitant medication 
Medications will be identified using the Novartis Drug and Therapy Dictionary (NovDTD) 
including Anatomical Therapeutic Chemical (ATC) code. Prior and concomitant treatments will 
be summarized by treatment group for the safety set.  
Prior and concomitant medications will be summarized by treatment group in separate tables.  
Medications will be presented in alphabetical order, by ATC codes and grouped by anatomical 
main group (the 1st level of the ATC codes). Tables will also show the overall number and 
percentage of subjects receiving at least one drug of a particular ATC code and at least one drug 
in a particular anatomical main group.  
Background therapies such as MTX or other DMARDs might be excluded from concomitant 
medications, if appropriate for the indication. 
Prior medications are defined as drugs taken and stopped prior to first dose of study treatment 
in core studies.  Any medication given at least once between the day of first dose of randomized 
study treatment and the last day of study visit will be a concomitant medication, including 
those which were started pre-baseline and continued into the RW period/ treatment period.  
Indication specific summaries of prior and/or concomitant medication might be presented as 
well. 
For psoriasis this will be done for: 
• the categories presented in Table 1-8, but as well for topical, phototherapy and 
photochemotherapy (yes/no) 
• ongoing use of emollients  
 
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized. 
Prior medications will not be re-summarized for extension. They have been summarized in core 
studies.  
Prior or concomitant medication will be identified based on recorded or imputed start and end 
dates of medication taken. Further rules will be given in PDS. 


Novartis 
Confidential 
Page 28 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-8 
Subgroups based on the previous psoriasis therapy 
Level 1 
description 
Level 1 
outcome 
Level 2 
description 
Level 2 
outcome 
Level 3 
description 
Level 3 
outcome 
Level 4 
description 
Level 4 
outcome 
previous 
therapy 
yes/no 
systemic 
No 
Yes 
number 
1 
2 
>=3 
failure* 
No 
Yes 
biologic 
No 
Yes 
failure* 
No 
Yes 
type of previous biologic 
anti-p40 
No 
Yes 
failure* 
no 
yes 
anti-TNF 
No 
Yes 
failure* 
no 
yes 
lack of primary 
efficacy 
no 
yes 
lack of secondary 
efficacy 
no 
yes 
lack of primary or 
secondary efficacy 
no 
yes 
lack of tolerability 
no 
yes 
non-biologic 
systemic 
No 
Yes 
failure* 
No 
Yes 
failure* to at 
least 2 
No 
Yes 
Only selected subgroups will be used for reporting 
*: at least one therapy with lack of primary efficacy or lack of secondary efficacy or lack of tolerability 
 
1.9 
Efficacy evaluation 
1.9.1 
Variables 
 
Table 1-9 lists the all primary, secondary and exploratory variables for this study. Only part of 
the variables will be included in the final analysis. The key secondary variables will be re-run 
for patients who randomized to RW period or for retreated patents after relapse. 
Table 1-9 
Primary, secondary and exploratory variables 
 


Novartis 
Confidential 
Page 29 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Variable 
Type 
Analysis 
cumulative rate of subjects who lost PASI 75 
response up to Week 68 (compared to placebo) after 
52 weeks of treatment 
Primary 
No analysis 
PASI 50/75/90/100 and IGA mod 2011 0 or 1 response over 
time 
Secondary 
Final analysis 
Re-run during RW period 
and for relapse patients 
after re-treated  
Loss of PASI 75 response over time after 52 weeks of 
treatment 
Secondary 
Re-run during RW period 
Loss of IGA 0 or 1 response over time after 52 weeks 
of treatment 
Secondary 
Re-run for PASI 75 
responders during RW 
period 
PASI score over time 
Secondary 
Final analysis 
IGA mod 2011 score over time 
Secondary 
Final analysis 
Relapse 
Secondary 
Final analysis 
Rebound 
Secondary 
Final analysis 
Time to PASI 75 response 
Secondary 
No analysis 
Time to IGA 0 or 1 response  
Secondary 
No analysis 
EQ-5D 
Secondary 
Final analysis 
DLQI 
Secondary 
Final analysis 
Re-run during RW period 
DLQI 0 or 1 achievement 
Secondary 
Final analysis 
Re-run during RW period 
HAQ-DI score over time1 
Exploratory 
Final analysis 
HAQ-DI response over time1 
Exploratory 
Final analysis 
1only for subjects with psoriatic arthritis (PsA) at baseline of core study 
1.9.1.1 
Definition of PASI and related variables  
The total BSA affected by plaque-type psoriasis was estimated from the percentages of areas 
affected, including head, trunk, upper limbs and lower limbs (see below for PASI assessment).  
The following calculations were done: each reported percentage was multiplied by its respective 
body region corresponding factor (head = 0.1, trunk = 0.3, upper limbs = 0.2, lower limbs = 
0.4).  The resulting 4 percentages will be added up to estimate the total BSA affected by plaque-
type psoriasis.  The PASI scoring system is further described in Table 1-12. 
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) was 
derived as indicated in Table 1-12.  The head, trunk, upper limbs and lower limbs are assessed 
separately for erythema, thickening (plaque elevation, induration), and scaling (desquamation).  
The average degree of severity of each sign in each of the four body regions is assigned a score 
of 0-4.  The area covered by lesions on each body region is estimated as a percentage of the total 
area of that particular body region.  Further practical details help the assessment: 


Novartis 
Confidential 
Page 30 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
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 was calculated 
using the formula: 
PASI = 0.1 (Eh + Ih + Dh)Ah + 0.2 (Eu + Iu + Du)Au + 0.3 (Et + It + Dt)At + 0.4 (El + Il + 
Dl)Al, 
where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, and h, 
u, t, and l denote head, upper extremities, trunk, and lower extremities, respectively (see Table 
1-10). 
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0. 
The investigator was only responsible for collecting the components or scoring signs and total 
regional area.  PASI calculations were done via the PASI Score eCRF.   
The PASI scores calculated via the PASI Score eCRF will be used in the analysis and for 
derivation of PASI response values, relapse and rebound (see below).  
It should be noted that the true area percentage values were rounded in the eCRF calculations 
up to the closest integer value. For example, the true area of 0.45% was rounded to 0% (giving 
area score of 0), and the true area of 0.5% was rounded to 1% (giving area score of 1). 
In order to investigate the effect of rounding the true area percentage values on the PASI scores, 
an additional calculation of PASI scores without rounding the true area percentage values will 
be done. The area affected by psoriasis within each anatomic area is estimated as a percentage 
and assigned a numeric value (area score) according to degree of involvement as follows: no 
involvement = 0; >0% to <10% = 1; 10% to <30% = 2; 30% to <50% = 3; 50% to <70% = 4; 
70% to <90% = 5; and 90% to 100% = 6. The PASI score will be calculated using the formula 
above. The PASI score calculated in this way will be referred to as the PASI score without 
rounding the true area percentage values. 
 


Novartis 
Confidential 
Page 31 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-2 
The PASI scoring system 
Body  
region 
Erythema (E) 
 
Thickening 
(plaque elevation, 
induration, I) 
Scaling  
(desquamation, D) 
Area score 
(based on true 
area %, A)* 
Head (H)† 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Trunk (T)‡ 
0=none  
1=slight  
2=moderate 
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Upper  
limbs (U) 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
Lower  
limbs (L)§ 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = 0% 
1 = 1-9% 
2 = 10-29% 
3 = 30-49% 
4 = 50-69% 
5 = 70-89% 
6 = 90-100% 
* Percentage (not score) of body region (not whole body) affected will be entered in the eCRF 
† Neck is assessed as part of the Head (H) body region. 
‡ Axillae and groin are assessed as part of the Trunk (T) body region. 
§ Buttocks are assessed as part of the Lower limbs (L) body region. 
 
The following definitions are possible efficacy evaluations that can be used in clinical trials in 
psoriasis (CHMP/EWP/2454/02, 2004):  
• PASI non response: subjects achieving <50% improvement (reduction) in PASI score 
compared to baseline are defined as PASI non responders 
• Partial response: subjects achieving ≥ 50% improvement (reduction) in PASI score  but 
less than 75% compared to baseline are defined as partial responders 
• 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 32 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
• PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 90 responders 
• PASI 100 response: complete clearing of psoriasis (PASI=0) 
• Relapse: when the achieved maximal PASI improvement from baseline PASI in core is 
reduced by >50%  
• Rebound-like event: defined as increase of PASI of more than 25% from baseline value  
or occurrence of new pustular, new erythrodermic or more inflammatory psoriasis after 
stopping therapy  
• Rebound: defined as rebound like event occurring within 8 weeks of stopping therapy  
The analysis of rebound will be done for the follow-up period. 
The number and percentage of subjects experiencing rebound and rebound like events will be 
presented by treatment group as follows: 
• For rebound, all assessments done up to 8 weeks will be summarized.  
• Similarly for rebound like events, all assessments done up to 12weeks will be 
summarized.  
1. Rebound up to 8 weeks: For this time-point the worst outcome (i.e. rebound like 
event=yes) prior to this cut-off is considered (e.g. if a subject had >25% PASI increase 
at Week 260, but not at Week 264 the subject would be considered as rebounder for 
this “up to 8 week timepoint”).   
• Rebound like events up to 12 weeks: For this time-point the worst outcome (i.e. rebound 
like event=yes) prior to this cut-off is considered.  
Definition of IGA mod 2011 score and IGA mod 2011 0 or 1 response 
The IGA mod 2011 rating scale for overall psoriatic disease (shown in Table 1-11 ) has been 
developed based on a previous version of the scale used in secukinumab phase II studies, and 
has been updated in collaboration with health authorities (in particular the FDA. ).The 
explanations/descriptions of the points on the scale have been improved to ensure appropriate 
differentiation between the points. 
The IGA mod 2011 used in this study is static, i.e., it refers exclusively to the subject’s disease 
state at the time of the assessments, and does not attempt a comparison with any of the subject’s 
previous disease states, whether at baseline or at a previous visit. 


Novartis 
Confidential 
Page 33 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-3 
The IGA mod 2011 rating scale 
Score 
Short Description 
Detailed Description 
0 
Clear 
No signs of psoriasis. Post-inflammatory hyperpigmentation may 
be present. 
1 
Almost clear 
Normal to pink coloration of lesions; no thickening; no to minimal 
focal scaling. 
2 
Mild 
Pink to light red coloration; just detectable to mild thickening; 
predominantly fine scaling. 
3 
Moderate 
Dull bright red, clearly distinguishable erythema; clearly 
distinguishable to moderate thickening; moderate scaling. 
4 
Severe 
Bright to deep dark red coloration; severe thickening with hard 
edges; severe / coarse scaling covering almost all or all lesions. 
Note:  Involvement of nails is not part of the assessment. 
Based on this scale, subjects will be considered as IGA mod 2011 0 or 1 responder if they 
achieve a score of 0 or 1 and improve by at least 2 points on the IGA scale compared to baseline. 
1.9.1.2 
Health Assessment Questionnaire - Disability Index (HAQ-DI) 
The Health Assessment Questionnaire (HAQ©) was developed by Stanford University and is 
one of the most widely used measures to assess the long-term influence of chronic disease on a 
subject's level of functional ability and activity restriction. The disability assessment component 
of the HAQ (Health Assessment Questionnaire – Disability Index), the HAQ-DI, assesses a 
subject's level of functional ability and includes questions of fine movements of the upper 
extremity, locomotor activities of the lower extremity, and activities that involve both upper 
and lower extremities. There are 20 questions in eight categories of functioning including 
dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each 
item asks over the past week "Are you able to …" perform a particular task. Each item is scored 
on a 4-point scale from 0 to 3, representing normal (normal, no difficulty [0]), some difficulty 
[1], much difficulty [2], and unable to do [3].  
Scoring for the eight functional categories and overall disability index scoring will be performed 
as follows:  
There are eight categories; first score within each category:  
 
Dressing and Grooming, includes items 1 and 2  
 
Arising, includes items 3 and 4  
 
Eating, includes items 5, 6 and 7  
 
Walking, includes items 8 and 9  
 
Hygiene, includes items 10, 11, and 12  
 
Reach, includes items 13 and 14  
 
Grip, includes items 15, 16 and 17  
 
Activities, includes items 18, 19, and 20 


Novartis 
Confidential 
Page 34 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
The score for each category will be the single response within the category with the highest 
score (greatest difficulty). For example, in the "Eating" category, there are two answers (one 
for each item). If "Cut your food with a knife or fork" is marked as "3" and "Lift a full cup or 
glass to your mouth" is marked as "0", then the score for the "Eating" category would be "3" 
(the response indicating the greatest difficulty within the category). If a component question is 
left blank or the response is too ambiguous to assign a score, then the score that that category 
will be determined by the remaining completed question(s). However, if any "aids or devices" 
and/or "help from another person" items at the bottom of each page are checked with the 
exception of “other”, the category to which they apply will be adjusted upward to "2". If the 
basic score is already "2" or "3", the score remains unchanged. "Aids or devices" and "help 
from another person" can only change a category's score to "2"; they do not change the score to 
a "1" or a "3". Companion aids/devices items for HAQ-DI categories are presented in Table 1-
12. No score will be adjusted for “other” ticked, regardless of the “other” specification. 
The score for the disability index will be the mean of the eight category scores. If more than 
two of the categories, or 25%, are missing, scale will not be scored. If fewer than 2 of the 
categories are missing, divide the sum of the categories by the number of answered categories. 
The higher score indicates greater disability. 
HAQ-DI response is defined by an improvement of at least 0.3 score points compared to 
baseline. 
Table 1-4 
Companion aids/devices items for HAQ-DI categories 
HAQ-DI Category  
Companion Item  
Dressing & Grooming   
Devices used for dressing (button hook, zipper pull, long handled 
shoe horn etc.)   
Arising   
Built up or special chair   
Eating   
Built up or special utensils   
Walking   
Cane walker, crutches   
Hygiene   
Raised toilet seat, bathtub seat, bathtub bar   
Long handled appliances in bathroom   
Reach   
Long handled appliances for reach   
Grip   
Jar opener (for jars previously opened)  
1.9.1.3 
Overview of analysis methods of efficacy variables 
An overview of statistical analyses and methods applied to psoriasis efficacy variables is given 
in Table 1-13. 
 
 


Novartis 
Confidential 
Page 35 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-5 
Overview of analysis methods for efficacy variables 
Variable(s) 
Summary 
statistics for 
binary/ 
categorical 
data  
Cochran-
Mantel-
Haenszel 
test 
Logistic 
regression 
Summary 
statistics for 
continuous 
data 
Time-to-
event data 
analysis 
Graphs 
PASI 50/75/90/100 over time 
X 
X 
X 
 
 
X1 
Loss of PASI 75 response over 
time during RW period 
X 
 
 
 
X 
 
Loss of IGA 0 or 1 response over 
time during RW period 
X 
 
 
 
X 
 
Absolute PASI score over time 
 
 
 
X 
 
 
% change PASI over time 
 
 
 
X 
 
 
IGA mod 2011 0 or 1 response 
over time 
X 
X 
X 
 
 
 
IGA mod 2011 score over time 
by categories 
 
 
 
X 
 
 
Relapse 
X 
 
 
 
X 
X 
Rebound 
X 
 
 
 
 
 
EQ-5D 
X 
 
 
X 
 
 
Absolute DLQI4 
 
 
 
X 
 
 
% change DLQI4 
 
 
 
X 
 
 
DLQI 0 or 1 achievement 
X 
 
 
 
 
 
HAQ-DI score over time 
 
 
 
X3 
 
 
HAQ-DI response over time 
X3 
 
 
 
 
 
 
1only for subjects who were PASI 75 responders at Week 52  
3only for subjects with psoriatic arthritis at baseline 
4additional analyses for subjects who were PASI 75 responders at Week 52 described below 
1.9.2 
Statistical hypothesis, model, and method of analysis 
 
The statistical hypotheses are that the cumulative rate for subjects who lost PASI 75 response 
up to Week 68 are not different between secukinumab 150 mg and corresponding placebo as 
well as between secukinumab 300 mg and corresponding placebo. 
 
Loss of PASI 75 response will be analyzed by means of a survival analysis defining “loss of 
PASI 75 response” as “failure”. The term cumulative rate corresponds to 1 minus the survival 
function within this survival analysis, and the cumulative rate as well as the survival functions 
are dependent on time t. 
 
Hence, the null hypothesis for each dose corresponds to the usual null hypothesis within a 
survival analysis: The survival functions of the two groups are not different and will be tested 
versus the alternative, that the survival functions are different.  
If the survival functions are different, they must be different at at least one time point within 
the analysis period. The analysis period in the primary analysis is Week 52 to Week 68. 


Novartis 
Confidential 
Page 36 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
 
Let pj(t) denote the proportion of PASI 75 responders at time t for treatment group j, and let 
p0,j(t) denote the proportion of PASI 75 responders at time t for placebo group j, j=1, 2, 
where 
 
• 0,j corresponds to placebo (secukinumab 150 mg in core studies) for j=1 and to placebo 
(secukinumab 300 mg in core studies) for j=2, 
• 1 corresponds to secukinumab 150 mg, 
• 2 corresponds to secukinumab 300 mg. 
 
The following hypotheses will be tested for 52 weeks≤ t ≤68 weeks 
• H1: p1(t) – p0,1(t) = 0 for all t, 52 weeks≤ t ≤68 weeks, versus HA1: there is at least one 
t with p1(t)– p0,1(t) ≥ 0, 
• H2: p2(t) – p0,2(t) = 0 for all t, 52 weeks≤ t ≤68 weeks, versus HA2: there is at least one 
t with p2(t)– p0,2(t) ≥ 0, 
 
In other words 
• H1: Secukinumab 150 mg is not different from placebo with respect to the cumulative 
rate for subjects who lost PASI 75 response up to Week 68 
• H2: Secukinumab 300 mg is not different from placebo with respect to the cumulative 
rate for subjects who lost PASI 75 response up to Week 68 
 
The primary analysis will not be conducted in the final analysis, instead loss of PASI 75 
response during RW will be tested. 
 
Number and percentage of subjects with loss of PASI 75 response based on the number of 
subjects in the full analysis set at risk as denominator will be provided by treatment group. 
 
For loss of PASI 75 response, between-treatment differences will be evaluated using a log-
rank test, stratified by geographical region and body weight stratum, to compare the survival 
functions between secukinumab treatment groups versus placebo. The hazard ratios for these 
comparisons for loss of PASI 75 response and their corresponding 95% confidence intervals 
will be computed using a stratified Cox proportional hazards regression model with treatment 
group, core study and baseline PASI of core study and baseline PASI of extension study as 
explanatory variable and stratified by geographical region and body weight stratum.  
 
Kaplan-Meier estimates including 95% confidence intervals for cumulative rate of subjects 
losing PASI 75 response will be calculated for each treatment group. 
 
The number of subjects with loss of PASI 75 response, number of subjects in the analysis set, 
estimate of cumulative rate during RW period, median event time, and its estimated standard 


Novartis 
Confidential 
Page 37 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
error, as estimable will be provided for each treatment group. In addition, for pre-specified 
time intervals (e.g., 4-week intervals) the following will be presented: 
 
• for each treatment group and time interval: subjects at risk, subjects with loss of PASI 
75 response, subjects with loss of PASI 75 response divided by subjects at risk, 
cumulative subjects with event and cumulative event probability including 95% 
confidence interval. 
• for treatment comparisons the log-rank test and Wilcoxon test as well as the hazard 
ratio derived via Cox regression. 
1.9.3 
Testing strategy 
 
The family wise error will be set to α=2.5% (one-sided). The two hypotheses H1 (referring to 
150 mg) and H2 (referring to 300 mg) will be tested at α/2=1.25% one-sided. In case, a null 
hypothesis has been rejected for one dose, but not for the other dose, the alpha can be shifted 
to the other dose and the null hypotheses can be retested at level α=2.5% (one-sided). 
 
 The graphical approach of Bretz et al. 2009 for sequentially rejective testing procedures is 
used to illustrate the testing strategy: 
 


Novartis 
Confidential 
Page 38 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Figure 1-1 
Testing strategy 
 
 
Note - Other secondary endpoints will not be included in the testing strategy. 
 
1.9.4 
Handling of missing values/censoring/discontinuations  
 
For the analyses re-run during RW period 
 
The loss of PASI 75 response during RW period will be re-run. The subjects who have no lost 
PASI 75 response during RW will be considered as censored observations. Subjects who have 
not lost PASI 75 response but with missing values during RW will be considered as censored 
at prior available visit. Subjects who administered psoriasis concomitant medication (as per 
[MAP Appendix]), will be considered as failures at time of first administration if this occurred 
before the loss of PASI 75. Subjects who did not have PASI 75 response but randomized in RW 
period will be censored at day 0.  Subjects with missing values at week X (X <156) and who 
have not lost PASI 75 response earlier, will be censored at week X (if they have not dropped 
out due to lack of efficacy or not administered psoriasis concomitant medication). Subjects who 
drop-out due to lack of efficacy will be considered as failure at time of drop-out. If drop-out 
was due to other reason, subjects will be considered as censored at time of drop-out. 
Intermediate missing values will not be considered.   
 
Other time-to-event analyses will be handled analogously. For imputation techniques, please 
refer to Table 1-16. 
 
For other analyses (not time to event) missing values with respect to response variables based 
on PASI score and IGA mod 2011 score will be imputed with multiple imputation regardless 
of the reason for missing data (e.g., premature study discontinuation, missed visit, 
administrative issues). 
 
Following the intent-to-treat principle for subjects who prematurely discontinue treatment, but 
who are observed in the follow-up period, efficacy data collected in follow-up periods will be 
linked to planned but missed study visits as well, following imputation schemes described in 
Sections 1.5.4.1 and 1.9.4.2. (e.g., if a subject discontinues treatment at Week 56, but has 
follow-up visit F4, the PASI score observed at Visit F4 might be used for Week 60 assessments). 


Novartis 
Confidential 
Page 39 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
For rebound and relapse no imputed data will be used and analyses will be based on observed 
data only.  
The last observation carried forward method (LOCF ) will be applied to PASI score and IGA 
mod 2011 score that are missing after baseline regardless to the reason for missing data (e.g. 
premature study discontinuation, missed visit, administrative issues). Note that LOCF 
imputations will not be considered for response variables based on PASI score or IGA score 
which will be imputed with non-response, see above. Baseline values will not be carried forward. 
 
If all post Randomization Visit efficacy values are missing for one efficacy parameter then 
these missing values will not be imputed and this subject will be removed from the analysis of 
the corresponding variable, i.e., it might be that the number of subjects providing data to an 
analysis is smaller than the number of subjects in the FAS. In addition, missing baseline 
values will not be imputed. 
 
For subjects who were re-treated after relapse with secukinumab 150 mg or secukinumab 300 
mg amongst PASI 75 responders at week 52, values of RW period are not carried forward to 
treatment period. 
 
For HAQ score and derived variables, EQ-5D and DLQI missing values will be replaced by 
LOCF. Missing responses will also be imputed by LOCF. Baseline values will not be carried 
forward. 
The laboratory values below Lower Level Of Quantification (LLQ) or above Upper Level of 
Quantification (ULQ) will be imputed as LLQ or ULQ, respectively. The numerical part of the 
reported result will be treated as the actual LLQ or ULQ. These laboratory values will be 
displayed in listings using the standard unit with the reported sign (“<” or “>”).” 
 
For the final analysis 
 
For subjects who prematurely discontinue treatment, but are observed in the follow-up period, 
efficacy data collected in follow-up periods will not be linked to planned study visits. 
The following missing data imputation methods will apply to PASI and IGA score or response 
variables in the final analysis: 
o Response variables based on PASI score and IGA mod 2011 categories will be generally 
be presented as ‘observed case’; i.e. all available data for each time point will be 
included in the analyses. 
o For subjects who received secukinumab dose from week 52, multiple imputation will 
be used as the sensitivity method 


Novartis 
Confidential 
Page 40 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
1.9.4.1 
Details for imputations (non- responder and LOCF) and visit 
windowing  
Note: These details are not applicable to time to event analysis. Only PASI and IGA mod 2011 
based response variables are imputed with non-response, other response variables (e.g. for 
HAQ-DI, EQ-5D, DLQI) will be imputed with LOCF. Baseline values will not be carried 
forward. If all post baseline values are missing for one efficacy parameter, then these missing 
values will not be imputed and this subject will be removed from the analysis of the 
corresponding variable. 
• Non- responder imputation for subjects with PASI 75 response at Week 52 - RW period 
(Week 52 up to Week 156) 
1. Assign period to each visit as per CRF visit (CRF period) or as per visit date for 
unscheduled visits (analysis period) 
2. Assign analysis visit windows (for RW period from week 52 up to Week 156) 
according to Section 1.5.4. Of note, RW CRF period visits will not be assigned to 
treatment analysis period, whereas follow-up period CRF  visits might be assigned to 
RW analysis period for subjects who do not enter treatment CRF period) 
3. If no CRF visit is assigned to an analysis visit as per Section 1.5.4, impute non-
response 
 
Note – Subjects with PASI 75 response at week 52 enter RW period. RW period is not fixed 
for all the subjects but varies for subject to subject based on occurrence of relapse. Subjects in 
RW period will enter treatment period only after first full relapse, if it occurs; otherwise not. 
Partial responders are not entering the RW period but go into the treatment period. 
 
• LOCF imputation  
1. Assign period to each visit as per CRF visit (CRF period) or as per visit date for 
unscheduled visits (analysis period) 
2. Assign analysis visit windows (for RW period from week 52 up to Week 156) according 
to Section 1.5.4. Of note, RW CRF period visits will not be assigned to treatment analysis 
period, whereas follow-up CRF period visits might be assigned to RW analysis period for 
subjects who do not enter treatment CRF period) 
3. If no CRF visit is assigned to an analysis visit as per Section 1.5.4, impute with LOCF 
 
Note: All data collected in the eCRF will be considered for LOCF imputation regardless of 
whether the data was considered in analysis visit windows. 
1.9.4.2 
Multiple imputations   
Loss of PASI 75 response will be evaluated as described above in section 1.9.2 with multiple 
imputations instead of non-responder imputation for missing values. Multiple imputation will 
also be used for PASI/IGA score and responses variables. 
 


Novartis 
Confidential 
Page 41 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Multiple imputation (MI) is a simulation based approach where missing values are replaced 
by multiple Bayesian draws from the conditional distribution of missing data given the 
observed data and covariates, creating multiple completed data sets. These completed data 
sets can then be analyzed using standard methods.  Rubin (1987) presented rules how to 
combine the multiple sets of estimates to produce overall estimates and confidence intervals 
that adequately incorporate missing data uncertainty. 
 
Missing values for the ‘change from baseline PASI score’ will be imputed based on an 
underlying normal distribution and using a Markov Chain Monte Carlo (MCMC) method. The 
change from baseline in PASI score appears to follow closer to a normal distribution than the 
actual PASI score.  
 
The imputations will be done separately for each treatment group including baseline weight, 
failure to at least one previous biologic (yes/no), and number of previous systemic therapies as 
additional covariates. Values post assessment timepoint of the primary endpoint will not be 
considered for imputations. 
 
The number of imputations will be set to 100, the seed for the random function will be set to 
457230201 for this study. To generate the multiple imputed data sets, the SAS procedure MI 
can be used as follows: 
The input data set <pasi> should have one record per subject with baseline PASI as well as all 
changes from baseline PASI score. 
 
ODS LISTING CLOSE; 
 
PROC MI DATA=<pasi> OUT=<impdata> SEED=457230201 NIMPUTE=100; 
EM maxiter=300; 
 VAR <baseline weight>  
     <failure to at least one biologic>  
     <number of previous systemic therapies>  
     <baseline PASI>   
     <change from baseline PASI week 52> 
     <change from baseline PASI week 56>  
     <change from baseline PASI week 60> 
     <change from baseline PASI week 64> 
     <change from baseline PASI week 68> 
      
  BY <treatment group>; 
RUN; 
ODS LISTING; 
 


Novartis 
Confidential 
Page 42 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
The imputed data are saved in data set <impdata>. The outcomes of interest, i.e. the loss of 
PASI 75 response will be calculated from change from baseline PASI scores. The day of visit 
at which the first occurrence of losing PASI 75 response will also be obtained. In the case of 
missing visits or visit dates the planned visit day will be used., e.g. as follows: 
 
DATA <impdata2>; 
 SET <impdata>; 
IF <change from baseline PASI week primary endpoint>/<baseline PASI>=0.75 THEN <PASI 75 response> =1; 
ELSE <PASI 75 response>=0; 
END; 
RUN; 
 
The treatment differences for each imputed data set will then be evaluated by using Cox 
proportional hazards regression as described section 1.9.2. This analysis will be done by 
_IMPUTATION_ for each pairwise comparison as described in section 1.9.5. The data set 
should be sorted such that the control group comes last. E.g as follows: 
 
ods table HazardRatios = hazardratios; 
proc phreg data = <impdata2>; 
class <treatment group> <core study> <geographical region> <body weight stratum> 
 model TIME*PASI75(1)= <treatment group> <core study> <core baseline PASI> <extension baseline PASI>/ties=exact; 
STRATA < geographical region> < body weight stratum> 
 by _Imputation_; 
run; 
 
data dhazardratios; 
 
 
set hazardratios; 
 
 
where Description in ( 'TRT01PN 1 vs 3' 'TRT01PN 2 vs 4'); 
 
 
if Description in ( 'TRT01PN 1 vs 3') then comp =1; 
 
 
else if Description in ( 'TRT01PN 2 vs 4') then comp =2; 
 
 
if HazardRatio NE . and HazardRatio > 0 then ESTIMATE=log(HazardRatio); 
 
 
if WaldLower NE . and HazardRatio > 0 then STDERR=log(WaldLower/HazardRatio)/-probit(1-0.05/2); 
 
 
if missing(ESTIMATE) or missing(STDERR) then delete; 
          effect=”LogHR”; 
 
run; 
 
• 
The PHREG procedure and following MIANALYZE procedure could then be run with 
by-variables for the comparison and response identifier. 
 
The MIANALYZE procedure expects the parameter estimate in the variables ESTIMATE, 
and the corresponding standard error in the variable STDERR. The dataset dhazardratios 
above contained the estimate and its standard error for log(Hazard ratio) 
 
The estimates and standard errors of the log of hazard ratio based on the 100 imputed data are 
then combined by applying Rubin’s rules for multiple imputed data sets, see Little and Rubin 
(2002).  
 
The SAS procedure MIANALYZE will be applied as follows: 


Novartis 
Confidential 
Page 43 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
ODS LISTING CLOSE; 
ODS OUTPUT ParameterEstimates=<results>; 
PROC MIANALYZE PARMS=<lgparms>; 
  BY comp; 
   MODELEFFECTS LogHR; 
RUN; 
ODS LISTING; 
 
DATA <results2>; 
  SET <results>; 
  or=EXP(estimate); 
  lowercl=EXP(LCLmean); 
  uppercl=EXP(UCLmean); 
  KEEP <By-variables> or lowercl uppercl probt; 
RUN; 
 
1. Cumulative Probabilities and CI: Use log(-log(x))-transformed estimates for the 
survival function and their associated standard errors for each imputed data set and 
combine the results using Rubin’s rules (PROC MIANALYZE). The transformation is 
done to ensure that resulting confidence intervals only include values between 0 and 1.  
1. 
Then back-transform combined estimates and associated CI intervals and 
calculate the ‘cumulative’ quantities. 
2. 
Calculate the mean across all imputed data sets for the columns: “subj. at risk” 
/ “subj. with event” / “subj. with event/at risk”/ “cum. subj. with event”, round 
them to the nearest integers as these will generally be non-integers.  
 
Steps for Cumulative Probabilities and CIs: 
1. 
Create 100 imputed datasets including time to loss of PASI 75 response for each 
patient using PROC MI. 
2. 
Run PROC LIFETEST for each imputed data set and store estimates for the survivor 
function (SURVIVAL) and the associated standard errors (STDERR) in the data set 
OUTSURV.  
 
proc lifetest data=adttepas method=km outsurv=outsurv; 
by _imputation_; 
strata arm; 
time aval*cnsr(1); 
run; 
 
3. 
In a data step use the data set OUTSURV to calculate  
1. 
T_SURVIVAL=log(-log(SURVIVAL)) 
2. 
T_STDERR= STDERR/(SURVIVAL*log(SURVIVAL)) 
 
data outsurv1; 
set outsurv; 


Novartis 
Confidential 
Page 44 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
T_SURVIVAL=log(-log(SURVIVAL)); 
                                 T_STDERR= STDERR/(SURVIVAL*log(SURVIVAL)) 
run; 
 
4. 
Use the data set OUTSURV1 as input for PROC MIANALYZE to combine the results 
for T_SURVIVAL and T_STDERR based on the multiply imputed data sets. As we 
have two strata and different time intervals, we combine the estimates separately for 
each combination =strata * time interval. 
 
ods output ParameterEstimates=Survival_MI; 
proc mianalyze data=outsurv1; 
      by combination; 
      modeleffects T_Survival; 
      stderr T_STDERR; 
   run; 
 
5. 
Back-transform the combined survival estimates to the original scale and calculate the 
cumulative probabilities and associated CIs 
 
data Survival_MI2; 
set Survival_MI; 
MI_survival=exp(-exp(Estimate)); 
                                LCL=(MI_survival)^exp(quantile('NORMAL',.975)*STDERR); 
                                UCL=(MI_survival)^exp(-quantile('NORMAL',.975)*STDERR); 
                                MI_cumulative= 1-MI_survival;  
                                LCL_cum=1-UCL; 
                                UCL_cum=1-LCL; 
run; 
 
p-values from Log-rank and Wilcoxon tests: Use transformed estimates for the Log-rank 
and Wilcoxon test statistics and their associated standard errors for each imputed data set 
using the Wilson-Hilferty transformation (Wilson & Hilferty, 1931; Goria, 1992) and 
combine the results using Rubin’s rules (PROC MIANALYZE). 
 
Steps for p-values from Log-rank and Wilcoxon tests 
1. Create 100 imputed datasets including time to loss of PASI 75 response for each patient 
using PROC MI. 
2. Run PROC LIFETEST for each imputed data set and store estimates for the test statistics 
and the associated standard errors (STDERR) in the data set HOMTESTS.  
3. Apply Wilson-Hilferty transformation to the Chi-square statistic and standardize the 
resulting normal variable as below e.g.; 
DATA HOMTESTS1;  


Novartis 
Confidential 
Page 45 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
  SET HOMTESTS; 
  CHI_VALUE_WH=((ChiSq/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF)); 
  CHI_STERR_WH = 1.0; 
RUN; 
4. Use the data set HOMTESTS1 as input for PROC MIANALYZE to combine the results 
for CHI_VALUE_WH and CHI_STERR_WH  based on the multiply imputed data 
sets 
ODS LISTING CLOSE; 
ODS OUTPUT ParameterEstimates=logrank_mi; 
PROC MIANALYZE data=logrank; 
 
 
by comp; 
 
 
modeleffects chi_value_wh; 
 
 
stderr chi_sterr_wh; 
RUN; 
ODS OUTPUT ParameterEstimates=wilcox_mi ; 
PROC MIANALYZE data=wilcox; 
 
by comp; 
 
modeleffects chi_value_wh; 
 
stderr chi_sterr_wh; 
RUN; 
ODS LISTING; 
1.9.5 
Secondary variables 
 
Secondary variables are: 
 
PASI 50/75/90/100 and IGA mod 2011 0 or 1 response over time in subjects who were 
PASI 75 responders at Week 52, over time for subjects who were re-treated after relapse with 
secukinumab 150 mg or 300 mg, and over time in subjects who were partial responders at 
Week 52. 
 
Loss of PASI 75 response over time in subjects who were PASI 75 responders at Week 52  
 
Loss of IGA 0 or 1 response over time in subjects who were PASI 75 responders as well as 
IGA 0 or 1 responders at Week 52  
 
PASI score over time in subjects who were PASI 75 responders at Week 52, over time for 
subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg, and over time 
in subjects who were partial responders at Week 52. 
 


Novartis 
Confidential 
Page 46 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
IGA mod 2011 score over time in subjects who were PASI 75 responders at Week 52, over 
time for subjects who were re-treated after relapse with secukinumab 150 mg or 300 mg, and 
over time in subjects who were partial responders at Week 52. 
 
Relapse in subjects who were PASI 75 responders at Week 52, over time for subjects who 
were re-treated after relapse with secukinumab 150 mg or 300 mg, and over time in subjects 
who were partial responders at Week 52. 
 
Rebound in subjects who were PASI 75 responders at Week 52, over time for subjects who 
were re-treated after relapse with secukinumab 150 mg or 300 mg, and over time in subjects 
who were partial responders at Week 52. 
 
 
EQ-5D in subjects who were PASI 75 responders at Week 52, over time for subjects who 
were re-treated after relapse with secukinumab 150 mg or 300 mg, and over time in subjects 
who were partial responders at Week 52. 
 
DLQI score as well as DLQI 0 or 1 achievement in subjects who were PASI 75 responders 
at Week 52, over time for subjects who were re-treated after relapse with secukinumab 150 
mg or 300 mg, and over time in subjects who were partial responders at Week 52. 
 
1.9.6 
Methods of analysis 
 
Final analysis 
 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time  
 
Descriptive statistics will be provided until the last visit. Summary statistics for PASI 50, 
PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit starting from Week 52 
onwards will be presented in contingency tables and will include absolute and relative 
frequencies. 
Confidence intervals for response rates will be derived as well based on the score method 
including continuity correction (Newcombe, 1998). 
 
 
 
PASI score over time 
 
Summary statistics will be provided for absolute PASI scores as well as for percent change 
from core baseline by visit starting from Week 52 onwards and treatment group. 
IGA mod 2011 score over time 


Novartis 
Confidential 
Page 47 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
 
Summary statistics for the IGA mod 2011 score over time will be presented by visit starting 
from Week 52 onwards and treatment group in contingency tables. 
 
Relapse 
 
Relapse will be analyzed analogously to loss of PASI 75 response in the follow-up period.  
 
A listing of these subjects will also be provided. 
 
Rebound 
 
The number and percentage of subjects experiencing rebound during follow-up period will be 
presented by visit and treatment group. 
 
For subjects who were PASI 75 responders and randomized to RW period 
 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time  
 
Descriptive statistics will be provided until the last visit. Summary statistics for PASI 50, PASI 
75, PASI 90, PASI 100 and IGA 0 or 1 response by visit starting from Week 52 onwards will 
be presented in contingency tables and will include absolute and relative frequencies. 
Confidence intervals for response rates will be derived as well based on the score method 
including continuity correction (Newcombe, 1998). 
 
For PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response at each visit starting from 
Week 52 onwards during RW period, each secukinumab dose regimen will be compared to 
placebo (up to last visit with more than 5% of subjects in placebo group) by means of the 
stratified Cochran-Mantel-Haenszel-test as well as by means of a logistic regression model with 
treatment group, geographical region, body weight stratum at core, and core baseline PASI as 
effects. 
 
Loss of PASI 75 response over time 
 
The loss of PASI 75 response during RW period will be repeated. In addition, the secukinumab 
treatment groups will also be compared, i.e. a Cox proportional hazards regression will be fitted 
as described above including all four treatment groups. Placebo (secukinumab 150 mg in core 
studies) and Placebo (secukinumab 300 mg in core studies) will be compared as well as 
secukinumab 150 mg and secukinumab 300 mg. 
 
Loss of IGA 0 or 1 response over time 
 


Novartis 
Confidential 
Page 48 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Loss of IGA 0 or 1 response over time will be analyzed analogously to the loss of PASI 75 
response, but it will be restricted to the subset of subjects who have been IGA 0 or 1 
responder at Week 52. 
 
For subjects who were re-treated after relapse with secukinumab 150 mg or 300 
mg 
 
PASI 50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response over time  
 
Descriptive statistics will be provided from relapse until week 156. Summary statistics for PASI 
50, PASI 75, PASI 90, PASI 100 and IGA 0 or 1 response by visit will be provided similar as 
for RW period. 
 
 
1.9.7 
Risk set, timing and censoring for time to event analysis 
 
Subjects at risk, timepoint “0” and censoring will be defined as described in Table 1-14 below.  
Table 1-64 
Time to event: definition of risk set, timing and censoring by variable 
 
Variable: 
Time to 
Risk set 
Time = 0 
Time of 
event 
Censoring 
Psoriasis 
ConMed 
Informative  
censoring 
Loss of 
PASI 75 
response 
All PASI 75 
responders 
at Week 52 
per analysis 
visit AND 
entering RW 
period as 
per CRF 
disposition 
page 
Week 52 
per analysis 
visit 
Date of 1st 
visit with 
OBSERVED 
loss of PASI 
75 response 
(i.e. no 
imputation 
for missing 
values) 
Last 
available 
visit up to 
Week 68  
per analysis 
visit for PEA 
& End of 
RW period 
for 
secondary 
analysis 
Event (if the 
subject took 
psoriasis 
ConMed, 
the subject 
is 
considered 
as having 
lost 
response) 
Study phase 
discontinuati
on with 
reason “lack 
of efficacy” 


Novartis 
Confidential 
Page 49 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Variable: 
Time to 
Risk set 
Time = 0 
Time of 
event 
Censoring 
Psoriasis 
ConMed 
Informative  
censoring 
Loss of IGA 
mod 2011 0 
or 1 
response 
All IGA 0 or 
1 
responders 
at Week 52 
amongst 
PASI 75 
responders 
as per 
analysis 
visit AND 
entering RW 
period as 
per CRF 
disposition 
page 
Week 52 
per analysis 
visit 
Date of 1st 
visit with 
OBSERVED 
loss of IGA 
mod 2011 0 
or 1 
response 
(i.e. no 
imputation 
for missing 
values) 
Last 
available 
visit up to 
Week 68  
per analysis 
visit for PEA 
& End of 
RW period  
Event (if the 
subject took 
psoriasis 
ConMed, 
the subject 
is 
considered 
as having 
lost 
response) 
Study phase 
discontinuati
on with 
reason “lack 
of efficacy” 
Relapse (in 
follow-up 
period) 
All subjects 
who were 
PASI 50 
responders  
(based on 
OBSERVED 
data)at least 
once during 
the RW or 
treatment 
period 
Date of last 
active 
treatment or 
last 
secukinuma
b placebo 
administrati
on 
Date of 1st 
visit with 
OBSERVED 
relapse (i.e. 
no 
imputation 
for missing 
values) after 
time = 0 
End of 
follow-up 
period as 
per CRF 
disposition 
page 
Event (if the 
subject took 
psoriasis 
ConMed, 
the subject 
is 
considered 
as having 
experienced 
relapse) 
Study phase 
discontinuati
on with 
reason “lack 
of efficacy” 
 
 
 
 
 
 
 
ConMed: Concomitant medication 
Psoriasis ConMed is defined in MAP appendix 


Novartis 
Confidential 
Page 50 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
 
 
 
 
 
 
  
 
 
 
 
 
1.9.9 
Biomarkers 
Not applicable. 
 
1.9.10 
Health-related Quality of Life (HRQoL) 
EQ-5D 
The EQ-5D is a questionnaire with 5 questions (regarding mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) each with three categories (no problem, moderate 
problem, severe problems) and a health state assessment from 0 (worst possible health state) to 
100 (best possible health state). The number and percentage of subjects in each of the three 
categories for each question will be presented by visit and treatment group. Chi-square tests 
will be used to compare treatments groups by visit.  
Summary statistics will be shown for the health state assessment by visit and treatment group.  
Dermatology Life Quality Index  
The DLQI© measures functional disability of subjects with dermatological disorders that are 
greater than 18 years of age and had been utilized as a relevant clinical measure in atopic 


Novartis 
Confidential 
Page 51 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
dermatitis, as well as other dermatitis clinical trials. The DLQI© is a simple, validated, self-
administered 10-item questionnaire. The instrument contains six functional scales (i.e., 
symptoms and feeling, daily activities, leisure, work and school, personal relationships, 
treatment). For the DLQI©, each question will be answered with the following response: “not 
at all,” “a little,” “a lot,” or “very much”. 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. 
 
For each of the seven scores the percentage change from extension baseline will be derived. 
Summary statistics will be provided for absolute values as well as for the percentage change 
by visit and treatment group.  
 
In addition, summary statistics will be provided for number of subjects achieving DLQI 0 or 
1.  
HAQ©-DI (for subjects with PSA at baseline of the core study) 
 
Summary statistics will be derived for HAQ©-DI score over time for all subjects with 
psoriatic arthritis recorded on the Psoriatic Arthritis History eCRF at screening visit of the 
core study. 
Absolute and relative frequencies for HAQ©-DI response will also be presented. HAQ©-DI 
response is defined by an improvement of 0.3 score points compared to baseline. 
 
1.10 
Standard safety evaluation 
All safety analyses will be based on the safety set. In general, summaries will be provided for 
extension phase i.e after first dose of study medication in extension.  In general, extension 
baseline will be used for all change from baseline analysis.  
Safety analysis will be based on treatment groups as defined in Table 1-3. 
 
1.10.1 
Adverse events 
 
Adverse events will be summarized for entire study period. 
For adverse events and other binary safety variables crude incidence and exposure time-
adjusted incidence will be derived as described below and summarized in Table 1-15. 
All adverse events are summarized based on treatment emergent only. The definition for 
“treatment emergent” is as below: 
1. events started after the first dose of study medication or events present prior to the first dose 
of study medication but increased in severity based on preferred term  
2. and started prior to the last dose plus 84 days (inclusive)  
All adverse events will be listed with “treatment emergent” flag displayed. 


Novartis 
Confidential 
Page 52 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-75 
Overview of analyses on some safety endpoints 
 
Analysis 
period 
AEs & 
SPP/RMP 
risks 
(special AE 
interest) 
 
SAEs 
AEs-SMQ 
AEs by 
severity 
study 
treatment 
related AEs, 
death&other 
significant 
AEs 
notables 
(lab/vitals/ 
ECG) 
entire 
treatment 
 
• crude 
incidence 
• exp.time 
adjusted 
incidence*  
 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
 
follow-up 2 
• crude 
incidence 
• crude 
incidence 
NA 
NA 
NA 
NA 
*Note, Exposure adjusted incidence rates will be provided and follow the guideline as below: 
1. Primary SOC level for AE and SAE 
2. Level 1 for risks and SMQ 
3. PT level for SAE 
4. PT level for AE  ≥ 2% or incidence rate per 100 subject years ≥ 5.0 in any AIN457 treatment 
group 
5. Other selected AEs of special interest on lower levels (e.g. PT or SMQ level 2), if 
appropriate 
 
AE of special interest: 
Table 1-86 
Overview of analyses on some safety endpoints 
 
AE of Special Interest: 
Notes (All levels are displayed) 
Inflammatory bowel disease (NMQ) (narrow) 
Include Crohns (PT) and Ulcerative 
colitis (PT) and others 
Opportunistic infections (NMQ) 
Candida infections (HLT) 
Herpes viral infections (HLT) 
Both Oral and other are included 
Staphylococcal infections (HLT) 
MACE (MI, Stroke, Cardiovascular death) (NMQ) 
Cardio-cerebrovascular-related events (NMQ) 
Malignant or unspecified tumours (SMQ) 
Including BCC, SCC in SMQ 
Malignant or unspecified tumours (SMQ excl BCC 
and SCC) (NMQ) 
Upper respiratory tract infections (HLT) 


Novartis 
Confidential 
Page 53 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
The crude incidence of treatment emergent adverse events will be summarized. Only primary 
paths within MedDRA will be considered for adverse event reporting. (see Section 2.6). 
 
AEs will be summarized by presenting, for each treatment group  the number and percentage 
of subjects having  at least one AE at each year interval per treatment group, having an AE in 
each primary system organ class and having each individual AE (preferred term). Summaries 
will also be presented for AEs by severity and for study treatment related AEs. If a subject 
reported more than one adverse event with the same preferred term, the adverse event with the 
greatest severity will be presented. If a subject reported more than one adverse event within 
the same primary system organ class, the subject will be counted only once with the greatest 
severity at the system organ class level, where applicable. 
 
Adverse events will also be summarized by SMQ according to MedDRA using a narrow search. 
The MedDRA version used for reporting the adverse events will be described in a footnote. 
The most common adverse events reported (≥ 2% in any group for each preferred term in the 
table by SOC and PT or ≥ 2% in any group for each SMQ table) will be presented in descending 
frequency according to its incidence in secukinumab 300 mg starting from the most common 
event.  
 
Confidence intervals for relative frequencies will be derived as well according to the score 
method including continuity correction by Newcombe, 1998. 
 
Separate summaries will be provided for death, serious adverse event, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment 
(including study treatment discontinuation). 
 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
X% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
 
The follow-up 2 period data are be presented separately in tables and listings. i.e., AE, 
SAEand concomitant medications. 
 
Algorithms for date imputations will be provided in PDS. 
 
The adverse events which occurred after the treatment errors in those subjects who received the 
wrong treatment in error at least once, will be listed. 
1.10.2 
Laboratory data 
 


Novartis 
Confidential 
Page 54 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Laboratory evaluations will be summarized for entire study period. 
 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology and clinical chemistry). In addition to the individual laboratory parameters, the 
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived and 
summarized. 
Descriptive summary statistics for the change from baseline extension to each study visit will 
be presented by laboratory test and treatment group. Change from extension baseline will only 
be summarized for subjects with both baseline and post baseline values and will be calculated 
as: 
change from baseline = post baseline value – baseline value 
Only “on-treatment” laboratory data will be summarized (i.e. assessments within last dose 
plus 84 days). All laboratory data will be listed with “on-treatment” flag displayed. Follow-up 
visits (CRF visits) may be summarized separately if required. 
The laboratory values below Lower Level Of Quantification (LLQ) or above Upper Level of 
Quantification (ULQ) will be imputed as LLQ or ULQ, respectively. The numerical part of the 
reported result will be treated as the actual LLQ or ULQ. These laboratory values will be 
displayed in listings using the standard unit with the reported sign (“<” or “>”).” 
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline will be analyzed analogously.  
 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme laboratory test.  For the shift tables, the 
normal laboratory ranges will be used to evaluate whether a particular laboratory test value was 
normal, low, or high (including category “high and low”).  These summaries will be presented 
by laboratory test and treatment group. 
The following laboratory parameters will be analyzed with respect to Common Terminology 
Criteria for Adverse Events (CTCAE) grades, given in Table 1-17: hemoglobin, platelets, white 
blood cell count, platelets, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), gamma-
glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG), amylase and lipase.  
The number and percentage of subjects with clinically CTCAE grade newly occurring or 
worsening after baseline will be presented. These summaries will be split into hematology and 
chemistry. 
 


Novartis 
Confidential 
Page 55 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-9 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.0 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN - 100 g/L  
<100 - 80g/L 
<80 g/L  
Life-threatening 
consequences; urgent 
intervention indicated 
Platelet count 
decreased 
<LLN – 75.0 x10e9 /L 
<75.0 - 50.0 x10e9 /L 
 
<50.0 – 25.0 x10e9 /L 
<25.0 x 10e9 /L 
White blood cell 
decreased 
 
<LLN - 3.0 x 10e9 /L 
<3.0 - 2.0 x 10e9 /L 
<2.0 - 1.0 x 10e9 /L 
<1.0 x 10e9 /L 
Neutrophil count 
decreased 
<LLN - 1.5 x 10e9 /L 
<1.5 - 1.0 x 10e9 /L 
<1.0 - 0.5 x 10e9 /L 
<0.5 x 10e9 /L 
Lymphocyte count 
decreased 
<LLN - 0.8 x 10e9/L 
<0.8 - 0.5 x 10e9 /L 
<0.5 - 0.2 x 10e9 /L 
<0.2 x 10e9 /L 
Creatinine increased 
 
>1 - 1.5 x baseline;  
>ULN - 1.5 x ULN 
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 
TBL increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
GGT increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALT increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
AST increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALP increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Glucose increased 
(Hyperglycemia )  
>ULN - 8.9 mmol/L 
>8.9 - 13.9 mmol/L 
>13.9 - 27.8 mmol/L 
>27.8 mmol/L 
Glucose decreased 
(Hypoglycemia) 
<LLN - 3.0 mmol/L 
<3.0 - 2.2 mmol/L 
<2.2 - 1.7 mmol/L 
<1.7 mmol/L 
Cholesterol high 
 
>ULN - 7.75 mmol/L 
>7.75 - 10.34 mmol/L 
>10.34 - 12.92 mmol/L 
>12.92 mmol/L 
Hypertriglyceridemia 
1.71 – 3.42 mmol/L 
>3.42 - 5.7mmol/L 
>5.7 - 11.4 mmol/L 
>11.4 mmol/L 
Amylase increased 
>UNL-1.5 ULN 
>1.5 UNL-2.0 ULN 
>2 UNL-5.0 ULN 
>5.0 ULN 
Lipase increased 
>UNL-1.5 ULN 
>1.5 UNL-2.0 ULN 
>2 UNL-5.0 ULN 
>5.0 ULN 
*Note: for creatinine increased the baseline criteria do not apply 
Shift tables will be presented comparing extension baseline laboratory result (CTCAE grade) 
with the worst post baseline results (expressed in CTCAE grade) during entire study period. 
Subjects with abnormal laboratory values will be listed and values outside the normal ranges 
will be flagged. 
 
The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
extension baseline (treatment emergent) will be presented for entire study period.  Absolute and 
relative frequencies will be derived for non-overlap groups: CTCAE grade 1, CTCAE grade 2, 
CTCAE grade 3, and CTCAE grade 4. Exposure adjusted incidence rate will be presented for 
nesting groups: CTC grade >=1, CTC grade >=2, CTC grade >=3, CTC grade 4. 
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories: 
• HDL: 
• <=LLN 
• <0.8 x LLN 
• LDL, cholesterol, triglycerides: 
• >=ULN  


Novartis 
Confidential 
Page 56 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
• >1.5 x ULN  
• >2.5 x ULN 
Subjects with newly occurring or worsening after baseline abnormalities in lipid parameters 
will be listed. If a subject experiences newly occurring or worsening of abnormality for a 
parameter the entire time course of that parameter will be listed. 
Newly occurring liver enzyme abnormalities will also be summarized based on the event criteria 
given in Table 1-18. 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN. 
Individual subject data listings will be provided for subjects with newly occurring or worsening 
abnormal laboratory data. Data of subjects with newly occurring liver enzyme abnormalities 
will be listed in an additional listing.  


Novartis 
Confidential 
Page 57 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Table 1-18 
Liver-related events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
AST 
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN 
TBL 
>1.5xULN; >2xULN; >3xULN, 
ALP 
>2xULN; >3xULN; >5xULN 
ALT or AST & 
TBL 
ALT or AST>3xULN & TBL >2xULN; 
ALT or AST >5xULN & TBL >2xULN; 
ALT or AST >8xULN & TBL >2xULN; 
ALT or AST >10xULN & TBL >2xULN 
ALP & TBL 
ALP >3xULN & TBL >2xULN 
ALP >5xULN & TBL >2xULN 
ALT or AST & 
TBL & ALP 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law) 
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result 
in severe DILI. 
Amylase 
 
Amylase >ULN 
Lipase 
Lipase>ULN 
Amylase or 
Lipase  
Amylase or Lipase>ULN  
Amylase &Lipase 
Amylase and Lipase>ULN 
Amylase 
Amylase >3xULN 
Lipase 
Lipase>3xULN 
Amylase or 
Lipase  
Amylase or Lipase>3xULN  
Amylase &Lipase 
Amylase and Lipase>3xULN 
Amylase or 
Lipase & 
concomitant  epig
astric pain 
Amylase or Lipase>3xULN and concomitant  epigastric pain 
Note: For Concomitant epigastric pain, SOC Gastrointestinal disorders and PT 
Abdominal pain upper will be used  
Amylase & 
Lipase & 
concomitant  epig
astric pain 
Amylase and Lipase>3xULN and concomitant  epigastric pain 
Note: For Concomitant epigastric pain, SOC Gastrointestinal disorders and PT 
Abdominal pain upper will be used 
Notes: 
1) In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased 
above ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the 
abnormality criteria 
 
1.10.3 
Vital signs 
 


Novartis 
Confidential 
Page 58 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Vital signs will be summarized for entire study period. 
 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
extension baseline for each post-baseline visit will be performed by vital sign and treatment 
group. Change from extension baseline will only be summarized for subjects with both baseline 
and post-baseline values and will be calculated as: 
change from baseline = post-baseline value – baseline value 
Only “on-treatment” vital signs will be summarized (i.e. assessments within last dose plus 84 
days). All vital signs will be listed with “on-treatment” flag displayed. Follow-up visits (CRF 
visits) may be summarized separately if required. 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 1-19 below. 
Listings will be provided on combined data of PASI 75 responders and partial responders. 
Table 1-19 
Criteria for notable vital sign abnormalities 
Vital sign (unit) 
Notable abnormalities 
Systolic blood pressure (mmHg) 
>= 140 mmHg or < 90 mmHg 
Diastolic blood pressure (mmHg) 
>=90 mmHg or <60 mmHg 
Pulse (bpm) 
> 100 bpm or <60 bpm 
 
1.10.4 
Electrocardiogram (ECG) 
 
ECG evaluations will be summarized for entire study period.  
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Both Bazett (QTcB) and 
Fridericia (QTcF) corrections will be presented for QTc.  
QTc will be summarized by computing the number and percentage of subjects with: 
• QTc > 500 msec  
• QTc > 480 msec 
• QTc > 450 msec 
• QTc changes from baseline > 30 msec 
• QTc changes from baseline > 60 msec 
• Sinus pause > 3 sec, if appropriate 
• PR > 250 msec 
Summary statistics will be presented for ECG variables by visit and treatment group. 
In addition, shift tables comparing baseline ECG results (normal, abnormal, not available, total) 
with the maximum on-study result (normal, abnormal, not available, total) will be provided. 


Novartis 
Confidential 
Page 59 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Only “on-treatment” ECG evaluations will be summarized (i.e. assessments within last dose 
plus 84 days). All ECG evaluations will be listed with “on-treatment” flag displayed. Follow-
up visits (CRF visits) may be summarized separately if required. 
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters.   
1.10.5 
Immunogenicity 
 A listing of immunogenicity data will be provided. 
1.11 
Sample size calculation 
 
Assumptions for the number of subjects eligible for RW (i.e for the analysis of primary 
endpoint): 
• Drop-out rate on secukinumab at Week 12 in core studies: 5% (estimate from 
CAIN457A2211) 
• Drop-out rate on placebo at Week 12 in core studies: 15% (from CAIN457A2211) 
• Placebo PASI 75 response rate at Week 12: 5% (conservative assumption) 
• Drop-out rate on secukinumab up to Week 52 in core studies: 15% (common for 
secukinumab induction and placebo induction regimens, as in Leonardi et al, 2008) 
•  PASI 75 response rate at Week 52 on secukinumab 150 mg in core studies: 65% 
(from dosing rationale in protocols of core studies) (power would be larger for 300 mg 
if we would assume similar loss of PASI75 rates) 
• Type-I-error rate is defined to one-sided 2.5% 
With these assumptions it is estimated to have 414 subjects eligible per dose to enter the RW, 
with a randomization ratio of 2:1 this would be 276 subjects on 150 mg and 138 subjects on 
placebo. With about 400 subjects the study would have more than 
90% power to detect differences in the cumulative rates if 10% of subjects on secukinumab 
lost PASI 75 response versus 23% on placebo, PASS 2008 software (Log Rank Survival 
Power Analysis - Simple).
 
 
 
 


Novartis 
Confidential 
Page 60 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
2 
Clinical Study Report -  
Appendix 16.1.9 Documentation of statistical methods 
 
Not Applicable 


Novartis 
Confidential 
Page 61 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
3 
References 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
Alberti KGMM, Eckel RH, Grundy SM, et al (2009) Harmonizing the metabolic syndrome: a 
joint interim statement of the international diabetes federation task force on epidemiology and 
prevention; national heart, lung, and blood institute; american heart association; world heart 
federation; international atherosclerosis society; and international association for the study of 
obesity. Circulation; 120: 1640-1645. 
 
 
Bishop YMM, Fienberg SE, Holland PW (1991) Discrete multivariate analysis. Cambridge MA, 
11th ed. The MIT Press 
Bretz F, Maurer W, Brannath W, Posch M (2009) A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine; 28: 586-604. 
 
 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413. 
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use. (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr 
document. London, UK. 
 
Fredriksson T, Pettersson U (1978) Severe psoriasis—oral therapy with a new retinoid. 
Dermatologica; 157:238–44. 


Novartis 
Confidential 
Page 62 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 
Gottlieb A, Griffiths CEM, Ho VC, et al (2005) Efficacy and tolerability of oral pimecrolimus 
in the treatment of moderate to severe chronic plaque type psoriasis: a double-blind, 
multicentre, randomized dose-finding trial.  Br J Dermatol; 152:1219-27. 
‘Japan Specific Requirements from PMDA’ guidance, available in Cabinets/CREDI 
TABULU/B&SR/CIS Process Documentation/Guidances (outside of ESOPS)/Working with 
Japan 
Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics; 53: 983-997.  
Lachin JM (2000) The assessment of relative risks . New York: Wiley 
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-week results from a 
randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet; 371:1665-74. 
Little, R.J.A and Rubin, D.B. (2002). Statistical Analysis with Missing Data. Wiley Series in 
Probabiliy and Statistics, Chapter 10. 
Menter A, Gottlieb A, Feldman S, et al (2008) Guidelines of care for the management of 
psoriasis and psoriatic arthritis – Section 1. Overview of psoriasis and guidelines of care for the 
treatment of psoriasis with biologics. J Am Acad Dermatol; 58:826-850. 
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872. 
Papp KA, Tyring S, Lahfa M et al (2005) A global phase II randomized controlled trial of 
etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol; 152:1304-
12. 
Papp KA, Langley RG, Lebwohl M, et al. (2008) Efficacy and safety of ustekinumab, a human 
interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a 
randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet; 371:1675-84 
Program Case Retrieval Sheet available in Cabinets/CREDI Projects/A/AIN457A/Integrated 
Medical Safety 
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley. 
Safety Profiling Plan stored in CREDI (Cabinets/CREDI Projects/A/AIN457A/Integrated 
Medical Safety) 
Sahai H, Khurshid Anwer (1993). Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867 
Sampson HA, Muñoz-Furlong A, Bock SA, et al (2005) Symposium on the Definition and 
Management of Anaphylaxis: Summary report. J Allergy Clin Immunol 2005;115:584-91. 
Sampson HA, Muñoz-Furlong A, Campbell RL, et al (2006) Second Symposium on the 
Definition and Management of Anaphylaxis: Summary Report - Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Ann 
Emerg Med;47(4):373-80. 


Novartis 
Confidential 
Page 63 
RAP Module 3 
9-Apr-2018 (1:15) 
Secukinumab / AIN457A2302E1 
 
Schaefer, J.L. (1997). Analysis of Incomplete Multivariate Data, Chapman&Hall. 
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375 
Weisman S, Pollack CR, Gottschalk RW (2003) Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis.  J Dermatolog Treat; 14: 158-165. 
Wilson, E.B., Hilferty, M.M. (1931).The distribution of chi-squared. Proceedings of the 
National Academy of Sciences, Washington, 17, 684–688.