Clinical trial NCT04209205
Conditions: Psoriatic Arthritis
Keywords: Active Psoriatic Arthritis Intravenous secukinumab PsA
Sponsor: Novartis Pharmaceuticals
Start date: 2020-01-29; Completion date: 2022-05-17
Enrollment: 381 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to provide up to 52 weeks of efficacy, safety and tolerability data to support registration of intravenous (i.v.) secukinumab (Initial dose of 6 mg/kg at Baseline (BSL) followed thereafter with 3 mg/kg administered every four weeks) in patients with active psoriatic arthritis (PsA) despite current or previous Non-steroidal anti-inflammatory drugs (NSAIDs), Disease-modifying antirheumatic drugs (DMARDs) and/or anti-tumor necrosis factor (TNF) therapy.

Detailed description:
This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design. A screening (SCR) period running up to 10 weeks before randomization was used to assess subject eligibility followed by a treatment period of 52 weeks.

At baseline, 381 patients with active psoriatic arthritis were randomized to one of the two treatment groups in a 1:1 randomization:

Group 1: Approximately 190 patients with active psoriatic arthritis; These patients received secukinumab 6 mg/kg i.v. at BSL, followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4.

Group 2: Approximately 190 patients with active psoriatic arthritis; These patients received i.v. placebo at BSL and at Weeks 4, 8, and 12, followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 16.

Study consisted of 4 periods: a screening period (up to 10 weeks), treatment period 1 (total duration of 16 weeks) and treatment period 2 (total duration of 36 weeks) followed by a safety follow up period of 8 weeks after the end of treatment visit (i.e., Week 52).

Primary endpoint analysis will be performed with Week 16 data (last patient completing Treatment period 1 (Week 16). Long-term efficacy and safety assessments will be performed up to Week 52.

Arms: arm 1: AIN457 6 mg/kg i.v. infusion at baseline, followed by AIN457 3 mg/kg i.v. infusion every 4 weeks starting at Week 4 through Week 48 (exposure through Week 52). arm 2: Matching placebo from baseline to Week 16 and switch to AIN457 3mg/kg i.v. infusion every 4 weeks through Week 48 (exposure through Week 52).
Interventions: intervention 1: AIN457 6 mg/kg i.v. intervention 2: Placebo intervention 3: AIN457 3 mg/kg
Intervention descriptions: intervention 1: AIN457 6 mg/kg delivered by i.v. infusion intervention 2: Matching placebo to AIN457 i.v. infusion intervention 3: AIN457 3 mg/kg delivered by i.v. infusion

Protocol documents:
Prot_000.pdf: 
 
 
 
Novartis Research and Development 
Secukinumab (AIN457) 
Clinical Trial Protocol CAIN457P12302 / NCT04209205  
A randomized, double-blind, placebo-controlled, parallel 
group, phase III multicenter study of intravenous 
secukinumab to compare efficacy at 16 weeks with placebo 
and to assess safety and tolerability up to 52 weeks in 
subjects with active Psoriatic Arthritis 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2019-001176-11 
Version number: 
00 (Original Protocol) 
Clinical Trial Phase: 
III 
Release date: 
24-Sep-2019 
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 
 


Novartis 
Confidential 
Page 2 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 19 
2 
Objectives and endpoints ................................................................................................... 19 
3 
Study design ...................................................................................................................... 22 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for study design ..................................................................................... 23 
4.1.1 
Rationale for choice of background therapy ......................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 26 
5 
Population .......................................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 27 
5.2 
Exclusion criteria ................................................................................................... 28 
6 
Treatment ........................................................................................................................... 31 
6.1 
Study treatment ...................................................................................................... 31 
6.1.1 
Investigational and control drugs .......................................................... 31 
6.1.2 
Additional study treatments .................................................................. 31 
6.1.3 
Treatment arms/group ........................................................................... 31 
6.1.4 
Treatment duration ................................................................................ 31 
6.2 
Other treatment(s) .................................................................................................. 31 
6.2.1 
Concomitant therapy ............................................................................. 32 
6.2.2 
Prohibited medication ........................................................................... 33 
6.2.3 
Rescue medication ................................................................................ 35 
6.3 
Subject numbering, treatment assignment, randomization .................................... 35 
6.3.1 
Subject numbering ................................................................................ 35 
6.3.2 
Treatment assignment, randomization .................................................. 35 


Novartis 
Confidential 
Page 3 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
6.4 
Treatment blinding ................................................................................................. 36 
6.5 
Dose escalation and dose modification .................................................................. 37 
6.5.1 
Dose modifications ................................................................................ 37 
6.5.2 
Follow-up for toxicities ......................................................................... 37 
6.6 
Additional treatment guidance ............................................................................... 37 
6.6.1 
Treatment compliance ........................................................................... 37 
6.6.2 
Recommended treatment of adverse events .......................................... 37 
6.6.3 
Emergency breaking of assigned treatment code .................................. 37 
6.7 
Preparation and dispensation ................................................................................. 38 
6.7.1 
Handling of study treatment and additional treatment .......................... 38 
7 
Informed consent procedures ............................................................................................ 39 
8 
Visit schedule and assessments ......................................................................................... 40 
8.1 
Screening ............................................................................................................... 47 
8.1.1 
Information to be collected on screening failures ................................. 47 
8.2 
Subject demographics/other baseline characteristics ............................................. 48 
8.3 
Efficacy .................................................................................................................. 48 
8.3.1 
American College of Rheumatology (ACR) response .......................... 49 
8.3.2 
Tender 78 joint count and swollen 76 joint count ................................. 49 
8.3.3 
Patient’s global assessment of disease activity ..................................... 50 
8.3.4 
Physician’s global assessment of disease activity ................................. 50 
8.3.5 
Patient’s assessment of PsA pain intensity ........................................... 50 
8.3.6 
Health Assessment Questionnaire - Disability Index (HAQ - DI) ........ 50 
 
 50 
8.3.8 
High Sensitivity C-reactive protein (hsCRP) ........................................ 51 
8.3.9 
Erythrocyte sedimentation rate (ESR) .................................................. 51 
 
 51 
8.3.11 
Psoriatic Arthritis Disease Activity Score (PASDAS) .......................... 51 
 
 
52 
8.3.13 
Minimal disease activity ....................................................................... 52 
8.3.14 
Leeds Dactylitis Index (LDI) ................................................................ 52 
8.3.15 
Leeds Enthesitis Index (LEI) ................................................................ 52 
8.3.16 
Psoriasis Area and Severity Index (PASI) ............................................ 53 
 
 54 
8.3.18 
Modified Nail Psoriasis Severity Index (mNAPSI) .............................. 55 
8.3.19 
Physician’s global assessment of fingernail disease severity (VAS) .... 57 
 
 57 


Novartis 
Confidential 
Page 4 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
 
 57 
8.4 
Safety ..................................................................................................................... 58 
8.4.1 
Laboratory evaluations .......................................................................... 60 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 60 
8.4.3 
Pregnancy and assessments of fertility ................................................. 61 
8.4.4 
Other safety evaluations ........................................................................ 61 
8.5 
Additional assessments .......................................................................................... 61 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 61 
 
 63 
 
 64 
 
 67 
9 
Study discontinuation and completion .............................................................................. 68 
9.1 
Discontinuation ...................................................................................................... 68 
9.1.1 
Discontinuation of study treatment ....................................................... 68 
9.1.2 
Withdrawal of informed consent ........................................................... 69 
9.1.3 
Lost to follow-up ................................................................................... 69 
9.1.4 
Early study termination by the sponsor ................................................. 70 
9.2 
Study completion and post-study treatment .......................................................... 70 
10 Safety monitoring and reporting ........................................................................................ 70 
10.1 
Definition of adverse events and reporting requirements ...................................... 70 
10.1.1 
Adverse events ...................................................................................... 70 
10.1.2 
Serious adverse events .......................................................................... 72 
10.1.3 
SAE reporting........................................................................................ 73 
10.1.4 
Pregnancy reporting .............................................................................. 74 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 74 
10.2 
Additional Safety Monitoring ................................................................................ 75 
10.2.1 
Liver safety monitoring ......................................................................... 75 
10.2.2 
Renal safety monitoring ........................................................................ 76 
11 Data Collection and Database management ...................................................................... 76 
11.1 
Data collection ....................................................................................................... 76 
11.2 
Database management and quality control ............................................................ 76 
11.3 
Site monitoring ...................................................................................................... 77 
12 Data analysis and statistical methods ................................................................................ 77 
12.1 
Analysis sets .......................................................................................................... 78 
12.2 
Subject demographics and other baseline characteristics ...................................... 78 
12.3 
Treatments ............................................................................................................. 79 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 80 


Novartis 
Confidential 
Page 5 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
12.4.1 
Definition of primary endpoint(s) ......................................................... 80 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 80 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 81 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 81 
12.5 
Analysis of secondary endpoints ........................................................................... 81 
12.5.1 
Efficacy 
 endpoint(s) .................................... 81 
12.5.2 
Safety endpoints .................................................................................... 86 
 
 87 
 
 87 
 
 88 
 
 88 
12.5.7 
Patient reported outcomes ..................................................................... 88 
 
 88 
12.7 
Interim analyses ..................................................................................................... 89 
12.8 
Sample size calculation .......................................................................................... 89 
12.8.1 
Primary endpoint(s) ............................................................................... 89 
12.8.2 
Secondary endpoint(s) ........................................................................... 89 
13 Ethical considerations and administrative procedures ...................................................... 90 
13.1 
Regulatory and ethical compliance ........................................................................ 90 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 90 
13.3 
Publication of study protocol and results............................................................... 91 
13.4 
Quality Control and Quality Assurance ................................................................. 91 
14 Protocol adherence ............................................................................................................ 91 
14.1 
Protocol amendments ............................................................................................. 92 
15 References ......................................................................................................................... 93 
16 Appendices ........................................................................................................................ 95 
16.1 
Appendix 1: Clinically notable laboratory values ................................................. 95 
16.2 
Appendix 2: The classification criteria for psoriatic arthritis (CASPAR) ............. 96 
 
 97 
16.4 
Appendix 4: American College of Rheumatology (ACR) Measures and 
Criteria of Response .............................................................................................. 97 
 
 98 
16.6 
Appendix 6:The Psoriasis Area and Severity Index (PASI) .................................. 99 
16.7 
Appendix 7:The modified Nail Psoriasis Severity Index (mNAPSI) .................. 101 
16.8 
Appendix 8: Standard reference table for the LDI .............................................. 102 
16.9 
Appendix 9: Health Assessment Questionnaire-Disability Index (HAQ-DI)© ... 103 




Novartis 
Confidential 
Page 7 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
List of abbreviations 
 
ACR 
American College of Radiology 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
b.i.d. 
twice a day 
 
  
BDR 
Bioanalytical Data Report 
BMI 
Body Mass Index 
BSA 
Body surface area 
BSL 
Baseline 
CFR 
Code of Federal Regulation 
Cmax 
Maximum concentration  
Cmax,ss 
Maximum concentration steady-state 
Cmin 
Minimum concentration 
Cmin,ss 
Minimum concentration steady-state 
CMO&PS 
Chief Medical Office and Patient Safety 
COAs 
Clinical Outcome Assessments 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical study report 
CTC 
Common Toxicity Criteria 
DMARD 
Disease Modifying Anti-rheumatic Drug 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA/EMEA  
European Medical Agency 
ESR 
Erythrocyte sedimentation rate  
FACIT-
Fatigue  
Functional Assessment of Chronic Illness Therapy-Fatigue 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GWA 
genome-wide association 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 


Novartis 
Confidential 
Page 8 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
HIV 
human immunodeficiency virus 
hsCRP 
high sensitivity C-Reactive Protein 
i.v. 
intravenous 
IB 
investigator brochure 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVR 
Interactive Voice Response 
LDI 
Leeds Dactylitis Index 
LDL 
Low-density lipoprotein 
LEI 
Leeds Enthesitis Index 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLQ 
Lower limit of quantification 
MCR 
Major Clinical Response 
MCS 
Mental Component Summary 
MDA 
minimal disease activity 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MMP 
Matrix Metalloproteinase 
MMRM 
Mixed effect Repeated Measures model 
mNAPSI 
Modified Nail Psoriasis Severity Index 
MRI 
Magnetic Resonance Imaging  
MTX 
Methotrexate 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
o.d. 
once a day 
p.o. 
oral 
PA 
posteroanterior 
PASDAS 
Psoriatic Arthritis Disease Activity Score 
PASI 
Psoriasis Area and Severity Index 
PCS 
Physical Component Summary 
 
 
 
 
PPD 
Purified Protein Derivative 
PRO 
Patient Reported Outcome 
PsA 
Psoriatic arthritis 
QMS 
Quality Management System 
RBC 
red blood cell(s) 


Novartis 
Confidential 
Page 9 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
RF 
Rheumatoid factor 
s.c. 
subcutaneous 
SAE 
serious adverse event 
SCR 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SJC 
Swollen Joint Count 
SNP 
single nucleotide polymorphism 
 
 
SST 
Serum separator tube  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TFQ 
Trial feedback Questionnaire 
TJC 
Tender Joint Count 
TNF/TNFα 
Tumor Necrosis Factor  
TNF-IR  
TNFα Inhibitor Incomplete Responder 
ULN 
upper limit of normal 
UV 
ultraviolet 
VAS 
Visual Analog Scale  
WBC 
white blood cell(s) 
WHO 
World Health Organization 
 
 


Novartis 
Confidential 
Page 10 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Control drug 
A study drug 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. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
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). 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well as their associated treatment controls. This includes any placebos, any 
active controls, as well as approved drugs used outside of their 
indication/approved dosage or tested in a fixed combination. Investigational 
treatment generally does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system 
Part 
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients with established 
disease and in those with newly-diagnosed disease. 
Patient 
An individual with the condition of interest 
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 drug administration and assessments; at this time all study drug 
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 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study 
drug/treatment 
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy. 


Novartis 
Confidential 
Page 11 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date 
Subject 
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient. 
Subject number 
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc. 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 
Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further study related contact, and does 
not allow analysis of already obtained biologic material 


Novartis 
Confidential 
Page 12 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Protocol summary 
Protocol 
number 
CAIN457P12302 
Full Title 
A randomized, double-blind, placebo-controlled, parallel group, phase III 
multicenter study of intravenous secukinumab to compare efficacy at 16 
weeks with placebo and to assess safety and tolerability up to 52 weeks in 
subjects with active Psoriatic Arthritis 
Brief title 
Study to demonstrate the efficacy, safety and tolerability of intravenous 
secukinumab up to 52 weeks in subjects with active Psoriatic Arthritis 
Sponsor and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional  
Purpose and 
rationale 
The purpose of this global study is to provide up to 52 weeks of efficacy, 
safety and tolerability data to support registration of intravenous (i.v.) 
secukinumab (Initial dose of 6 mg/kg at Baseline (BSL) followed thereafter 
with 3 mg/kg administered every four weeks) in patients with active psoriatic 
arthritis (PsA) despite current or previous NSAID, DMARD and/or anti-TNF 
therapy. 
Efficacy and safety data from this clinical study will be used to support the 
registration of i.v. secukinumab in the US and other countries for treatment of 
patients with active psoriatic arthritis. 
 
Primary 
Objective(s) 
To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo in subjects with active psoriatic arthritis (PsA) based on the 
proportion of patients achieving an American College of Rheumatology 50 
(ACR50) response. 
Secondary 
Objectives 
The efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving an ACR20 response. 
The efficacy of i.v secukinumab at Week 16 is superior to placebo based on 
the proportion of patients achieving Minimal Disease Activity MDA 5/7.  
The efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving a PASI90 response in the subgroup 
of subjects who have ≥3% skin involvement with psoriasis. 
The improvement (change) from baseline on i.v. secukinumab is superior to 
placebo for the PASDAS at Week 16. 
The improvement (change) from baseline on i.v. secukinumab is superior to 
placebo for the HAQ-DI at Week 16. 
The improvement (change) from baseline on i.v. secukinumab is superior to 
placebo for the SF36-PCS at Week 16. 
The improvement (change) from baseline on i.v. secukinumab is superior to 
placebo for the FACIT-fatigue at Week 16. 
The improvement (change) from baseline on i.v. secukinumab is superior to 
placebo for the mNAPSI at Week 16 for the subgroup of patients with nail 
involvement. 


Novartis 
Confidential 
Page 13 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects with resolution of dactylitis by the Leeds 
Dactylytis Index in the subset of subjects who have dactylitis at baseline. 
The efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects with resolution of enthesitis by the Leeds 
Enthesitis Index in the subset of subjects who have enthesitis at baseline. 
The overall safety and tolerability of i.v. secukinumab compared to placebo 
as assessed by vital signs, clinical laboratory values, and adverse events 
monitoring. 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, 
parallel-group design. A screening (SCR) period running up to 10 weeks 
before randomization will be used to assess subject eligibility followed by a 
treatment period of 52 weeks. 
At baseline, approximately 380 patients with active psoriatic arthritis will be 
randomized to one of the two treatment groups in a 1:1 randomzation: 
Group 1: Approximately 190 patients with active psoriatic arthritis; These 
patients will receive secukinumab 6 mg/kg i.v. at BSL, followed by the 
administration of secukinumab 3 mg/kg i.v. every four weeks starting at 
Week 4. 
Group 2: Approximately 190 patients with active psoratic arthritis; These 
patients will receive i.v. placebo at BSL and at Weeks 4, 8, and 12, followed 
by the administration of secukinumab 3 mg/kg i.v. every four weeks starting 
at Week 16. 
Study will consist of 4 periods: a screening period (up to 10 weeks), 
treatment period 1 (total duration of 16 weeks) and treatment period 2 (total 
duration of 36 weeks) followed by a safety follow up period of 8 weeks after 
the end of treatment visit (i.e., Week 52).  
Primary endpoint analysis will be performed with Week 16 data (last patient 
completing Treatment period 1 (Week 16). Long-term efficacy and safety 
assessments will be performed up to Week 52. 
Population 
The study population will consist of male or female subjects at least 18 
years of age, fulfilling the Classification criteria for Psoriatic Arthritis 
(CASPAR), and PsA for at least 6 months and have active PsA disease 
defined as ≥3 swollen and ≥3 tender joints.  
Subjects must report active disease despite current or previous NSAIDs, 
DMARDs and / or TNF inhibitor therapy or intolerance to these therapies. 
Concomitant therapy with MTX (≤25 mg/week) will be acceptable, if dose 
has been stable for at least four weeks prior to the randomization visit and 
should remain on a stable dose up to Week 16. 
Randomization will be stratified by previous TNFα inhibitor-use (TNFα 
inhibitor-naïve vs. TNFα inhibitor-inadequate responder). 
Key Inclusion 
criteria 
Subjects eligible for inclusion in this study have to fulfill all of the following 
criteria:  
Diagnosis of PsA classified by CASPAR criteria and with symptoms for at 
least 6 months with moderate to severe PsA who must have at BSL ≥3 
tender joints out of 78 and ≥3 swollen joints out of 76 (dactylitis of a digit 
counts as one joint each). 
Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) 
antibodies negative at screening. 


Novartis 
Confidential 
Page 14 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Subjects with PsA should have taken NSAIDs for at least 4 weeks prior to 
randomization with inadequate control of symptoms or at least one dose if 
stopped due to intolerance to NSAIDs. 
Subjects who are regularly taking NSAIDs as part of their PsA therapy are 
required to be on a stable dose for at least 2 weeks before study 
randomization and should remain on a stable dose up to Week 16. 
Subjects taking corticosteroids must be on a stable dose of ≤10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization and 
should remain on a stable dose up to Week 16. 
Subjects taking MTX (≤ 25 mg/week) are allowed to continue their 
medication if the dose and route of administration is stable for at least 4 
weeks before randomization and should remain on a stable dose up to 
Week 16. 
Key Exclusion 
criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in 
this study: 
Chest X-ray or chest MRI with evidence of ongoing infectious or malignant 
process, obtained within 3 months prior to screening and evaluated by a 
qualified physician 
Subjects taking high potency opioid analgesics (e.g. methadone, 
hydromorphone, morphine) 
Previous exposure to secukinumab or other biologic drug directly targeting 
IL-17 or IL-17 receptor 
Ongoing use of prohibited psoriasis treatments / medications (e.g., topical 
corticosteroids, UV therapy) at randomization. The following wash-out 
periods need to be observed: 
Oral or topical retinoids- 4 weeks 
Photochemotherapy (e.g. PUVA)- 4 weeks 
Phototherapy (UVA or UVB)- 2 weeks 
Topical skin treatments (except in face, eyes, scalp and genital area during 
screening, only corticosteroids with mild to moderate potency)- 2 weeks 
Any intramuscular or intravenous corticosteroid treatment within 4 weeks 
before randomization.  
Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks 
before randomization. 
Subjects who have previously been treated with more than 3 different TNF 
inhibitors (investigational or approved). 
Subjects who have ever received biologic immunomodulating agents, 
investigational or approved except for those targeting TNFα. 
Previous treatment with any cell-depleting therapies including but not 
limited to anti-CD20 or investigational agents (e.g., CAMPATH, anti-CD4, 
anti-CD5, anti-CD3, anti-CD19) 
Study treatment 
At baseline, eligible subjects will be randomized to one of the following two 
treatment arms in a 1:1 ratio 
Group 1: secukinumab i.v. (6 mg/kg) at BSL, followed by secukinumab 3 
mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure 
through week 52). 
Group 2: placebo i.v. at BSL, Week 4, 8 and 12 followed by secukinumab 3 
mg/kg i.v. every four weeks starting at Week 16 through Week 48 
(exposure through week 52). 


Novartis 
Confidential 
Page 15 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Efficacy 
assessments 
Key assessments for ACR response (Primary Objective) 
Swollen Joint Count (SJC)/Tender Joint Count (TJC) 
Patient’s global assessment of disease activity (VAS) 
Physician’s global assessment of disease activity (VAS) 
Patient’s assessment of PsA pain intensity (VAS) 
Health Assessment Questionnaire – Disability Index (HAQ-DI©) 
high sensitivity C-Reactive Protein (hsCRP) and/ or Erythrocyte 
Sedimentation Rate (ESR) 
Key assessments for Secondary Objectives: 
Minimal disease activity 
Psoriasis Area and Severity Index (PASI) 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
Health Assessment Questionnaire – Disability Index (HAQ- DI) 
Short Form Health Survey (SF-36) 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Modified Nail Psoriasis Severity Index (mNAPSI) 
Leeds Dactylitis Index (LDI) 
Leeds Enthesitis Index (LEI) 
Key safety 
assessments 
Following are the key safety assessments: 
Evaluation of AE's/ SAE’s 
Physical examination and Vital signs 
QuantiFERON TB-Gold test or PPD skin test 
Electrocardiogram 
Local tolerability (Injection site reactions) 
Laboratory evaluations (Hematology, Clinical Chemistry, Lipid Panel, 
Urinalysis and cardiovascular panel) 
 
Other 
assessments  
Quality of Life questionnaires/ Patient reported outcomes (PROs) 
 
 
 
Data analysis 
The primary endpoint in the study is the proportion of subjects who achieve 
an ACR50 response at Week 16. The statistical hypothesis for ACR50 
being tested is that there is no difference in the proportion of subjects 
fulfilling the ACR50 criteria at Week 16 in the i.v. regimen vs. placebo. 
Let Pj denote the proportion of ACR50 responders at Week 16 for treatment 
regimens j, j = 0, 1 where 
--0 corresponds to placebo, 
--1 corresponds to i.v. regimen 
In statistical terms, H1:P1= P0, HA1: P1 ≠P0 , for the i.v. secukinumab 
regimen, i.e. 
H1: i.v. regimen is not different to placebo for signs and symptoms (ACR50 
response) at Week 16 


Novartis 
Confidential 
Page 16 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The primary endpoint of ACR50 at Week 16 in the FAS will be evaluated 
using a logistic regression with treatment and randomization stratum (TNFα 
status –naïve or IR) as factors and weight as a covariate. Marginal 
response proportion will be computed for comparisons of i.v. regimen vs. 
placebo utilizing the logistic regression model fitted. 
Safety analyses will include summaries of AEs, laboratory measurements, 
and vital signs. 
Key words 
Active Psoriatic Arthritis, Intravenous secukinumab  


Novartis 
Confidential 
Page 17 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
1 
Introduction 
1.1 
Background 
Psoriatic arthritis (PsA) is a chronic immune-mediated disease encompassing a spectrum of 
overlapping clinical entities (Moll and Wright 1973). About 10 - 40% of patients with psoriasis 
suffer from PsA. Efforts were aimed at defining more stringent classification criteria for 
standardized recruitment into clinical trials (McGonagle and Tan 2007). PsA is associated with 
significant morbidity and disability, and thus constitutes a major socioeconomic burden. It is 
not only more common but also more severe than previously thought (Gladman 1990). The 
majority of patients will have psoriasis prior to the occurrence of the associated arthritis and are 
typically under treatment for their skin disease. For musculoskeletal disease manifestations, 
initially NSAIDs are used to alleviate symptoms. Typically disease modifying anti-rheumatic 
drugs (DMARDs) are used for PsA, including methotrexate (MTX), sulfasalazine, 
cyclosporine, and leflunomide; however, these are often inadequate because they only partially 
control established disease (Mease 2008). 
Psoriatic arthritis (PsA) referred to as spondyloarthritides (SpA). The scientific community is 
split over the question whether to view these conditions together or consider them as separate 
entities (Nash et al 2005). For example, inflammatory back pain associated with psoriasis fit 
two classifications (1) Ankylosing spondylitis with psoriasis or (2) psoriatic spondylitis 
(Gladman 2007). However, while diverse in their clinical presentations, common 
environmental as well as genetic factors associated with susceptibility to SpA are suspected 
(Turkiewicz and Moreland 2007). This latter notion was corroborated by findings in a large-
scale single nucleotide polymorphism (SNP) scan study, where IL-23R variants that were 
previously linked to Crohn`s disease and psoriasis (diseases that may both co-exist with 
spondylarthritides) conferred risk to developing ankylosing spondylitis (Barrett et al 2008). 
Together, a common pathway including the IL-23/IL-17 axis have been shown to play a role in 
seronegative SpAs including psoriatic arthritis. 
Several lines of evidence support the notion of prominent T cell involvement in the pathogenesis 
of PsA. Memory CD4+ and CD8+ cells are present in skin lesions as well as the inflamed 
synovium that express activation markers and have characteristics of oligoclonal expansion 
(Curran et al 2004, Tassiulas et al 1999). Clinical trials demonstrated efficacy of T cell targeted 
therapy in PsA (cyclosporine A, CTLA4 Ig, alefacept). TNF-blocking therapy was successfully 
introduced to the treatment of patients with PsA (Mease et al 2000). Despite these efforts, an 
unmet clinical need exists for patients with PsA for better disease control and long-term 
prevention of structural damage beyond mere abrogation of inflammatory processes. Thus, 
current treatment options for patients with intolerance or an inadequate response to anti-­TNF-
α agents are limited. 
IL-17 antagonism represents a therapeutic approach aimed at interference with the chronic 
inflammatory process by selectively targeting the predominant proinflammatory cytokine of the 
helper Th17 cell subset. Additional effects of anti-IL17 on bone homoeostasis via RANKL 
(Receptor activator of nuclear factor kappa-Β ligand) and IL-1, upstream of TNFα, can be 
inferred from animal studies (Koenders et al 2005). Assuming a potential role of IL-17 cells in 
the inflammatory infiltrate in PsA, it can be speculated that locally disturbed homeostasis of 
osteoclastogenic and osteoblastogenic mechanisms characteristic of PsA might be affected by 


Novartis 
Confidential 
Page 18 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
IL-17 blockade, thus potentially providing a therapeutic advancement to prevent structural 
damage in PsA. 
Secukinumab (AIN457) is a high-affinity fully human monoclonal anti-human antibody that 
neutralizes IL-17A activity. IL-17A is the key cytokine in the newly discovered Th17 pathway 
which is thought to be an important mediator of autoimmunity. Neutralization of IL-17A has 
strong pre-clinical and clinical target validation, and documentation of efficacy in a proof of 
concept study (CAIN457A2101) and pivotal registration studies in PsA (CAIN457F2306 and 
CAIN457F2312). Registration studies conducted in patients with PsA suggest that a clinically 
meaningful response for signs and symptoms is induced as early as 2 weeks after start of 
secukinumab treatment, with further improvement up to Week 6 and maintenance of response 
up to Week 16. 
In several large placebo-controlled Phase 3 studies (CAIN457F2306, CAIN457F2306E1, 
CAIN457F2312, CAIN457F2318, CAIN457F2336 and CAIN457F2342), secukinumab 
consistently demonstrated both statistically significant and clinically meaningful differences in 
ACR20 response compared to placebo in adult patients with active PsA. The majority of 
patients treated with the recommended 150 mg and 300 mg regimens achieved an ACR20 
response in joint-related signs and symptoms, achieved benefit in skin endpoints (as shown by 
PASI 75, PASI 90 response rates and IGA mod 2011 0 or 1 response), improvement in physical 
function, improvement in quality of life and inhibition of structural progression. Statistical 
significance of secukinumab vs placebo at Week 16/24 for the primary endpoint and most 
secondary endpoints was achieved in all five PsA phase 3 trials. 
In Studies CAIN457F2312, CAIN457F2318, CAIN457F2336 and CAIN457F2342 dose 
escalation from 150 mg to 300 mg had pronounced efficacy improvements in patients with low 
response levels at the time of dose escalation. These improvements were sustained across many 
endpoints assessing both skin and arthritic components of PsA (e.g., ACR, PASI, DAS28-CRP, 
SF36). Therefore, treatment with secukinumab may also reduce loss of cartilage and erosion of 
bone in PsA and may result in improvement of symptoms and functional joint manifestations 
in afflicted patients. 
As of 25 June 2019, over 27,000 subjects have been enrolled in studies with secukinumab with 
over 22,000 having received active drug at doses ranging from single and/or multiple doses of 
0.1 mg/kg to 30 mg/kg intravenous and 25 mg to 300 mg subcutaneous. Overall, healthy 
subjects and patients have received secukinumab across various indications (RA, AS, PsA, 
multiple sclerosis, uveitis, Crohn’s disease, dry eye, and polymyalgia rheumatica) at doses 
ranging from single and multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c. 
Full safety results from all completed studies show comparable numbers of adverse events in 
subjects treated with secukinumab compared to placebo without indication of any specific organ 
toxicity. 
A more detailed review of the pre-clinical and clinical information on secukinumab is available 
in the Investigators Brochure. 
Previous registration and other Phase 3 studies have used mainly subcutaneous administration 
preceded by Intravenous (i.v.) or Subcutaneous (s.c.) loading while this study is posited to now 
explore the efficacy and safety with i.v. administration of secukinumab. 


Novartis 
Confidential 
Page 19 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
1.2 
Purpose 
The purpose of this global study is to provide up to 52 weeks of efficacy, safety and tolerability 
data to support the registration of intravenous (i.v.) secukinumab (initial dose of 6 mg/kg at 
baseline (BSL) followed thereafter with 3 mg/kg administered every four weeks) in patients 
with active psoriatic arthritis (PsA) despite current or previous NSAID, DMARD and/or anti-
TNF therapy. 
Efficacy and safety data from this clinical study will be used to support the registration of i.v. 
secukinumab in the US and other countries for treatment of patients with active psoriatic 
arthritis. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary 
objective(s) 
• 
To demonstrate that the efficacy of i.v. secukinumab 
at Week 16 is superior to placebo in subjects with 
active psoriatic arthritis (PsA) based on the proportion of 
patients achieving an American College of Rheumatology 
50 (ACR50) response. 
• 
A subject is defined as an 
ACR50 responder if, and only if, 
the following three conditions 
hold: 
1. 
they 
have 
a 
≥ 
50% 
improvement in the number of 
tender joints (based on 78 
joints) 
2. 
they 
have 
a 
≥ 
50% 
improvement in the number of 
swollen joints (based on 76 
joints) 
3. 
they 
have 
a 
≥ 
50% 
improvement in three of the 
following five domains: 
• 
Patient’s 
global 
assessment 
of 
disease 
activity (measured on a 
VAS scale, 0-100) 
• 
Physician’s 
global 
assessment 
of 
disease 
activity (measured on a 
VAS scale, 0-100) 
• 
Patient’s assessment of 
PsA pain (measured on a 
VAS scale, 0-100) 
• 
Health 
Assessment 
Questionnaire – Disability 
Index (HAQ-DI©) score 
• 
Acute 
phase 
reactant 
(hsCRP or ESR)  


Novartis 
Confidential 
Page 20 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Objective(s) 
Endpoint(s) 
Secondary objective(s) 
Endpoint(s) 
for 
secondary 
objective(s) 
• 
The efficacy of i.v. secukinumab at Week 16 is superior to 
placebo based on the proportion of subjects achieving an 
ACR20 response. 
• 
ACR20 = 20% improvement in 
at least 3 of the 5 measures and 
20% 
improvement 
in 
the 
swollen and tender joint count. 
• 
The efficacy of i.v secukinumab at Week 16 is superior to 
placebo based on the proportion of patients achieving 
Minimal Disease Activity MDA 5/7.  
• 
Proportion of patients achieving 
MDA 5/7 defined as having met 
≥5 of the following criteria: ≤1 
tender joint, ≤1 swollen joint, 
PASI ≤1 or body surface area 
≤3%, patient assessment of 
pain (VAS) ≤15, patient global 
assessment of disease (VAS) 
≤20, 
HAQ-DI 
≤0.5, 
tender 
entheseal points ≤1). 
• 
The efficacy of i.v. secukinumab at Week 16 is superior to 
placebo based on the proportion of subjects achieving a 
PASI90 response in the subgroup of subjects who have 
≥3% skin involvement with psoriasis. 
• 
The 
proportion 
of 
patients 
achieving a 90% reduction of 
the PASI score in patients with 
≥ 3%  body surface area 
(BSA) psoriasis at baseline. 
• 
The improvement (change) from baseline on i.v. 
secukinumab is superior to placebo for the PASDAS at 
Week 16. 
• 
Change in PASDAS score 
relative to baseline. 
• 
The improvement (change) from baseline on i.v. 
secukinumab is superior to placebo for the HAQ-DI at 
Week 16. 
• 
Assess the functional ability of 
subjects with PsA using the 
Health 
Assessment 
Questionnaire – Disability Index 
(HAQ- DI) relative to baseline. 
• 
The improvement (change) from baseline on i.v. 
secukinumab is superior to placebo for the SF36-PCS at 
Week 16. 
• 
Absolute and percent change 
from baseline in SF-36 Physical 
Component Score. 
• 
The improvement (change) from baseline on i.v. 
secukinumab is superior to placebo for the FACIT-fatigue 
at Week 16. 
• 
Absolute and percent change 
from baseline in FACIT-Fatigue 
scores. 
• 
The improvement (change) from baseline on i.v. 
secukinumab is superior to placebo for the mNAPSI at 
Week 16 for the subgroup of patients with nail involvement. 
• 
Change 
from 
baseline 
in 
mNAPSI score in patients with 
nail involvement. 
• 
The efficacy of i.v. secukinumab at Week 16 is superior to 
placebo based on the proportion of subjects with resolution 
of dactylitis by the Leeds Dactylytis Index in the subset of 
subjects who have dactylitis at baseline. 
• 
Proportion of patients with 
complete resolution of dactylitis 
as determined by the Leeds 
Dactylitis Index (LDI) in patients 
with dactylitis at baseline. 
• 
The efficacy of i.v. secukinumab at Week 16 is superior to 
placebo based on the proportion of subjects with resolution 
of enthesitis by the Leeds Enthesitis Index in the subset of 
subjects who have enthesitis at baseline. 
• 
Proportion of patients with 
complete 
resolution 
of 
enthesitis as determined by the 
Leeds Enthesitis Index (LEI) in 
patients 
with 
enthesitis 
at 
baseline. 


Novartis 
Confidential 
Page 21 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Objective(s) 
Endpoint(s) 
• 
The overall safety and tolerability of i.v. secukinumab 
compared to placebo as assessed by vital signs, clinical 
laboratory values, and adverse events monitoring. 
 
• 
Assessment of Physical exams, 
ECGs, vital signs, laboratory 
assessments. 


Novartis 
Confidential 
Page 22 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
3 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-
group design to study the efficacy, safety and tolerability of treatment with intravenous 
secukinumab in patients with active PsA.  
The study population comprises approximately 380 patients with active PsA, despite current or 
previous NSAID, DMARD and / or TNF inhibitor therapy or intolerance to these therapies. 
At baseline, patients will be randomized to one of the two treatment groups in a 1:1 
randomization: 
• Group 1: approximately 190 patients; These patients will receive secukinumab 6 mg/kg 
i.v. at Baseline (BSL), followed by the administration of secukinumab 3 mg/kg i.v. every 
four weeks starting at Week 4. 
• Group 2:  approximately 190 patients; These patients will receive i.v. placebo at BSL, 
Weeks 4, 8, and 12, followed by the administration of secukinumab 3 mg/kg i.v. every four 
weeks starting at Week 16. 
This study will consist of 4 periods: a screening period (up to 10 weeks), treatment period 1 
(total duration of 16 weeks) and treatment period 2 (total duration of 36 weeks) followed by a 
safety follow up period of 8 weeks after the end of treatment visit (i.e., Week 52). 
To ensure a balance across both arms, patients previously treated with TNF-inhibitors will be 
stratified at randomization. No more than 25% of previously treated TNF-inhibitor patients will 
be enrolled in the study, with this cutoff applied to each group at randomization (no more than 
48 patients per group). 
Because PsA is considered a chronic disease with no ‘true’ and lasting placebo response, all 
patients, including those on placebo, will switch to open-label i.v. secukinumab at Week 16. 
However, all patients and investigators/ site staff will remain blinded to the original randomized 
treatment group assignment (i.v. secukinumab treatment or placebo). 
An end of treatment visit (Week 52) will be done 4 weeks after last study treatment 
administration, and a post treatment follow-up visit (Week 60) is to be done 8 weeks after end 
of the treatment visit for all subjects (regardless of whether they complete the entire study as 
planned or discontinue prematurely). 
All intravenous infusions will be performed at the study site and site personnel will administer 
the infusions to subjects. 
Rescue medication is not allowed until Week 16. However, subjects who are deemed by the 
investigator not to be benefiting from the study treatment based on safety and efficacy 
assessments or for any reason of their own accord will be free to discontinue participation in 
the study at any time. 


Novartis 
Confidential 
Page 23 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The study will have a primary endpoint at Week 16. A Primary endpoint analysis will be 
performed with Week 16 data (last patient completing Treatment Period 1). Long-term efficacy 
and safety assessments will be performed up to Week 52. 
  
Figure 3-1 
Study Design 
 
4 
Rationale 
4.1 
Rationale for study design 
4.1.1 
Rationale for choice of background therapy 
Traditional clinical management of PsA by pharmacotherapy involves the hierarchial use of 
NSAID's, DMARD's and TNF-inhibitor or anti-IL-17A inhibitor biologic therapies. 
This study plans to enroll PsA patients with active disease, despite current or previous NSAIDs, 
DMARDs and/or TNF inhibitor therapy or intolerance to these therapies. A background of 
NSAID therapy and/or concomitant therapy with MTX (≤25 mg/week) will be acceptable, if 
dose and route of administration have been stable for at least four weeks prior to the 
randomization visit. Inclusion of patients with active PsA who have previously been treated 
with TNF inhibitors (up to 25% in each group) make the background patient population more 
representative of the real world clinical scenario. 


Novartis 
Confidential 
Page 24 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
4.2 
Rationale for dose/regimen and duration of treatment 
Phase 3 studies in subjects with active PsA (CAIN457F2312, CAIN457F2318 and 
CAIN457F2342) demonstrated the superior efficacy of secukinumab 150 mg s.c. and 300 mg 
s.c. regimens over placebo. Secukinumab 150 mg s.c. and 300 mg s.c. regimens had a rapid 
onset of response and similar magnitude of efficacy across several endpoints. 
While secukinumab 150 mg s.c. and 300 mg s.c. regimens are both more efficacious than 
placebo regardless of TNF-naive or TNF-IR status, the 300 mg s.c. regimen provided the 
greatest efficacy across multiple PsA domains including ACR20, ACR50,
HAQ-DI, 
PASI90, SF-36 PCS, in the resolution of dactylitis and enthesitis as well as in the 
inhibition of structural progression. 
In a pooled analysis of 2049 patients with PsA in the phase III program, evidence of higher 
efficacy was shown in the overall population and several subsets of PsA patients including, but 
not limited to, TNF-IR patients and patients who do not use concomitant MTX, favoring 
secukinumab 300 mg s.c. over 150 mg s.c. at Week 16 for several endpoints. This trend was 
maintained up to Week 52. 
Furthermore, secukinumab 300 mg s.c. was more efficacious than 150 mg s.c. in achieving 
clinically meaningful improvements in skin disease, particularly with respect to clear/almost 
clear skin (PASI90, 
) in subjects with moderate to severe psoriasis (defined 
as ≥ 10% BSA). 
In addition, pertaining to safety assessments, there were no clinically meaningful differences 
among the secukinumab doses of 300 mg and 150 mg in the exposure adjusted incidence rates 
of the key risks over the entire treatment period in the phase III trials in PsA patients. 
The overall safety data in the PsA population was consistent with prior extensive experience in 
psoriasis and show that secukinumab 300 mg and 150 mg are acceptable for chronic use in adult 
patients with active PsA. However, despite the demonstrated clinical efficacy with 150 mg s.c. 
and 300 mg s.c, the fixed dose nature of these posologies imposes constraints in certain patient 
populations. Towards overcoming these constraints and to offer a weight based posology with 
its attendant flexibility, a regimen of i.v. secukinumab is being developed. The proposed i.v. 
regimen of secukinumab - 6 mg/kg at BSL and 3 mg/kg every 4 weeks thereafter – is a result 
of extensive 
 analysis and modelling based on data with 150 mg s.c. and 300 
mg s.c. secukinumab. 
This i.v. regimen of secukinumab - 6 mg/kg at BSL and 3 mg/kg every 4 weeks thereafter - is 
modelled to target a Cmin that is consistently above that achieved with 150 mg s.c. with a 
maximum plasma concentration (Cmax) and average plasma concentration (Cavg) close to that 
achieved with 300 mg. s.c. as illustrated in Figure 4-1. Hence, the proposed i.v. regimen of 
secukinumab is expected to deliver an exposure that would approximate the 300 mg s.c. 
Given the amount of data collected so far 
 
, it is expected that the clinical response with the proposed i.v. regimen will 
be similar with that observed with the s.c. regimen. 


Novartis 
Confidential 
Page 25 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Figure 4-1 
Median concentration profiles 
 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A placebo arm is included in this study as a comparator up to the primary endpoint at Week 16. 
Due to the nature of the disease and the outcome measures used (ACR50 response criteria) a 
placebo arm is necessary to compare efficacy measurements. The maintenance of the placebo 
treatment up to the primary endpoint at Week 16 is supported from an ethical standpoint by 
precedent of multiple placebo-controlled trials in PsA. Moreover, the inclusion of a placebo 
group is in accordance with health authority guidelines (including FDA 1999/EMA 2009). The 
parallel-group placebo controlled design used in this study is aligned with Phase III trials of 
other biologics in this disease area including registration studies of s.c. secukinumab in PsA and 
is also in accordance with EMA guidelines (EMA 2009). The treatment duration of the placebo 
group is kept to a minimum and the placebo group will be re-assigned to active treatment at the 
end of Week 16. The regular assessment of disease activity ensures that subjects who are 
experiencing worsening of disease in any of the treatment groups can exit the study at any time 
upon their own accord or based on the advice of the investigator. 
4.4 
Purpose and timing of interim analyses/design adaptations 
The primary endpoint analysis (Week 16 analysis) will be performed after all subjects complete 
the Week 16 visit in order to support regulatory filing(s). 
Subsequent to the primary endpoint analysis, additional analyses are planned for regulatory 
submission and/or publication purposes for longer-term assessments of efficacy and safety after 
subjects have completed Week 60. 
Additional analyses may be performed to support health authority interactions, as necessary. 


Novartis 
Confidential 
Page 26 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The investigators, site personnel and monitors will continue to remain blinded to the original 
treatment assignment groups until Week 60 analysis has been completed. 
4.5 
Risks and benefits 
Secukinumab has shown either preliminary or confirmed efficacy in several inflammatory 
diseases including psoriasis, psoriatic arthritis and ankylosing spondylitis. The safety profile of 
secukinumab is primarily based on the aggregate safety data from 10 large completed phase 
II/III psoriasis trials. The evaluation of safety data from completed phase II/III PsA trials did 
not show additional safety concerns. 
Secukinumab is generally safe and well-tolerated. The most frequently reported adverse events 
are infections, especially upper respiratory tract with secukinumab relative to placebo. 
There was an increase in mucosal or cutaneous candidiasis with secukinumab compared to 
placebo, but the cases were mostly mild or moderate in severity, non-serious, and responsive to 
standard treatment. 
There was a small increase in mild neutropenia cases with secukinumab compared to placebo. 
Common Toxicity Criteria (CTC) AE grade 3 neutropenia (<1.0-0.5x109/L) was uncommonly 
observed with secukinumab, most were transient and reversible without a temporal relationship 
to serious infections. 
Hypersensitivity reactions, including urticarial and a rare event of anaphylactic reaction to 
secukinumab, were also observed in clinical studies. 
Taking into account the individual risks as outlined above, the expected risk profile of the i.v. 
regimen of secukinumab from a mechanism of action perspective is anticipated to be similar or 
improved compared to the approved inflammatory cytokine-targeting therapies. The risk to 
subjects in this trial will be minimized by compliance with the eligibility criteria, close clinical 
monitoring and extensive guidance to the investigators, provided in the current version of the 
Investigator’s Brochure (IB). Appropriate eligibility criteria and specific dose-limiting toxicity 
definitions, as well as specific stopping rules, are included in this protocol. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study. 
From the standpoint of the overall risk-benefit assessment, the current trial with secukinumab 
is justified. 
5 
Population 
The study population will be comprised of the following subjects who have passed screening 
assessments, comply with eligibility criteria and have provided written consent: 
Male and female subjects aged at minimum 18 years at time of consent, with active PsA 
fulfilling the CASPAR criteria (Refer to Appendix 16.2). Subjects must have symptoms for at 
least 6 months with moderate to severe PsA and must have ≥3 tender joints out of 78 and ≥3 


Novartis 
Confidential 
Page 27 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
swollen joints out of 76 at BSL (dactylitis of a digit in the foot or hand counts as one tender and 
swollen joint). 
Subjects must have either signs of skin manifestations of plaque psoriasis or present nail 
changes consistent with psoriasis or a documented history of plaque psoriasis. 
Subjects must report active disease despite current or previous NSAIDs, DMARDs and / or 
TNF inhibitor therapy or intolerance to these therapies. Concomitant therapy with MTX (≤25 
mg/week) will be acceptable, if dose and route of administration have been stable for at least 
four weeks prior to the randomization visit. 
Subjects can be re-screened only once and no re- screening study related procedures should be 
performed prior to written re-consent by the subject. Mis-randomized subjects will not be re-
screened. 
This is an international study and it is expected that approximately 380 subjects will be enrolled. 
A screening failure rate of 30% and post-randomization dropout rate of 10% is anticipated. 
Enrollment will stop as soon as the target number of randomized subjects is reached. 
5.1 
Inclusion criteria 
Patients who are TNF-IR’s (primary or secondary failure of efficacy, failure to tolerate or 
contraindication) are allowed to enter the study (up to 25% of patient numbers). Subjects 
eligible for inclusion in this study must meet all of the following criteria: 
1. Subject must be able to understand and communicate with the investigator and comply with 
the requirements of the study and must give a written, signed and dated informed consent 
before any study assessment is performed. 
2. Male or non-pregnant, non-lactating female subjects at least 18 years of age. 
3. Diagnosis of PsA classified by CASPAR criteria and with symptoms for at least 6 months 
with moderate to severe PsA who must have at Baseline ≥3 tender joints out of 78 and ≥3 
swollen joints out of 76 (dactylitis of a digit counts as one joint each) 
4. RF and anti-CCP antibodies negative at screening. 
5. Diagnosis of active plaque psoriasis or nail changes consistent with psoriasis or a 
documented history of plaque psoriasis. 
6. Subjects with PsA should have taken NSAIDs for at least 4 weeks prior to randomization 
with inadequate control of symptoms or at least one dose if stopped due to intolerance to 
NSAIDs. 
7. Subjects who are regularly taking NSAIDs and/or acetaminophen/paracetamol as part of 
their PsA therapy are required to be on a stable dose for at least 2 weeks before study 
randomization and should remain on a stable dose up to Week 16. 
8. Subjects taking corticosteroids must be on a stable dose of ≤10 mg/day prednisone or 
equivalent for at least 2 weeks before randomization and should remain on a stable dose up 
to Week 16. 
9. Subjects taking MTX (≤ 25 mg/week) are allowed to continue their medication if the dose 
and route of administration is stable for at least 4 weeks before randomization and should 
remain on a stable dose up to Week 16. 
10. Subjects on MTX must be on folic acid supplementation at randomization. 


Novartis 
Confidential 
Page 28 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
11. Subjects who are on a conventional synthetic (CS) DMARD other than MTX must 
discontinue the DMARD 4 weeks prior to randomization visit except for leflunomide, which 
has to be discontinued for 8 weeks prior to randomization unless a cholestyramine washout 
has been performed. 
12. Subjects who have been on a TNF inhibitor must have experienced an inadequate response 
to previous or current treatment with a TNF inhibitor given at an approved dose for at least 
3 months or have stopped treatment due to safety/tolerability problems after at least one 
administration of a TNF inhibitor. 
13. Subjects who have previously been treated with TNF inhibitors (investigational or 
approved) will be allowed entry into study after appropriate wash-out period prior to 
randomization: 
• 4 weeks or longer for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 
hours (s.c. route) 
• 8 weeks or longer for Remicade® (infliximab) – with a terminal half-life of 8.0-
9.5 days (s.c. and i.v. infusion) 
• 10 weeks or longer for Humira® (adalimumab) – with a terminal half-life of 10-
20 days (average 2 weeks) (s.c. route) 
• 10 weeks or longer for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
(s.c. and i.v. infusion) 
• 10 weeks or longer for Cimzia® (certolizumab) – with a terminal half-life of approx. 
14 days (s.c. route) 
5.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects. 
1. Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, 
obtained within 3 months prior to screening and evaluated by a qualified physician 
2. Subjects taking high potency opioid analgesics (e.g., methadone, hydromorphone, 
morphine) 
3. Ongoing use of prohibited psoriasis treatments / medications (e.g., topical corticosteroids, 
UV therapy) at randomization. The following wash-out periods need to be observed: 
a. Oral or topical retinoids- 4 weeks 
b. Photochemotherapy (e.g. PUVA)- 4 weeks 
c. Phototherapy (UVA or UVB)- 2 weeks 
d. Topical skin treatments (except in face, eyes, scalp and genital area during screening, 
only corticosteroids with mild to moderate potency)- 2 weeks 
4. Any intramuscular or intravenous corticosteroid treatment within 4 weeks before 
randomization. 
5. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization. 
6. Subjects who have previously been treated with more than 3 different TNF-a inhibitors 
(investigational or approved). 


Novartis 
Confidential 
Page 29 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
7. Subjects who have ever received biologic immunomodulating agents, investigational or 
approved except for those targeting TNFα. 
8. 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. 
9. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unwilling to use effective contraception during the entire study or 
longer if required by locally approved prescribing information (e.g. 20 weeks in EU). 
Effective contraception is defined as either: 
a.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: 
a.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]. 
b.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. 
c.Use of established oral, injected or implanted hormonal methods of contraception, 
intrauterine device (IUD) or intrauterine system (IUS). In case of use of oral 
contraception women should have been stable on the same pill for a minimum of 
12 weeks before taking study treatment. 
NOTE: Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous 
amenorrhea as defined by the Central Lab FSH and/or estradiol levels. 
10. Active ongoing inflammatory diseases other than PsA that might confound the evaluation 
of the benefit of secukinumab therapy such as inflammatory bowel disease (IBD). 
11. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator 
immunocompromises the subject and/or places the subject at unacceptable risk for 
participation in an immunomodulatory therapy. 
12. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure [New York Heart 
Association status of class III or IV], uncontrolled diabetes. 
13. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum bilirubin. 
The investigator should be guided by the following criteria: 


Novartis 
Confidential 
Page 30 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
a. Any single parameter may not exceed 2 x upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more as soon 
as possible, and in all cases, at least prior to enrollment/randomization, to rule out lab error 
b. If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should be 
differentiated into the direct and indirect reacting bilirubin. In any case, serum bilirubin 
should not exceed the value of 1.6 mg/dL (27 µmol/L) 
14. History of renal trauma, glomerulonephritis, or subjects with one kidney only, or a serum 
creatinine level exceeding 1.5 mg/dL (132.6µmol/L) 
15. Screening total WBC count <3,000/µL, or platelets <100,000/µL or neutrophils <1,500/µL 
or hemoglobin <8.5 g/dL (85g/L) 
16. Active systemic infections during the last two weeks (exception: common cold) prior to 
randomization 
17. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by either a positive PPD skin test (the size of induration will be 
measured after 48-72 hours, and a positive result is defined as an induration of ≥ 5mm or 
according to local practice/guidelines) or a positive QuantiFERON TB-Gold test as 
indicated in the assessment schedule. Subjects with a positive test may participate in the 
study if further work up (according to local practice/guidelines) establishes conclusively 
that the subject has no evidence of active tuberculosis. If presence of latent tuberculosis is 
established then treatment according to local country guidelines must have been initiated. 
18. Known infection with HIV, hepatitis B or hepatitis C at screening or randomization. 
19. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratoses that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed). 
20. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the subject unsuitable for the trial. 
21. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins). 
22. Any medical or psychiatric condition which, in the investigator’s opinion, would preclude 
the participant from adhering to the protocol or completing the study per protocol. 
23. Donation or loss of 400 mL or more of blood within 8 weeks before randomization. 
24. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization. 
25. Plans for administration of live vaccines during the study period or within 6 weeks 
preceding randomization.  
26. Use of other investigational drugs at the time of enrollment, or within 5 half- lives of 
enrollment, or within 4 weeks until the expected pharmacodynamic effect has returned to 
baseline, whichever is longer; or longer if required by local regulations. 
27. History of hypersensitivity to any of the study drug constituents. 
28. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting 
IL-17 or the IL-17 receptor. 


Novartis 
Confidential 
Page 31 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
29. Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 
or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19). 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis will supply the following study treatments:  
Investigational Treatment: 
• Secukinumab liquid in vial (LiV) for i.v. infusion provided in glass vials, each containing 
125 mg / 5 mL secukinumab Concentrate for solution for infusion  
Reference Therapy: 
• Secukinumab placebo Concentrate for solution for i.v. infusion provided in 5 mL LiV 
The LiV glass vials are packed in double-blind (treatment period 1, up to and including Week 
12) and open label fashion (treatment period 2, from Week 16 onwards). For detailed 
instructions for storage, handling and administration of study treatment, please refer to 
the Pharmacist Manual. 
The study medication will be labeled as follows: 
• Double-blind Secukinumab Liquid in Vial will be labeled as AIN457 125 mg/5 ml/ 
Placebo. 
• Open-label Secukinumab Liquid in Vial will be labeled as AIN457 125 mg/5 ml. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
At baseline, eligible subjects will be randomized to one of the following two treatment arms in 
a 1:1 ratio (see Figure 3-1). 
Group 1: secukinumab i.v. (6 mg/kg) at BSL, followed by secukinumab 3 mg/kg i.v. every 
four weeks starting at Week 4 through Week 48 (exposure through week 52). 
Group 2: placebo i.v. at BSL, Week 4, 8 and 12 followed by secukinumab 3 mg/kg i.v. every 
four weeks starting at Week 16 through Week 48 (exposure through week 52). 
6.1.4 
Treatment duration 
The planned duration of treatment is 52 weeks. Subjects may be discontinued from treatment 
earlier due to unacceptable toxicity, disease progression and/or at the discretion of the 
investigator or the subject. 
6.2 
Other treatment(s) 
No additional treatment beyond investigational drug is provided in this trial. 


Novartis 
Confidential 
Page 32 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
6.2.1 
Concomitant therapy 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
The investigator should instruct the subject to notify the study site about any new medications 
over-the-counter drugs, supplements, and vitamins) administered after the subject is enrolled 
into the study. All medications (other than study treatment), procedures and significant non-
drug therapies (including physical therapy and blood transfusions) must be recorded on the Prior 
and Concomitant medications or Procedures and Significant Non Drug Therapy eCRF. The 
reason, name of the drug, procedure or non-drug therapy should be listed. 
Guidelines for the use of specific medications are provided below. 
Methotrexate (MTX) 
Subjects taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 16. 
Leflunomide wash-out with cholestyramine 
In case of leflunomide treatment before study randomization, a drug wash-out of 8 weeks must 
be performed. However, another wash-out procedure can be considered. Cholestyramine may 
be given orally at a dose of 8 g three times daily (t.i.d) to wash-out leflunomide. Cholestyramine 
reduced plasma levels of the active leflunomide metabolite by approximately 40% in 24 hours 
and by 49% to 65% in 48 hours, in three healthy volunteers. The administration of 
cholestyramine is recommended in subjects who require a drug elimination procedure. If a 
subject receives 8 g t.i.d. for 11 days, the subject can be safely randomized 4 weeks after the 
beginning of the 11-day treatment period. 
Systemic corticosteroids 
Treatment with systemic corticosteroids is permitted up to a maximum daily dosage of 10 mg 
prednisone equivalent and if the dose was stable within the 2 weeks preceding randomization. 
The subject should remain on a stable dose until Week 16. 
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after Week 
16, although the corticosteroid dose should not be reduced more than 1 mg prednisone 
equivalent every 4 weeks. 
However, any change in the dose of oral corticosteroids during the trial should be recorded on 
the corresponding eCRF. 
Intra-articular corticosteroids are not permitted within 4 weeks prior to baseline and up to Week 
16. After Week 16, no more than 1 joint per 24-week period may be injected. No single injection 
should exceed 40 mg of triamcinolone (or equivalent) and the total dose of intra-articular 
corticosteroid may not exceed 80 mg of triamcinolone (or equivalent) during any 52-week 
period. Injection of intra-articular corticosteroids is not permitted within 8 weeks prior to Week 
52. The joints injected with intra-articular corticosteroids will be assessed as both swollen and 
tender in the SJC and TJC, from injection time onwards. 
Non-steroidal anti-inflammatory drugs (NSAIDs) (including selective COX-2 inhibitors), 
low strength opioids and acetaminophen/paracetamol 


Novartis 
Confidential 
Page 33 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Subjects on regular use of NSAIDs or paracetamol/acetaminophen should be on stable dose for 
at least 2 weeks before randomization to allow inclusion in the study. 
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN within the 
2 weeks before randomization can continue to do so in the study; however, they have to refrain 
from any intake during at least 24 hours before a visit with disease activity assessment. Regular 
dosing with low strength opioids is not permitted. 
After the Week 16 assessments are completed, a change in the NSAID intake regimen is 
permitted. 
Any change of the NSAID/paracetamol/acetaminophen treatment during the trial should be 
recorded on the corresponding eCRF page. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in Table 6-1 is NOT allowed after the start of the washout 
period unless specified otherwise below. 
Live vaccines should not be given until 12 weeks after last study treatment administration. 
Table 6-1 
Prohibited medication 
 
Medication 
Washout period 
(before randomization) 
Action 
(after randomization) 
Any biologic drugs, including 
but not limited to TNFα 
inhibitors, secukinumab, or 
other biologic drugs targeting 
IL-17 or IL-17 receptor 
• 
Etanercept 
• 
Infliximab 
• 
Adalimumab, golimumab, 
certolizumab 
Biological immunomodulating 
agents > 3 different TNFα 
Inhibitors: never 
• 
4 weeks 
• 
8 weeks 
• 
10 weeks 
Discontinue investigational 
treatment 
Any cell-depleting therapies 
including but not limited to anti-
CD20 or investigational agents 
[e.g., alemtuzumab (Campath), 
anti-CD4, anti-CD5, anti-CD3, 
and anti-CD19] 
Never 
Discontinue investigational 
treatment 
Conventional 
synthetic DMARDs (with the 
exception of MTX ) and ts-
DMARDs including apremilast, 
tofacitinib etc 
4 weeks 
Discontinue investigational 
treatment 
Leflunomide 
8 weeks 
Discontinue investigational 
treatment 
Leflunomide with 
cholestyramine washout 
4 weeks 
Discontinue investigational 
treatment 


Novartis 
Confidential 
Page 34 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Medication 
Washout period 
(before randomization) 
Action 
(after randomization) 
Any investigational treatment or 
participation in any 
interventional trial 
4 weeks or 5 half-lives 
(whichever is longer) 
Discontinue investigational 
treatment 
Unstable dose of NSAIDs 
(including selective COX-2 
inhibitors) 
2 weeks 
Discontinue investigational 
treatment. (Dose adjustments 
allowed after week 16)  
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis.  
Analgesics other than NSAIDs, 
paracetamol/acetaminophen, 
and low strength opioids PRN + 
2 weeks 
Discontinue investigational 
treatment 
Systemic corticosteroids > 10 
mg prednisone equivalent (until 
Week 16)* 
2 weeks 
If administered due to a 
medical urgency unrelated to 
the patient’s arthritis, study 
treatment should be interrupted 
until the steroid is discontinued. 
If not administered for a 
medical urgency or for use 
related to the patient’s arthritis, 
then discontinuation of 
investigational treatment may 
be required on a case by case 
basis 
Unstable dose of systemic 
corticosteroids ≤ 10 mg 
prednisone equivalent (until 
Week 16)* 
2 weeks 
Discontinue investigational 
treatment (Dose adjustments 
allowed after week 16) 
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis.  
Intra-articular corticosteroids 
injections, (until Week 16)* 
4 weeks 
Discontinue investigational 
treatment 
Intramuscular or intravenous 
corticosteroid treatment 
4 weeks 
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis 
Live vaccinations 
6 weeks 
If administered due to a 
medical urgency, study 
treatment should be interrupted 
for 4 months. If administered 
not for a medical urgency then 
discontinue investigational 
treatment 
Oral or topical retinoids 
4 weeks 
Discontinue investigational 
treatment 
Photochemotherapy (e.g. 
PUVA) 
4 weeks 
Discontinue investigational 
treatment 


Novartis 
Confidential 
Page 35 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Medication 
Washout period 
(before randomization) 
Action 
(after randomization) 
Phototherapy (UVA or UVB) 
2 weeks 
Discontinue investigational 
treatment 
Topical skin treatments (except 
in face, eyes, scalp and genital 
area; only corticosteroids with 
mild to moderate potency) 
2 weeks 
Discontinue investigational 
treatment 
* see details about corticosteroid management in Section 6.2.1.  
+ Regular dosing with low strength opioids is not permitted. 
6.2.3 
Rescue medication 
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the trial or worsening / exacerbation of their disease. 
Rescue medication must not be used before completion of Week 16 assessments. Although no 
subject will be restricted from receiving necessary rescue medications for lack of benefit or 
worsening of disease, if rescue with prohibited biologics (as described in Section 6.2.2 ) occurs 
prior to completion of Week 16 assessments, subjects will be discontinued from study 
treatment. Subjects who are deemed not to be benefiting from the study treatment based upon 
safety and efficacy assessments by the investigator or for any reason on their own accord will 
be free to discontinue participation in the study at any time. 
Changes in NSAIDs concomitant therapy is permitted after Week 16 assessments as per 
investigator’s clinical judgment. After Week 16, the dose and regimen of other concomitant 
medications may be adjusted slowly at the investigator’s discretion and recorded appropriately 
on the CRF page. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Once assigned to a subject, the Subject No. will not be reused. Upon signing the informed 
consent form, the subject is assigned to the next sequential Subject No. available.  
6.3.2 
Treatment assignment, randomization 
At BSL, all eligible subjects will be randomized via Interactive Response Technology (IRT) to 
one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of investigational treatment 




Novartis 
Confidential 
Page 37 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The high sensitivity C-reactive protein (hsCRP) results from samples collected during the 
treatment period will be revealed only after database lock and analyses are completed. 
6.5 
Dose escalation and dose modification 
No study treatment dose escalations and/or adjustments are permitted. 
6.5.1 
Dose modifications 
Temporary interruptions (e.g., in case of ongoing AE, surgical procedure at based of treating 
physician's discretion) of study medication are permitted. Study medication should be 
reintroduced under careful monitoring if the investigator feels if it is in the best interest of the 
subject. These dose interruptions must be recorded on the appropriate CRF. 
6.5.2 
Follow-up for toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant abnormal laboratory value, must be followed up in accordance with what 
is clinically indicated per the investigator until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrist, etc., should be consulted as deemed necessary. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
All dates and times of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page. 
Drugs administered prior to start of treatment and other drugs/procedures continuing or started 
during the study treatment period will be entered in the Prior/Concomitant medications or 
Significant non-drug therapies eCRF page. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in Section 6.5.2 . Compliance will also be assessed by a Novartis monitor using 
information provided by the authorized site personnel. 
6.6.2 
Recommended treatment of adverse events 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 


Novartis 
Confidential 
Page 38 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide to the subject: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact the 
investigator's backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
Study drug must be discontinued after emergency unblinding. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 




Novartis 
Confidential 
Page 40 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments and when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible.  The study treatment should not be 
administered within less than 14 days after the previous administration.  
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for an end of treatment 
visit 4 weeks after the last study treatment. At this visit, all of the assessments listed for the final 
visit will be performed (correspond to the last visit for the subject’s current period of treatment 
(treatment period 1 or 2): i.e., Week 16 or Week 52). At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF. A follow-up visit is to be done 8 weeks after the end of 
treatment visit, for all subjects, regardless of whether they complete the entire study as planned 
or discontinue prematurely 
If they refuse to return for these assessments or are unable to do so, every effort should be made 
to contact them or collect knowledgeable information by telephone to determine the reason. 












Novartis 
Confidential 
Page 46 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Period 
Screening2 
Treatment Period 1 
Treatment Period 2 
Follow-up 
Visit Name 
Screening 
visit 1 (-10 
to -4 BSL) 
Screening 
visit 2 (≤ - 
4 to BSL) 
Baseline Week 
4 
Week 
8 
Week 
12 
Week 
16 
week 
20 
week 
24 
Week 
25 
Week 
28 
week 
32 
week 
36 
Week 
40 
Week 
44 
Week 
48 
Week 
52 
Week 60 
Visit Numbers1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 If the subject’s washout period ≤ 4 weeks, Screening visit 1 (SV1) and Screening visit 2 (SV2) can be performed on the same day.  
3 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion criteria are not met 
are captured on the Inclusion/Exclusion eCRF.   
4 Hepatitis B and/or hepatitis C and/or HIV serology testing to be performed during screening period only if required as per local medical practice or local regulations 
prior to initiation of therapy. These assessments will be documented in source records only and will not be entered into the eCRF. 
5 A chest x-ray or MRI is required if it was not performed and evaluated within 3 months prior to screening. The x-ray should be performed after it is certain the subject 
meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The x-ray may be replaced by an MRI assessment. 
6 A copy of the x-ray or radiologist’s report must be kept in the source documentation. 
7 The PPD skin test can be performed at any time during the screening period, but it must be read within 72 hours and before randomization. 
8 AEs / SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page. 
9 Sample must be obtained fasting. 
  
11 Kits will be provided by central lab and test is to be performed locally.  


Novartis 
Confidential 
Page 47 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
8.1 
Screening 
Screening will consist of two visits and will be flexible in duration (4-10 weeks), based on the 
time required to washout prior anti-rheumatic medications, during which time the subject will 
sign the ICF, be evaluated for eligibility and have sufficient time for potential medication 
washout, in addition to all other assessments indicated in Table 8-1. 
During the first screening visit, initial assessments will be performed as outlined in Table 8-1. 
At that visit the duration of the washout period will be determined. The second screening visit 
will be performed as follows: 
• If the washout period is ≤ 4 weeks the investigator should proceed directly to visit 2 on the 
same day and complete all assessments 
• If the washout period is more than 4 weeks, the subject will be instructed to initiate 
necessary washout regimen, and return for Visit 2 within 4 weeks of the target 
randomization date (i.e., in all cases, Visit 2 should not happen earlier than 4 weeks prior 
to randomization. 
If subjects do not have a chest X-ray or MRI available within 3 months of screening, the X-ray 
should be performed after it is certain the subject meets inclusion/exclusion criteria in order to 
minimize unnecessary exposure to radiation. 
All subjects evaluated at Visit 1 and 2 for Inclusion/Exclusion criteria should not be screen 
failed on the basis of a medication requiring washout, unless the subject will be unable to 
complete the washout in the appropriate time frame before randomization. 
8.1.1 
Information to be collected on screening failures 
Subjects who discontinue from the study prior to randomization are considered screening 
failures. 
If a subject discontinues before entering the double-blind treatment period at BSL, IRT must be 
notified within 2 days and the reason for not being randomized will be entered on the 
appropriate eCRF page. In addition, only the following eCRFs should be completed: 
Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion eCRF, and the Adverse 
event (AE) eCRF should be completed for any Serious Adverse Events (SAEs) that occurred 
during the screening period. 
Adverse events that are not serious will be followed by the investigator and collected only in 
the source data. 
All subjects who have signed informed consent and are randomized into the double-blind 
treatment period at BSL will have all adverse events occurring after informed consent is 
signed recorded on the Adverse Event CRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the root cause for the test abnormality occurred prior to the 
informed consent signature. 


Novartis 
Confidential 
Page 48 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all subjects and 
recorded in the eCRF include: 
• Age, sex, race, ethnicity and source of subject referral 
• Relevant PsA/Psoriasis and general medical history/current medical condition data until 
the start of study treatment, such as date of diagnosis of PsA/Psoriasis, previous 
PsA/Psoriasis therapies with the status of prior TNFα inhibitor use, cardiovascular medical 
history, and smoking history 
Whenever possible, diagnoses and not symptoms will be recorded. 
8.3 
Efficacy 
The efficacy outcome measures used in this study are the standard measures used across all PsA 
trials and required for filing. All efficacy assessments should be performed prior to 
administration of study treatment. 
• American College of Rheumatology (ACR) 20, 50 and 70 responses 
• Swollen Joint Count (SJC)/Tender Joint Count (TJC) 
• Patient’s global assessment of disease activity (VAS) 
• Physician’s global assessment of disease activity (VAS) 
• Patient’s assessment of PsA pain intensity (VAS) 
• Health Assessment Questionnaire – Disability Index (HAQ-DI©) 
 
 
• High sensitivity C-Reactive Protein (hsCRP) 
• Erythrocyte Sedimentation Rate (ESR) 
 
 
 
 
• Psoriatic Arthritis Disease Activity Score (PASDAS) 
• Patient’s global assessment of psoriasis and arthritis disease activity (VAS) 
• Minimal disease activity 
• Leeds Dactylitis Index (LDI) and dactylitis count 
• Leeds Enthesitis Index (LEI) 
 
 
• Psoriasis Area and Severity Index (PASI) 
 
 
• Modified Nail Psoriasis Severity Index (mNAPSI) 
• Physician global fingernail disease severity assessment (VAS) 
 
 
 
Patient reported outcomes (PROs) will be collected using the ediary technology.  




Novartis 
Confidential 
Page 50 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
for swollen joint count. Dactylitis of a digit in the foot or hand counts as one tender and swollen 
joint.  
Data is recorded for all tender and swollen joints (right or left side), i.e. a box (no, yes or not 
applicable) needs to be ticked for all joints. The total number of tender and swollen joints (right 
and left) will be automatically calculated in the eCRF. 
8.3.3 
Patient’s global assessment of disease activity 
The patient’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from ”very good” to ”very poor”, after the question, "Considering all the ways psoriatic 
arthritis affects you, please indicate with a vertical mark ( | ) through the horizontal line how 
well you are doing today”.  
8.3.4 
Physician’s global assessment of disease activity 
The physician’s global assessment of disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question, "Considering 
all the ways the disease affects your patient, draw a line on the scale for how well his or her 
condition is today”. To enhance objectivity, the physician must not be aware of the specific 
patient’s global assessment of disease activity, when performing his own assessment on that 
subject. 
8.3.5 
Patient’s assessment of PsA pain intensity 
The patient’s assessment of pain will be performed using 100 mm visual analog scale (VAS) 
ranging from “no pain” to “unbearable pain” after the question “Please indicate with a vertical 
mark ( | ) through the horizontal line the most pain you had from your psoriatic arthritis today”. 
8.3.6 
Health Assessment Questionnaire - Disability Index (HAQ - DI) 
The HAQ-DI© was developed by Stanford University and is one of the most widely used 
measures to assess the long-term influence of chronic disease on a subject's level of functional 
ability and activity restriction. The disability assessment component of the HAQ, the HAQ-DI, 
assesses a subject's level of functional ability and includes questions of fine movements of the 
upper extremity, locomotor activities of the lower extremity, and activities that involve both 
upper and lower extremities. There are 20 questions in eight categories of functioning including 
dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The stem of each 
item asks over the past week "Are you able to …" perform a particular task. Each item is scored 
on a 4-point scale from 0 to 3, representing normal (normal, no difficulty [0]), some difficulty 
(1), much difficulty (2), and unable to do (3).  
The purpose of the HAQ-DI in this study is to assess the functional ability of subjects with PsA. 
Refer to Table 8-1 and Appendix 16.9 for more details. 






Novartis 
Confidential 
Page 53 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
8.3.16 
Psoriasis Area and Severity Index (PASI) 
The PASI assesses the extent of psoriasis on four body surface areas (head, trunk and upper and 
lower limbs) and the degree of plaque erythema, scaling and thickness. A PASI score 
(Fredriksson and Pettersson 1978, Weisman et al 2003) will be derived as indicated in Table 8-
2. 
The head, trunk, upper limbs and lower limbs are assessed separately for erythema, thickening 
(plaque elevation, induration), and scaling (desquamation). The average degree of severity of 
each sign in each of the four body regions is assigned a score of 0-4. The area covered by lesions 
on each body region is estimated as a percentage of the total area of that particular body region. 
Further practical details help the assessment: 
• The neck is assessed as part of the head. 
• The axillae and groin are assessed as part of the trunk. 
• The buttocks are assessed as part of the lower limbs. 
When scoring the severity of erythema, scales should not be removed. 
Table 8-2 
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 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Trunk (T)‡ 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Upper limbs (U) 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 


Novartis 
Confidential 
Page 54 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Body region 
Erythema (E)   
Thickening 
(plaque 
elevation, 
induration, I) 
Scaling 
(desquamation, 
D) 
Area score 
(based on true 
area%, A)* 
Lower limbs (L)§ 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0=none 1=slight 
2=moderate 
3=severe 4=very 
severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
* Percentage (not score) of body region (not whole body) affected will be entered in the CRF 
† 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 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 
following formula: 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
where E = erythema; I = induration; D = desquamation; A = area; H = Head; U = Upper limbs; 
T = Trunk; and L = Lower limbs 
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0. The investigator is responsible for collecting the components or 
scoring signs and total regional area. More information is provided in Table 8-1 and 
Appendix 16.6. 


Novartis 
Confidential 
Page 55 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
8.3.18 
Modified Nail Psoriasis Severity Index (mNAPSI) 
The mNAPSI is an instrument to assess psoriatic nail involvement in subjects with PsA and nail 
psoriasis. It will be collected only in subjects with psoriatic nail involvement. The modifications 
on the original NAPSI to create the mNAPSI were made by rheumatologists, with 
dermatologists’ input, as a tool for clinical trials. The creators’ goal was to develop a tool to 
assess disease severity and response to treatment in clinical trials, keeping in mind that the 
assessor in a clinical trial most likely would not be a trained dermatologist (Cassell et al 2007). 
Detailed information is provided in Appendix 16.7. 
For the evaluation of the mNAPSI three features or groups of features (onycholysis and oil-
drop dyschromia, pitting and crumbling) of each fingernail will be graded on a scale from 0 to 
3: 
• Onycholysis: Separation of the nail plate from the nail bed. The separated part of the nail 
is opaque and can have white, yellow, or greenish tinge. If there is a piece of nail missing, 
estimate where the nail normally would have ended at the end of the nail bed, and count 
that missing part as involved in onycholysis. 
• Oil-drop (salmon patch) dyschromia: Reddish-brown discoloration under the nail plate. 
Onycholysis and oil-drop dyschromia are considered together. When looking at the nail, 
combine the total percentage area of the nail that is affected by either and use that combined 
total to score the nail.  


Novartis 
Confidential 
Page 56 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Table 8-4 
 Score for percent of nail with onycholysis or oil-drop dyschromia 
Score 
Percent of nail with onycholysis or oil-drop 
dyschromia present 
0 
No onycholysis or oil drop dyschromia present 
1 
1–10% of the nail has onycholysis or oil-drop 
dyschromia 
2 
11–30% of the nail has onycholysis or oil-drop 
dyschromia 
3 
> 30% of the nail has onycholysis or oil-drop 
dyschromia 
• Pitting: Small, sharply defined depressions in the nail surface. Pits are discrete 
abnormalities (“ice-pick-like”). If there is nail plate crumbling that is confluent with pits, 
do not score for pits. If the pits are separate from crumbling, they may be scored 
regardless of whether crumbling is present or not.  
Table 8-5 
Score for number of pits 
Score 
Number of pits 
0 
0 
1 
1–10 
2 
11–49 
3 
> 50 
• Nail plate crumbling: Crumbling or fragmentation of friable nail plate which may be 
associated with confluent pitting. Crumbling involves alteration of the nail plate surface. 
Horizontal ridging of the nail, “wave-like” appearance, and horizontal lines are all features 
of crumbling. 
Table 8-6 
Score for percent of nail with crumbling present 
Score 
Percent of nail with crumbling present 
0 
No crumbling 
1 
1–25% of the nail has crumbling 
2 
26–50% of the nail has crumbling 
3 
> 50% of the nail has crumbling 
The next 4 abnormalities (leukonychia, splinter hemorrhages, hyperkeratosis, and red spots in 
the lunula) are scored only as either present or absent for each fingernail. A score of 1 indicates 
present and a score of zero indicates not present. 
1. Leukonychia: White spots in the nail plate due to psoriasis in the mid matrix. Leukonychia 
are just color changes. If it appears that there is depression or irregularity to the nail 
surface, this may be pitting or crumbling, not leukonychia. If the leukonychia is adjacent 
to or confluent with crumbling or pits, it is counted as part of the crumbling or pitting and 
not as a separate abnormality. 
2. Splinter hemorrhages: Small, longitudinal, linear, dark brown hemorrhage under the 
fingernail. 
3. Nail bed hyperkeratosis: Thickened keratin in the nail bed. 
4. Red spots in the lunula: Small pink or red macules in the lunula. 


Novartis 
Confidential 
Page 57 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
8.3.19 
Physician’s global assessment of fingernail disease severity (VAS) 
The physician’s assessment of nail disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question “After you have 
viewed all the fingernails of a subject, consider all aspects of the subject’s fingernails and place 
a vertical line on the scale giving a global assessment of their fingernails”. 




Novartis 
Confidential 
Page 59 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Information for all physical examinations must be 
included in the source documentation at the study 
site. Clinically relevant findings that are present 
prior to signing informed consent form must be 
recorded on the appropriate CRF that captures 
medical history screen on the CRF. Significant 
findings that occur after signing informed consent 
form which meet the definition of an Adverse 
Event must be recorded as an adverse event. 
Vital signs 
Vital signs will include blood pressure and pulse 
rate measurements after 5 minutes rest in sitting 
position. If possible, vital signs assessments 
should be performed by the same study site staff 
member using the same validated device 
throughout the study. 
Height and weight 
Height in centimeters (cm) and body weight, to 
the nearest 0.1 kilogram (kg), in indoor clothing 
but without shoes, will be measured. 
If possible, body weight assessments should be 
performed by the same study site staff member 
using the same scale throughout the study. 
  
  
 
QuantiFERON TB-Gold test or PPD skin test 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at screening. 
Subjects with a positive test may participate in the study if further work up (according to local 
practice/guidelines), establishes conclusively that the subject has no evidence of active 
tuberculosis, OR, if presence of latent tuberculosis is established, then treatment according to 
local country guidelines must have been initiated prior to enrollment.  
QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test is to be performed at the second SCR visit and the results to be 
known prior to randomization to determine the subject’s eligibility for the trial. The test will be 
used to screen the subject population for latent tuberculosis infection. 
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
PPD skin test 
A PPD skin test is to be performed at screening and read before randomization to determine the 
subject’s eligibility for the trial, if a QuantiFERON test is not performed. The test dose is 
bioequivalent to 5 tuberculin units of standard PPD injected intradermally, usually into the volar 
surface of the forearm. The site is cleaned and the PPD extract is then injected into the most 
superficial layer under the skin. If given correctly, the injection should raise a small wheal of 
about 5 mm, which resolves within 10-15 minutes. 
Because the reaction (induration), will take 48-72 hours to develop, the subjects must return to 
the study site within that time for evaluation of the injection site. This will determine whether 


Novartis 
Confidential 
Page 60 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
the subject has had a significant reaction to the PPD test. A reaction is measured in millimeters 
of induration (hard swelling) at the site. A PPD skin induration ≥5 mm (or according to local 
practice/guidelines) is interpreted as a positive result. 
8.4.1 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens listed below (except urinalysis). 
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided in the laboratory manual. For the identification of clinically notable values, see 
Appendix 16.1 . All subjects with laboratory tests containing clinically significant abnormal 
values are to be followed until the values return to normal ranges or until a valid reason, other 
than treatment related AE, is defined. 
Table 8-9 
Specifications of Laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hemoglobin, platelets, red blood cell (RBC), 
white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled 
visits. 
Clinical Chemistry 
Serum chemistries will include glucose, urea, 
creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, 
potassium, bicarbonate, calcium, phosphorus, 
total protein, albumin, and uric acid. 
Urinalysis 
Dipsticks will be provided by the central 
laboratory to the sites for local urinalysis 
assessments. The urinalysis results for standard 
parameters such as protein, glucose, blood, and 
WBCs will be recorded in the appropriate eCRF. 
Lipid Panel 
A lipid profile including High Density Lipoprotein 
(HDL), Low Density Lipoprotein (LDL), total 
cholesterol, and triglycerides will be measured 
from a fasting blood sample. 
Cardiovascular Panel 
A cardiovascular profile including lipoprotein (a), 
apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be measured from a blood 
sample. 
Pregnancy Test 
Serum / Urine pregnancy test (Refer to 
Section 8.4.3) 
8.4.2 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed as indicated in Table 8-1. ECGs must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection followed by vital signs 
and blood sampling. The Fridericia QT correction formula (QTcF) should be used for clinical 
decisions. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 


Novartis 
Confidential 
Page 61 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings must be discussed with the sponsor before administration of 
investigational treatment. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate. 
8.4.3 
Pregnancy and assessments of fertility 
The study treatment must not be given to pregnant women; therefore, effective methods of birth 
control must be used for women of childbearing potential (see exclusion criteria definitions, 
Section 5.2). 
A serum β-hCG test will be performed in all women at screening. All women who are not 
surgically sterile or post-menopausal (as defined in Section 5.2) at screening, will have local 
urine pregnancy tests as indicated in Table 8-1. A positive urine pregnancy test requires 
immediate interruption of study treatment until serum β-hCG is performed and found to be 
negative. If positive, the subject must discontinue study treatment. 
8.4.4 
Other safety evaluations 
Chest X-ray 
Standard chest X-ray (PA view) will be performed except for those who have had a valid chest 
X-ray or MRI done within 3 months of first dosing. 
8.5 
Additional assessments 
The other assessments planned for the study are: 
• Quality of Life questionnaires/ Patient reported outcomes (PROs) 
 
 
 
 
 
 
8.5.1 
Clinical Outcome Assessments (COAs) 
The impact of PsA on various aspects of subjects’ health-related quality of life (HRQoL) will 
be assessed using the following validated instruments. 


Novartis 
Confidential 
Page 62 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
8.5.1.3 
FACIT-Fatigue v4 
The FACIT-Fatigue© is a 13-item questionnaire (Cella 1997, Yellen et al 1997) that assesses 
self-reported fatigue and its impact upon daily activities and function. 
The purpose of FACIT-Fatigue© in this study is to assess the impact of fatigue on subjects with 
PsA. 
8.5.1.5 
Trial feedback Questionnaire (TFQ) 
This trial will include an anonymized questionnaire, ‘Trial Feedback Questionnaire’ for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses would be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or adverse events 


Novartis 
Confidential 
Page 63 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
and therefore would not be trial data. Should any spontaneous information be collected about 
AEs, this would be transferred to the safety database. 
8.5.1.7 
SF-36 v2 
The SF-36 is a widely used and extensively studied instrument to measure health-related quality 
of life among healthy subjects and subjects with acute and chronic conditions. It consists of 
eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily 
Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two 
overall summary scores, the Physical Component Summary (PCS) and the Mental Component 
Summary (MCS) also can be computed. The SF-36 has proven useful in monitoring general 
and specific populations, comparing the relative burden of different disease, differentiating the 
health benefits produced by different treatments, and in screening individual subjects. 
The purpose of the SF-36 version 2, in this study is to assess the HRQoL (Health-related quality 
of life) of subjects. Given the chronic nature of this disease, recall period of 1 week will be used 
in this study as outlined in the assessment schedule (Table 8-1). 


Novartis 
Confidential 
Page 64 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 


Novartis 
Confidential 
Page 65 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 


Novartis 
Confidential 
Page 66 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 


Novartis 
Confidential 
Page 67 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 


Novartis 
Confidential 
Page 68 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
The following circumstances require study treatment discontinuation: 
• Withdrawal of informed consent 
• Emergence of the following adverse events: 
a. Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with an unacceptable 
co-medication 
b. Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed 
c. Life-threatening infection 
d. Severe hypersensitivity reaction or anaphylactic reaction 
• Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the subject at a safety risk for continuation in the study 
(A general guidance on clinically notable laboratory values is provided in Appendix 1). 
• Pregnancy 
• Use of any biologic immunomodulating agent except secukinumab 
• Any protocol deviation that results in a significant risk to the subject’s safety 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given subject if there is a lack of improvement or worsening 
of their symptoms, or if on balance, he/she thinks that continuation would be detrimental to the 
subject’s well-being. 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' section). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the subject/pre-designated contact as specified in the lost to follow-up section. 
This contact should preferably be done according to the study visit schedule. 


Novartis 
Confidential 
Page 69 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
Subjects who prematurely discontinue or withdraw during a specific treatment period (i.e., 
Week 16 for treatment period 1 or Week 52 for treatment period 2) should return to site 4 weeks 
after the last study treatment for the final visit within that treatment period. Subjects should also 
return for the follow-up visit (Week 60) 12 weeks after the last study treatment (see Table 8-
1). The final visit should be performed before any new treatment is initiated. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. Refer to Section 6.6.3. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 


Novartis 
Confidential 
Page 70 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. 
A subject should not be formally considered lost to follow-up until due diligence has been 
completed or his/her scheduled End of Study visit would have occurred. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible and treated as a prematurely withdrawn 
subject. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the subject’s interests. The 
investigator or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
A subject will be considered to have completed the study if he/she received a total of 52 weeks 
of study treatment and upon completion of the scheduled study assessments and procedures up 
to and including Week 60. 
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion eCRF 
page. 
In any case, the investigator or site staff must contact the IRT as soon as possible to record the 
subject’s study completion (Week 60) and/or discontinuation. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic DMARD. In case of a biologic treatment, 
a waiting period of 3 months before initiating the treatment is recommended. 
If, at study completion, the investigator determines that a subject could benefit from continued 
secukinumab treatment, the physician may request access from Novartis, at no cost to the 
subject, if not commercially available and accessible. 
 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 


Novartis 
Confidential 
Page 71 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis/ qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. 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 
2. its relationship to the study treatment.  If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Conditions that were already present after signing the informed consent should be recorded in 
medical history of the subject. 


Novartis 
Confidential 
Page 72 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the causal relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.  
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
seriousness criteria: 
1. fatal 
2. life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
3. results in persistent or significant disability/incapacity 
4. constitutes a congenital anomaly/birth defect 
5. requires inpatient hospitalization or prolongation of existing hospitalization, 
The seriousness criteria for hospitalization SHOULD NOT be considered for the following: 
• 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 
• social reasons and respite care in the absence of any deterioration in the subject’s general 
condition 


Novartis 
Confidential 
Page 73 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
• 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 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced from the 30 day period after the last study visit only reported to Novartis 
if the investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one must 
be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements on 
investigator's signature can be found in the investigator folder provided to each site. 
If the SAE is previously not documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 


Novartis 
Confidential 
Page 74 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the Novartis Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment to any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 


Novartis 
Confidential 
Page 75 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors will be recorded in the CRF as AEs with contributing factors captured as 
concomitant medication or procedures as appropriate  
Please refer to Table 16-4 in Appendix 16.11 for complete definitions of liver laboratory 
triggers and liver events. 
Every liver event defined in Appendix 16.11, Table 16-4 should be followed up by the 
investigator or designated personnel at the trial site, as summarized below. Additional details 
on actions required in case of liver events are outlined in Table 16-5. Repeat liver chemistry 
tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 


Novartis 
Confidential 
Page 76 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
10.2.2 
Renal safety monitoring 
To date, there has been no safety signal for nephrotoxicity with secukinumab in over 12,000 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the kidney. All subjects with laboratory tests resulting in 
clinically significant abnormal values (see Appendix 1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined. Standard renal function tests (blood urea nitrogen, serum creatinine) will 
be obtained at regular intervals, but special measures for renal safety monitoring are not 
planned. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. The 
Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
MedDRA terminology. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis. 


Novartis 
Confidential 
Page 77 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
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. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/ moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, 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. Additionally, a central analytics organization may analyze data & identify risks & trends 
for site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file.  The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
Summary statistics for continuous variables include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, and maximum. For binary or discrete variables the 
absolute number of subjects in each category and relative frequencies will be provided. 
Unless otherwise specified, p-values will be presented as 2-sided p-values and the type I error 
rate (alpha) will be 5%. 


Novartis 
Confidential 
Page 78 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Inferential efficacy comparisons with placebo will generally focus on the first 16 weeks of 
treatment unless otherwise specified. 
Efficacy and safety data for the placebo-controlled period (or the entire treatment period as 
appropriate) will be presented by treatment groups. Subjects may be included in more than one 
treatment group for some analyses (e.g. exposure-adjusted AEs over the entire treatment 
period). 
Note that the treatment groups for a subject may differ depending on the time period of the 
analysis and whether one assesses the subject for efficacy or safety (see Section 12.1 for 
details). 
Data may also be presented by a combination of the ‘original’ and ‘switch’ treatment groups. 
These treatment groups represent the treatment combinations the subjects experience over the 
course of the entire trial. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
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 Interactive Voice 
Response (IVR) will be excluded from the randomized set. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IVR prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized subjects are treated as screen failures. 
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 with actual anti-TNF 
status.  
Dactylitis subset: The dactylitis subset will include all FAS subjects who have dactylitis at 
baseline. 
Enthesitis subset: The enthesitis subset will include all FAS subjects who have enthesitis at 
baseline. 
Psoriasis subset: The psoriasis subset will include all FAS subject who have >= 3% of the body 
surface area (BSA) affected by psoriatic skin involvement at baseline. 
Nail subset: The nail subset will include all FAS subject who have psoriasis currently in nails 
at baseline. 
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. Subjects will be evaluated according to treatment received. 
12.2 
Subject demographics and other baseline characteristics 
Demographics and baseline characteristics 


Novartis 
Confidential 
Page 79 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Summary statistics will be presented for continuous demographic and BSL 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. 
The following demographic variables and BSL disease characteristics will be summarized by 
treatment groups: 
• Gender, age, race, ethnicity, weight, height, and BMI 
• Anti-TNF treatment history (naïve or inadequate responder), 
 and other 
disease-related measures (e.g. 
 presence of enthesitis, presence of dactylitis, time 
since first diagnosis of psoriatic arthritis, PASDAS, subjects with psoriasis ≥ 3%), number 
of prior biologic PsA therapies, dose of MTX or other DMARD at randomization.  
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. 
12.3 
Treatments 
Study treatment  
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo administrations received will be presented by treatment group.  
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of subjects with cumulative exposure levels (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- BSL 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. 


Novartis 
Confidential 
Page 80 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
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 prior and concomitant PsA therapy will be 
presented by randomized treatment group as well as the reasons for stopping their therapies 
(primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other). 
12.4 
Analysis of the primary endpoint(s) 
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 12.5.  
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy variable will be ACR50 response at Week 16. The analysis of the primary 
efficacy variable will be based on the FAS subjects. Primarily, CRP will be used instead of ESR 
to calculate ACR response; ESR will only be used in the event CRP is missing. 
The primary estimand is defined as follows: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
psoriatic arthritis population 
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving ACR50 response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: Difference in marginal response proportions for comparison 
between treatments 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypothesis for ACR50 being tested is that there is no difference in the proportion 
of subjects fulfilling the ACR50 criteria at Week 16 in i.v. secukinumab vs. placebo regimen. 
Let pj denote the proportion of ACR50 responders at Week 16 for treatment regimens j, j=0, 1 
where 
• 0 corresponds to placebo regimen, 
• 1 corresponds to i.v. regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, for the i.v. secukinumab regimen, i.e. 
H1: The i.v. secukinumab. regimen is not different to placebo regimen with respect to signs and 
symptoms (ACR50 response) at Week 16 
The primary endpoint of ACR50 at Week 16 in the FAS will be evaluated using a logistic 
regression with treatment and randomization stratum (TNFα status –naïve or IR) as factors and 
weight as a covariate. Difference in marginal response proportions will be computed for 
comparisons of i.v. secukinumab vs. placebo regimen utilizing the logistic regression model 
fitted. 


Novartis 
Confidential 
Page 81 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
12.4.3 
Handling of missing values/censoring/discontinuations 
Missing data for ACR50 response and other binary efficacy variables (e.g. ACR20, 
 
HAQ-DI© response, etc.) for data up to Week 16 will be handled as follows: 
• Subjects who drop out of the trial for any reason will be considered non-responders from 
the time they drop out through Week 16 based on the estimands.  
• Subjects who do not have the required data to compute ACR response (i.e. tender and 
swollen joint counts and at least three of the five ACR core set variables) at BSL and at 
the specific time point will be classified as non-responders. 
Continuous variables (e.g. 
, 
, etc.) will be analyzed using a mixed-effects 
repeated measures model (MMRM) which is valid under the missing at random (MAR) 
assumption. For analyses of these parameters, if all post-BSL values are missing then these 
missing values will not be imputed and this subject will be removed from the analysis of the 
corresponding variable, i.e. it might be that the number of subjects providing data to an analysis 
is smaller than the number of subjects in the FAS. 
12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. These analyses will center on the 
deviations in model assumptions, and the treatment of missing data. 
Sensitivity analyses 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, ACR50 response at Week 16, further logistic regression models may be conducted 
which explore the impact of other BSL or disease characteristics on response. 
Supportive analyses 
The impact of missing data on the analysis results will be assessed as well by repeating the 
logistic regression model using ways to handle missing data. These may include, but are not 
limited to: 
• Tipping point analysis 
Additional supportive analyses will be conducted to examine the effect of TNFα status (naïve 
or IR) and/or other cDMARDs along with study drug and/or the effect of treatment 
discontinuation without rescue medication but remaining in the study on the primary endpoint. 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy 
 endpoint(s) 
Efficacy variables 
The secondary efficacy variables are listed below. Secondary efficacy variables will be 
analyzed using the FAS population unless otherwise specified. 
• ACR20 response at Week 16 
• Minimal disease activity (MDA) response at Week 16 


Novartis 
Confidential 
Page 82 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
• PASI90 response for psoriasis subset at Week 16 
• Change from baseline in PASDAS score at Week 16 
• Change from baseline in HAQ-DI© score at Week 16 
• Change from baseline in SF36-PCS at Week 16 
• Change from baseline in FACIT-Fatigue score at Week 16 
• Change from baseline in mNAPSI for nail subset at Week 16 
• Resolution of dactylitis for dactylitis subset at Week 16 
• Resolution of enthesitis for enthesitis subset at Week 16 
Testing strategy 
• The following hypotheses will be included in the testing strategy, and type-I-errors will be 
set such that a family-wise type-I-error of 5% is kept: 
Primary objectives 
• H1: i.v. secukinumab regimen is not different to placebo regimen with respect to ACR50 
response at Week 16 
Secondary objectives 
• H2: i.v. secukinumab regimen is not different to placebo regimen with respect to ACR20 
response at Week 16 
• H3: i.v. secukinumab regimen is not different to placebo regimen with respect to MDA 
response at Week 16 
• H4: i.v. secukinumab regimen is not different to placebo regimen with respect to PASI90 
response at Week 16 in the subset of subjects who have ≥3% skin involvement with 
psoriasis at baseline 
• H5: i.v. secukinumab regimen is not different to placebo regimen with respect to the 
change from baseline in PASDAS at Week 16 
• H6: i.v. secukinumab regimen is not different to placebo regimen with respect to the 
change from baseline in HAQ-DI© score at Week 16 
• H7: i.v. secukinumab regimen is not different to placebo regimen with respect to change 
from baseline in SF36-PCS score at Week 16 
• H8: i.v. secukinumab regimen is not different to placebo regimen with respect to change 
from baseline in FACIT-Fatigue score at Week 16 
• H9: i.v. secukinumab regimen is not different to placebo regimen with respect to change 
from baseline in mNAPSI score at Week 16 in the subset of subjects with PsA and nail 
psoriasis at BSL. 
• H10: i.v. secukinumab regimen is not different to placebo regimen with respect to 
resolution of dactylitis response at Week 16 in the subset of subjects who have dactylitis at 
BSL. 
• H11: i.v. secukinumab regimen is not different to placebo regimen with respect to 
resolution of enthesitis response at Week 16 in the subset of subjects who have enthesitis 
at BSL. 


Novartis 
Confidential 
Page 83 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The graphical approach of (Bretz et al 2009) for sequentially rejective testing procedures is 
used to illustrate the testing strategy: 
Figure 12-1 
Hierarchical Testing Strategy 
  


Novartis 
Confidential 
Page 84 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The family-wise error will be set to two-sided α=5% and it will be controlled with the proposed 
hierarchical testing strategy. 
The hypotheses (H1) for the primary objective (ACR50 at Week 16) for the i.v. regimen vs. 
placebo will be tested at α. If H1 is rejected, then the hypothesis H2 will be tested at α. If H2 is 
rejected, then the hypothesis H3 will be tested and so on. 
Estimand definition for the secondary variables 
Estimand definition for the secondary binomial variables is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
Psoriatic arthritis population, unless otherwise specified. 
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving variable response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: Difference in marginal response proportions between treatments 
The estimand of binary variables is (i.v. secukinumab regimen vs placebo) obtained from a 
logistic regression model with treatment and randomization stratum (TNFα status –naïve or IR) 
as factors and weight as a covariate at week 16 in the FAS population. Difference in marginal 
response proportions will be computed for comparisons of i.v. regimen vs. placebo regimen 
utilizing the logistic regression model fitted. In the analysis subjects dropping out or being 
unblinded before week 16 or having missing response data at week 16 are considered as non-
responders. 
Estimand definition for the secondary continuous variables is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
Psoriatic arthritis population 
B. Variable: change from baseline in the variable of interest 
C. Intercurrent event: had no intercurrent events occured before week 16 
D. Population-level summary: difference in variable means between the treatment conditions 
The estimand of continuous variables at week 16 is (i.v. regimen vs placebo) obtained from a 
repeated measures model in the FAS population assuming subjects dropping out or having 
missing data at week 16 are missing-at-random (MAR). MAR imputation will be implemented 
through an MMRM model. 
ACR20 at Week 16 
Response at Week 16 to ACR20 in the FAS will be evaluated using a logistic regression model 
with treatment and randomization stratum (TNFα status –naïve or IR) as factors and weight as 
a covariate. Difference in marginal response proportions will be computed for comparisons of 
i.v. regimen vs. placebo regimen utilizing the logistic regression model fitted.  
Minimal disease activity 
The proportion of subjects achieving minimal disease activity (MDA) (Coates et al 2010) which 
is assessed as 5 of the 7 following: ≤ 1 tender joint count, ≤ 1 swollen joint count, PASI ≤ 1 or 


Novartis 
Confidential 
Page 85 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
BSA≤3%, patient pain VAS ≤ 15, patient global assessment of disease activity VAS ≤ 20, HAQ-
DI© ≤ 0.5, tender entheseal points ≤ 1).  
Logistic regression model with treatment and randomization stratum (TNFα status –naïve or 
IR) as factors and weight as a covariate will be used. Difference in marginal response 
proportions will be computed for comparisons of i.v. regimen vs. placebo regimen utilizing the 
logistic regression model fitted. 
PASI90 response 
PASI90 at Week 16 will be evaluated for those subjects in whom the assessment occurred due 
to sufficient skin involvement (at least 3% BSA affected with psoriasis, which is planned to be 
a subset of the FAS). These binary variables will be evaluated in the same fashion as ACR 
response, i.e. a logistic regression model with treatment and randomization strata as factors and 
weight as a covariate. 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
Between-treatment differences in the change in PASDAS will be evaluated using a Mixed effect 
Repeated Measures model (MMRM) with treatment regimen, analysis visit and TNF-alpha 
inhibitor status as factors, and weight and BSL PASDAS score as continuous covariates. 
Treatment by analysis visit and BSL by analysis visit will be included as interaction terms in 
the model. An unstructured covariance structure will be assumed for this model. The 
significance of the treatment effects for i.v. regimens at different analysis visits will be 
determined from the pairwise comparisons performed between i.v. regimens and placebo at the 
appropriate analysis visits. 
Physical function (HAQ-DI©) 
Between-treatment differences in the change in HAQ-DI© will be evaluated using a MMRM 
with treatment regimen, analysis visit and TNF-alpha inhibitor status as factors, and weight and 
BSL HAQ-DI© score as continuous covariates. Treatment by analysis visit and BSL by analysis 
visit will be included as interaction terms in the model. An unstructured covariance structure 
will be assumed for this model. The significance of the treatment effects for i.v. regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
i.v. regimens and placebo at the appropriate analysis visits. 
SF36-PCS 
Between-treatment differences in the change from baseline for SF36-PCS summary score will 
be evaluated using a MMRM with treatment group, analysis visit and TNF-alpha inhibitor status 
as factors and BSL SF-36 score and weight as continuous covariates. Treatment by analysis 
visit and BSL SF-36 score by analysis visit will be included as interaction terms in the model. 
An unstructured covariance structure will be assumed for the model. The significance of the 
treatment effects for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab regimens and placebo at the 
appropriate analysis visits. 
FACIT-Fatigue© 
Between-treatment differences in the change from baseline for FACIT-Fatigue© scores will be 
evaluated using a MMRM with treatment group, analysis visit and TNF-alpha inhibitor status 


Novartis 
Confidential 
Page 86 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
as factors and BSL and weight as continuous covariates. Treatment by analysis visit and BSL 
by analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the treatment effects for i.v. 
regimens at different analysis visits will be determined from the pairwise comparisons 
performed between i.v. regimens and placebo at the appropriate analysis visits. 
Modified Nail Psoriasis Severity Index (mNAPSI) 
Between-treatment differences in the mNAPSI change from baseline for scores will be 
evaluated using a MMRM with treatment group, analysis visit and TNF-alpha inhibitor status 
as factors and BSL and weight as continuous covariates. Treatment by analysis visit and BSL 
by analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the treatment effects for i.v. 
regimens at different analysis visits will be determined from the pairwise comparisons 
performed between i.v. regimens and placebo at the appropriate analysis visits 
(Cassel et al 2007). 
Dactylitis at Week 16 
Presence of dactylitis at Week 16 in the subset of subjects who have dactylitis at BSL will be 
evaluated using a logistic regression model with treatment and randomization stratum (TNFα 
status –naïve or IR) as factors and weight as a covariate. 
Enthesitis at Week 16 
Presence of enthesitis at Week 16 in the subset of subjects who have enthesitis at BSL will be 
evaluated using a logistic regression model with treatment and randomization stratum (TNFα 
status –naïve or IR) as factors and weight as a covariate. 
12.5.2 
Safety endpoints 
Adverse events 
Treatment emergent AEs (events that started after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity based on preferred 
term) will be summarized up to 12 weeks (84 days) after the last dose. 
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 AE with the same preferred 
term, the AE with the greatest severity will be presented. If a subject reported more than one 
AE 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. SAEs will also be 
summarized. 
These summaries may be presented separately by placebo controlled period and entire study.. 
As appropriate, the incidence of AEs will be presented per 100 subject years of exposure. 
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to dose adjustment (including study treatment 
discontinuation). 


Novartis 
Confidential 
Page 87 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
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 BSL and post- BSL. 
In addition, shift tables were also presented comparing baseline laboratory result expressed as 
Common Terminology Criteria for Adverse Events (CTCAE) grade with the worst results up 
to Week 16 and entire treatment period. 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post- BSL 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 BSL and post-BSL values. 




Novartis 
Confidential 
Page 89 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
 
12.7 
Interim analyses 
The primary endpoint analysis will be performed in an interim analysis after all subjects have 
completed the Week 16 visit. The investigators, site personnel and monitors will continue to 
remain blinded to the original treatment assignment that each subject received at randomization 
until after the database lock for Week 60 analysis. 
Subsequent to the primary endpoint analysis, additional analyses are planned after subjects have 
completed the Week 60 assessments and may be used for regulatory submission and/or 
publication purposes. The final analysis will be conducted after all subjects complete the study. 
Additional analyses may be performed to support interactions with health authorities, as 
necessary. 
12.8 
Sample size calculation 
An overall type I error (2-sided) 5% will be used to control type I error. Since one i.v. regimen 
will be tested versus placebo with respect to the primary endpoint (ACR50 response at Week 
16), the type-I-error is 5% two-sided for comparison. The total sample size of 190 subjects per 
each group is deemed appropriate to achieve adequate power for the primary and secondary 
endpoints for this study. 
12.8.1 
Primary endpoint(s) 
Analysis of a phase III study (FUTURE 5) showed a placebo response rate of 8.1%, 
secukinumab 150 mg with SC loading response rate of 35.9%, and secukinumab 300 mg with 
SC loading response rate of 39.6% at week 16 for ACR50. Assuming that the response rate of 
i.v. regimen is between the response rates of secukinumab 150 mg with SC loading and 300 mg 
with SC loading, 190 subjects per group would yield approximately 99% power to detect a 
treatment difference between 27.8% (based on the difference between secukinumab 150 mg 
with SC loading and Placebo) and 31.5% (based on the difference between secukinumab 300 
mg with SC loading and Placebo) for the primary endpoint of ACR50 in the FAS population 
(two-sample Chi-Squared Test, Nquery 7.0). 
Table 12-1 
Summary of power for binary primary endpoint 
Endpoint  
(Week 16) 
Placebo 
Response 
Rate 
Secukinumab with 150 mg 
SC loading 
Secukinumab with 300 mg 
SC loading 
ACR50 
8.1% 
Response 
Rate 
Power  
N=190/arm 
Response 
Rate 
Power 
N=190/arm 
35.9% 
99% 
39.6% 
99% 
12.8.2 
Secondary endpoint(s) 
A summary of the assumptions and power for the primary and secondary efficacy parameters 
using the FUTURE5 study week 16 data is shown in the Table 12-2 for binary endpoints and 
Table 12-3 for continuous endpoints. 




Novartis 
Confidential 
Page 91 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection, an investigator allowed to collect additional data or conduct any additional 
procedures for any purpose involving any investigational drugs under the protocol, other than 
the purpose of the study. If despite this interdiction prohibition, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 


Novartis 
Confidential 
Page 92 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any 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 according to 
local regulations. 






Novartis 
Confidential 
Page 95 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel. 
Table 16-1 
Safety Analyses: Expanded Limits and Notable Criteria 
  
  
Notable Criteria 
Laboratory Variable 
  
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
  
>3 x ULN 
>3 x ULN 
SGPT (ALT) 
  
>3 x ULN 
>3 x ULN 
Bilirubin 
  
>2 x ULN 
>2 x ULN 
Alkaline phosphatase 
  
>2.5 x ULN 
>2.5 x ULN 
  
  
  
  
RENAL FUNCTION, METABOLIC AND ELECTROLYTE VARIABLES 
Creatinine (serum) 
  
>2 x ULN 
>2 x ULN 
HEMATOLOGY VARIABLES 
Hemoglobin: 20 g/L decrease from baseline 
Platelet count: <100x10E9/L 
White blood cell count: <0.8 x LLN 
Neutrophils: <0.9 x LLN 


Novartis 
Confidential 
Page 96 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
16.2 
Appendix 2: The classification criteria for psoriatic arthritis 
(CASPAR) 
To meet the Classification of Psoriatic Arthritis (CASPAR) criteria for diagnosis of psoriatic 
arthritis according to (Taylor et al 2006), a subject must have inflammatory articular disease 
(joint, spine or entheseal) and at least 3 points from the following 5 categories: 
1. Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis (2 points) 
• Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a 
rheumatologist or dermatologist.†  
• A personal history of psoriasis is defined as a history of psoriasis that may be obtained 
from a patient, family physician, dermatologist, rheumatologist, or other qualified health 
care provider. 
• A family history of psoriasis is defined as a history of psoriasis in a first- or second-degree 
relative according to patient report. 
1. Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination (1 point) 
2. A negative test result for the presence of rheumatoid factor by any method except latex (1 
point) 
3. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis 
recorded by a rheumatologist (1 point) 
4. Radiographic evidence of juxta-articular new bone formation appearing as ill-defined 
ossification near joint margins (but excluding osteophyte formation) on plain radiographs 
of the hand or foot (1 point) 
Total score: _______  
(The CASPAR criteria eCRF will autopopulate the total number of points of the CASPAR 
criteria met by the subject. If the total score ≥ 3, the subject meets CASPAR criteria for PsA 
diagnosis.) 
† Current psoriasis is assigned a score of 2; all other features are assigned a score of 1 






Novartis 
Confidential 
Page 99 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
16.6 
Appendix 6:The Psoriasis Area and Severity Index (PASI) 
The PASI is a system used for assessing and grading the severity of psoriatic lesions and their 
response to therapy. The PASI produces a numeric score that can range from 0 to 72. The 


Novartis 
Confidential 
Page 100 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
severity of disease is calculated as follows. In the PASI system, the body is divided into 4 
regions: the head (h), trunk (t), upper extremities (u), and lower extremities (l), which account 
for 10%, 30%, 20% and 40% of the total BSA, respectively. Each of these areas is assessed 
separately for erythema, induration and desquamation (scaling), which are each rated on a scale 
of 0 to 4. The scoring system for the signs of the disease (erythema, induration, and 
desquamation (scaling)) are: 
0 = none; 1= slight; 2 = moderate; 3 = severe; and 4 = very severe.  
The scale for estimating the area of involvement for psoriatic lesions is outlined below. 
0 = no involvement 
1 = 1% to 9% involvement 
2 = 10% to 29% involvement 
3 = 30% to 49% involvement 
4 = 50% to 69% involvement 
5 = 70% to 89% involvement 
6 = 90% to 100% involvement 
To help with the area assessments, the following conventions should be noted: 
• the neck is considered part of the head 
• the axillae and groin are part of the trunk 
• the buttocks are part of the lower extremities 
The PASI formula is: PASI = 0.1 (Eh + Ih + Dh) Ah + 0.3 (Et +It+ Dt) At+ 0.2 (Eu + Iu + Du) 
Au+ 0.4 (El +II+ Dl) AI (where E= erythema, I = induration, D = desquamation and A = area) 
 
PASI Scoring Worksheet 
 
Head 
Upper extremities Trunk 
Lower 
extremities 
Redness † 
 
 
 
 
Thickness † 
 
 
 
 
Scale † 
 
 
 
 
Sum of rows 1, 2, and 3 
 
 
 
 
Area score ‡ 
 
 
 
 
Score of row 4 x row 5 
x the area multiplier 
Row 4 x row 5  
x 0.1 
Row 4 x row 5 
 x 0.2 
Row 4 x row 5 
 x 0.3 
Row 4 x row 5 
 x 0.4 
Sum row 6 for each 
column for PASI score 
 
 
 
 
a. Divide body into four areas: head, arms, trunk to groin, and legs to top of buttocks. 
b. Generate an average score for the erythema, thickness, and scale for each of the 4 areas (0=clear, 1-
4=increasing severity). 
c. Sum scores of erythema, thickness, and scale for each of the 4 area. 


Novartis 
Confidential 
Page 101 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
d. Generate a percentage for skin covered with psoriasis for each area and convert that to a 0-6 scale. ‡ 
e. Multiply score of item c above times item d above for each area and multiply that by 0.1, 0.2, 0.3 and 0.4 
for head, arms, trunk, and legs, respectively. 
f. Add these scores to get the PASI score. 
† Erythema, thickness, and scale are measured on a 0-4 scale (none, slight, mild, moderate, severe) 
‡ Area scoring criteria (score: % involvement). 
 
 
0: 0% (clear) 
 
 
1: <10% 
 
 
2: 10-<30% 
 
 
3: 30-<50% 
 
 
4: 50-<70% 
 
 
5: 70-<90% 
 
 
6: 90-100% 
Derived from Feldman SR, Krueger GG (2005). Psoriasis assessment tool in clinical trials. Ann Rheum Dis; 
64 (Suppl 2);ii65-8, ii69-73. 
 
16.7 
Appendix 7:The modified Nail Psoriasis Severity Index (mNAPSI) 
Modified NAPSI Instructions 
This tool will ask you to assess each abnormality for each of a subject’s fingernails. If you 
question which grade to give, your answer should be the lower of the grades. Three features or 
groups of features (pitting, onycholysis and oil-drop dyschromia, and crumbling) of each 
fingernail will be graded on a scale from 0 to 3, according to the directions below. Four features 
(leukonychia, splinter hemorrhages, hyperkeratosis, and red spots in the lunula) will be graded 
as either present or absent for each fingernail. After you have viewed all the fingernails of a 
subject, consider all aspects of all of the subject’s fingernails and place a mark on the visual 
analog scale giving a global assessment of their fingernails. 
1. Onycholysis: Separation of the nail plate from the nail bed. The separated part of the nail is 
opaque and can have white, yellow, or greenish tinge. If there is a piece of nail missing, estimate 
where the nail normally would have ended at the end of the nail bed, and count that missing 
part as involved in onycholysis. 
Oil-drop (salmon patch) dyschromia: Reddish-brown discoloration under the nail plate. 
Onycholysis and oil-drop dyschromia are considered together. When looking at the nail, 
combine the total percentage area of the nail that is affected by either and use that combined 
total to score the nail. 
Score 
Percent of nail with onycholysis or oil-drop 
dyschromia present 
0 
No onycholysis or oil drop dyschromia present 
1 
1–10% of the nail has onycholysis or oil-drop 
dyschromia 
2 
11–30% of the nail has onycholysis or oil-drop 
dyschromia 


Novartis 
Confidential 
Page 102 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
3 
> 30% of the nail has onycholysis or oil-drop 
dyschromia 
2. Pitting: Small, sharply defined depressions in the nail surface. Pits are discrete abnormalities 
(“ice-pick-like”). If there is nail plate crumbling that is confluent with pits, do not score for pits. 
If the pits are separate from crumbling, they may be scored regardless of whether crumbling is 
present or not. 
Score 
Number of pits 
0 
0 
1 
1–10 
2 
11–49 
3 
> 50 
3. Nail plate crumbling: Crumbling or fragmentation of friable nail plate which may be 
associated with confluent pitting. Crumbling involves alteration of the nail plate surface. 
Horizontal ridging of the nail, “wave-like” appearance, and horizontal lines are all features of 
crumbling. 
Score 
Percent of nail with crumbling present 
0 
No crumbling 
1 
1–25% of the nail has crumbling 
2 
26–50% of the nail has crumbling 
3 
> 50% of the nail has crumbling 
The next 4 abnormalities are scored only by their presence or absence. A score of 1 indicates 
present and a score of zero indicates not present. 
1. Leukonychia: White spots in the nail plate due to psoriasis in the mid matrix. 
Leukonychia are just color changes. If it appears that there is depression or irregularity to 
the nail surface, this may be pitting or crumbling, not leukonychia. If the leukonychia is 
adjacent to, or confluent with crumbling or pits, it is counted as part of the crumbling or 
pitting and not as a separate abnormality. 
2. Splinter hemorrhages: Small, longitudinal, linear, dark brown hemorrhage under the 
fingernail. 
3. Nail bed hyperkeratosis: Thickened keratin in the nail bed. 
4. Red spots in the lunula: Small pink or red macules in the lunula. 
16.8 
Appendix 8: Standard reference table for the LDI 
Table 16-2 
Table- hands (in cm) 
Digit 
Men 
Women 
Thumb 
7.0 
5.8 
Index 
6.3 
5.4 
Middle 
6.3 
5.4 
Ring 
5.9 
5.0 
Little 
5.2 
4.4 


Novartis 
Confidential 
Page 103 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Table 16-3 
Table- feet (in cm) 
Digit 
Men 
Women 
Central toe 
8.2 
7.2 
Second 
5.2 
4.6 
Middle 
5.0 
4.4 
Fourth 
5.0 
4.4 
Little 
5.2 
4.5 
16.9 
Appendix 9: Health Assessment Questionnaire-Disability Index 
(HAQ-DI)© 
The HAQ-DI© (Fries et al 1980) is a validated measure of physical disability and functional 
status. It has four dimensions: disability, pain, drug side effects and dollar costs, although, the 
latter three are rarely used in clinical trials. In this trial only the disability dimension will be 
used. The disability dimension consists of 20 multiple choice items concerning difficulty in 
performing eight common activities of daily living; dressing and grooming, arising, eating, 
walking, reaching, personal hygiene, gripping and activities. Subjects choose from four 
response categories, ranging from ‘without any difficulty' to 'unable to do'. The ACR 
Rheumatology Committee on Outcome Measures in RA recommends the use of this 
questionnaire in clinical trials. 
Scoring of the HAQ-DI© 
The HAQ-DI© will be scored in accordance with the recommendation from the developers 
outlined in the “HAQ PACK” from Stanford University, California. 
The following coding is to be used for the 8 categories of the disability outcome dimension: 
 
Without ANY Difficulty 
0 
With SOME Difficulty 
1 
With MUCH Difficulty 
2 
UNABLE to do 
3 
Within each of the 8 categories only the item indicating the most severe impairment contributes 
to the category score. If the subject requires the use of aids, devices, or help from another to 
accomplish any of the activities in an associated category, then the score for that category will 
be assigned the value 2, unless the score is already 3 (i.e. scores of 0 or 1 are increased to 2). 
Associated categories are defined in the “HAQ PACK”. From the scores for each category a 
Standard Disability Index (SDI) is computed by summing the computed scores for each 
category and dividing by the number of categories answered. The SDI is not computed if the 
subject does not have scores for at least 6 categories. This SDI is the HAQ-DI© score, which 
will be used in the statistical analyses of this instrument. The range for this score is (0, 3). 
HAQ-DI© Data Collection 
The HAQ-DI© is to be completed by the subject in their local languages, using an electronic 
device. The questionnaires should be completed by the subjects in a quiet area free from 
disturbance, and before any visit assessments. Subjects should receive no help from family 


Novartis 
Confidential 
Page 104 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the subject’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a subject has missed a question or given more than one response 
per question, then this should be brought to subject. Incomplete questions should not be 
accepted without first encouraging the subject to complete unanswered questions. 
16.11 
Appendix 11: Liver event and laboratory trigger definitions and 
follow-up requirements 
Table 16-4 
Liver Event and Laboratory Trigger Definitions 
  
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 x ULN < ALT / AST ≤ 5 x ULN 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
  
ALP > 2 × ULN (in the absence of known bone 
pathology) 
  
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome) 


Novartis 
Confidential 
Page 105 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
  
ALT or AST > 3 × ULN and INR > 1.5 
  
Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase in 
ALP to > 2 × ULN) 
  
Any clinical event of jaundice (or equivalent 
term) 
  
ALT or AST > 3 × ULN accompanied by 
(general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia 
  
Any adverse event potentially indicative of a liver 
toxicity * 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
Table 16-5 
Follow up Requirements for Liver Events and Laboratory Triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and INR > 1.5 
Discontinue the study drug 
immediately 
Hospitalize, if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
Repeat LFT within 48 hours 
If elevation persists, continue 
follow-up monitoring 
If elevation persists for more 
than 2 weeks, discontinue the 
study drug 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 


Novartis 
Confidential 
Page 106 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN accompanied by 
symptomsb 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN 
(patient is asymptomatic) 
Repeat LFT within the next 
week 
If elevation is confirmed, initiate 
close observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
  
  
> 2 × ULN (in the absence of 
known bone pathology) 
Repeat LFT within 48 hours 
If elevation persists, establish 
causality 
Complete liver eCRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
TBL (isolated) 
  
  
> 2 × ULN (in the absence of 
known Gilbert syndrome) 
Repeat LFT within 48 hours 
If elevation persists, 
discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 1.5 to ≤ 2 × ULN 
(patient is asymptomatic) 
Repeat LFT within the next 
week 
If elevation is confirmed, initiate 
close observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Jaundice 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Establish causality 
Complete liver eCRF 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
Consider study drug 
interruption or discontinuation 
Hospitalization if clinically 
appropriate 
Establish causality 
Complete liver eCRF 
Investigator discretion 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN 
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 


Novartis 
Confidential 
Page 107 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
Criteria 
Actions required 
Follow-up monitoring 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated 
level after a maximum of 6 months, (4) liver transplantation, and (5) death. 
16.12 
Appendix 12: Guidelines for administering the PRO 
questionnaires 
Before trial start 
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial and 
identify any items where a subject’s response might highlight issues of potential concern.  
 
For example, one question in the SF-36 asks ‘How much of the time in the past 4 weeks- have 
you felt downhearted and blue?’ If a subject responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator. 
Before completion 
Subjects should be provided with the correct questionnaire at the appropriate visits and in the 
appropriate language.  
Subjects should have adequate space and time to complete the forms 
Subjects should be provided with a firm writing surface (such as a table or a clip board) 
Questionnaire should be administered before the clinical examination 
During completion 
Administrator may clarify the questions but should not influence the response 
Only one response for each question 
Also see “Addressing Problems and Concerns” 
After completion 
Check for completeness and not for content* 
Data should be sent from the eCRF / electronic device 
Data should be reviewed by Investigator for AEs 
*However, any response which may directly impact or reflect the subject’s medical condition 
(e.g. noting of depression) should be communicated by the study coordinator to the 
investigator). 
Addressing Problems and Concerns 
Occasionally a subject may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below. 


Novartis 
Confidential 
Page 108 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
The subject does not want to complete the questionnaire(s) 
Tell the subject that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental and social health problems of subjects. Emphasize that such 
information is as important as any other medical information and that the questionnaire(s) is 
simple to complete. Suggest that the questionnaire(s) may be different from anything the 
respondent has filled in the past. If the subject still declines, retrieve the questionnaires. Record 
the reason for the decline and thank the subject. 
The subject is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain subject responses by reading out loud each 
question, followed by the corresponding response categories, and entering the subject’s 
response. No help should be provided to the subject by any person other than the designated 
study coordinator. The coordinator should not influence subject responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim. 
The subject wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the subject provide responses to the 
questions. Unless specified in the study protocol, proxy data are not an acceptable substitute for 
subject self-report. Subjects should be discouraged from asking a family member or friend for 
help in completing a questionnaire. 
The subject does not want to finish completing the questionnaire(s) 
If non-completion is a result of the subject having trouble understanding particular items, ask 
the subject to explain the difficulty. Re-read the question for them verbatim but do not rephrase 
the question. If the respondent is still unable to complete the questionnaire, accept it as 
incomplete. Thank the subject. 
The subject is concerned that someone will look at his/her responses 
Emphasize that all responses are to be kept confidential. Point out that their names do not appear 
anywhere on the questionnaire, so that their results will be linked with an ID number and not 
their name. Tell the subject that his/her answers will be pooled with other subjects’ answers 
and that they will be analyzed as a group rather than as individuals. Tell the subject that 
completed forms are not routinely shared with treating staff and that their responses will only 
be seen by you (to check for completeness) and by the investigator. Any response which may 
directly impact on or reflect their medical condition (e.g. noting of severe depression) will be 
communicated by the coordinator to the physician. 
The subject asks the meaning of a question/item 
While completing the questionnaire, some subjects might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the subject by rereading the 
question for them verbatim. If the subject asks to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question. Subjects should 
answer the questions based on what they think the questions mean. 
 


Novartis 
Confidential 
Page 109 
Clinical Trial Protocol (Version No. 00) 
 
Protocol No. CAIN457P12302 
 
A General Information about all questionnaire(s): 
All questionnaires have to be completed by the subjects in their local languages using an 
electronic device. The questionnaires should be completed by the subjects in a quiet area free 
from disturbance, and before any visit assessments. Subjects should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the subject’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a subject has missed a question or given more than one response 
per question, then this should be brought to subject. Incomplete questions should not be 
accepted without first encouraging the subject to complete unanswered questions. 
The investigator must complete the subject/visit information on the electronic device and ensure 
that the center number, subject’s number and initials are identical to the CRF. As there are no 
source data for this questionnaire, the data queries will be restricted to subject/visit information. 
 

SAP_001.pdf: 


Novartis 
For business use only 
Page 2 
SAP 
 
CAIN457P12302 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study Design ............................................................................................................ 9 
1.2 
Study Objectives and Endpoints ............................................................................ 10 
1.2.1 
Primary Objective ................................................................................. 10 
1.2.2 
Secondary Objectives ............................................................................ 10 
 
 11 
2 
Statistical Methods ............................................................................................................ 12 
2.1 
Data Analysis General Information ....................................................................... 12 
2.2 
Analysis Sets and Treatment Groups ..................................................................... 13 
2.2.1 
Subgroup of Interest .............................................................................. 13 
2.2.2 
Treatment Groups .................................................................................. 13 
2.3 
Patient Disposition, Demographics and Other Baseline Characteristics ............... 14 
2.3.1 
Patient Disposition ................................................................................ 14 
2.3.2 
Background and Demographic Characteristics ..................................... 14 
2.3.3 
Medical History ..................................................................................... 14 
2.4 
Treatments (Study Treatment, Concomitant Therapies, Compliance) .................. 14 
2.4.1 
Study Treatment / Compliance .............................................................. 14 
2.4.2 
Prior, Concomitant and Post Therapies ................................................. 15 
2.5 
Efficacy Evaluation ............................................................................................... 15 
2.5.1 
Description of Efficacy Variables ......................................................... 15 
2.5.2 
Description of Health-related Quality of Life Endpoints ...................... 24 
2.5.3 
Handling of missing data ...................................................................... 26 
 
 26 
 
 26 
 
 27 
2.7 
Safety analyses ....................................................................................................... 27 
2.7.1 
Adverse events (AEs) ............................................................................ 27 
2.7.2 
Laboratory data ..................................................................................... 29 
2.7.3 
Vital signs.............................................................................................. 32 
 
 32 
 
 32 


Novartis 
For business use only 
Page 3 
SAP 
 
CAIN457P12302 
 
 
 32 
 
 33 
 
 33 
2.11 
Interim analysis ...................................................................................................... 33 
3 
Sample size calculation ..................................................................................................... 33 
3.1.1 
Primary endpoint(s) ............................................................................... 33 
3.1.2 
Secondary endpoint(s) ........................................................................... 34 
4 
Appendix ........................................................................................................................... 35 
4.1 
Visit Windows ....................................................................................................... 35 
4.1.1 
Visit windows........................................................................................ 35 
4.2 
Detailed on implementation of statistical methodology and assumptions ............. 38 
4.2.1 
Analysis of continuous data .................................................................. 38 
4.2.2 
Analysis of binary (and categorical) data .............................................. 39 
4.2.3 
Multiple Imputation .............................................................................. 40 
4.2.4 
Crude incidence and relativ risk estimates ............................................ 42 
4.2.5 
Exposure adjusted incidence rate and related risk estimates ................ 42 
5 
Reference ........................................................................................................................... 43 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 4 
SAP 
 
CAIN457P12302 
 
List of tables 
Table 2-1 
The PASI scoring system ...................................................................... 20 
 
 21 
 
 24 
Table 2-4 
Overview of analyses on some safety endpoints ................................... 28 
Table 2-5 
CTCAE grades for laboratory parameters to be analyzed .................... 30 
Table 2-6 
Liver-related events ............................................................................... 31 
Table 2-7 
Criteria for notable vital sign abnormalities .......................................... 32 
Table 3-1 
Summary of power for binary primary endpoint .................................. 34 
Table 3-2 
Summary of power for binary secondary endpoints ............................. 34 
Table 3-3 
Summary of power for continuous secondary endpoints ...................... 34 
Table 4-1 
Analysis visit windows ......................................................................... 35 
Table 4-2 
Rules for flagging variables .................................................................. 37 
Table 4-3 
Examples for calculating exposure time for incidence rates (IR) ......... 43 
 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 10 
 
 
 


Novartis 
For business use only 
Page 5 
SAP 
 
CAIN457P12302 
 
Document History-Changes compared to previous final version of SAP 
Date 
Time point 
Reason for 
update 
Outcome for 
update 
Section and title 
impacted (Current) 
03-May-
2022 
Prior to DB lock 
NA 
N/A - First version 
NA 
 


Novartis 
For business use only 
Page 6 
SAP 
 
CAIN457P12302 
 
List of abbreviations 
ACR 
American College of Rheumatology 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
b.i.d. 
twice a day 
 
  
BDR 
Bioanalytical Data Report 
BMI 
Body Mass Index 
BSA 
Body surface area 
BSL 
Baseline 
CFR 
Code of Federal Regulation 
Cmax 
Maximum concentration  
Cmax,ss 
Maximum concentration steady-state 
Cmin 
Minimum concentration 
Cmin,ss 
Minimum concentration steady-state 
CMO&PS 
Chief Medical Office and Patient Safety 
COAs 
Clinical Outcome Assessments 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
Clinical study report 
CTC 
Common Toxicity Criteria 
DMARD 
Disease Modifying Anti-rheumatic Drug 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EMA/EMEA  European Medical Agency 
ESR 
Erythrocyte sedimentation rate  
FACIT-
Fatigue  
Functional Assessment of Chronic Illness Therapy-Fatigue 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GWA 
genome-wide association 
HAQ-DI 
Health Assessment Questionnaire – Disability Index 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
HIV 
human immunodeficiency virus 
 


Novartis 
For business use only 
Page 7 
SAP 
 
CAIN457P12302 
 
hsCRP 
high sensitivity C-Reactive Protein 
i.v. 
intravenous 
IB 
investigator brochure 
IBD 
inflammatory bowel disease 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVR 
Interactive Voice Response 
LDI 
Leeds Dactylitis Index 
LDL 
Low-density lipoprotein 
LEI 
Leeds Enthesitis Index 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLQ 
Lower limit of quantification 
MCR 
Major Clinical Response 
MCS 
Mental Component Summary 
MDA 
minimal disease activity 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MMP 
Matrix Metalloproteinase 
MMRM 
Mixed effect Repeated Measures model 
mNAPSI 
Modified Nail Psoriasis Severity Index 
MRI 
Magnetic Resonance Imaging  
MTX 
Methotrexate 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
o.d. 
once a day 
p.o. 
oral 
PA 
posteroanterior 
PASDAS 
Psoriatic Arthritis Disease Activity Score 
PASI 
Psoriasis Area and Severity Index 
PCS 
Physical Component Summary 
 
 
 
 
PPD 
Purified Protein Derivative 
PRO 
Patient Reported Outcome 
PsA 
Psoriatic arthritis 
QMS 
Quality Management System 
RBC 
red blood cell(s) 
RF 
Rheumatoid factor 


Novartis 
For business use only 
Page 8 
SAP 
 
CAIN457P12302 
 
s.c. 
subcutaneous 
SAE 
serious adverse event 
SCR 
serum creatinine 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SJC 
Swollen Joint Count 
SNP 
single nucleotide polymorphism 
 
 
SST 
Serum separator tube  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBL 
total bilirubin 
TFQ 
Trial feedback Questionnaire 
TJC 
Tender Joint Count 
TNF/TNFα 
Tumor Necrosis Factor  
TNF-IR  
TNFα Inhibitor Incomplete Responder 
ULN 
upper limit of normal 
UV 
ultraviolet 
VAS 
Visual Analog Scale  
WBC 
white blood cell(s) 
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 9 
SAP 
 
CAIN457P12302 
 
1 
Introduction 
Data will be analyzed by Novartis according to the data analysis section 12 of the clinical 
study protocol. The statistical methodology is described below and any deviations from the 
protocol are documented. Additional detailed information regarding the analysis methodology 
is contained in the Appendix section.  
This version of SAP covers the statistical and analytical plans of the CAIN457P12302 trial 
regarding the final DBL.As this is the Final DBL, analysis will only be done for long-term 
efficacy and safety. Analyses pertaining to Week 16 will not be repeated. Tables and listing 
for demographics, baseline disease characteristic, prior medication and medical history will  
not be reproduced. Any analyses related to the testing hierarchy will not be reproduced. 
1.1 
Study Design 
This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-
group design to study the efficacy, safety and tolerability of treatment with intravenous 
secukinumab in patients with active PsA.  
The study population comprises approximately 380 patients with active PsA, despite current or 
previous NSAID, DMARD and / or TNF inhibitor therapy or intolerance to these therapies. 
At baseline, patients will be randomized to one of the two treatment groups in a 1:1 
randomization: 
• Group 1: approximately 190 patients; These patients will receive secukinumab 6 mg/kg 
i.v. at Baseline (BSL), followed by the administration of secukinumab 3 mg/kg i.v. every 
four weeks starting at Week 4. 
• Group 2:  approximately 190 patients; These patients will receive i.v. placebo at BSL, 
Weeks 4, 8, and 12, followed by the administration of secukinumab 3 mg/kg i.v. every four 
weeks starting at Week 16. 
This study will consist of 4 periods: a screening period (up to 10 weeks), treatment period 1 
(total duration of 16 weeks) and treatment period 2 (total duration of 36 weeks) followed by a 
safety follow up period of 8 weeks after the end of treatment visit (i.e., Week 52). 
To ensure a balance across both arms, patients previously treated with TNF-inhibitors will be 
stratified at randomization. No more than 25% of previously treated TNF-inhibitor patients will 
be enrolled in the study, with this cutoff applied to each group at randomization (no more than 
48 patients per group). 
Because PsA is considered a chronic disease with no ‘true’ and lasting placebo response, all 
patients, including those on placebo, will switch to open-label i.v. secukinumab at Week 16. 
However, all patients and investigators/ site staff will remain blinded to the original randomized 
treatment group assignment (i.v. secukinumab treatment or placebo). 
An end of treatment visit (Week 52) will be done 4 weeks after last study treatment 
administration, and a post treatment follow-up visit (Week 60) is to be done 8 weeks after end 
of the treatment visit for all subjects (regardless of whether they complete the entire study as 
planned or discontinue prematurely). 


Novartis 
For business use only 
Page 10 
SAP 
 
CAIN457P12302 
 
All intravenous infusions will be performed at the study site and site personnel will administer 
the infusions to subjects. 
Rescue medication is not allowed until Week 16. However, subjects who are deemed by the 
investigator not to be benefiting from the study treatment based on safety and efficacy 
assessments or for any reason of their own accord will be free to discontinue participation in 
the study at any time. 
The study will have a primary endpoint at Week 16. A Primary endpoint analysis will be 
performed with Week 16 data (last patient completing Treatment Period 1). Long-term efficacy 
and safety assessments will be performed up to Week 52. 
Figure 1-1 
Study Design 
 
1.2 
Study Objectives and Endpoints 
1.2.1 
Primary Objective 
To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo in 
subjects with active psoriatic arthritis (PsA) based on the proportion of patients achieving an 
American College of Rheumatology 50 (ACR50) response. 
1.2.2 
Secondary Objectives 
To evaluate: 


Novartis 
For business use only 
Page 11 
SAP 
 
CAIN457P12302 
 
• The efficacy of i.v. secukinumab at Week 16 is superior to placebo based on the proportion 
of subjects achieving an ACR20 response. 
• The efficacy of i.v secukinumab at Week 16 is superior to placebo based on the proportion 
of patients achieving Minimal Disease Activity MDA 5/7.  
• The efficacy of i.v. secukinumab at Week 16 is superior to placebo based on the proportion 
of subjects achieving a PASI90 response in the subgroup of subjects who have ≥3% skin 
involvement with psoriasis. 
• The improvement (change) from baseline on i.v. secukinumab is superior to placebo for the 
PASDAS at Week 16. 
• The improvement (change) from baseline on i.v. secukinumab is superior to placebo for the 
HAQ-DI at Week 16. 
• The improvement (change) from baseline on i.v. secukinumab is superior to placebo for the 
SF36-PCS at Week 16. 
• The improvement (change) from baseline on i.v. secukinumab is superior to placebo for the 
FACIT-fatigue at Week 16. 
• The improvement (change) from baseline on i.v. secukinumab is superior to placebo for the 
mNAPSI at Week 16 for the subgroup of patients with nail involvement. 
• The efficacy of i.v. secukinumab at Week 16 is superior to placebo based on the proportion 
of subjects with resolution of dactylitis by the Leeds Dactylytis Index in the subset of 
subjects who have dactylitis at baseline. 
• The efficacy of i.v. secukinumab at Week 16 is superior to placebo based on the proportion 
of subjects with resolution of enthesitis by the Leeds Enthesitis Index in the subset of 
subjects who have enthesitis at baseline. 
• The overall safety and tolerability of i.v. secukinumab compared to placebo as assessed by 
vital signs, clinical laboratory values, and adverse events monitoring. 


Novartis 
For business use only 
Page 12 
SAP 
 
CAIN457P12302 
2 
Statistical Methods 
2.1 
Data Analysis General Information 
Summary statistics for continuous variables include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, and maximum. For binary or discrete variables the 
absolute number of subjects in each category and relative frequencies will be provided. 
Unless otherwise specified, p-values will be presented as 2-sided p-values and the type I error 
rate (alpha) will be 5%. 
Inferential efficacy comparisons with placebo will generally focus on the first 16 weeks of 
treatment unless otherwise specified. 
Efficacy and safety data for the placebo-controlled period (or the entire treatment period as 
appropriate) will be presented by treatment groups. Subjects may be included in more than one 
treatment group for some analyses (e.g. exposure-adjusted AEs over the entire treatment period). 
Note that the treatment groups for a subject may differ depending on the time period of the 
analysis and whether one assesses the subject for efficacy or safety. 
Data may also be presented by a combination of the ‘original’ and ‘switch’ treatment groups. 
These treatment groups represent the treatment combinations the subjects experience over the 
course of the entire trial. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Efficacy data following treatment switch 
Data will also be presented after Week 16, by a combination of the ‘original’ and ‘switch’ 
treatment groups and will be referred to as treatment sequence. These treatment sequences 
represent the treatment combinations the subjects experience over the course of the entire trial 




Novartis 
For business use only 
Page 14 
SAP 
 
CAIN457P12302 
 
Randomized treatment: 
• AIN457 6mg/kg - 3mg/kg  
• Placebo     
Treatment sequence: 
• AIN457 6mg/kg - 3mg/kg  
• Stay with AIN457 3mg/kg-IV 
• Placebo –AIN457 3mg/kg-IV 
• Switch to AIN457 3mg/kg-IV 
Additional sequences could be reported such as Any AIN457-IV if applicable.  
2.3 
Patient Disposition, Demographics and Other Baseline 
Characteristics 
2.3.1 
Patient Disposition 
The number and percentage of subjects in the randomized set who completed the study periods 
and who discontinued the study prematurely (including the reason for discontinuation) will be 
presented at the end of each treatment period (e.g. Week 16, and entire treatment period), if 
appropriate, for each treatment group and all subjects. 
For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated. 
2.3.2 
Background and Demographic Characteristics 
Data on background and demographic characteristics have been summarized in Week 16 
Interim Analysis (IA) report. No such tables will be presented at Final DBL analysis.  
2.3.3 
Medical History 
Medical history has been summarized in Week 16 IA report, so no such summary table or listing 
will be repeated at Final DBL analysis. 
2.4 
Treatments (Study Treatment, Concomitant Therapies, 
Compliance) 
2.4.1 
Study Treatment / Compliance 
The analysis of study treatment data will be based on the safety set. The 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, ≥ 4 weeks, ≥ 8 weeks, 
etc.) will be presented. 
Duration of exposure of a treatment will be defined as the time from first dose of the treatment 
to the time of treatment switch (for subjects who switch treatment) or minimum of (last dose of 
the treatment + 84 days) and (last visit date). Patients who switch treatment during the study 
(e.g. from placebo to active treatment) will have exposure to both medications/doses using the 
appropriate start and stop dates. 


Novartis 
For business use only 
Page 15 
SAP 
 
CAIN457P12302 
 
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100 subject years) = duration of exposure (years) / 100 
The analyses of duration of exposure described above will be done for the entire study treatment 
period. 
2.4.2 
Prior, Concomitant and Post Therapies 
Prior medications have been summarized in Week 16 IA report. No summary tables or listings 
will be repeated at the Final DBL. 
Any medication given at least once between the day of first dose of study treatment and the date 
of within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered. 
Concomitant medications will be presented 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. 
Concomitant surgeries and procedures will be summarized by primary system organ class and 
MedDRA preferred term. 
The number and percentage of subjects receiving concomitant psoriatic arthritis therapy will be 
presented by treatment group as well as the reasons for stopping their therapies (primary lack 
of efficacy, secondary lack of efficacy, lack of tolerability, other). 
2.5 
Efficacy Evaluation 
2.5.1 
Description of Efficacy Variables 
ACR 20/50/70 
The ACR response will be used to determine efficacy. A subject is defined as an ACR 50 
responder if, and only if, the following three conditions hold: 
≥ 50% improvement in the number of tender joints (based on 78 joints) 
≥ 50% improvement in the number of swollen joints (based on 76 joints) 
≥ 50% improvement in three of the following five measures: 
Patient’s global assessment of disease activity (measured on a VAS scale, 0-100) 
Physician’s global assessment of disease activity (measured on a VAS scale, 0-100) 
Patient’s assessment of PsA pain (measured on a VAS scale, 0-100) 
Health Assessment Questionnaire- Disability Index (HAQ-DI©) score 
Acute phase reactant (hsCRP or ESR) 
ACR20 = 20 % improvement in at least 3 of the 5 measures and 20 % improvement in the 
swollen and tender joint count. 
ACR50 = 50 % improvement in at least 3 of the 5 measures and 50 % improvement in the 
swollen and tender joint count. 




Novartis 
For business use only 
Page 17 
SAP 
 
CAIN457P12302 
 
Associated categories are defined in the “HAQ PACK”. From the scores for each category a 
Standard Disability Index (SDI) is computed by summing the computed scores for each 
category and dividing by the number of categories answered. The SDI is not computed if the 
subject does not have scores for at least 6 categories. This SDI is the HAQ-DI© score, which 
will be used in the statistical analyses of this instrument. The range for this score is (0, 3). 
HAQ-DI response is defined by an improvement of at least 0.35 score points compared to 
baseline. 
Minimal disease activity  
A subject will be considered a responder of minimal disease activity (MDA, see Coates 2010) 
if he/she achieves at least 5 of the following 7 items: 
≤ 1 tender joint count 
≤ 1 swollen joint count  
PASI ≤ 1 or body surface area (BSA) ≤3% 
Patient’s assessment of PsA pain VAS ≤ 15  
Patient’s global assessment of disease activity VAS ≤ 20  
HAQ-DI ≤ 0.5 
tender entheseal points ≤ 1 
 


Novartis 
For business use only 
Page 18 
SAP 
 
CAIN457P12302 
Leeds Enthesitis Index (LEI) 
LEI is a validated enthesitis index that uses 6 sites for evaluation of enthesitis: lateral epicondyle 
humerus L + R, proximal achilles L + R and medial condyle femur L + R. Tenderness on 
examination is recorded as either present (1) or absent (0) for each of the 6 sites, for an overall 
score range of 0–6. Higher count represents greater enthesitis burden.  
 


Novartis 
For business use only 
Page 19 
SAP 
 
CAIN457P12302 
 
Resolution of enthesitis 
If enthesitis is present with any of the 6 sites (lateral epicondyle humerus L + R, proximal 
achilles L + R and medial condyle femur L + R), the patient is counted as a patient with 
enthesitis. The resolution of enthesitis is calculated based on complete resolution of enthesitis 
as determined by the Leeds Enthesitis Index (LEI) in patients with enthesitis at baseline. 
Leeds Dactylitis Index (LDI) 
The LDI measures the ratio of the circumference of the affected digit to the circumference of 
the digit on the opposite hand or foot: a minimum difference of 10% is used to define a dactylitic 
digit. If both sides are considered involved, a table of normative values is used to provide the 
comparison. The ratio of circumference is multiplied by a tenderness score, originally based on 
the Ritchie index (graded 0–3), but a later modification amended this to a binary score (0 for 
nontender, 1 for tender) — this later modification is referred to as the LDI basic, and is adopted 
in this study. For each dactylitic digit, the final score is: 
[{(A/B) - 1} * 100 ] * C, 
where A is circumference of involved digit, B circumference of opposite (unaffected or from 
reference) and C is tenderness (0 or 1 in this case). The results from each digit with dactylitis 
are then summed to produce a final score. Only involved digits are assessed. 
Dactylitis count 
The dactylitis count is the number of fingers and toes with dactylitis based on the LDI, with a 
range of 0-20.  
Resolution of dactylitis 
If dactylitis according to the LDI is present with any finger or toe, the patient is counted as a 
patient with dactylitis. The resolution of dactylitis is calculated based on complete resolution of 
dactylitis as determined by the Leeds Dactylitis Index (LDI) in patients with dactylitis at 
baseline. 
Psoriasis Area and Severity Index (PASI) 
The PASI assessment will be conducted for subjects in whom at least 3% of the body surface 
area (BSA) was affected by psoriatic skin involvement at baseline (Psoriasis Subset). The PASI 
assesses the extent of psoriasis on four body surface areas (head, trunk and upper and lower 
limbs) and the degree of plaque erythema, scaling and thickness. A PASI score will be derived 
as indicated in Table 2-1. 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. 


Novartis 
For business use only 
Page 20 
SAP 
 
CAIN457P12302 
 
Table 2-1 
The PASI scoring system 
Body  
region 
Erythema (E) 
 
Thickening 
(plaque elevation, 
induration, I) 
Scaling 
(desquamation) (D) 
Area score 
(based on true 
area %, A)* 
Head  (H)** 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Trunk,   
(T)*** 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Upper  
limbs (U) 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Lower  
limbs  
(L)**** 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0=none  
1=slight  
2=moderate  
3=severe 
4=very severe 
0 = no 
involvement 
1 = >0-< 10% 
2 = 10-<30% 
3 = 30-<50% 
4 = 50-<70% 
5 = 70-<90% 
6 = 90-100% 
Percentage (not score) of body region (not whole body) affected will be entered in the eCRF 
**Neck is assessed as part of the Head (H) body region. 
***Axillae and groin are assessed as part of the Trunk (T) body region. 
****Buttocks are assessed as part of the Lower limbs (L) body region. 
Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 
10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated 
using the formula: 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
The keys for the letters are provided in Table 2-1. 


Novartis 
For business use only 
Page 21 
SAP 
 
CAIN457P12302 
 
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 total score comes from eCRF. 
Modified Nail Psoriasis Severity Index (mNAPSI) 
The mNAPSI is an instrument to assess psoriatic nail involvement in subjects with PsA and nail 
psoriasis. It will be collected only in subjects with psoriatic nail involvement. The modifications 
on the original NAPSI to create the mNAPSI were made by rheumatologists, with 
dermatologists’ input, as a tool for clinical trials. The creators’ goal was to develop a tool to 
assess disease severity and response to treatment in clinical trials, keeping in mind that the 
assessor in a clinical trial most likely would not be a trained dermatologist. The mNAPSI scores 
range from 0-130 for all finger nails. The total mNAPSI score will be calculated as the sum of 
all the scores from available nails.  
 


Novartis 
For business use only 
Page 22 
SAP 
 
CAIN457P12302 
 
Psoriatic Arthritis Disease Activity Score (PASDAS) 
PASDAS is a new composite measure developed to access disease activity in Psoriasis 
(GRACE Project) (Helliwell 2012). It is calculated by utilizing seven measures; the seven 
components are: Patient reported measures (excluding mental component summary score (MCS) 
of the medical outcomes survey Short Form-36 (SF-36-PCS)), skin, peripheral joint counts 
(Tender and Swollen joint counts), Dactylitis (LDI), Enthesitis (LEI), acute phase response 
(CRP) and Patient & Physician global VAS scores.  
PASDAS = (((0.18 x √Physician global VAS)  
+ (0.159 x √Patient global VAS)  
- (0.253 x √SF36-PCS)  
+ (0.101 x LN (Swollen joint count + 1))  
+ (0.048 x LN (Tender joint count + 1))  
+ (0.23 x LN (Leeds Enthesitis Count + 1))  
+ (0.377x LN (Dactylitis count + 1))  
+ (0.102 x LN (CRP + 1)) +2)*1.5. 
If any component measurement is missing, PASDAS will be missing. The patient global VAS 
defined in the PASDAS score is “VAS for PASDAS assessment” which measures patient’s 
global assessment of PSORIASIS and ARTHRITIS disease activity. The Physician global VAS 
is the Physician’s global assessment of PsA disease activity. Tender Dactylitis count is from 
“Leeds Dactylitis Instrument” CRF page with “Was dactylitis present?” = “Yes” and 
“Tender/non-tender” = “Tender”. 
66-swollen / 68-tender joint counts for PASDAS assessment:  
There are only 66 swollen and 68 tender joint counts which will be used for PASDAS 
assessment. That is the 10 joints in CRF: CMC1, DIP2 (FOOT), DIP3 (FOOT), DIP4 (FOOT), 
and (DIP5 (FOOT) both left and right, should not be counted in the swollen/tender joint count 
in PASDAS formula.  
If the number of joints for which data were available (e.g., T) is less than 66/68 for the 
swollen/tender joint assessment, the number of swollen/tender joints (e.g., t) will be scaled up 
proportionately (i.e., 66*t/T or 68*t/T for swollen or tender joint count).  
VAS for PASDAS assessment:  
Global Disease Activity: The patient’s assessment of PSORIASIS and ARTHRITIS will be 
performed using 100 mm VAS ranging from “Excellent” to “Poor” after the question 
"Considering all the ways PSORIASIS and ARTHRITIS affects you, please indicate with a 
vertical mark ( | ) through the horizontal line how well you are doing over the past week”. 
Physician’s global assessment of fingernail disease severity (VAS) 
The physician’s assessment of nail disease activity will be performed using 100 mm VAS 
ranging from no disease activity to maximal disease activity, after the question “After you have 


Novartis 
For business use only 
Page 23 
SAP 
 
CAIN457P12302 
 
viewed all the fingernails of a subject, consider all aspects of the subject’s fingernails and place 
a vertical line on the scale giving a global assessment of their fingernails”. 
 
 
 


Novartis 
For business use only 
Page 24 
SAP 
 
CAIN457P12302 
2.5.2 
Description of Health-related Quality of Life Endpoints 
SF-36 
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy subjects and patients with acute and 
chronic conditions. It consists of eight subscales that can be scored individually: Physical 
Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- 
Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 
burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients. The eight domains are based on a scale from 0-100 while 
PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. 
FACIT - Fatigue  
The Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue©) is a 13- 
item questionnaire that assesses self-reported fatigue and its impact upon daily activities and 
function. 
Subjects respond to each item on a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = 
somewhat; 3 = quite a bit; 4 = very much) based on their experience of fatigue during the past 
2 weeks. The scale score is computed by summing the item scores, after reversing those items 
that are worded in the negative direction. Numbering the questions from 1 to 13, it is evident 
that questions 7 and 8 are worded in the positive direction (4 indicates a desirable response) and 
all other questions are worded in the negative directions (4 indicates an undesirable response). 
Thus, it is necessary to reverse the responses for all but questions 7 and 8 (i.e. original response 
of 0 gets mapped to 4, 1=3, 2=2, 3=1, and 4=0) for scoring purposes. 
When there are missing item scores, the subscale score was computed by summing the non-
missing item scores, multiplying by 13 (the total number of items in the scale) and dividing by 
the number of non-missing items (i.e. normalizing the results). The latter rule applied only when 
at least half of the items (seven or more) are non-missing.  
FACIT Fatigue subscale scores range from 0 to 52, where higher scores represent less fatigue 
(Cella D et al., 2004). 


Novartis 
For business use only 
Page 25 
SAP 
 
CAIN457P12302 




Novartis 
For business use only 
Page 27 
SAP 
 
CAIN457P12302 
2.7 
Safety analyses 
Summaries will be performed for the entire treatment period. Safety analyses will be performed 
on treatment received or actual treatment as described below: 
The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire study. 
Subjects who switch treatment during the study (e.g. from placebo to active treatment) will be 
counted to both groups using the appropriate start and stop exposure date. 
2.7.1 
Adverse events (AEs) 
Treatment emergent AEs (events that started after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity based on preferred 
term) will be summarized up to 12 weeks (84 days) after the last dose. 
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 AE with the same preferred 
term, the AE with the greatest severity will be presented. If a subject reported more than one 
AE within the same primary system organ class, the subject will be counted only once with the 


Novartis 
For business use only 
Page 28 
SAP 
 
CAIN457P12302 
 
greatest severity at the system organ class level, where applicable. SAEs will also be 
summarized. 
As appropriate, the incidence of AEs will be presented per 100 subject years of exposure. 
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to dose adjustment (including study treatment discontinuation). 
Adverse events reported will be presented in descending frequency according to its incidence 
in i.v. secukinumab group starting from the most common event. Summaries (crude incidences 
only) will also be presented for AEs by severity and for study treatment related AEs. If a 
particular AE ‘severity’ is missing, this variable will be listed as missing and treated as missing 
in summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable.   
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
leading to temporary dose interruption. 
Adverse events will also be reported separately by SMQ according to MedDRA. The MedDRA 
version used for reporting the study will be described in a footnote. 
Non-treatment emergent adverse events will be listed. 
Algorithms for date imputations will be provided in Programming Datasets Specifications. 
For serious adverse events (SAEs) occurred during screening a listing will be prepared for all 
subjects screened including screening failures. 
The safety analyses that will be performed for treatment emergent AEs and on treatment labs 
and vital signs for each analysis period is described in Table 2-4. 
Table 2-4 
Overview of analyses on some safety endpoints 
Analysis 
period 
AEs & 
SAEs 
AEs by 
severity 
Study drug 
related 
AEs 
AEs-SMQ 
Risk 
  
Day 1 – 
Week 16 
crude 
incidence 
crude 
incidence 
crude 
incidence 
crude 
incidence 
crude 
incidence 
  
Entire 
Treatment  
 
crude 
incidence 
exposure 
time 
adjusted 
incidence* 
crude 
incidence 
 
crude 
incidence 
 
exposure 
time 
adjusted 
incidence 
crude 
incidence 
exposure 
time 
adjusted 
incidence 
  
 


Novartis 
For business use only 
Page 29 
SAP 
 
CAIN457P12302 
 
Analysis 
period 
AEs & 
SAEs 
AEs by 
severity 
Study drug 
related 
AEs 
AEs-SMQ 
Risk 
  
*Exposure-adjusted incidence rates will be done for the following : 
at the PSOC for AE and SAE and Level 1 for Risks and SMQ analyses 
at the PT level for common AEs, which is defined as at least 2% of the patients in the i.v. 
secukinumab during the initial treatment period or events that had an incidence rate of at least 
5.0 cases per 100 subject-years in the combined i.v. secukinumab groups during the entire 
treatment period  
2.7.2 
Laboratory data 
The summary of lab data will only include on treatment data, which are defined as those lab 
assessments after the first dose of study treatment and on or before last dose + 84 days. 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived and 
summarized. 
For urinalysis, frequency tables will be presented. 
Descriptive summary statistics for the change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test and treatment group. Change 
from baseline will only be summarized for subjects with both baseline and post baseline values 
and will be calculated as: 
change from baseline = post baseline value – baseline value 
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline,  will be analyzed analogously.  
In addition, shift tables may be provided for 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. If appropriate, the shifts to the most extreme laboratory test value within a treatment 
phase will be presented as well (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 numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-5: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG). 
These summaries will be split into hematology and chemistry.  


Novartis 
For business use only 
Page 30 
SAP 
 
CAIN457P12302 
 
Table 2-5 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.0 
Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
 
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 
Hypertriglyceride
mia 
1.71 - 3.42 
mmol/L 
>3.42 - 
5.7mmol/L 
>5.7 - 11.4 
mmol/L 
>11.4 mmol/L 
*Note: for “creatinine increased” the baseline criteria do not apply 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the entire study analyzed. Of note, baseline 
will be defined as last assessment prior to first dosing in initial treatment phase.  
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 


Novartis 
For business use only 
Page 31 
SAP 
 
CAIN457P12302 
 
• <0.8 x LLN 
• LDL, cholesterol, triglycerides: 
• >=ULN  
• >1.5 x ULN  
• >2.5 x ULN 
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 2-6: 
Table 2-6 
Liver-related events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
TBL 
>1.5xULN, >2xULN, >3xULN, 
ALP 
>2xULN, >3xULN. >5xULN 
ALT or AST & 
TBL 
ALT or AST>3xULN & TBL >2xULN; 
ALT or AST >5xULN & TBL >2xULN; 
ALT or AST >8xULN & TBL >2xULN; 
ALT or AST >10xULN & TBL >2xULN 
ALP & TBL 
ALP >3xULN & TBL >2xULN 
ALP >5xULN & TBL >2xULN 
ALT or AST & 
TBL & ALP 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law) 
Note: elevated ALP may suggest obstruction as a consequence of gall 
bladder or bile duct disease; ALP may also be increased in malignancy. FDA 
therefore terms Hy’s Law cases as indicators of pure hepatocellular injury. 
This does not mean that cases of ALT or AST >3xULN & TBL >2xULN & ALP 
≥2xULN may not result in severe DILI. 
Notes: 
1) In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased 
above ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the 
abnormality criteria 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN. 
Individual subject data listings may be provided for subjects with abnormal laboratory data. 
Data of subjects with newly occurring or worsening liver enzyme abnormalities may be listed 
in an additional listing. 
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.  


Novartis 
For business use only 
Page 32 
SAP 
 
CAIN457P12302 
 
2.7.3 
Vital signs 
The summary of vital signs will only include on treatment data, which are defined as those vital 
sign measurements after the first dose of study treatment and on or before last dose + 84 days. 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as: 
change from baseline = post-baseline value – baseline value 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-7 below. 
Table 2-7 
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 


Novartis 
For business use only 
Page 33 
SAP 
 
CAIN457P12302 
2.11 
Interim analysis 
The 16-weeks has already been performed after all patients completed the assessment for the 
primary and key secondary variables. 
3 
Sample size calculation 
An overall type I error (2-sided) 5% will be used to control type I error. Since one i.v. regimen 
will be tested versus placebo with respect to the primary endpoint (ACR50 response at Week 
16), the type-I-error is 5% two-sided for comparison. The total sample size of 190 subjects per 
each group is deemed appropriate to achieve adequate power for the primary and secondary 
endpoints for this study. 
3.1.1 
Primary endpoint(s) 
Analysis of a phase III study (FUTURE 5) showed a placebo response rate of 8.1%, 
secukinumab 150 mg with SC loading response rate of 35.9%, and secukinumab 300 mg with 
SC loading response rate of 39.6% at week 16 for ACR50. Assuming that the response rate of 
i.v. regimen is between the response rates of secukinumab 150 mg with SC loading and 300 mg 
with SC loading, 190 subjects per group would yield approximately 99% power to detect a 




Novartis 
For business use only 
Page 35 
SAP 
 
CAIN457P12302 
 
mNAPSI 
-2.49 
-9.31 
9.503 
99% 
-9.18 
9.503 
99% 
FACIT 
1.98 
6.18 
9.303 
99% 
6.8 
9.303 
99% 
SF36-
PCS 
1.83 
6.3 
7.304 
99% 
7.62 
7.33 
99% 
PASDAS 
-0.91 
-2.02 
1.359 
99% 
-2.37 
1.361 
99% 
 
 
 
 
 
 
 
 
4 
Appendix 
4.1 
Visit Windows  
4.1.1 
Visit windows 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified in Table 4-2.  
For lab/vital signs, follow-up (F/U) visit is excluded from analysis visit mapping window. Only 
assessments that come as F/U nominal visit will be directly assigned as analysis F/U visit. Other 
assessments that are beyond the last on-treatment visit window or after nominal F/U visit date 
won't be mapped to any analysis visit. F/U visit will not be included in the summary tables by 
visit. 
Of note, subjects are allowed to have gaps in visits.  All data collected will be displayed in 
listings.  
Table 4-1 
Analysis visit windows  
Analysis 
Visit 
Target 
Day 
Group 
1 
Group 
2 
Group 3 
Group 4 
Group 
5 
Group 6 
Group 7 
Group 8 
Group 
9 
Group 
10 
Baseline 
1 
≤1* 
≤1* 
≤1* 
≤1* 
≤1* 
≤1* 
≤1* 
Week 4 
29 
2 – 43 
2 – 43 
2 – 43 
2 – 43 
 2 – 43 
2 – 43 
 
Week 8 
57 
44 – 71 
44 – 71 
44 – 71 
44 – 
71 
 44 – 71 
44 – 71 
2 – 71 
Week 12 
85 
72 – 99 
72 – 99 
72 – 99 
72 – 
99 
72 – 99 
72 – 99 
 
Week 16 
113 
100 – 
127 
100 – 
141 
100 – 
141 
100 – 
141 
 100 – 
127 
100 – 
141 
72– 
141 
Week 20 
141 
128 – 
155 
 
 
 
128 – 
155 
 
 
Week 24 
169 
156 – 
183 
142 – 
183 
142 – 
183 
142 – 
197 
156 – 
183 
142 – 
197 
142 – 
291 
Week 25 
176 
 
  
 
 
  
 
  




Novartis 
For business use only 
Page 37 
SAP 
 
CAIN457P12302 
 
conventions will be used to determine the appropriate measurement to be summarized in the 
event of multiple measurements within a visit window. 
Table 4-2 
Rules for flagging variables 
Timing of 
measurement 
Type of data 
Rule 
Baseline 
All data 
The last non-missing measurement made prior to or on 
the date of administration of the first dose of study 
treatment (the reference start date / Day 1). If a patient 
did not receive any dose of study treatment then the 
randomization date will be used. Only date part is 
considered if just one assessment on Day 1. 
If there are multiple assessments on Day 1, following 
rules will apply: 
If assessment time exists,  
select the last available measurement prior to 
reference start date/time considering time; 
if no measurement prior to reference start date/time 
considering time, select the earliest measurement post 
reference start date/time considering time . 
If assessment time does not exist, select the available 
measurement from the lowest CRF visit number. 
For X-ray, a baseline value is the last measurement 
prior to dosing if available. Otherwise, take the first 
value within 30 days post dosing. 
For MRI, a baseline value is the last measurement 
prior to dosing if available. Otherwise, take the first 
value within 7 days post dosing.   
Post-baseline 
efficacy 
All data 
For visits without switch of treatment in the window, the 
measurement closest to the target will be used. In the 
event two measurements are taken equally apart (e.g. 
1 before target date and 1 after) the first one will be 
used.  
Cases where the same parameter is recorded more 
than once on the same date will be handled as follows: 
If time of completion exists the earliest measurement 
will be used; 
If time does not exist the measurement from the lowest 
CRF visit number will be used. 


Novartis 
For business use only 
Page 38 
SAP 
 
CAIN457P12302 
 
Timing of 
measurement 
Type of data 
Rule 
Post-baseline 
safety 
Summary visit 
information 
(e.g. lab, etc.) 
For visits without switch of treatment in the window, the 
measurement closest to the target will be used. In the 
event two measurements are taken equally apart (e.g. 
1 before target date and 1 after) the first one will be 
used.  
Cases where the same parameter is recorded more 
than once on the same date will be handled as follows: 
If time of completion exists the earliest measurement 
will be used; 
If time does not exist the measurement from the lowest 
CRF visit number will be used. 
Post-baseline 
safety  
Notable 
abnormalities 
(e.g. lab) 
The most extreme measurement in the window will be 
used.  Note this means a patient can have a notably 
high and notably low measurement within a window.  
 
4.2 
Detailed on implementation of statistical methodology and 
assumptions 
4.2.1 
Analysis of continuous data 
4.2.1.1 
Summary statistics for continuous data 
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group.  
4.2.1.2 
Mixed-effects repeated measures model 
Endpoints with continuous data type expected to be normally distributed (e.g, 
) will be 
analyzed using a mixed-effects repeated measures model (MMRM) with stratification factor  
and analysis visit as factors; and weight, baseline value, baseline by visit interaction as 
covariates. An unstructured correlation matrix will be used thus allowing adjustment for 
correlations between time points within subjects.  
SAS code for mixed model: 
proc mixed data=aaa; 
class USUBJID AVISITN STRATA; 
model 
CHG= 
STRATA 
AVISITN 
WEIGHT 
BASE 
BASE*AVISITN 
           / s ddfm=kr; 
lsmeans AVISITN / diff cl; 


Novartis 
For business use only 
Page 39 
SAP 
 
CAIN457P12302 
 
repeated AVISITN / type=un subject=USUBJID; 
Run; 
In case the MMRM model does not converge the following sequential steps will be used: 
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2. 
2. change type=un to type=cs. If still no convergence, perform step 3. 
3. remove covariates in the following order until convergence: WEIGHT, BASE*AVISITN,  
STRATA. 
4.2.2 
Analysis of binary (and categorical) data 
4.2.2.1 
Analyses of Frequencies  
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. For n subjects, each at risk to experience a certain 
event with probability π, the crude incidence is estimated as p=x/n, where x is the number of 
subjects with the event. 
If applicable, 95% confidence intervals for the relative frequences will be derived as well based 
on the score method including continuity correction Newcombe 1998: 
With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), 
n  as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n ) it is 
p
q
−
=1
 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
In addition, if L > p then L = p and if U < p then U = p. 
For binary response variables (e.g. for ACR20/50/70, HAQ-DI responder, PASI 75, IGA 
response) the placebo-adjusted response rates including 95% confidence interval will be derived.  
SAS code for risk difference: 
Proc freq data=acr order=formatted;  
Tables response*trt/ riskdiff; 
Run; 


Novartis 
For business use only 
Page 40 
SAP 
 
CAIN457P12302 
 
(Note the response value should be sorted with ‘1’ ahead of ‘0’.) 
Fisher’s exact test will be applied to rare events (e.g., MCR), pairwise treatment group 
comparisons to placebo or active controls. 
SAS code for Fisher’s exact test: 
Proc freq data=mcr order=formmatted; 
Tables response*trt/Fisher; 
Run; 
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses. 
Figures will be provided for primary and secondary variables, with means displayed across time 
for all the treatment groups. 
4.2.3 
Multiple Imputation 
A multiple imputation will be performed based on MAR for AIN457 6mg/kg - 3mg/kg for 
baseline weight, baseline and post-baseline of each parameter for visits up to the primary time 
point (e.g Week 52) using Markov Chain Monte Carlo (MCMC) method with EM algorithm. 
Impute the missing values 100 times (NIMPUTE) with a seed=457<studycode> as shown 
below: 
proc mi data= out=imp minmaxiter=10000000 nimpute=100 seed=4572302; 
            by trt; 
            var weight_base strata var1_base var1_week1-var1_week52; 
            mcmc chain=multiple initial=em;   
run;  
If needed repeat for each component necessary to calculate the final score, e.g. as follows:  
proc mi data=imp out=imp2 minmaxiter=10000000 nimpute=100 seed=4572302; 
            by trt _imputation_; 
            var weight_base strata var2_base var2_week1-var2_week52; 
            mcmc chain=multiple initial=em;   
run; 
Post-processing of out of range imputed values will be processed with the min and max values 
of each variable. 
The score and ACR response can now be calculated based on the complete data. The response 
rate will be calculated for each imputation and then combined using Rubin’s rules. 
In order to calculate the response rate for each imputation, PROC FREQ will be used as follows. 


Novartis 
For business use only 
Page 41 
SAP 
 
CAIN457P12302 
 
Calculate binomial proportion and standard error for each imputation. 
proc freq data=<ACR20>; 
  by treat visit _imputation_ ; 
  tables <response> / binomial (level=2 cl=wilson correct) ; 
  ods output BinomialProp=imp_bpr; 
run; 
 
Transpose the dataset for subsequent use with PROC MIANALYZE. 
proc transpose data=imp_bpr out=imp_trs(drop=_name_) ; 
  by treat visit _imputation_ ; 
  var nvalue1; id name1; idlabel label1; 
run; 
Apply LOGIT transformation: y=log(p/(1-p)) and std. err. transformation: <new se> = se/(p*(1-
p))  
data logit; 
  set imp_trs(rename=(_bin_=p e_bin=se)); 
  by treat visit _imputation_ ; 
  lmean=log(p/(1-p)); 
  lse=se/(p*(1-p)); 
run; 
The transformed binomial proportion estimates and standard errors are combined by applying 
Rubin’s rules for multiple imputed data sets. 
proc mianalyze data=logit; 
  by treat visit ; 
  modeleffects lmean; 
  stderr lse; 
  ods output ParameterEstimates=logitres; 
run; 
The combined data should be transformed back using the following formula: p=1/(1+exp(-y)) 
data miexpres; 
  set logitres; 
  by treat visit ; 
  resti = 1/(1+exp(-estimate)); 


Novartis 
For business use only 
Page 42 
SAP 
 
CAIN457P12302 
 
  rlow = 1/(1+exp(-lclmean)); 
  rupp = 1/(1+exp(-uclmean)); 
run; 
Of note, sometimes all responses may be imputed to 0 or 1 at a given combination of response 
variable, treatment group and visit. Such cases should be considered separately. The combined 
final response rate would be the same as the original response but the 95% CI will be undefined. 
4.2.4 
Crude incidence and relativ risk estimates  
4.2.4.1 
Odds ratio and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g. placebo or comparator) with n0 subjects at risk,  of whom x1 and x0 experience a certain 
event with probability π1 and π0 respectively, the odds ratio is estimated as 
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p
−
−
  with p1= x1/n1 and p0=x0/n0.  A conditional exact 100*(1-α)% confidence interval 
will be obtained by using the SAS procedure PROC FREQ with statement EXACT OR. 
4.2.5 
Exposure adjusted incidence rate and related risk estimates 
4.2.5.1 
Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 
∑
=
=
n
j
jt
T
1
 and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood, 1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai, 
1993; Ulm, 1990): 
Lower confidence limit   
T
c
L
D
2,2
/
5.0
α
=
 for D>0, 0 otherwise, 
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0
+
−
=
α
 
where
k
c ,
α
 is the αth quantile of the Chi-square distribution with k degrees of freedom. 
The example below shows how this should be handled for cases where subjects switch treatment.  
In particular for summarizing ‘Any secukinumab’ as a group, one should take into consideration 
the sequence of treatments while calculating exposure time for subjects.   


Novartis 
For business use only 
Page 43 
SAP 
 
CAIN457P12302 
 
Table 4-3 
Examples for calculating exposure time for incidence rates (IR) 
1st 
treatment 
1st   
exposure 
2nd 
treatment 
2nd 
exposure 
Event days (in 
terms of study 
day) 
Exposure for IR 
Placebo 
100 days 
150 mg  
200 days 
50 (1st trt) 
110 (10 days 
into 2nd trt) 
Placebo:  50 days 
(event) 
150 mg:  10 days 
(event) 
Any AIN:  10 days 
(event) 
5 
Reference 
[SOP-7012382] Analyzing and Reporting Data (PSP 012) 
[SOP-0015116] Developing and Completing the Clinical Study Report 
[SOP-0018880] Defining, Processing, and Reporting Protocol Deviations  
AIN457A efficacy MAP M3, available in Cabinets//CREDI Projects/A/AIN457A 
/Administrative files/CIS (Clinical Information Sciences)/Biostatistics 
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. 
Coates LC, Fransen J, Helliwell PS (2010) Defining minimal disease activity in psoriatic 
arthritis: a proposed objective target for treatment. Ann Rheum Dis.69(1):48-53. 
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use. (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr 
document. London, UK. 
CSR template available in the CREDI template area: Cabinets/CREDI Templates /CTD 
Fredriksson T, Pettersson U (1978) Severe psoriasis—oral therapy with a new retinoid. 
Dermatologica; 157:238–44. 
Garwood, F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 


Novartis 
For business use only 
Page 44 
SAP 
 
CAIN457P12302 
 
Gottlieb A, Griffiths CEM, Ho VC, et al (2005) Efficacy and tolerability of oral pimecrolimus 
in the treatment of moderate to severe chronic plaque type psoriasis: a double-blind, 
multicentre, randomized dose-finding trial. Br J Dermatol; 152:1219-27. 
Helliwell PS, Fitzgerald O, Fransen J et al (2012) The development of candidate composite 
disease activity and responder indices for psoriatic arthritis (GRACE project). Ann Rheum 
Dis 2012 ;0:1–6. doi:10.1136/annrheumdis-2012-201341  
Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from Restricted 
Maximum Likelihood. Biometrics; 53: 983-997.  
Koch GG, Tangen CM, Jung JW, et al. (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statistics in Medicine; 17:1863-92. 
Lachin JM (2000) The assessment of relative risks . New York: Wiley 
Leonardi CL, Powers JL, Matheson RT, et al (2003) Etanercept as monotherapy in patients 
with psoriasis. N Engl J Med 349:2014-22. 
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 
Probability and Statistics, Chapter 10. 
Lubeck, DP. (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis. Pharmacoeconomics 22(1): 27-38. 
McInnes, I.B. et al. (2013) Efficacy and safety of ustekinumab in patients with active psoriatic 
arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled 
PSUMMIT 1 trial.Lancet . ISSN 1474-547X (doi:10.1016/S0140-6736(13)60594-2) 
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. 
Ostergaard, Mikkel et al (2009). The OMERACT Psoriatic Arthritis Magnetic Resonance 
Imaging Scoring System (PsAMRIS): Definitions of Key Pathologies, Suggested MRI 
Sequences, and Preliminary Scoring System for PsA Hands. The Journal of Rheumatology 
36:8 1816-1824. 
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 


Novartis 
For business use only 
Page 45 
SAP 
 
CAIN457P12302 
 
Compound Case Retrieval Strategy available in Cabinets/CREDI 
Projects/A/AIN457A/Integrated Medical Safety 
Ritchlin C, Rahman P, Kavanaugh A, et al. (2013). Efficacy and safety of the anti-IL-12/23 
p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite 
conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 
1-year results of the phase 3, multicentre, double-blind, placebo controlled, randomised 
PSUMMIT 2 trial. Ann Rheum Dis. 2014 Jan 30. doi: 10.1136/annrheumdis-2013-204655. 
[Epub ahead of print] 
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. 
Schaefer, J.L. (1997). Analysis of Incomplete Multivariate Data, Chapman&Hall. 
Tyring S, Gottlieb A, Papp KA, et al (2006) Etanercept and clinical outcomes, fatigue, and 
depression in psoriasis: double-blind placebo-controlled randomised phase III trial. Lancet 
367:29-35. 
Ulm K (1990). A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375 
Van der Heijde DM (1999). How to Read Radiographs According to Sharp/van der Heijde 
Method. J Rheumatol. 26(3):743-745. 
Van der Heijde D, Sharp J, Wassenberg S, Gladman DD (2005) Psoriatic arthritis imaging: a 
review of scoring methods. Ann Rheum Dis; 64: Suppl 2:ii 61-64. 
Weisman S, Pollack CR, Gottschalk RW (2003) Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat; 14: 158-165. 
Zink RC and Koch GG (2012). NParCov3: A SAS/IML Macro for Nonparametric 
Randomization-Based Analysis of Covariance. Journal of Statistical Software; 50(3): 1-17. 
Predictive margins and average marginal effects:http://support.sas.com/kb/63/038.html