A Randomized, Double-blind, Parallel-group, Multicenter Study of Secukinumab to Compare 300 mg and 150 mg at Week 52 in Patients With Ankylosing Spondylitis Who Are Randomized to Dose Escalation After Not Achieving Inactive Disease During an Initial 16 Weeks of Open-label Treatment With Secukinumab 150 mg (ASLeap)
Phase: PHASE4
Conditions: Ankylosing Spondylitis
Sponsor: Novartis Pharmaceuticals

US Clinical Development and Medical Affairs 
AIN457/Secukinumab 
Clinical Trial Protocol CAIN457FUS06 / NCT03350815
A randomized, double-blind, parallel-group, multicenter 
study of secukinumab to compare 300 mg and 150 mg at 
Week 52 in patients with Ankylosing Spondylitis who are 
randomized to dose escalation after not achieving inactive 
disease during an initial 16 weeks of open-label treatment 
with secukinumab 150 mg (ASLeap)  
Document type: 
Amended Protocol Version 
EUDRACT number: 
Not Applicable 
Version number: 
v04 (Track Changes) 
Clinical trial phase: 
IV 
Release date: 
20-Aug-2020
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.4 (May 2017) 

Novartis 
Confidential 
Page 2 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of Terms ............................................................................................................... 8 
Protocol Summary ............................................................................................................... 9 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Rationale for protocol amendment ........................ Error! Bookmark not defined. 
1.3 
Changes to protocol ............................................... Error! Bookmark not defined. 
1.4 
Purpose .................................................................................................................. 20 
2 
Study objective and endpoints ........................................................................................... 20 
2.1 
Objectives and related endpoints ........................................................................... 20 
3 
Investigational Plan ........................................................................................................... 24 
3.1 
Study design .......................................................................................................... 24 
3.2 
Rationale for study design ..................................................................................... 25 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 26 
3.4 
Rationale for choice of comparator ....................................................................... 27 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 27 
3.6 
Risks and benefits .................................................................................................. 27 
4 
Population .......................................................................................................................... 28 
4.1 
Inclusion Criteria ................................................................................................... 28 
4.2 
Exclusion Criteria .................................................................................................. 29 
5 
Treatment ........................................................................................................................... 32 
5.1 
Study treatment ...................................................................................................... 32 
5.1.1 
Investigational and control drugs .......................................................... 32 
5.1.2 
Additional treatment.............................................................................. 32 
5.2 
Treatment arms ...................................................................................................... 32 
5.3 
Treatment assignment and randomization ............................................................. 34 
5.4 
Treatment Blinding ................................................................................................ 34 
5.5 
Treating the patient ................................................................................................ 35 
5.5.1 
Patient numbering ................................................................................. 35 
5.5.2 
Dispensing the study drug ..................................................................... 35 
5.5.3 
Handling of study and additional treatment .......................................... 35 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 36 

Novartis 
Confidential 
Page 3 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 37 
5.5.6 
Rescue medication ................................................................................ 38 
5.5.7 
Concomitant medication ....................................................................... 38 
 
 39 
5.5.9 
Emergency breaking of assigned treatment code .................................. 40 
5.6 
Study completion and discontinuation .................................................................. 41 
5.6.1 
Study completion and post-study treatment .......................................... 41 
5.6.2 
Discontinuation of study treatment ....................................................... 41 
5.6.3 
Withdrawal of informed consent ........................................................... 42 
5.6.4 
Loss to follow-up .................................................................................. 42 
5.6.5 
Early study termination by the sponsor ................................................. 43 
6 
Visit schedule and assessments ......................................................................................... 43 
6.1 
Rescreening............................................................................................................ 50 
6.2 
Information to be collected on screening failures .................................................. 50 
6.3 
Patient demographics/other baseline characteristics ............................................. 50 
6.4 
Treatment exposure and compliance ..................................................................... 51 
6.5 
Efficacy .................................................................................................................. 51 
6.5.1 
ASDAS and ASDAS response categories ............................................. 51 
6.5.2 
Assessment of Spondylo-Arthritis International Society criteria 
(ASAS) .................................................................................................. 52 
 
 54 
6.5.4 
ASAS Health Index (ASAS-HI) ........................................................... 54 
 
 54 
6.5.6 
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue) ................................................................................... 54 
6.5.7 
Appropriateness of efficacy assessments .............................................. 54 
6.6 
Safety ..................................................................................................................... 54 
6.6.1 
Determination of tuberculosis status ..................................................... 55 
6.6.2 
Chest x-ray ............................................................................................ 56 
6.6.3 
Electrocardiogram (ECG) ..................................................................... 56 
6.6.4 
Physical examination ............................................................................ 57 
6.6.5 
Vital signs.............................................................................................. 57 
6.6.6 
Height and weight ................................................................................. 57 
6.6.7 
Laboratory evaluations .......................................................................... 57 
6.6.8 
Pregnancy and assessments of fertility ................................................. 58 
6.6.9 
Documented radiologic evidence fulfilling the NY criteria for AS ...... 58 
6.6.10 
Tolerability of secukinumab ................................................................. 58 

Novartis 
Confidential 
Page 4 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
6.6.11 
Local tolerability ................................................................................... 58 
6.6.12 
Appropriateness of safety measures ...................................................... 59 
 
 59 
 
 59 
 
 60 
 
 60 
7 
Safety Monitoring .............................................................................................................. 61 
7.1 
Adverse events ....................................................................................................... 61 
7.2 
Serious Adverse Events ......................................................................................... 62 
7.2.1 
Definition of SAE ................................................................................. 62 
7.3 
Liver safety monitoring ......................................................................................... 64 
7.4 
Renal safety monitoring ......................................................................................... 64 
7.5 
Reporting of study treatment errors including misuse/abuse ................................ 64 
7.6 
Pregnancy Reporting ............................................................................................. 65 
8 
Data review and database management ............................................................................. 65 
8.1 
Site monitoring ...................................................................................................... 65 
8.2 
Data collection ....................................................................................................... 66 
8.3 
Database management and quality control ............................................................ 66 
8.4 
Data monitoring committee ................................................................................... 67 
8.5 
Adjudication committee......................................................................................... 67 
9 
Data analysis ...................................................................................................................... 67 
9.1 
Analysis sets .......................................................................................................... 67 
9.2 
Patient demographics and other baseline characteristics ....................................... 68 
9.3 
Treatments ............................................................................................................. 68 
9.4 
Analysis of the primary variable(s) ....................................................................... 68 
9.4.1 
Primary variable(s) ................................................................................ 68 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 68 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 68 
9.4.4 
Sensitivity analyses ............................................................................... 69 
9.5 
Analysis of secondary variables ............................................................................ 69 
9.5.1 
Efficacy variables .................................................................................. 69 
9.5.2 
Safety variables ..................................................................................... 69 
 
 70 
9.7 
Interim analyses ..................................................................................................... 71 
9.8 
Sample size calculation.......................................................................................... 71 
10 Ethical considerations ........................................................................................................ 71 

Novartis 
Confidential 
Page 5 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
10.1 
Regulatory and ethical compliance ........................................................................ 71 
10.2 
Informed consent process ...................................................................................... 72 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 72 
10.4 
Publication of study protocol and results............................................................... 72 
10.5 
Quality control and quality assurance.................................................................... 73 
11 Protocol adherence ............................................................................................................ 73 
11.1 
Protocol amendments............................................................................................. 73 
12 References ......................................................................................................................... 74 
13 Appendices ........................................................................................................................ 77 
 
 77 
 
 78 
13.3 
Appendix 3: Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................................. 79 
 
 79 
13.3.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 79 
13.3.3 
Appendix 4: Guidelines for administering the PRO questionnaires ..... 80 
 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 20 
Table 5-1 
Prohibited medication ........................................................................... 39 
Table 6-1 
Assessment schedule ............................................................................. 45 
Table 7-1 
Guidance for capturing the study treatment errors including misuse ... 65 
 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 25 
 

Novartis 
Confidential 
Page 6 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
List of abbreviations 
 
AE 
Adverse event 
ALT/SGPT 
Alanine aminotransferase/serum glutamic pyruvic transaminase 
AS 
Ankylosing Spondylitis 
ASAS 
Ankylosing SpondyloArthritis International Society 
ASAS-HI 
ASAS Health Index 
ASDAS 
Ankylosing Spondylitis Disease Activity Score  
ASQoL 
Ankylosing Spondylitis Quality of Life 
AST/SGOT 
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase  
BASDAI 
Bath Ankylosing Spondylitis Disease Activity index  
 
 
BMI 
Body mass index 
BSL 
Baseline 
COPD 
Chronic obstructive pulmonary disorder  
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 
DS&E 
Drug Safety & Epidemiology 
DSM 
Drug supply management 
eCRF 
Electronic Case Report/Record Form 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA/EMEA 
European Medicines (Evaluation) Agency 
FACIT-Fatigue© 
Functional Assessment of Chronic Illness Therapy – Fatigue 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
 
 
IB 
Investigator’s brochure 
IBD 
Inflammatory Bowel Disease 
ICF 
Informed consent form  
IEC 
Independent Ethics Committee 
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IFU 
Instructions for use 
IL 
Interleukin 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 

Novartis 
Confidential 
Page 7 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
IUD 
Intra Uterine Device 
IUS 
Intra Uterine System 
i.v. 
intravenous(ly) 
LFT 
Liver function test 
LLN 
Lower limit of normal  
 
 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging/image  
mmHg 
Millimeter mercury 
MTX 
Methotrexate 
NRS 
Numeric rating scale 
NSAID 
Non-steroidal anti-inflammatory drug 
PBO 
Placebo 
PFS 
Prefilled syringe 
PPD 
Purified protein derivative 
PRN 
Pro re nata (as required) 
PRO 
Patient Reported Outcome 
PsA 
Psoriatic arthritis  
QoL 
Quality of Life 
RA 
Rheumatoid arthritis  
RBC 
Red blood cell 
SAE 
Serious adverse event 
s.c. 
Subcutaneous(ly) 
SCR 
Screening 
SD 
Standard deviation  
SE 
Sleep efficiency  
SI 
Sacroiliac  
SpA 
Spondyloarthritis 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
SV1 
Screening Visit 1 
SV2 
Screening Visit 2 
ULN 
Upper limit of normal 
VAS 
Visual analog scale 
 
 
WBC 
White blood cell 
WHO 
World Health Organization 

Novartis 
Confidential 
Page 8 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Glossary of Terms 
 
Assessment 
A procedure used to generate data required by the study 
Cohort  
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time 
Control drug 
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the drug being tested in the 
trial 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational drug 
The drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug” or “investigational 
medicinal product.” 
Investigational treatment 
All investigational drug(s) whose properties are being tested in 
the study as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination.  
Investigational treatment generally does not include protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies that dispense medication using an IRT 
system 
Protocol 
A written account of all the procedures to be followed in a trial, 
which describes all the administrative, documentation, analytical 
and clinical processes used in the trial. 
Premature subject withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless 
the patient will be followed for progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), active drug run-ins or background 
therapy  
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 

Novartis 
Confidential 
Page 9 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Amendment 04  
Amendment rationale  
This protocol has been modified to add telemedicine/telephone study visits with direct to patient 
shipment of study drug as options available to participants unable to travel to the clinic for a 
study visit as the result of the COVID19 pandemic. Given the study design, which already 
allows flexible (home nursing) visits, the addition of telemedicine/telephone study visits with 
direct to patient shipment of study drug is believed to pose minimal risk to patient safety and 
data integrity.   
The definition of withdrawal of consent was also updated.    
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.  
Summary of previous amendments  
Amendment 3 (15-Oct-2018) 
The protocol has been modified to require a patient’s documented radiologic evidence to be 
read by a central reader at Screening Visit 2, correct the total minimum number of weeks during 
the screening period in Figure 3-1, clarify the women of childbearing potential exclusion, 
amend the wash-out period length for TNFα inhibitors in Table 5-1 and exclusion 10, clarify 
that a chest x-ray is required within 3 months prior to screening in section 6.6.2, to bullet the 
list of parameters used for the ASDAS calculation in section 6.5.1, add a section reference to 
Table 6-1 Assessment schedule and make grammatical corrections. 
Amendment 2 (07-Feb-2018) 
The protocol has been modified to correct the definition of an Inadequate Responder, revise the 
screening period assessments related to the delivery of the wearable sensor, reconcile visit 
assessment inconsistencies, remove duplicate text and revise concomitant medication 
requirements.  Additionally, copy/paste errors have been removed and protocol clarifications 
have been made at certain points. 
Amendment 1 (14-Dec-2017) 
The protocol has been modified to change from the use of visual analog scales (VAS) to numeric 
rating scales (NRS) for the following patient reported outcomes measures: Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI), 
 

Novartis 
Confidential 
Page 10 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 Additionally, reconciliation of minor inconsistences and protocol 
clarifications have been made at certain points. 
 

Novartis 
Confidential 
Page 11 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Protocol Summary 
 
Protocol number 
CAIN457FUS06 
Full Title 
A randomized, double-blind, parallel-group, multicenter study of 
secukinumab to compare 300 mg and 150 mg at Week 52 in patients with 
Ankylosing Spondylitis who are randomized to dose escalation after not 
achieving inactive disease during an initial 16 weeks of open-label 
treatment with secukinumab 150 mg (ASLeap)   
Brief title 
 
Study estimating the clinical difference between 300 mg and 150 mg of 
secukinumab following dose escalation to 300 mg in patients with 
ankylosing spondylitis 
Sponsor and Clinical 
Phase 
Novartis  
Phase IV 
Investigation type 
Interventional 
Study type 
Randomized, double-blind, parallel-group, multicenter  
Purpose and rationale 
The purpose of this study is to estimate the difference in clinical response 
between 300 mg and 150 mg of secukinumab at Week 52, which follows 
randomization to dose escalation at Week 16 for patients with Ankylosing 
Spondylitis who inadequately respond to open-label secukinumab 150 mg. 
This study will also investigate the association between treatment and 
sleep disturbances, as well as daytime activity patterns. 
In January 2020, the FDA approved 300 mg as a dosage to be considered 
if a patient continues to have active ankylosing spondylitis. There 
continues to be a need to understand the impact of 300 mg in the treatment 
of AS in response to not achieving a pre-established target clinical 
response on 150 mg, such as disease remission, to evaluate the impact of 
increased dose on subsequent clinical outcomes, for which this study aims 
to assess. 
Primary Objective(s)  
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg treatment groups at Week 52 based on the 
proportion of subjects achieving ASDAS inactive disease (< 1.3) status 
who did not meet ASDAS inactive disease criteria at Week 12 and Week 
16. 
Secondary Objectives 
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the proportion of subjects achieving a ASDAS clinically important 
improvement from their Week 16 ASDAS score (reduction in 
ASDAS  ≥ 1.1 from Week 16) 
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the change from Week 16 in the total Bath Ankylosing Spondylitis 
Disease Activity Index (BASDAI) 
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the proportion of subjects achieving BASDAI50 response  

Novartis 
Confidential 
Page 12 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the proportion of subjects achieving an Assessment of 
Spondyloarthritis International Society criteria 20 response 
(ASAS20)  
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the proportion of subjects achieving ASAS40 response 
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on the proportion of subjects achieving ASAS partial remission (a 
value not above 2 units in each of the four main domains on a scale 
of 10)   
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on change from Week 16 in the total score of ASAS Health Index 
(ASAS-HI)   
• 
To estimate the difference between secukinumab 300 mg and 
secukinumab 150 mg blinded treatment groups at Week 52 based 
on change from Week 16 in the total score of FACIT-Fatigue  
• 
The overall safety and tolerability of secukinumab 
Study design 
This study design includes an initial 16 week open-label period (Treatment 
Period 1) followed by a randomized, double-blind, parallel-group period 
(Treatment Period 2).   
During the initial 16 weeks of the trial, all patients will receive open-label 
150 mg secukinumab.   
At Week 16, based on whether they have met the definition of ASDAS 
inactive disease, patients will be placed into one of the following three 
groups for the remaining 36 weeks of the trial.  
• 
Responders: Patients that achieve ASDAS inactive disease (total 
score < 1.3) at both Week 12 and Week 16 and who do achieve a 
decrease (improvement) from baseline in total ASDAS score at 
both Week 12 and Week 16.  Patients will enter Treatment Period 
2 and continue receiving secukinumab 150 mg through Week 48. 
• 
Inadequate Responders: Patients who have active disease, 
defined as an ASDAS total score of ≥ 1.3 at either Week 12 or 
Week 16, and do achieve a decrease (improvement) from baseline 
in total ASDAS score at both Week 12 and Week 16.  Patients will 
enter Treatment Period 2 and be randomized (1:1, double-blinded) 
to secukinumab 300 mg or secukinumab 150 mg through Week 
48. 
• 
Non-responders: Patients who exhibit no change or an increase 
(worsening) from baseline in total ASDAS score at either Week 12 
or Week 16. Patients will terminate the study at Week 16. 
Population 
The study population will consist of male and female patients, ≥ 18 years 
of age with a clinical diagnosis of moderate to severe AS fulfilling the 
Modified New York criteria for AS and with moderate to severe disease 

Novartis 
Confidential 
Page 13 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
despite previous or current NSAIDs / non-biologic DMARDs and/or anti-
TNFα therapy. 
Patients must have a history of active AS, as measured by the following 
three assessments: 
• 
Total BASDAI of ≥ 4 on a numeric rating scale (NRS) of 0-10 at 
baseline 
• 
Spinal pain as measured by BASDAI question #2 of ≥ 4 on a NRS 
of 0-10 at baseline 
• 
Total back pain of ≥ 4 on a NRS of 0-10 at baseline 
The study aims to enroll approximately 270 patients at approximately 82 
centers in the United States.  Since a 25% screen failure rate is expected, 
approximately 360 patients will be screened. 
Key Inclusion criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of  the 
following criteria: 
1. 
Patient must be able to understand and communicate with the 
investigator and comply with the requirements of the study and must 
give a written, signed and dated informed consent before any study 
assessment is performed 
2. 
Male or non-pregnant, non-lactating female patients at least 18 years 
of age 
3. 
Diagnosis of moderate to severe AS with prior documented radiologic 
evidence (x-ray or radiologist’s report) fulfilling the Modified New York 
criteria for AS 
 
4. 
Active AS assessed by total BASDAI of ≥ 4 (NRS of 0-10) at baseline 
5. 
Spinal pain as measured by BASDAI question #2 of ≥ 4 (NRS of 0-
10) at baseline 
6. 
Total back pain of ≥ 4 (NRS of 0-10) at baseline 
7. 
Patients should have been on NSAIDs at the maximum tolerated 
dose for at least 4 weeks prior to their Baseline Visit, with an 
inadequate response or for less than 4 weeks if withdrawn for 
intolerance, toxicity or contraindications 
8. 
Patients who are regularly taking NSAIDs (including COX-1 or COX-
2 inhibitors) as part of their AS therapy are required to be on a stable 
dose for at least 2 weeks before their Baseline Visit 
9. 
Patients who have been on a TNFα inhibitor (not more than one) must 
have experienced an inadequate response to previous or current 
treatment given at an approved dose for at least 3 months prior to 
baseline or had been intolerant upon administration of that anti-TNFα 
agent 
Key Exclusion criteria 
Patients/subjects fulfilling any of the following criteria during the Screening 
Period or at the Baseline Visit are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure 
that the study population will be representative of all eligible 
patients/subjects. 
1. Patients with total ankylosis of the spine 

Novartis 
Confidential 
Page 14 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
2. Use of other investigational drugs within 5 half-lives of enrollment, or 
within 4 weeks before the Baseline Visit, whichever is longer.  
3. History of hypersensitivity to any of the study drugs or its excipients or 
to drugs of similar chemical classes. 
4. Chest x-ray, CT scan, or chest magnetic resonance imaging (MRI) with 
evidence of ongoing infectious or malignant process, obtained within 3 
months prior to screening and evaluated by a qualified physician.  
5. Previous exposure to secukinumab or any other biologic drug directly 
targeting IL-17, IL-12/23, or the IL-17 receptor, or any other biologic 
immunomodulating agent, except those targeting TNFα 
6. Patients who have taken more than one anti-TNFα agent 
7. Any intramuscular or intravenous corticosteroid injection within 2 
weeks before baseline  
8. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 
weeks before baseline 
9. Active ongoing inflammatory diseases other than AS that might 
confound the evaluation of the benefit of secukinumab therapy, 
including inflammatory bowel disease or uveitis 
10. 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) 
Study treatment 
All patients will receive active secukinumab.  During the first 16 weeks of 
the trial, all patients will receive 150 mg secukinumab.  During the 
remaining 36 weeks of the trial, patients will receive either 150 mg or 300 
mg secukinumab.  
Efficacy assessments 
• 
Ankylosing Spondylitis Disease Activity Score (ASDAS) and ASDAS 
response categories  
• 
Assessment of Spondyloarthritis International Society criteria (ASAS) 
• 
  
• 
  
• 
 
• 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
• 
 
• 
ASAS-Health Index (ASAS-HI) 
 
 
 
• 
FACIT- Fatigue 
Key safety 
assessments 
• 
AEs and SAEs including injection site reactions 
• 
ECGs 
• 
Physical examination 

Novartis 
Confidential 
Page 15 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
• 
Vital signs 
• 
Laboratory assessments  
• 
Assessment 
of 
anti-secukinumab 
antibody 
development 
(immunogenicity) 
Other assessments 
• 
 
 
• 
 
 
 
 
Data analysis 
The analysis will be conducted on all patient data at the time the trial ends.  
Efficacy, safety, and other data from Treatment Period 1, randomized 
double-blind Treatment Period 2 for inadequate responders, and blinded 
Treatment Period 2 for responders will be summarized.  For continuous 
variables, summary statistics (mean, standard deviation, median, 25th and 
75th percentiles, interquartile range, minimum, and maximum) at each time 
point and for change from baseline to Week 16, and change from Week 16 
to each time point by treatment group will be reported.  For discrete 
variables, frequency counts and percentages at each time point will be 
reported by treatment group. 
The following analysis sets will be used for the statistical reporting and 
analyses: 
Enrolled Set:  The Enrolled Set consists of all enrolled patients for the initial 
16-week, Treatment Period 1. 
Responder Set: The Responder Set consists of all patients who are labeled 
as responders at the end of Treatment Period 1, and enter Treatment 
Period 2 receiving blinded secukinumab 150 mg every 4 weeks through 
Week 48. 
Randomized Set: The Randomized Set consists of all randomized patients.  
Safety Set: The Safety Set includes all patients who received at least one 
dose of study treatment during Treatment Period 2.  Patients will be 
analyzed according to the study treatment received. 
Full Analysis Set:  The Full Analysis Set comprises all patients to whom 
study treatment has been assigned by randomization.  Patients 
inappropriately randomized (e.g., IRT was called in error for randomization 
of a screen failed patient) will be excluded from this analysis set.  According 
to the intent-to-treat principle, patients will be analyzed according to the 
treatment they have been assigned to during the randomization procedure. 
The primary efficacy variable is the ASDAS inactive disease response 
(yes, no).  The primary analysis time point is at Week 52. 
The primary efficacy variable will be analyzed at each time point using a 
logistic regression model with treatment, TNF-alpha inhibitor status (naive, 
inadequate responder), and baseline body weight as explanatory variables 
(Stokes, Davis, and Koch, 2012).  The odds ratios and 95% confidence 
intervals for the odds ratios will be reported, based on the fitted model. 

Novartis 
Confidential 
Page 16 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Post-randomization patients who discontinue prematurely for any reason 
will be considered non-responders from the time they discontinued.  In an 
additional analysis, missing data for ASDAS inactive disease response will 
be imputed using multiple imputation. 
The secondary efficacy variables are the following: 
1. 
Reduction in ASDAS ≥ 1.1 from Week 16 (yes, no) 
2. 
Change from Week 16 in total BASDAI 
3. 
BASDAI50 response (yes, no)  
4. 
ASAS20 response (yes, no)  
5. 
ASAS40 response (yes, no)  
6. 
ASAS partial remission (yes, no) 
7. 
Change from Week 16 in ASAS-Health Index 
8. 
Change from Week 16 in FACIT-Fatigue 
Analyses of secondary efficacy variables 1 and 3-6 at each time point will 
be similar to the analyses of the primary efficacy variable.   
Secondary efficacy variables 2, 7, and 8 will be analyzed at each time point 
by an analysis of covariance model with treatment, Week 16 value, TNF-
alpha inhibitor status (naive, inadequate responder), and baseline body 
weight as explanatory variables.  The least squares means of the treatment 
groups, least squares mean difference, and 95% confidence interval for 
the difference will be reported, based on the fitted linear model.  Missing 
data will be imputed using the last-observation-carried-forward method.  In 
an additional analysis, missing data will be imputed using multiple 
imputation.  
Analyses of the primary and secondary efficacy variables will be based on 
the Full Analysis Set. 
The assessment of safety will be based mainly on the frequency of adverse 
events and laboratory data.   For safety analyses, the Enrolled Set will be 
used for Treatment Period 1, and the Safety Set will be used for Treatment 
Period 2. 
The sample size was calculated based on the primary efficacy variable 
(i.e., ASDAS inactive disease response) at Week 52 for the Full Analysis 
Set.  The expected ASDAS inactive disease response rates for 
secukinumab 300 mg and 150 mg treatment groups at Week 52 are 20% 
and 10%, respectively (corresponding to an odds ratio of 2.25), partly 
based on results from AIN457F2310 (MEASURE 2) study.  With 
approximately 97 patients in each treatment group (total of 194 
randomized patients), one will be able to estimate the difference between 
ASDAS inactive disease response rates of the two treatment groups at 
Week 52 with a “margin of error” (half-width of confidence interval) of 10% 
(corresponding to a standard error of 5%) for a two-sided 95% confidence 
interval (Julious and Patterson, 2004; nQuery Advisor 7.0). 
It is expected that the study will need to enroll approximately 270 patients 
for Treatment Period 1, to randomize approximately 194 patients who do 
not achieve ASDAS inactive disease status at Week 16 (inadequate 
responders).  This assumes that 10% of the 270 enrolled patients will 
discontinue during Treatment Period 1; among the remaining enrolled 

Novartis 
Confidential 
Page 17 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
patients, it is assumed that approximately 10% will be responders, 80% 
will be inadequate responders, and 10% will be non-responders. 
Key words 
Ankylosing spondylitis, ASDAS inactive disease, sacroiliitis, secukinumab 

Novartis 
Confidential 
Page 18 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
1 
Introduction 
1.1 
Background 
Ankylosing spondylitis (AS) is a chronic inflammatory disease which belongs to a group of 
conditions known as spondyloarthritides. AS is mainly characterized by involvement of the 
axial skeleton and sacroiliac joints, but it also affects peripheral joints, entheses and 
extraarticular organs. A significant proportion of patients may present with associated 
extraarticular manifestations such as uveitis, psoriasis, inflammatory bowel disease (IBD), 
cardiovascular and pulmonary abnormalities. Generalized osteoporosis, as well as regional 
osteopenia are common in AS patients and predispose them to non-traumatic fractures in spite 
of young age and gender (male). The presence of the HLA-B27 human leukocyte antigen is 
strongly associated with AS: 90–95% of patients with AS who have European ancestry carry 
this marker. AS affects up to 1.1% of the population, is associated with significant morbidity 
and disability, and thus constitutes a major socioeconomic burden.  
First-line medication of mild AS consists of non-steroidal anti-inflammatory drugs (NSAIDs). 
Treatment of NSAID-refractory AS is hampered by the lack of efficacy of virtually all standard 
disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX). As an 
exception, peripheral arthritis associated with AS may respond to sulfasalazine and 
methotrexate. Tumor necrosis factor (TNF) blocking agents were successfully added to the 
armamentarium to treat AS (Braun 2002) and subsequently demonstrated prolonged efficacy 
up to eight years of follow-up (Baraliakos 2011). However, upon discontinuation of TNF 
blockers the disease relapses quickly (Baraliakos 2005), indicating that the inflammatory 
process may have only been inhibited but not completely abolished. 
Patients with AS report chronic and extensive sleep disturbance due to pain and stiffness during 
the night (Leverment 2017).  Often patients get out of bed and walk around during the night to 
reduce pain and stiffness, which can lead to daytime fatigue (Rudwaleit 2006).  In AS patients 
poor quality sleep is strongly correlated with increased pain, lower quality of life, higher 
depressed mood, higher disease activity and reduced physical function (Batzman 2013). 
Treatment with anti-TNF golimumab has been shown to significantly reduce sleep disturbances 
in AS patients over 14 weeks as assessed by questionnaire (Deodhar 2010).  The effect of 
secukinumab on AS related sleep disturbance has not yet been studied.  Additionally, there is a 
general lack of data to investigate associations between sleep disturbance and daytime fatigue 
levels in AS. 
Although studies have been conducted with subjective measures of sleep in patient with AS, 
there have been limited assessments with quantitative measure of sleep disturbance, such as 
with polysomnography. A recent polysomnography study of 59 patients with AS demonstrated 
impairments in sleep architecture between patients on NSAID therapy, with improvements seen 
in total sleep time and sleep efficiency by patients treated with TNF inhibitors (In 
2016).  Another valid objective measure of sleep, and daytime activity, is actigraphy that 
measures activity with a wearable accelerometer, a digital sensor that can be worn on the wrist 
that measures the accelerations of the device in motion along reference axes. Actigraphic 
assessment data from an accelerometer typically involves integration of acceleration data 
(collected in units of ms-1s-1) with respect to time (Chen 2005), with a typical sample at a rate 
of 32-100 Hz (cycles per second). Acceleration data is condensed and stored in the device in 

Novartis 
Confidential 
Page 19 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
fixed ‘epochs’ of time. Actigraphic assessment of sleep disruption and daytime activity is less 
burdensome for patients than traditional daily assessments and much less intrusive than 
polysomnography while providing data that is not effected by recall or reporting biases.  While 
untested in patients with AS, actigraphy has been successfully used in prospective 
interventional studies to assess the impact of pharmacological treatment on both sleep and 
daytime physical activity, in atopic dermatitis (Nemoto 2016), heart failure (Redfield 2015), 
and osteoarthritis (Trudeau 2015). 
Secukinumab (AIN457) is a high-affinity human monoclonal anti-human antibody that 
neutralizes IL-17A activity. IL-17A is the key cytokine in the Th17 and innate immune 
pathways which is thought to be an important mediator of autoinflammation. Secukinumab is 
currently approved by the FDA to treat moderate to severe plaque psoriasis, active psoriatic 
arthritis, and active ankylosing spondylitis (Cosentyx® package insert).  
Secukinumab has been previously evaluated in active AS in the MEASURE 1 and MEASURE 
2 studies of 590 patients with AS (Baeten et al., 2015), demonstrating the efficacy of 
secukinumab 150 mg (S.C.) versus placebo on ASAS20 at Week 16 in both studies. Inconsistent 
results were seen with 75 mg, and 300 mg was not included as a dosage in these two pivotal 
Phase III studies. As such, secukinumab received initial FDA approval for only 150 mg of 
secukinumab every 4 weeks with or without loading in the treatment of active ankylosing 
spondylitis. A subsequent Phase III study (MEASURE 3) was conducted that included a 300 
mg dose group, which demonstrated a significant difference from placebo on ASAS20 at Week 
16, however the efficacy did not clinically differ from the 150 mg dose group at Week 16. Of 
note, this study involved an intravenous loading regimen of 10 mg/kg secukinumab at Week 0, 
2 and 4, followed by s.c. dosing every 4 weeks of 150 mg or 300 mg. This intravenous loading 
regimen conferred initially higher concentrations of secukinumab such that a meaningful 
assessment between the 300 mg and 150 mg doses would not be attainable at the Week 16 
primary analysis time point. However, at Week 52 and beyond, presumably when the 
pharmacokinetic influence of the intravenous load had waned, evaluation of higher hurdle 
efficacy measures (e.g., ASDAS-inactive disease, ASAS Partial Remission), revealed higher 
efficacy responses for 300 mg compared with 150 mg. Thus, AS patients may benefit from a 
300mg regimen, however further study is required to explore dose-based differences with the 
approved s.c. loading regimen. Further, previous studies have not evaluated dose-escalation 
such as 150 mg to 300 mg in a patient subgroup that had not met a pre-defined response 
threshold to determine if greater efficacy could subsequently be achieved. The FDA has 
subsequently approved 300 mg as a dosage to be considered if a patient continues to have active 
ankylosing spondylitis in January 2020. 
There continues to be a need  to understand the impact of 300 mg in the treatment of AS, 
specifically within the context of enacting a therapeutic dosage change in patients who have not 
met an a prioi established target clinical response, such as a non-response threshold, or a high-
response target, such as disease remission or a comparable analogue. As 300 mg is an available 
dose with an established safety profile comparable to 150 mg in both moderate to severe plaque 
psoriasis and active psoriatic arthritis and has demonstrated clinically meaningful differences 
compared to 150 mg on certain clinical measures (e.g., PASI, ACR50, ACR70), and patient 
subgroups (anti-TNF inadequate responders), it is appropriate to pursue the study of 300 mg in 
AS.       

Novartis 
Confidential 
Page 20 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
As of 25-Jun-2017, over 11,140 healthy subjects and patients have received at least one dose of 
secukinumab in clinical studies. Secukinumab studies have investigated various indications 
(Rheumatoid Arthritis (RA), AS, Psoriatic Arthritis (PsA), psoriasis, multiple sclerosis, uveitis, 
Crohn’s disease, dry eye syndrome, polymyalgia rheumatica, diabetes mellitus) 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. 
As of Jan -2016, secukinumab has been approved for the treatment of AS in the European 
Union, the US and multiple other countries. Full safety results from completed studies for AS, 
PsA and psoriasis show that secukinumab generally is safe and well tolerated. Please refer to 
the latest Investigator’s Brochure (IB) for a more detailed review of the risk:benefit profile of 
secukinumab which supports the clinical development for the treatment of AS patients with 
secukinumab. 
 
1.2 
Purpose 
The purpose of this study is to estimate the difference in clinical response between 300 mg and 
150 mg of secukinumab at Week 52, which follows randomization to dose escalation at Week 
16 for patients with Ankylosing Spondylitis who inadequately respond to open-label 
secukinumab 150 mg. This study will also investigate the association between treatment and 
sleep disturbances, as well as daytime activity patterns. 
2 
Study objective and endpoints 
2.1 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints  
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s)  
1. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
ASDAS inactive disease (< 1.3) status who 
did not meet ASDAS inactive disease criteria 
at Week 12 and Week 16. 
1. The primary efficacy variable is the ASDAS 
inactive disease response (yes, no).  The 
primary analysis time point is at Week 52. 
Secondary objective(s) 
Endpoint(s) for secondary objective(s)  
1. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
a ASDAS clinically important improvement 
from their Week 16 ASDAS score (reduction 
in ASDAS  ≥ 1.1 from Week 16) 
2. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the change from Week 16 in the 
1. Reduction in ASDAS ≥ 1.1 from Week 16 
(yes, no)  
2. Change from Week 16 in total BASDAI 
3. BASDAI50 response (yes, no)  
4. ASAS20 response (yes, no)  
5. ASAS40 response (yes, no)  
6. ASAS partial remission (yes, no)  
7. Change from Week 16 in ASAS-Health Index 

Novartis 
Confidential 
Page 21 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Objective(s) 
Endpoint(s) 
total Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) 
3. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
BASDAI50 response  
8. Change from Week 16 in FACIT-Fatigue 
 

Novartis 
Confidential 
Page 22 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Objective(s) 
Endpoint(s) 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
4. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
an Assessment of Spondyloarthritis 
International Society criteria 20 response 
(ASAS20)  
5. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
ASAS40 response 
6. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on the proportion of subjects achieving 
ASAS partial remission (a value not above 2 
units in each of the four main domains on a 
scale of 10)   
7. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on change from Week 16 in the total 
score of ASAS Health Index (ASAS-HI)   
8. To estimate the difference between 
secukinumab 300 mg and secukinumab 150 
mg blinded treatment groups at Week 52 
based on change from Week 16 in the total 
score of FACIT-Fatigue  
9. The overall safety and tolerability of 
secukinumab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Novartis 
Confidential 
Page 23 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 

Novartis 
Confidential 
Page 24 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
3 
Investigational Plan 
3.1 
Study design 
 
This study will use a randomized, double-blind, parallel-group design, multicenter design. 
There are 3 study periods:   
 
1. Screening: A screening period will take place over two separate visits, with the first 
visit used to assess eligibility and to washout prohibited medications (up to 11 weeks). 
The second screening visit, which will occur at a minimum of 2 weeks prior to the 
baseline visit for all patients. 
 
 
  Note: Patients that do not require a washout, and who satisfy all 
inclusion and none of the exclusion criteria at the first screening visit can initiate 
the second screening visit one week after their first screening visit.  
2. Treatment Period 1: Patients who meet all of the inclusion criteria and none of the 
exclusion criteria will have a Baseline Visit performed to start Treatment Period 1.  
During this 16-week period, all patients will receive open-label secukinumab 150 mg 
[1 x 1.0mL s.c.] at baseline, Weeks 1, 2, 3, 4, 8, and 12.   
 
At Week 16, patients will be placed into one of the following groups: 
 
a. Responders:  Patients achieving ASDAS inactive disease (total score < 1.3) at both 
Week 12 and Week 16 and who do achieve a decrease (improvement) from baseline in 
total ASDAS score at both Week 12 and Week 16.  
b. Inadequate responders:  Patients who have active disease, defined as an ASDAS total 
score of ≥1.3 at either Week 12 or Week 16, and who do achieve a decrease 
(improvement) from baseline in total ASDAS score at both Week 12 and Week 16.   
c. Non-responders: Patients who exhibit no change or an increase (worsening) from 
baseline in total ASDAS score at either Week 12 or Week 16  
Note: To minimize patient burden, at the Week 16 visit, the hs-CRP measurement that is part 
of the ASDAS calculation will be imputed from the Week 12 hs-CRP results to allow for 
assignment into the groups above. Historically, hs-CRP levels have varied little between 
Week 12 and Week 16 or in previous studies of secukinumab in active AS.     
 
3. Treatment Period 2:  Upon completion of the Week 16 visit,  
 
a. Responders will enter Treatment Period 2 and continue to receive secukinumab 150 
mg every 4 weeks through Week 48 as well as one matched placebo dose (s.c. 
injection) to maintain the integrity of the blind for the randomized Inadequate 
Responder group. 
 

Novartis 
Confidential 
Page 25 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
b. Inadequate responders will enter Treatment Period 2 and will be randomized  
(1:1, double-blinded) to secukinumab 300 mg or secukinumab 150 mg very 4 weeks 
through Week 48. Subjects will know that they are on secukinumab, but will be 
blinded to dose, as they will not know whether they are receiving 150 mg or 300 mg. 
 
c. Nonresponders will be discontinued from the study at Week 16. 
 
The only condition that will be placed on enrollment targets is that no less than 60% of patients 
(162 patients) are TNFα inhibitor naive (or, no more than 40% of patients are TNF-IR). In 
theory the percentage of TNFα inhibitor naive patients could reach 100%, although that is not 
anticipated.  
Patients may discontinue the study at any time. If rescue treatment with prohibited medications 
 occurs, patients will be discontinued from the study and should 
return for an End of Study Visit (see Table 6-1). The End of Study Visit should be scheduled 
approximately four weeks after the last study treatment, and should be performed before any 
new treatment is initiated. After the End of Study Visit, any SAEs that occur in the following 
30 days must be reported.  
Figure 3-1 
Study design 
 
 
 
3.2 
Rationale for study design 
The subject population will be described in more detail in Section 4 below.  
The two visit Screening Period is designed to allow for both (1) washout of prohibited 
medications, and 
 
-13 to ≥3

Novartis 
Confidential 
Page 26 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 
 
 
 
 
The randomized, blinded, parallel-group design used in this study is based on the primary focus 
of this study, which is to estimate the difference in clinical response between either remaining 
on 150 mg or escalating to 300 mg of secukinumab after not achieving a measured state of 
inactive disease at the Week 12 and Week 16 time points. The responder status at Week 12 and 
Week 16, as well as the primary objective at Week 52 is determined with the validated ASDAS 
clinical scoring measure of disease activity status which will establish patients who score within 
the “inactive disease” classification of this measure (a total score of < 1.3). Week 52 has been 
selected as the primary analysis time point to allow sufficient time (36 weeks) for a clinical 
response to be observed following dose escalation to 300 mg at Week 16 vs those patients who 
remain on 150 mg for the entire 52-week period.  
Following the Week 16 visit, randomized inadequate responder patients and investigators will 
be blind to the dose of secukinumab through the use of a matched placebo injection (identical 
in appearance) in the 150 mg s.c. group. The blinding of the secukinumab treatments (150 mg 
or 300 mg) will allow for an evaluation of a potential dose-response of the 150 mg and 300 mg 
secukinumab doses on both efficacy and safety outcomes.  
Responder patients, those who achieve ASDAS inactive disease at Week 12 and Week 16, will 
continue on secukinumab 150 mg to evaluate the longer-term treatment response up to Week 
52. To support the integrity of the blind for the randomized inadequate responder group, the 
responder patients will also be dose blinded between Week 16 and Week 48 by receiving a 
single matching placebo injection to their secukinumab 150 mg injection. Thus, all responder 
and inadequate responder patients will be blinded to dose and will receive two matched 
injections every 4 weeks. While the responder group is not the primary focus of this study, this 
subgroup will provide meaningful exploratory analyses of the clinical characteristics and 
duration of response in patients who achieve a high-level efficacious response to secukinumab 
at Week 16.  
The population of non-responders, expected to be low in number, will be discontinued from the 
study at Week 16 as these patients would be considered a primary failure of therapy. Non-
responders, by the criteria of no measured improvement, or a worsening of disease activity after 
16 weeks of treatment are not expected to improve with a dose escalation, and thus are to 
terminate the study to seek alternative treatments options that may benefit their disease.   
3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment   
The secukinumab dosing regimens in this study are based upon the currently approved dose for 
active ankylosing spondylitis, which is 150 mg s.c. every 4 weeks (without or with a loading 
regimen of 150 mg at Weeks 0, 1, 2, 3, and 4.  

Novartis 
Confidential 
Page 27 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
The rationale for the use of 300 mg of secukinumab in this study of patients with ankylosing 
spondylitis is motivated by the fact that 300 mg is an approved dose to treat patients with 
moderate-to-severe plaque psoriasis and active psoriatic arthritis. In psoriatic arthritis, it is 
labeled as an escalation dose for patients who remain with active disease while on a 150 mg 
dosing regimen. In both the psoriasis and psoriatic arthritis clinical studies, several measures 
demonstrated higher responses with 300 mg versus 150 mg, including the clearance of psoriatic 
plaques, as well as in patients who were previous inadequate responders to anti-TNFα therapies. 
Further, 300 mg treatment groups demonstrated a comparable safety profile to 150 mg every 4 
weeks. (Langley 2014, Mease 2015).  
This study will evaluate whether a higher dose of secukinumab will have an effect on subjects 
with AS, specifically signs and symptoms of AS and the achievement of state of inactive disease 
based on the ASDAS measure.  The duration of treatment of initial open-label 150 mg for 16 
weeks is based on Week 16 being the primary analysis time point for the previous Phase 3 
secukinumab studies in AS. While statistical separation on the ASAS20 measure occurs as early 
as Week 1, greater responses are seen out to Week 16 and beyond (Baeten et al., 2015). In 
addition, patients will receive the loading regime of weekly dose of secukinumab 150 mg at 
Baseline, and Week 1, 2, 3, and 4, to be consistent with previous Phase 3 studies. Patients will 
be assessed at each of these weekly time points at the clinical site to evaluate the onset of clinical 
response and ensure patients are trained and comfortable administering the pre-filled syringe.  
The evaluation of clinical effect over the long-term extension of studies, reveal a steady incline 
in response on several measures, particularly for BASDAI and ASAS40, over the Week 16 to 
Week 52 to Week 104 timeframes (Marzo-Ortega 2017). Therefore, the 36-week duration of 
Treatment Period 2 will provide a sufficient period of time to observe any treatment differences 
between the 300 mg and 150 mg groups. 
 
3.4 
Rationale for choice of comparator 
This study does not include a placebo arm. Efficacy in terms of signs and symptoms is well 
established for secukinumab 150 mg for patients with active AS. Moreover, a placebo cohort 
would not be deemed ethically justifiable for this 1-year study, considering AS is known to be 
a chronic progressive disease with structural damage. 
3.5 
Purpose and timing of interim analyses/design adaptations  
Not applicable. 
3.6 
Risks and benefits 
Secukinumab has shown efficacy in several inflammatory diseases and approved by the FDA 
and EMA for the treatment of adults with active AS, active PsA, and plaque psoriasis. 
Significant differences from placebo, etanercept and ustekinumab have been demonstrated in 
the treatment of psoriasis (Langley 2014; Thaçi 2015), as well as significant difference from 
placebo in the treatment of joint pain, swelling, health-related quality of live, and radiographic 
progression in PsA (Mease 2015; McInnes 2015; van der Heijde, 2016) and AS (Baeten et al 
2015; Braun 2016). 

Novartis 
Confidential 
Page 28 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
The large safety dataset of secukinumab across indications involving over 9,600 subjects did 
not show unexpected safety issues relative to the known mode of action. Secukinumab was 
generally safe and well-tolerated. The most frequently reported adverse events (AEs) are non-
serious mild to moderate infections, mainly upper respiratory tract infections with secukinumab 
relative to placebo. In addition, there was an increase in localized mucosal or cutaneous 
candidiasis with secukinumab compared with placebo, but the cases were generally mild or 
moderate in severity, non-serious, and responsive to standard treatment and did not require 
discontinuation of secukinumab. There was also a small increase in neutropenia cases with 
secukinumab compared with placebo. Most cases were mild to moderate, transient and 
reversible and without a temporal relationship to infections. Common Toxicity Criteria (CTC) 
AE grade 3 neutropenia (< 1.0-0.5 x 109/L) was uncommonly observed with secukinumab. 
Hypersensitivity reactions include urticaria and rare events of anaphylactic reaction to 
secukinumab have also been observed in clinical studies. 
Taking  into  account  the  individual  risks  as  outlined  above,  the  expected  risk  profile  of 
secukinumab from a mechanism of action perspective is anticipated to be similar or improved 
compared to the approved inflammatory cytokine-targeting therapies. The risk to patients in 
this  trial  will  be  minimized  by  compliance  with  the  eligibility  criteria,  close  clinical 
monitoring and extensive guidance to the investigators, provided in the current version of the 
IB. From the standpoint of the overall risk-benefit assessment, current trial with secukinumab 
is justified. 
4 
Population 
The study population will consist of male and female patients, ≥ 18 years of age with a clinical 
diagnosis of moderate to severe AS fulfilling the Modified New York criteria for AS 
 
 and with moderate to severe disease despite previous or current NSAIDs / non-
biologic DMARDs and/or anti-TNFα therapy. 
Patients must have a history of active AS, as measured by the following three assessments: 
• Total BASDAI of ≥ 4 on a NRS of 0-10 at baseline 
• Spinal pain as measured by BASDAI question #2 of ≥ 4 on a NRS of 0-10 at baseline 
• Total back pain ≥ 4 on a NRS of 0-10 at baseline  
The study aims to enroll approximately 270 patients at approximately 82 centers in the United 
States.  Since a 25% screen failure rate is expected, approximately 360 patients will be screened.  
Patients who drop out after they have been randomized will not be replaced. 
4.1 
Inclusion Criteria 
Patients/subjects eligible for inclusion in this study must fulfill all of the following criteria: 
 
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study assessment is performed 
2. Male or non-pregnant, non-lactating female patients at least 18 years of age 

Novartis 
Confidential 
Page 29 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
3. Diagnosis of moderate to severe AS with prior documented radiologic evidence (x-ray or 
radiologist’s report) fulfilling the Modified New York criteria for AS 
 
4. Active AS assessed by total BASDAI of ≥ 4 (NRS of 0-10) at baseline 
5. Spinal pain as measured by BASDAI question #2 of ≥ 4 (NRS of 0-10) at baseline 
6. Total back pain of ≥ 4 on a NRS of 0-10 at baseline 
7. Patients should have been on NSAIDs at the maximum tolerated dose for at least 4 weeks 
prior to their Baseline Visit, with an inadequate response or for less than 4 weeks if 
withdrawn for intolerance, toxicity or contraindications 
8. Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their AS therapy are required to be on a stable dose for at least 2 weeks before their 
Baseline Visit 
9. Patients who have been on a TNFα inhibitor (not more than one) must have experienced an 
inadequate response to previous or current treatment given at an approved dose for at least 
3 months prior to baseline or had been intolerant upon administration of an anti-TNFα agent 
10. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after appropriate wash-out period prior to their Baseline Visit: 
• 4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 hours (s.c. 
route) 
• 8 weeks for Remicade (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. 
infusion) 
• 11 weeks for Humira (adalimumab) – with a terminal half-life of 10-20 days (average 2 
weeks)(s.c. route) 
• 11 weeks for Simponi (golimumab) – with a terminal half-life of 11-14 days 
• 11 weeks for Cimzia (certolizumab) – with a terminal half-life of 14 days  
11. Patients taking MTX (≤ 25 mg/week), sulfasalazine (≤ 3 g/day), or leflunomide (≤20 
mg/day) are allowed to continue their medication and must have taken it for at least 2 
months and have to be on a stable dose for at least 4 weeks prior to baseline 
12. Patients on MTX must be on a stable folic acid supplementation before their Baseline Visit.  
13. Patients who are on a DMARD other than MTX, sulfasalazine or leflunomide must 
discontinue the DMARD 4 weeks prior to baseline 
14. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day 
prednisone or equivalent for at least 2 weeks before baseline 
4.2 
Exclusion Criteria 
 
Patients fulfilling any of the following criteria during the Screening Period or at the Baseline 
Visit are not eligible for inclusion in this study. No additional exclusions may be applied by the 
investigator, in order to ensure that the study population will be representative of all eligible 
patients/subjects. 

Novartis 
Confidential 
Page 30 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
1. Patients with total ankylosis of the spine 
2. Use of other investigational drugs within 5 half-lives of enrollment, or within 4 weeks 
before the Baseline Visit, whichever is longer  
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes 
4. Chest x-ray, CT scan, or chest magnetic resonance imaging (MRI) with evidence of 
ongoing infectious or malignant process, obtained within 3 months prior to screening and 
evaluated by a qualified physician  
5. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17, IL-
12/23, or the IL-17 receptor, or any other biologic immunomodulating agent, except those 
targeting TNFα 
6. Patients who have taken more than one anti-TNFα agent 
7. Any intramuscular or intravenous corticosteroid injection within 2 weeks before baseline  
8. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
baseline 
9. Previous treatment with any cell-depleting therapies including but not limited to anti-
CD20, investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19) 
10. Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, 
morphine) 
11. Active systemic infections during the last two weeks (exception: common cold) prior to 
baseline 
12. Active ongoing inflammatory diseases other than AS that might confound the evaluation 
of the benefit of secukinumab therapy, including inflammatory bowel disease or uveitis 
13. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at unacceptable risk for 
participation in an immunomodulatory therapy 
14. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension, congestive heart failure (New York Heart Association status of 
class III or IV), uncontrolled diabetes, or very poor functional status unable to perform 
self-care 
15. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum 
bilirubin. The Investigator should be guided by the following criteria: 
• Any single parameter 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/baseline, to rule out lab 
error 
16. Serum creatinine level exceeding 2.0 mg/dL (176.8 µmol/L) at screening  
17. Screening total WBC count < 3,000/μL, or platelets < 100,000/μL or neutrophils 
<1,500/μL or hemoglobin < 8.5 g/dL (85 g/L) 

Novartis 
Confidential 
Page 31 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
18. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
screening  
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. Patients with other clinically significant conditions (not associated with the study 
indication) which in the judgement of the investigator might interfere with the assessment 
of this study, or puts the subject at increased risk  
21. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
22. Inability or unwillingness to receive injections with the PFS 
23. 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 
24. Donation or loss of 400 mL or more of blood within 8 weeks before baseline 
25. History or evidence of ongoing alcohol or drug abuse, within the last 6 months before 
baseline 
26. Patients who know they will be unable to complete 1 year of study treatment period 
27. Administration of live vaccines during the study period or 6 weeks prior to baseline 
28. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by either a positive purified protein derivative (PPD) skin test (the 
size of induration will be measured after 48-72 hours, and a positive result is defined as an 
induration of ≥ 5 mm or according to local practice/guidelines) or a positive central 
laboratory TB blood screening test as indicated in the assessment schedule in Table 6-1. 
Patients with a positive test may participate in the study if further work up (according to 
local practice/guidelines) establishes conclusively that the patient has no evidence of 
active tuberculosis. If presence of latent tuberculosis is established, then treatment 
according to local country guidelines must have been initiated 
29. Pregnant or nursing (lactating) women where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test 
30. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, are excluded from the study unless they are using highly effective 
methods of contraception during dosing and for 16 weeks after stopping of study 
medication. All women of child-bearing potential must have a negative serum pregnancy 
test at Screening Visit 2, regardless of the method of contraception being used.  Highly 
effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking study 

Novartis 
Confidential 
Page 32 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
drug. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, 
the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate < 
1%), for example hormone vaginal ring or transdermal hormone contraception.  In case 
of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study drug. 
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 have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Novartis will supply the following study treatments in packaging of identical appearance: 
• Secukinumab 150 mg provided in 1.0 mL in a prefilled syringe (PFS) for s.c. injection. 
• Secukinumab placebo provided in 1.0 mL a PFS for s.c. injection (for matching 150 mg 
dose to blind 300 mg dosing) 
NOTE: The PFS are packed in an open-label fashion from baseline through the Week 12 visit. 
Beginning Week 16, the PFS are packed in a double-blinded fashion for the remainder of the 
study. 
5.1.2 
Additional treatment  
No additional treatment beyond investigational drug and control drug are included in this trial. 
5.2 
Treatment arms 
Treatment Period 1 

Novartis 
Confidential 
Page 33 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Once screening has been completed and patients have met the eligibility criteria, all patients 
will undergo 16 weeks of open-label treatment with secukinumab 150 mg s.c. self-administered 
at the site at baseline, Weeks 1, 2, 3, 4, 8, and 12. 
All assessments at the scheduled visit will be performed before the patients receive the 
injection with the appropriate study medication for that visit. 
At Week 12 and Week 16, all patients will be assessed for achieving the ASDAS inactive 
disease (<1.3) status, as well as for an inadequate response or a non-response.  Patients will then 
be divided into three groups: 
 
1. Responders: Patients achieving ASDAS inactive disease (total score < 1.3) status at Week 
12 and Week 16 and who do achieve a decrease (improvement) from baseline in total 
ASDAS score at both Week 12 and Week 16.   
 
2. Inadequate responders: Patients who have active disease, defined as an ASDAS total score 
of ≥1.3 at either Week 12 or Week 16, and who do achieve a decrease (improvement) 
from baseline in total ASDAS score at both Week 12 and Week 16.   
 
3. Non-responders: Patients who exhibit no change or an increase (worsening) from baseline 
in total ASDAS score at either Week 12 or Week 16 
 
Treatment Period 2 (Responders and Non-responders) 
Responders: Patients achieving responder status will enter Treatment Period 2 and continue to 
receive 150 mg s.c. (one s.c. injection of secukinumab 150 mg) at Weeks 16, 20, 24, 28, 32, 
36, 40, 44, and 48, as well as one matched placebo dose (s.c. injection) to maintain the 
integrity of the blind for the randomized Inadequate Responder group. This Responder group 
will be evaluated for maintenance of ASDAS inactive disease while remaining on 150 mg of 
secukinumab. All assessments at the scheduled visit will be performed before the patients 
receive the injection with the appropriate study medication for that visit. 
NOTE: To minimize patient burden, at the Week 16 visit, the hs-CRP measurement that is part 
of the ASDAS calculation will be imputed from the Week 12 hs-CRP results to allow for 
assignment into the groups above. Historically, hs-CRP levels have varied little between Week 
12 and Week 16 in previous studies of secukinumab in active AS.  
Non-responders: Nonresponders will terminate the study at Week 16.    
 
Treatment Period 2 (Inadequate Responders) 
Inadequate responders will be randomized via the Interactive Response Technology (IRT) 
system in a 1:1 ratio to receive either secukinumab 300 mg (two s.c. injections of the 150 mg 
dose) or secukinumab 150 mg (one s.c. injection of the 150 mg dose and one s.c. injection of 
placebo) at Weeks 16, 20, 24, 28, 32, 36, 40, 44, and 48.  

Novartis 
Confidential 
Page 34 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Patients will self-administer all secukinumab doses up to Week 48 after they have received 
training by the site to self-administer their secukinumab dose. While patients are encouraged 
to self-inject, continued assistance by the site or home nurse is acceptable. All assessments at 
the scheduled visit will be performed before the patients receive the injection with the 
appropriate study medication for that visit. 
5.3 
Treatment assignment and randomization 
At Baseline through Week 12, the Interactive Response Technology (IRT) system will be used 
at each visit to dispense open-label treatment to enrolled patients.  The system will specify 
unique medication numbers that will correspond to open-label treatment to be dispensed. 
Responders: At Week 16 through Week 48, the IRT system will be used at each visit to 
dispense treatment and matching placebo to ASDAS-inactive disease responders.  The system 
will specify unique medication numbers that will correspond to treatment to be dispensed. 
Inadequate Responders: At Week 16, all ASDAS-inactive disease inadequate responder 
eligible patients will be randomized via IRT to one of the treatment groups in a ratio of 1:1 
(secukinumab 300 mg or secukinumab 150 mg). The IRT system will assign a randomization 
number to the subject, which will be used to link the subject to a treatment group in the system 
and will specify unique medication numbers for treatment to be dispensed to the subject. The 
randomization number will not be communicated to any of the site staff. The IRT system will 
be used at each visit from Week 16 through Week 48 to dispense treatment. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A subject 
randomization list will be produced by the IRT system provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s).  
Randomization will be stratified by TNF-alpha inhibitor status (naive, inadequate 
responder).  The stratification ensures balanced allocation of patients to treatment groups within 
the TNF-alpha inhibitor status strata.   
The randomization scheme for patients will be reviewed and approved by a member of the 
Novartis Biometrics group.  
 
5.4 
Treatment Blinding 
Patients, investigators/site staff, persons performing assessments, and Novartis study personnel 
will remain blinded to individual treatment assignment from the time of randomization (Week 
16) for the inadequate responder group and responder group until the final database lock using 
the following methods: 
1. Randomization data will be kept strictly confidential until the time of unblinding, and will 
not be accessible by anyone else involved in the study with the following exceptions: 

Novartis 
Confidential 
Page 35 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
• Specific vendors whose role in trial conduct requires their unblinding (e.g., IRT 
system) 
• Drug Supply Management (DSM); 
2. The identity of secukinumab and placebo prefilled syringes (PFS) will be concealed by 
identical packaging, labeling, schedule of administration, and appearance. 
There will be a database lock after all patients have completed the Week 52 visit and data are 
clean and complete.  
Unblinding will only occur in the case of subject emergencies (see Section 5.5.9) and at the 
conclusion of the study. 
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each subject is uniquely identified in the study by a combination of his/her four digit center 
number and three digit subject number. The center number is assigned by Novartis to the 
investigative site. After the subject has signed the ICF, the investigator or his/her staff will 
contact the IRT system and provide the requested identifying information for the subject to 
register them into the IRT system. The site must select the CRF book with a matching Patient 
Number from the EDC system to enter data.  At each site, the subjects are numbered 
sequentially.  (e.g. the first subject is assigned subject number 001, and subsequent patients are 
assigned consecutive numbers; the second subject is assigned subject number 002; the third 
subject is assigned subject number 003). Once assigned to a subject, a subject number will not 
be reused. If the subject fails to be randomized for any reason, the IRT system must be notified 
within 2 days and the reason for not being randomized will be entered on the Screening Phase 
Disposition Form within the eCRF. The appropriate eCRF(s) pages should also be completed. 
5.5.2 
Dispensing the study drug 
All doses of study treatment will be self-administered by patients at the study site (or at home) 
after they have received training by the site on how to self-administer.  
The study treatment packaging has a 2-part label. A unique medication number is printed on 
each part of this label, which corresponds to placebo or active treatment. Investigator staff will 
identify the study treatment packages to dispense to the subject by contacting the IRT and 
obtaining the medication numbers. Immediately before dispensing the package to the subject, 
detach the outer part of the label from the packaging and affix it to the source document (Drug 
Label Form) for that subject’s unique subject number. 
5.5.3 
Handling of study and additional treatment  
5.5.3.1 
Handling of study treatment  
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment should be stored according to the instructions 

Novartis 
Confidential 
Page 36 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. 
Medication labels will be in English and comply with legal requirements in the U.S. They will 
include storage conditions for the study treatment but no information about the patient except 
for the medication number. 
The PFS (150 mg active/placebo) sealed in their outer box must be stored in a locked 
refrigerator between 2°C and 8°C (36°F and 46°F) and protected from light. They must be 
carefully controlled in accordance with regulations governing investigational medicinal 
products and local regulations. 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the Investigator 
folder at each site. 
Destruction of the unused drug should be done according to local requirements and after 
approval by Novartis clinical team. 
5.5.3.2 
Handling of additional treatment  
5.5.4 
Instructions for prescribing and taking study treatment 
All study treatment will be self-administered subcutaneously after visit study assessments have 
been completed. Qualified staff will administer the injection only to those patients who are not 
able to self-administer the PFS injection. Detailed instructions on the self-administration of the 
study treatment will be described in the Instructions For Use (IFU) and provided to each subject. 
The first study treatment administration will occur at the Baseline Visit after 
inclusion/exclusion criteria have been confirmed, all study scheduled assessments have been 
performed, and the scheduled blood samples have been drawn. 
The patient will be instructed by the site staff, utilizing the IFU, on how to self-inject via PFS. 
Patients will be asked to raise any questions, if they have any, and then to proceed with self - 
injection. Self-injection will take place under the supervision of a site staff member. At the 
Week 1 and subsequent visits, patients will be asked to refer to the IFU and to proceed with 
self-injection of the study drug. While patients are encouraged to self-inject, continued 
assistance by the site or home nurse is acceptable. 
Study treatment will be administered weekly following the baseline dose (Weeks 1, 2, 3, and 4) 
and every 4 weeks thereafter (at Week 8 until Week 48). 
All dates and times of injections self-administered by the subject during the study must be 
recorded on the Dosage Administration Record eCRF. Immediately before dispensing the drug 
package to the subject, detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that subject’s unique subject number.  

Novartis 
Confidential 
Page 37 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
The Investigator should promote compliance by instructing the subject to attend the study visits 
as scheduled and by stating that compliance is necessary for the subject’s safety and the validity 
of the study. The subject should be instructed to contact the Investigator if he/she is unable for 
any reason to attend a study visit as scheduled or if he/she is unable for any reason to take the 
study treatment as prescribed.  For patients unable to travel to the clinic for their study visit, 
flexible study visits (home nursing study visits) and telemedicine/telephone visits with direct to 
patient shipment of study drug are alternative options for all post-Baseline study visits.  For 
more information regarding flexible study visits, please refer to the Site Manual for Home Visits 
(Flexible Study Visits). 
5.5.4.1 
Administration 
Secukinumab Solution for Subcutaneous Injection (active or placebo, respectively) will be 
provided in prefilled syringes (PFS).  
Single syringes will be packed in individual boxes. The boxes containing the safety prefilled 
syringes with study treatment solution should be kept at 2 to 8°C (36°F and 46°F) and protected 
from light. Prior to administration the boxes containing the safety prefilled syringes with study 
treatment solution should be allowed to come to room temperature unopened for about 20 
minutes before administration. Used safety syringe should be disposed immediately after use in 
a sharps container. 
Patients will be instructed at baseline by the site staff on how to self-inject either secukinumab 
or placebo (blinded) via PFS following the IFU. After the Baseline Visit, the injections will be 
self-administered into the appropriate site of the body (thighs, arms, abdomen), and each 
injection should be given at a different injection site. Each new injection should be given at 
least one inch from the previously used site. If subject chooses the abdomen, 2 inches area 
around navel should be avoided. Investigational drug should not be injected into areas where 
the skin is tender, bruised, red, or hard, or where subject has scars or stretch marks. Injection 
sites should be changed to reduce the risk of reaction. 
All study treatment will be self-administered subcutaneously after visit study assessments have 
been completed. While patients are encouraged to self-inject, continued assistance by the site 
or home nurse is acceptable. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Study treatment dose adjustments are not permitted.  
Study treatment interruptions are not permitted with the following exceptions: 
• If, in the opinion of the investigator, a subject is deemed to be placed at a significant safety 
risk unless dosing is temporarily interrupted. In such cases study treatment should be 
interrupted only during the time that this risk is present and ongoing. Study treatment can 
be restarted at the next scheduled visit after resolution of the safety risk. 
• The effect of secukinumab on live vaccines is unknown; therefore live vaccines should not 
be administered during participation in the study. In case a live vaccine has been 
administered due to a medical urgency, the subject must be discontinued from study 
treatment as per Section 5.6.2. Non-live vaccinations are permitted during the study. 

Novartis 
Confidential 
Page 38 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Study treatment interruptions must be recorded on the corresponding Dosage Administration 
Record eCRF page and all assessments should be completed as scheduled.  
5.5.6 
Rescue medication 
Rescue medication is not permitted during the study. Patients will be free to discontinue 
participation in the study at any time. 
5.5.7 
Concomitant medication 
Patients should be instructed to notify the study site about any new medications he/she takes 
after being enrolled into the study. All medications, procedures and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the patient was 
enrolled into the study must be recorded in the appropriate eCRF. 
Guidelines for the use of specific medications are provided below: 
Methotrexate (MTX) 
Patients taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
the Baseline Visit and maintained stable throughout the duration of the study. 
Folic acid 
Patients on MTX must be taking folic acid supplementation before the Baseline Visit and during 
the study to minimize the likelihood of MTX associated toxicity. 
Sulfasalazine 
Subjects taking sulfasalazine (≤ 3 g/day) must be on a stable dose for at least 4 weeks before 
the Baseline Visit and maintained stable throughout the duration of the study.  
Leflunomide 
Subjects taking luflunomide (≤ 20 mg/day) must be on a stable dose for at least 4 weeks before 
the Baseline Visit and maintained stable throughout the duration of the study. 
Low Strength opioids 
Subjects are allowed to take low strength opioids PRN. However, patients should not take a 
dose of low strength opioids within 24 hours of a study visit. High potency opioid analgesics 
(e.g., methadone, hydromorphone, morphine) are prohibited in this study.  
Systemic corticosteroids 
Treatment with systemic corticosteroids is permitted up to a maximum daily dosage of 10 mg 
prednisone equivalent and the dose is stable within the 2 weeks preceding the Baseline Visit. 
The subject should remain on a stable dose throughout the duration of the study. 
Higher-dose, time-limited corticosteroid courses (bursts) may be permitted for exacerbations of 
medical conditions unrelated to AS (e.g., asthma, chronic obstructive pulmonary disease 
(COPD), contact dermatitis) after baseline. Any change in the dose of systemic corticosteroids 
during the trial must be recorded on the corresponding CRF. 

Novartis 
Confidential 
Page 39 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding the Baseline Visit 
and up to Week 52.  
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors) and acetaminophen 
Patients on regular use of NSAIDs or acetaminophen should be on stable dose for at least 2 
weeks before the Baseline Visit to allow inclusion in the study. They should remain on stable 
dose in the study up to Week 52.  
Subjects taking NSAIDs or acetaminophen PRN within the 2 weeks before baseline can 
continue to do so in the study; however, they have to refrain from any intake during the 24 hours 
before a visit.  
Any change of the NSAIDs or acetaminophen treatment during the trial should be recorded on 
the corresponding eCRF page 

Novartis 
Confidential 
Page 40 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, study treatment discontinuation and knowledge of 
the possible treatment assignments are sufficient to treat a study patient who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT system. 
When the Investigator contacts the IRT system to break a treatment code for a patient, he/she 
must provide the requested patient identifying information and confirm the necessity to break 
the treatment code for the patient. The Investigator will then receive details of the 
investigational drug treatment for the specified patient and a confirmation via email and/or fax. 
The system will automatically inform the Novartis monitor for the site and the Clinical Trial 
Lead (CTL) that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a procedure in place in case of an 
emergency. The Investigator will inform the patient how to contact his/her backup in cases of 
emergency when he/she is unavailable. The Investigator will provide protocol number, study 
treatment name if available, patient number, and instructions for contacting Novartis Country 
Pharma Organization CPO (or any entity to which it has delegated responsibility for emergency 
code breaks) to the patient in case an emergency treatment code break is required at a time when 
the Investigator and backup are unavailable. 

Novartis 
Confidential 
Page 41 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
The last scheduled administration of therapy will be at Visit 18/Week 48. A subject’s study 
participation is completed once Visit 19/Week 52 has been completed. After this date, any SAEs 
that occur in the following 30 days must be reported. The investigator will also follow any AEs 
for which there is no outcome that can be reported at the final study visit. Pregnancies will be 
followed until the outcome of the pregnancy is known.  
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the corresponding CRFs.  
In any case, the investigator or site staff must contact the IRT system as soon as possible to 
record the subject’s study completion (Week 52) and/or withdrawal from the trial.  
The study as a whole will be completed once all enrolled patients have completed the study per 
the protocol and the clinical database has been locked. Recruitment into the study will be 
terminated by the sponsor once the targeted number of randomized patients has been met or is 
foreseen to be met with the patients already in screening. Patients who have been screened and 
have a screening visit recorded in the IRT system at the time that the planned enrollment number 
is met will be allowed to enter the trial and to be randomized if they are eligible. 
Upon completion of study participation, patients will return to individual medical treatment, as 
determined by their treating physician.  
The Investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
5.6.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the subject or the investigator.   
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment would result in a significant safety risk for a subject. Patients that discontinue study 
treatment cannot continue in the trial. They must be discontinued from the trial 
altogether. 
The following circumstances require study treatment discontinuation and consequently 
discontinuation from the trial: 
• Withdrawal of informed consent 
• Emergence of the following adverse events: 
a. Any severe or serious adverse event that in the judgment of the investigator/qualified 
site staff, taking into account the subject’s overall status, prevent the subject from 
continuing study treatment; 
b. 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 
. 

Novartis 
Confidential 
Page 42 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
c. Life-threatening infection 
• Pregnancy; 
 
 
 
• Emergency unblinding 
• Patient refusal to complete PRO questionnaires at Baseline, Week 12 or Week 16 
• Any other protocol deviation that results in a significant risk to the subject’s safety; 
For any subject whose treatment code has been broken inadvertently for any reason, the 
appropriate personnel from the site and Novartis will assess whether study treatment should be 
discontinued.  
The investigator must also contact the IRT system to register the subject’s discontinuation from 
study treatment. 
Patients may voluntarily withdraw from the study for any reason at any time. They may be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
5.6.3 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time.  
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore, and does not want any further visits or assessments, and does not want any further 
study-related contacts.  
If premature withdrawal occurs for any reason, the investigator must make every effort (e.g. 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient source and on the appropriate study completion eCRF.  
Patients who withdraw consent should return for an End of Study Visit (see Table 6-1). The 
End of Study Visit should be scheduled approximately four weeks after the last study treatment, 
and should be performed before any new treatment is initiated. After the End of Study Visit, 
any SAEs that occur in the following 30 days must be reported. The investigator will also follow 
any AEs for which there is no outcome that can be reported at the final study visit. Pregnancies 
will be followed until the outcome of the pregnancy is known. 
Patients who are prematurely withdrawn from the study will not be replaced by newly enrolled 
patients. 
5.6.4 
Loss to follow-up 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
subject, e.g. dates of telephone calls, registered letters, etc. 

Novartis 
Confidential 
Page 43 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrollment). Should this be necessary, the subject 
should be seen as soon as possible and treated as a prematurely withdrawn as described in 
Section 5.6.2. The investigator may be informed of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing Institutional Review Board/Independent 
Ethics Committee (IRBs/ECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
Assessments that will only be reported in the source documentation are marked with an ‘S’. 
Patients/subjects must be seen for all visits on the designated day, or as close to it as possible. 
Missed or rescheduled visits should not lead to automatic discontinuation. For patients unable 
to travel to the clinic for their study visit, flexible study visits (home nursing study visits) and 
telemedicine/telephone visits with direct to patient shipment of study drug are alternative 
options for all post-Baseline study visits.  For more information regarding flexible study visits, 
please refer to the Site Manual for Home Visits (Flexible Study Visits).Patients who 
prematurely discontinue the study for any reason should be scheduled for an End of Study Visit 
as soon as possible, at which time all of the assessments listed will be performed. At this End 
of Study Visit, all dispensed investigational product should be reconciled and the adverse event 
and concomitant medications reconciled on the CRF. 
If patients do not have a chest X-ray available within 3 months of screening, the X-ray should 
be performed only after it is certain the subject meets inclusion/exclusion criteria in order to 
minimize unnecessary exposure to radiation.  
Patients evaluated at Screening 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 the Baseline Visit. 
Screening will be flexible in duration based on the time required to be evaluated for eligibility. 
Sufficient time is allowed for potential medication washout, in addition to all other assessments 
indicated in Table 6-1. Upon the completion of screening and confirmation that all inclusion 
and none of the exclusion criteria have been met, the subject may begin the Baseline Visit. 
Screening will consist of two consecutive visits. During Screening Visit 1 (SV1) and Screening 
Visit 2 (SV2), initial assessments will be performed as outlined in Table 6-1. 
 
 
 
 
 
Patients who may be eligible for Screening Visit 2 immediately following Screening Visit 1 
should have at least one week in between these two screening visits.   

Novartis 
Confidential 
Page 44 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
Premature Discontinuation 
For patients who discontinue study treatment prematurely for any reason after baseline, an 
End of Study Visit must be performed approximately four weeks after the last dose of study 
treatment.  In accordance with SAE reporting guidelines, any SAEs reported in the 30 days 
after the End of Study Visit, regardless of causality, must be reported to Novartis within 24 
hours of learning of its occurrence and recorded in the eCRF. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation. 
Unscheduled visits 
Patients may be seen at any time for an unscheduled visit, e.g., if they experience deterioration 
or AEs that in the opinion of the investigator/qualified site staff need intervention or repeat 
laboratory testing. The assessment(s) performed at an unscheduled visit must include at 
minimum: an assessment of concomitant medication and procedures/significant non-drug 
therapies, vital signs, and an AE/SAE assessment. Any additional assessments performed are at 
the investigator/qualified site staff’s discretion. During an unscheduled visit, study treatment 
will not be administered. 

Novartis 
Confidential 
Page 45 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Table 6-1 
Assessment schedule 
 
Period 
SCR1 
Treatment Period 1 
(Open-Label) 
Treatment Period 2  
 (Double-Blind or Open-Label) 
 
 
 
Week 
-13 
to 
-3 
-2 
to 
BL 
BL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/Study 
Completion/ 
EOS2 
Telemedicine/
telephone 
visit 
Unscheduled 
Notes 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Obtain 
informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
10.2 
Inclusion / 
exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See sections  
4.1 – 4.2 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.3 
General 
Medical history 
/ previous 
therapies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.3 
Relevant AS 
medical history 
/ current 
medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.3 
Washout 
evaluation / 
instruction 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Table 5-
1 
Modified NY 
criteria 
S 
S 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
13.2 
Radiologic 
evidence (x-
ray) to central 
reader 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.9 

Novartis 
Confidential 
Page 46 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Period 
SCR1 
Treatment Period 1 
(Open-Label) 
Treatment Period 2  
 (Double-Blind or Open-Label) 
 
 
 
Week 
-13 
to  
-3 
-2  
to 
BL 
BL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/Study 
Completion/ 
EOS2 
Telemedicine/
telephone 
visit 
Unscheduled 
Notes 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and 
alcohol history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.3 
Cardiovascular 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.3 
Physical Exam3 
 
S 
S 
 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
See section 
6.6.4 
Weight 
 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
See section 
6.6.6 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.6 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
See section 
6.6.5 
Chest X-ray 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.2 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.3 
Prior/ 
Concomitant 
medication/ 
non-drug 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See section 
5.5.7 

Novartis 
Confidential 
Page 47 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Period 
SCR1 
Treatment Period 1 
(Open-Label) 
Treatment Period 2  
 (Double-Blind or Open-Label) 
 
 
 
Week 
-13 
to  
-3 
-2 
to 
BL 
BL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/Study 
Completion/ 
EOS2 
Telemedicine/
telephone 
visit 
Unscheduled 
Notes 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT transaction 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
X 
 
See section 
5.3 
Administration 
of s.c. study 
treatment via 
PFS  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
See section 
5.5.4 
Adverse 
Events/SAEs 
(inc. injection 
site reaction & 
occurrence of 
infections) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See section  
7.1 – 7.2 
QuantiFERON 
TB-Gold test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.1 
Hematology, 
blood 
chemistry4 
 
X 
X 
 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
See section 
6.6.7.1 -
6.6.7.2 
Serum 
pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.8 
Urinalysis/Urin
e pregnancy 
test 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
See section 
6.6.7.3 and 
6.6.8 
HLA-B27 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See section 
6.6.7.4  

Novartis 
Confidential 
Page 48 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Period 
SCR1 
Treatment Period 1 
(Open-Label) 
Treatment Period 2  
 (Double-Blind or Open-Label) 
 
 
 
Week 
-13 
to  
-3 
-2  
to 
BL 
BL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/Study 
Completion/ 
EOS2 
Telemedicine/
telephone 
visit 
Unscheduled 
Notes 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Responder 
status 
assessment 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
See section 
3.1 
BASDAI 
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
See section 
6.5.2.7 
Patient’s global 
assessment of 
disease activity  
X5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
See section 
6.5.2.4 
ASAS-HI 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
See section 
6.5.4 
FACIT-Fatigue 
v4 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
See section 
6.5.6 

Novartis 
Confidential 
Page 49 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Period 
SCR1 
Treatment Period 1 
(Open-Label) 
Treatment Period 2  
 (Double-Blind or Open-Label) 
 
 
 
Week 
-13 
to  
-3 
-2 
to 
BL 
BL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52/Study 
Completion/ 
EOS2 
Telemedicine/
telephone 
visit 
Unscheduled 
Notes 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
 
 
 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
period 1 
completion 
form 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Treatment 
period 2 
completion 
form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
   
2 Patients who discontinue prematurely or withdraw consent should return for an End of Study Visit. The End of Study Visit should be scheduled approximately four (4) weeks after the last study  
treatment and should be performed before any new treatment is initiated. 
3 The Physical Exam is documented in the source; not in the database. If flexible study visits are permitted, a limited physical assessment will be performed by the home nurse in place of a complete physical 
examination. 
4 Fasting sample 
5 Measures captured only for TNF inhibitor inadequate responders currently on a TNF inhibitor and prior to discontinuation/washout. 
 

Novartis 
Confidential 
Page 50 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
6.1 
Rescreening 
Rescreening may be allowed under certain conditions.  Requests from the investigator/site staff 
to rescreen patients will be handled on a case-by-case basis with Medical Director approval 
required before proceeding with the rescreening.  Rescreening cannot be done if the patient 
previously entered Treatment Period 1 or Treatment Period 2. 
If a patient rescreens for the study, the patient must sign a new ICF and be issued a new patient 
number prior to any screening assessments being conducted under the new patient number.  The 
date of the new informed consent signature must be entered in the Informed Consent eCRF 
corresponding to the new patient number. 
For rescreening, all screening assessments must be performed per protocol, except the 
tuberculosis (TB) work up (if applicable).  If the date of the TB work up is less than 12 weeks 
from the projected baseline date, then it is not required that the TB work up be repeated; 
however, the rescreened patient MUST repeat the QuantiFERON test performed by the central 
laboratory. 
6.2 
Information to be collected on screening failures  
All patients who sign informed consent but discontinue prior to the Baseline Visit at Visit 3 are 
considered screening failures. The IRT system must be notified about the discontinuation, and 
the primary reason for the screen failure should be entered in the Screening Phase Disposition 
eCRF.  
In addition, only the following eCRFs should be completed: Demography eCRF, Informed 
Consent eCRF, Inclusion/Exclusion eCRF, and the adverse event (AE) eCRF should be 
completed for any Serious Adverse Events (SAEs) that occurred during the Screening Period. 
Adverse events that are not serious will be followed by the investigator and collected only in 
the source data. 
6.3 
Patient demographics/other baseline characteristics 
At Screening Visit 1, subject demographic and baseline characteristic data to be collected on 
all subjects and to be recorded in the CRF include: 
• Age, sex, race, ethnicity 
• Relevant AS and general medical history/current medical condition data until the start 
of investigational treatment: date of AS symptom onset (specifically axial symptom 
onset in the back, buttock or hip pain), date of AS diagnosis, targeted medical history 
events related to AS, such as the history of extra-axial involvement (uveitis, psoriasis, 
inflammatory bowel disease, enthesitis, peripheral arthritis), number of previous 
DMARDs used, previous AS therapies, functional status class according to New York 
criteria, cardiovascular medical history and smoking history. 
Where possible, diagnoses and not symptoms will be recorded. 

Novartis 
Confidential 
Page 51 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Investigators will have the discretion to record abnormal test findings on the CRF capturing 
medical history whenever in their judgment the test abnormality occurred prior to the informed 
consent signature.  
6.4 
Treatment exposure and compliance  
All dates and times of study treatment administration will be recorded on the appropriate CRF. 
Drugs administered prior to start of treatment and other drugs/procedures continuing or started 
during the study treatment period will be entered in the appropriate CRF. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in Section 5.5.5. Compliance will be assessed by a field monitor using
 information provided by the subject and the authorized site personnel. All study treatment 
dispensed and returned must be recorded in the Drug Accountability Log. 
6.5 
Efficacy 
• Ankylosing Spondylitis Disease Activity Score (ASDAS) and ASDAS response categories  
• Assessment of Spondyloarthritis International Society criteria (ASAS) 
• Patient’s global assessment of disease activity  
• Patient’s assessment of back pain intensity 
 
 
• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
 
 
• ASAS-Health Index (ASAS-HI) 
 
 
• FACIT- Fatigue 
All efficacy assessments should be performed prior to administration of study treatment. Details 
relating to the administration of all PROs are provided in Appendix 4. 
6.5.1 
ASDAS and ASDAS response categories 
The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess 
disease activity in AS. The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) will 
be utilized to assess the disease activity status. Parameters used for the ASDAS calculation 
include:  
1. Spinal pain (BASDAI question 2),  
2. The patient’s global assessment of disease activity,  
3. Peripheral pain/swelling (BASDAI question 3),  
4. Duration of morning stiffness (BASDAI question 6) and  
5. C-reactive protein (CRP) in mg/L (Sieper 2009, Lukas 2009).  
Disease activity states are inactive disease, moderate disease activity, high disease activity, and 
very high disease activity. The 3 values selected to separate these states were: 

Novartis 
Confidential 
Page 52 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
• < 1.3 between inactive disease and moderate disease activity,  
• < 2.1 between moderate disease activity and high disease activity, and  
• 3.5 between high disease activity and very high disease activity.  
Selected cutoffs for improvement scores were a change ≥ 1.1 unit for “clinically important 
improvement” and a change ≥ 2.0 units for “major improvement” (Machado 2011). 
6.5.2 
Assessment of Spondylo-Arthritis International Society criteria (ASAS)  
The ASAS response measures consist of the following assessment domains (Sieper 2009). 
ASAS domains: 
• Patient’s global assessment of disease activity measured on a NRS 
• Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a NRS 
• Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by a NRS 
• Inflammation represented by mean duration and severity of morning stiffness, 
represented by the average of the last 2 questions on the 6-question BASDAI as 
measured by a NRS 
6.5.2.1 
ASAS Responder Criteria 20% (ASAS20) 
ASAS 20 response is defined as an improvement of ≥ 20% and ≥ 1 unit on a scale of 10 in at 
least three of the four domains and no worsening of ≥ 20% and ≥ 1 unit on a scale of 10 in the 
remaining domain. Assessments will be made relative to patient’s baseline values.  
6.5.2.2 
ASAS Responder Criteria 40% (ASAS40) 
ASAS 40 response is defined as an improvement of ≥ 40% and ≥ 2 units on a scale of 10 in at 
least three of the four domains and no worsening at all in the remaining domain. Assessments 
will be made relative to patient’s baseline values. 
6.5.2.3 
ASAS partial remission criteria  
The ASAS partial remission criteria are defined as a value not above 2 units in each of the four 
domains on a scale of 10. 
 
  
  
 
 
 

Novartis 
Confidential 
Page 53 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5.2.7 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  
The BASDAI will be completed at Visits 2 – 19.  It consists of a 0 through 10 scale (0 being no 
problem and 10 being the worst problem, captured using a NRS), which is used to answer 6 
questions pertaining to the 5 major symptoms of AS: 
1. Fatigue 
2. Spinal pain 
3. Joint pain / swelling 
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments) 
5. Morning stiffness severity 
6. Morning stiffness duration 
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken. The mean of questions 5 and 6 is added to the scores from questions 
1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 BASDAI score. Scores of 
4 or greater suggest suboptimal control of disease, and subjects with scores of 4 or greater are 
usually good candidates for either a change in their medical therapy or for enrollment in clinical 
studies evaluating new drug therapies directed at AS. BASDAI is a quick and simple index 
taking between 30 seconds and 2 minutes to complete. Note: BASDAI is only assessed at 
Screening Visit 1 for TNF inhibitor inadequate responders currently on a TNF inhibitor and 
prior to discontinuation/washout. 
 

Novartis 
Confidential 
Page 54 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 
 
 
 
 
 
6.5.4 
ASAS Health Index (ASAS-HI) 
The ASAS-HI is administered at Visit 3 and Visits 7 – 19.  It is a self-administered questionnaire 
and measures functioning and health over 17 aspects of health and 9 environmental factors in 
patients with spondyloarthritis. Items include pain, maintaining a body position, moving 
around, toileting, energy/drive, motivation, sexual functions, driving, community life, handling 
stress, recreation/leisure, emotional functions, washing oneself, economic self-sufficiency, and 
sleep. Patients score each item as “I agree” and “I do not agree”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.5.6 
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue) 
The FACIT-Fatigue© is a 13-item questionnaire (Cella 1993; Yellen 1997) that assesses self-
reported fatigue and its impact upon daily activities and function. It is administered at Visits 3 
– 19. 
6.5.7 
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are the standard measures used across all 
ankylosing spondylitis studies. 
6.6 
Safety 
Safety assessments will consist of evaluating all AEs and SAEs including injection site 
reactions, ECGs, physical examination, vital signs and laboratory assessments, and assessment 
of anti-secukinumab antibody development (immunogenicity). 

Novartis 
Confidential 
Page 55 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g. evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered. 
• Determination of tuberculosis status  
• Chest X-ray 
• Electrocardiogram 
• Physical examination 
• Vital signs 
• Height and weight 
• Laboratory evaluations (Hematology, Clinical Chemistry, LFTs, Urinalysis) 
• Pregnancy and assessment of fertility 
• Tolerability of secukinumab 
• Local tolerability (Injection site reactions) 
• Evaluation of AE/ SAE’s 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g., evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered. 
6.6.1 
Determination of tuberculosis status  
Determination of tuberculosis (TB) status will be required before administration of study 
treatment. TB status must be determined by medical history, signs, symptoms, and TB testing 
(QuantiFERON-TB Gold assay). If the QuantiFERON-TB Gold Assay test is positive or 
indeterminate, a TB workup should be performed as defined by local guidelines to 
determine the subject’s TB status. 
QuantiFERON TB-Gold In-Tube assay 
A QuantiFERON® TB-Gold In-Tube assay will be performed to assess the TB status at 
screening for all patients. This test will only be used to determine subject’s eligibility for the 
trial. The test will be used to screen the subject population for latent tuberculosis infection 
(Doherty et al 2008). 
This blood-based assay is specific for Mycobacterium tuberculosis and is not influenced by 
previous Bacillus Calmette-Guérin vaccination or exposure to other Mycobacteria species. 
This test, in contrast to the purified protein derivative (PPD) skin test, is also insensitive to a 
booster effect since the subject is not exposed to the vaccine. The assay measures the production 
of interferon-gamma and presents it relative to a negative and a positive control sample (Manuel 
and Kumar 2008)  
The QuantiFERON®-TB Gold assay test will be supplied by the central laboratory. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided in the Laboratory Manual. 
The results of a TB workup for a subject with a positive or indeterminate test must be recorded 
in the eCRF. 

Novartis 
Confidential 
Page 56 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
• If the test result is negative, the subject may be randomized. 
• If the test result is positive, the investigator should perform a TB workup for the test result 
as per local procedures. 
• Patients positive for latent TB per workup may be randomized to the trial if sufficient 
treatment has been initiated according to local routine clinical practice and will be 
maintained for the prescribed duration. 
• Patients positive for active TB per workup are not eligible for the study. 
• Patients negative for TB (no signs of latent or active TB) per workup may be randomized 
to the trial.  
• If the test result is indeterminate, it is recommended to repeat the test once. The 
investigator may decide to skip the repetition of the test and proceed directly to the 
workup (however this is not recommended). If a TB workup was conducted prior to 
screening, results from the workup can be used to assess eligibility if the workup was 
conducted within 12 weeks prior to baseline. 
• If the second test is negative, the subject may be randomized. 
• If the second test is positive or indeterminate, the investigator should perform a TB 
workup as per local guidelines. The subject will not be eligible for randomization if: 
“active tuberculosis is present”, or if “latent tuberculosis is present” and is untreated as per 
local guidelines. 
6.6.2 
Chest x-ray 
A chest X-ray, CT scan, or MRI obtained locally within 3 months prior to screening will be 
used to determine eligibility. If patients do not have a chest X-ray, CT scan, or MRI available 
within 3 months prior to screening, a chest X-ray only must be done after it is fairly certain the 
subject meets the other inclusion/exclusion criteria in order to minimize unnecessary exposure 
to X-ray radiation for patients. 
If the chest X-ray, CT scan, or MRI evaluated by a qualified physician shows evidence of 
ongoing infection or malignancy and the subject was not treated subsequent to the X-ray (CT 
scan or MRI), the subject will not be eligible to enter the study. 
6.6.3 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as indicated in Table 6-1. ECGs must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. Each ECG tracing should be labeled with study number, subject 
initials, subject number, date and time, and filed in the study site source documents. 
Clinically relevant abnormalities should be recorded on the relevant medical history/Current 
medical conditions eCRF page for the baseline ECG.  
Clinically relevant abnormalities noted after the baseline ECG should be reported as AE (see 
Section 7). 

Novartis 
Confidential 
Page 57 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
6.6.4 
Physical examination  
A complete physical examination will be performed by a professionally trained physician or 
health professional licensed to perform physical examinations and listed on FDA Form 1572, 
at the scheduled study visits as indicated in Table 6-1. 
The physical examination will include the examination of general appearance, skin, neck, eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological system. 
If flexible study visits are permitted, a limited physical assessment will be performed by the 
home nurse in place of a complete physical examination. For more information regarding 
flexible study visits, please refer to the Site Manual for Home Visits (Flexible Study Visits). 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF which meet the 
definition of an AE must be recorded in the Adverse Event eCRF. 
6.6.5 
Vital signs  
Vital signs will be assessed at Visits 2 – 19 and will include BP, pulse rate and body temperature 
measurements. After the subject has been sitting for five minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be measured using a validated 
device with an appropriately sized cuff. 
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study. 
Clinically notable vital signs are defined in 
 
6.6.6 
Height and weight 
Height (without shoes) will be measured at Screening Visit 2.  Body weight (in indoor clothing 
but without shoes) will be measured at Screening Visit 2 and Visits 3, 10 and 19. If possible, 
body weight assessments should be performed using the same scale throughout the study. The 
Body Mass Index will be calculated by the eCRF system. 
6.6.7 
Laboratory evaluations  
A central laboratory will be used for analysis of all specimens collected listed below (except 
urinalysis). Details on the collection, shipment of samples and reporting of results by the central 
laboratory are provided in the laboratory manual. For the identification of clinically notable 
values, see 
 All patients with laboratory tests containing clinically significant 
abnormal values are to be followed until the values return to normal ranges or until a valid 
reason, other than treatment related AE, is defined. 
6.6.7.1 
Hematology  
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at Screening Visit 2, and Visits 3, 9, 10, 13, 16 and 19. 

Novartis 
Confidential 
Page 58 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
6.6.7.2 
Clinical chemistry  
Measured at Screening Visit 2, and Visits 3, 9, 10, 13, 16 and 19, serum chemistry will include 
glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT (SGPT), GGT, alkaline 
phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, total protein, albumin, 
and uric acid.  
6.6.7.3 
Urinalysis  
Urinalysis will be performed at Visits 3, 7, 9, 10, 12, 14, 16 and 19. Dipsticks will be provided 
by the central laboratory to the sites for local urinalysis assessments. The urinalysis results for 
standard parameters such as protein, glucose, blood and WBCs will be recorded in the 
appropriate eCRF page.  
6.6.7.4 
HLA-B27 
HLA-B27 will be performed at Screening Visit 2. 
6.6.8 
Pregnancy and assessments of fertility  
Secukinumab must not be given to pregnant women; therefore effective methods of birth control 
must be used for women of child-bearing potential (see exclusion criteria definitions, Section 
4.2). 
A serum β-hCG test will be performed in all women of child bearing potential at Screening 
Visit 2; and a local urine pregnancy test at Visits 3, 7, 9, 10, 12, 14, 16 and 19.  A positive urine 
pregnancy test requires immediate interruption of study treatment until serum β-hCG is 
performed and found to be negative. If positive, the subject must be discontinued from the trial. 
6.6.9 
Documented radiologic evidence fulfilling the NY criteria for AS 
All patients will require a centrally read x-ray at Screening Visit 2. The outcome of the centrally 
read x-ray will not determine eligibility of the subject. For patients that are post-baseline, the 
x-ray should be sent to the central reader immediately.  
Investigator sites will receive training on the submission process from the central reader.  Once 
training is completed, sites will be expected to implement this requirement.  
6.6.10 
Tolerability of secukinumab 
Tolerability will be assessed by adverse events, laboratory values and injection site reaction.  
6.6.11 
Local tolerability  
The local tolerability at the site of s.c. injection of the study treatment will be assessed in case 
of any local reaction, until this has disappeared. 
The assessment of pain, redness, swelling, induration, hemorrhage and itching will be 
performed by a physician and will be recorded on the appropriate CRF capturing AEs, including 
the severity (mild, moderate, severe) and the duration of the adverse reaction. 

Novartis 
Confidential 
Page 59 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
6.6.12 
Appropriateness of safety measures  
The safety measures used in this study are reliable and relevant standard measures for a biologic 
in AS. The safety assessments selected are standard and adequate for this indication/subject 
population. A chest X-ray at screening (or within 3 months prior to screening) is performed to 
rule out the presence of a pulmonary malignancy or infectious process, in particular 
tuberculosis. The radiation exposure that results from the chest X-ray safety measurements are 
estimated to be far below 1 mS. Effective radiation doses under 3 mS (300 mrem), are 
considered to be minimal risk. Therefore, the radiation exposure in this study involves minimal 
risk and is necessary to ensure reliable safety measures before the treatment with a biologic. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 

Novartis 
Confidential 
Page 60 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Novartis 
Confidential 
Page 61 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
7 
Safety Monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms  
• they are considered clinically significant  
• they require therapy  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. 
 
 
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information. 
• the severity grade  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• relationship to the study treatment (no/yes) 
• duration (start and end dates) or if the event is ongoing an outcome of not recovered/not 
resolved should be reported. 
• whether it constitutes a serious adverse event 
 
 
• action taken regarding study treatment  
• All adverse events should be treated appropriately. Treatment may include one or more of 
the following:  
• no action taken (i.e. further observation only)  

Novartis 
Confidential 
Page 62 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
• study treatment temporarily interrupted  
• study treatment permanently discontinued due to this adverse event  
• concomitant medication given  
• non-drug therapy given  
• patient hospitalized/patient’s hospitalization prolonged  
• outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal or unknown) 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents. However, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious Adverse Events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 

Novartis 
Confidential 
Page 63 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
• is medically significant, i.e. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to Novartis DS&E as per Section 7.2.1.1. 
7.2.1.1 
SAE Reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after the 30 day period following the last study visit should only be 
reported to Novartis safety 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 must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 

Novartis 
Confidential 
Page 64 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
There has been no safety signal for liver toxicity with secukinumab to date in approximately 
13,000 patients and healthy subjects exposed, and from a mechanism of action standpoint there 
is no known effect of blocking IL-17A on the liver. Standard liver function tests will be obtained 
at regular intervals, but special measures for liver safety monitoring are not planned. For further 
information on standard liver function tests, see 
  
7.4 
Renal safety monitoring 
There has been no safety signal for nephrotoxicity with secukinumab to date in approximately 
13,000 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 
containing clinically significant abnormal values (see 
 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. 
7.5 
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 collected in 
the appropriate dose medication 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. 

Novartis 
Confidential 
Page 65 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Table 7-1 
Guidance for capturing the study treatment errors including misuse 
Treatment error 
type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE 
form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated 
with an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with 
an SAE 
7.6 
Pregnancy Reporting 
All pre-menopausal women who are not surgically sterile will have a urine pregnancy test. A 
positive urine pregnancy test requires immediate interruption of study drug until serum β-hCG 
is performed and found to be negative. 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of patient records, the accuracy of entries on the (e)CRFs, the adherence to the protocol and to 
Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is being 
stored, dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits.   
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 

Novartis 
Confidential 
Page 66 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to US CFR 21 Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 
they have been trained.  All 3rd party data will be transferred to database including laboratory 
and actigraphy data from the Phillips Actiwatch device.  
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
CRO working on behalf of Novartis. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive copies of the patient data for archiving at the investigational site.  
8.3 
Database management and quality control  
A CRO working on behalf of Novartis will review the data entered into the eCRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. Randomization codes and data about all study drug(s) assigned to the subject 
will be tracked using an Interactive Response Technology (IRT). The system will be supplied 
by a vendor, who will also manage the IRT database. The database will be sent electronically 
to Novartis (or a designated CRO). Each occurrence of a code break via IRT will be reported 
to the clinical team and study monitor.  The code break functionality will remain available until 
study completion or upon request of Novartis. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to a 
designated CRO. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 

Novartis 
Confidential 
Page 67 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
changes to the database after that time can only be made after written agreement by Novartis 
management. 
8.4 
Data monitoring committee 
Not required. 
8.5 
Adjudication committee 
Not required. 
9 
Data analysis 
It is planned that the data from all centers that participate in this protocol will be combined, so 
that an adequate number of patients will be available for analysis. 
The analysis will be conducted on all patient data at the time the trial ends.  
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Upon completion of Treatment Period 1 (Week 16), responders will enter Treatment Period 2 
and continue to receive secukinumab 150mg every 4 weeks through Week 48. Inadequate 
responders will enter Treatment Period 2 and will be randomized (1:1, double-blinded) to 
secukinumab 300 mg or secukinumab 150 mg very 4 weeks through Week 48. Nonresponders 
will be discontinued from the study at Week 16. 
Efficacy, safety, and other data from Treatment Period 1, randomized Treatment Period 2 for 
inadequate responders, and blinded Treatment Period 2 for responders will be summarized.  For 
continuous variables, summary statistics (mean, standard deviation, median, 25th and 75th 
percentiles, interquartile range, minimum, and maximum) at each time point and for change 
from baseline to Week 16, and change from Week 16 to each time point by treatment group 
will be reported.  For discrete variables, frequency counts and percentages at each time point 
will be reported by treatment group. 
9.1 
Analysis sets 
The following analysis sets will be used for the statistical reporting and analyses: 
Enrolled Set:  The Enrolled Set consists of all enrolled patients for the initial 16-week, 
Treatment Period 1. 
Responder Set: The Responder Set consists of all patients who are labeled as responders at the 
end of Treatment Period 1, and enter Treatment Period 2 receiving blinded secukinumab 150 
mg every 4 weeks through Week 48. 
Randomized Set: The Randomized Set consists of all randomized patients.   
Safety Set: The Safety Set includes all patients who received at least one dose of study treatment 
during Treatment Period 2.  Patients will be analyzed according to the study treatment received. 

Novartis 
Confidential 
Page 68 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Full Analysis Set:  The Full Analysis Set comprises all patients to whom study treatment has 
been assigned by randomization.  Patients inappropriately randomized (e.g., IRT was called in 
error for randomization of a screen failed patient) will be excluded from this analysis set.  
According to the intent-to-treat principle, patients will be analyzed according to the treatment 
they have been assigned to during the randomization procedure. 
9.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively for the Enrolled Set, for the Responder Set, and by treatment group 
for the Full Analysis Set and Safety Set. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, for the Enrolled Set, for the Responder Set, and by 
treatment group for the Safety Set. 
9.3 
Treatments 
The duration of exposure (in days) will be summarized by means of descriptive statistics for the 
Enrolled Set, for the Responder Set, and for each treatment group for the Safety Set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, for the Enrolled Set, for the Responder Set, and by 
treatment group for the Safety Set. 
 
9.4 
Analysis of the primary variable(s) 
9.4.1 
Primary variable(s) 
The primary efficacy variable is the ASDAS inactive disease response (yes, no).  The primary 
analysis time point is at Week 52. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Let πj denote the probability of an ASDAS inactive disease at Week 52 for treatment group j, j 
= 1, 2, where 1 and 2 correspond to secukinumab 150 mg and secukinumab 300 mg, 
respectively.  Accordingly, πj/(1 – πj) is the odds for treatment group j, j = 1, 2. 
The primary efficacy variable will be analyzed at each time point using a logistic regression 
model with treatment, TNF-alpha inhibitor status (naive, inadequate responder), and baseline 
body weight as explanatory variables (Stokes, Davis, and Koch, 2012).  The odds ratios and 
95% confidence intervals for the odds ratios will be reported, based on the fitted model.  
The primary analysis of the primary efficacy variable will be based on the Full Analysis Set. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Post-randomization patients who discontinue prematurely for any reason will be considered 
non-responders from the time they discontinued.   

Novartis 
Confidential 
Page 69 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
In an additional analysis, missing data for ASDAS inactive disease response will be imputed 
using multiple imputation. 
9.4.4 
Sensitivity analyses 
A 95% confidence interval for the difference between the two treatment groups in the proportion 
of patients who have ASDAS inactive disease will be calculated using the normal 
approximation to the binomial distribution for the Full Analysis Set. 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
The secondary efficacy variables are the following: 
1. Reduction in ASDAS ≥ 1.1 from Week 16 (yes, no) 
2. Change from Week 16 in total BASDAI 
3. BASDAI50 response (yes, no)  
4. ASAS20 response (yes, no)  
5. ASAS40 response (yes, no)  
6. ASAS partial remission (yes, no) 
7. Change from Week 16 in ASAS-Health Index 
8. Change from Week 16 in FACIT-Fatigue 
Analyses of secondary efficacy variables 1 and 3 – 6 at each time point will be similar to the 
primary and sensitivity analyses of the primary efficacy variable.   
Secondary efficacy variables 2, 7, and 8 will be analyzed at each time point by an analysis of 
covariance model with treatment, Week 16 value, TNF-alpha inhibitor status (naive, 
inadequate responder), and baseline body weight as explanatory variables.  The least squares 
means of the treatment groups, least squares mean difference, and 95% confidence interval for 
the difference will be reported, based on the fitted linear model.  Missing data will be imputed 
using the last-observation-carried-forward method.  In an additional analysis, missing data 
will be imputed using multiple imputation.  
Analyses of the secondary efficacy variables will be based on the Full Analysis Set. 
9.5.2 
Safety variables 
For safety analyses, the Enrolled Set will be used for Treatment Period 1, and the Safety Set 
will be used for Treatment Period 2. All listings and tables will be presented for Treatment 
Period 1, for responders who enter Treatment Period 2, and by treatment group for inadequate 
responders who are randomized. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and patient. 
The number (and percentage) of patients with adverse events will be summarized in the 
following ways: 

Novartis 
Confidential 
Page 70 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
by treatment, primary system organ class and preferred term; 
by treatment, primary system organ class, preferred term and maximum severity; 
by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, 
serious adverse events, and other significant adverse events leading to discontinuation. 
A patient with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, patient, and visit/time, and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 
12-lead ECG 
All ECG data will be listed by treatment group, patient and visit/time; abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, patient, and visit/time, and if reference 
ranges are available, abnormalities will be flagged. Summary statistics will be provided by 
treatment and visit/time. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 

Novartis 
Confidential 
Page 71 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
 
  
 
 
 
 
 
  
 
9.7 
Interim analyses 
No interim analysis is planned. 
9.8 
Sample size calculation 
The sample size was calculated based on the primary efficacy variable (i.e., ASDAS inactive 
disease response) at Week 52 for the Full Analysis Set.  The expected ASDAS inactive disease 
response rates for secukinumab 300 mg and 150 mg treatment groups at Week 52 are 20% and 
10%, respectively (corresponding to an odds ratio of 2.25), partly based on results from 
AIN457F2310 (MEASURE 2) study.  With approximately 97 patients in each treatment group 
(total of 194 randomized patients), one will be able to estimate the difference between ASDAS 
inactive disease response rates of the two treatment groups at Week 52 with a “margin of error” 
(half-width of confidence interval) of 10% (corresponding to a standard error of 5%) for a two-
sided 95% confidence interval (Julious and Patterson, 2004; nQuery Advisor 7.0). 
It is expected that the study will need to enroll approximately 270 patients for the 16-week 
open-label period, to randomize approximately 194 patients who do not achieve ASDAS 
inactive disease status at Week 16 (inadequate responders).  This assumes that 10% of the 270 
enrolled patients will discontinue during the 16-week open-label period; among the remaining 
enrolled patients, it is assumed that approximately 10% will be responders, 80% will be 
inadequate responders, and 10% will be non-responders. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki. 

Novartis 
Confidential 
Page 72 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
10.2 
Informed consent process 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents.  
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval. 
 
 
 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 

Novartis 
Confidential 
Page 73 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
10.5 
Quality control and quality assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those involved 
in conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures, and are performed according to written 
Novartis processes. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
All significant protocol deviations will be recorded and reported in the CSR.  
11.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to patients may be implemented immediately provided the Health Authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any patient included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring should be followed. 
 
 
 

Novartis 
Confidential 
Page 74 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
12 
References 
References are available upon request.  
Baeten D, Sieper J, Braun J, et al (2015) Secukinumab, an interleukin-IL17A inhibitor, in 
ankylosing spondylitis. N Eng J Med; 373:2534-48. 
Baraliakos X, Landewe R, Hermann K-G, et al (2005) Inflammation in ankylosing 
spondylitis: a systematic description of the extent and frequency of acute spinal changes using 
magnetic resonance imaging. Ann Rheum Dis; 64:730-34. 
Baraliakos X, Listing J, Fritz C, et al (2011) Persistent clinical efficacy and safety of 
infliximab in ankylosing spondylitis after 8 years--early clinical response predicts long-term 
outcome. Rheumatology; 50:1690-9. 
Batmaz, Ibrahim, et al. "Sleep quality and associated factors in ankylosing spondylitis: 
relationship with disease parameters, psychological status and quality of life." Rheumatology 
international 33.4 (2013): 1039-1045. 
Braun J, Baraliakos X, Deodhar A, Baeten D, Sieper J, Emery P, Readie A, Martin R, Mpofu 
S, Richards HB (2017) Effect of secukinumab on clinical and radiologic outcomes in 
ankylosing spondylitis: 2-year results from the randomized phase III MEASURE 1 study. Ann 
Rheum Dis; 76:1070-1077. 
Carney CE, Buysse DJ, Ancoli-Israel S, Edinger JD, Krystal AD, Lichstein K, Morin C. 
(2012) The consensus sleep diary: standardizing prospective sleep self-monitoring. 
SLEEP;35(2):287-302.Cella DF, Tulsky DS, Gray G, et al. (1993) The Functional Assessment 
of Cancer Therapy (FACT) scale: Development and validation of the general measure. 
Journal of Clinical Oncology; 11(3):570-9. 
Chen KY, Bassett DR (2005) The technology of accelerometry-based activity monitors: 
current and future. Med Sci Sports Exerc; 37(11 Suppl):S490-500 
Cosentyx [package insert] (2016) East Hanover NJ: Novartis. 
Deodhar, Atul, Jürgen Braun, Robert D. Inman, Michael Mack, Shreekant Parasuraman, 
Jacqueline Buchanan, Benjamin Hsu, Tim Gathany, and Désirée Van Der Heijde. 
"Golimumab reduces sleep disturbance in patients with active ankylosing spondylitis: results 
from a randomized, placebo‐controlled trial." Arthritis care & research 62, no. 9 (2010): 1266-
1271. 
Doherty SD, Van Voohes A, Lebwohl MG (2008) National Psoriasis Foundation consensus 
statement on screening for latent tuberculosis infection in patients with psoriasis treated with 
systemic and biologic agents. J Am Acad Dermatol; 59(2):209-17. 
Gladman DD (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9:455-60. 
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. (2003) Assessment of enthesitis 
in ankylosing spondylitis. Ann Rheum Dis; 62:127-32. 
In E, Turgut T, Gulkesen A, Yolbas S, Akgol G, Koca SS (2016) Sleep quality is related to 
disease activity in patients with ankylosing spondylitis. J Clin Rheumatol; 22(5):248-252 
Julious SA, Patterson SD (2004) Sample sizes for estimation in clinical research. 
Pharmaceutical Statistics; 3:213-215. 

Novartis 
Confidential 
Page 75 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
Langley RG, Elewski BE, Lebwohl M, et al (2014) Secukinumab in plaque psoriasis–results 
of two phase 3 trials. N Engl J Med; 371(4):326–38. 
Lukas C, Landewé R, Sieper J (2009) Development of an ASAS-endorsed disease activity 
score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis; 68(1):18-24. 
Machado PM, Landewé RB, van der Heijde DM (2011) Endorsement of definitions of disease 
activity states and improvement scores for the Ankylosing Spondylitis Disease Activity Score: 
results from OMERACT 10. J Rheum; 38(7):1502-06. 
Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Diagn; 8(3):247-56. 
 
Marzo-Ortega H, Sieper J, Kivitz A, Blanco R, Cohen M, Martin, R, Readie A, Richards HB, 
Porter B (2017) Secukinumab and sustained improvement in signs and symptoms of patients 
with active ankylosing spondylitis through two years: results from a phase III study. Arth 
Care & Res; 69(7):1020-1029. 
Mease PJ, McInnes IB, Kirkham B, et al (2015) Secukinumab inhibition of interleukin-17A in 
patients with psoriatic arthritis. N Engl J Med; 373(14):1329-39. 
McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, van der Heijde D, 
Landewe R, Conaghan PG, Gottlieb A, Richards H, Pricop L, Ligozio G, Patekar M, Mpofu 
(2015) Lancet; 386:1137-1146. 
Nemoto, O., M. Furue, H. Nakagawa, M. Shiramoto, R. Hanada, S. Matsuki, S. Imayama et 
al. (2016) The first trial of CIM331, a humanized antihuman interleukin-31 receptor A 
antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, 
tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-
controlled study. British Journal of Dermatology; 174: 296-304. 
Redfield, Margaret M., Kevin J. Anstrom, James A. Levine, Gabe A. Koepp, Barry A. 
Borlaug, Horng H. Chen, Martin M. LeWinter et al. (2015) Isosorbide mononitrate in heart 
failure with preserved ejection fraction. New England Journal of Medicine; 373:2314-2324. 
Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing 
spondylitis: a reassessment of the clinical history for application as classification and 
diagnostic criteria. Arthritis Rheum 2006; 54: 569–78. 
Sieper J, Rudwaleit M, Baraliakos X, et al (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis.; 
68 Suppl 2:ii1-44. 
Stokes ME, Davis CS, Koch GG (2012) Categorical data analysis using the SAS system. 3rd 
ed; Cary, NC: SAS Institute, Inc. 
Trudeau J, Van Inwegen R, Eaton T, Bhat G, Paillard F,  Ng D, Tan K, Katz NP (2015) 
Assessment of Pain and Activity Using an Electronic Pain Diary and Actigraphy Device in a 
Randomized, Placebo-Controlled Crossover Trial of Celecoxib in Osteoarthritis of the Knee. 
Pain Practice; 15:247-255. 

Novartis 
Confidential 
Page 76 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
van der Heijde D, Landewe RB, Mease PJ, McInnes IB, Conaghan PG, Pricop L, Ligozio G, 
Richards HB, Mpofu S (2016) Arth & Rheumatol; 68(8):1914-1921 
Yellen SY et al. (1997) Measuring Fatigue and Other Anemia-Related Symptoms with the 
Functional Assessment of Cancer Therapy (FACT) Measurement System. Journal of Pain and 
Symptom Management; 13:63-74. 

Novartis 
Confidential 
Page 77 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
13 
Appendices 

Novartis 
Confidential 
Page 78 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 

Novartis 
Confidential 
Page 79 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
13.3 
Appendix 3: Assessment of SpondyloArthritis International 
Society criteria (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper 2009). 
ASAS domains: 
1. Patient’s global assessment of disease activity measured on a NRS 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a NRS 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by a NRS 
4. Inflammation represented by mean duration and severity of morning stiffness, 
represented by the average of the last 2 questions on the 6-question BASDAI as 
measured by a NRS 
 
 
 
 
 
 
 
13.3.2 
 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured using a NRS), which is used to answer 6 questions pertaining to the 5 major 
symptoms of AS: 
1. How would you describe your overall level of fatigue/tiredness? 
2. How would you describe your overall level of neck, back or hip pain resulting from AS? 
3. How would you describe your overall level of pain/swelling in joints other than the neck, 
back or hips? 
4. How would you describe your overall level of discomfort from any areas tender to the 
touch or pressure? 
5. How would you describe your overall level of morning stiffness from the time you wake 
up? 
6. How long does your morning stiffness last from the time you wake up? 
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (questions 5 and 6) is taken. The mean of questions 5 and 6 is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10. 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical studies evaluating new drug therapies directed at Ankylosing 
Spondylitis. BASDAI is a quick and simple index (taking between 30 seconds and 2 minutes to 
complete). 

Novartis 
Confidential 
Page 80 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
13.3.3 
Appendix 4: Guidelines for administering the PRO questionnaires 
 
1. Study coordinators should familiarize themselves with the PRO questionnaire(s) in the 
trial and identify any items where a patient’s response might highlight issues of potential 
concern. For example, one question in the SF-12 ‘How much of the time in the past 4 
weeks- have you felt downhearted and blue?’ If a patient responds ‘most or all of the 
time’, then the study coordinator should inform the study investigator. 
2. Patients should have adequate space and time to complete their questionnaires. 
3. Questionnaires should be administered and completed before the clinical examination. 
4. The administrator may clarify the questions but should not influence the response. 
5. Patients should choose one response for each question.  
Addressing Problems and Concerns 
Occasionally a patient may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below. 
The patient does not want to complete the questionnaire(s) 
Tell the patient that completion of the questionnaire(s) is an important part of their participation 
in the study.  Patients that refuse to complete PRO questionnaires at Baseline, Week 12 or Week 
16 must be discontinued from the study per Section 5.6.2.  The goal of these questionnaires is 
to better understand the physical, mental, and social health problems of patients. Emphasize 
that this information is as important as any of the other medical information, and that the 
questionnaire(s) is simple to complete. Suggest that the questionnaire(s) may be different from 
anything the respondent has filled in the past.  
The patient is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain patient responses by reading out loud each 
question, followed by the corresponding response categories, and entering the patient’s 
response. No help should be provided to the patient by any person other than the designated 
study coordinator. The coordinator should not influence patient responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim. 
The patient wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the patient provide responses to the 
questions. Unless specified in the study protocol proxy data are not an acceptable substitute for 
patient self-reported. Patients should be discouraged from asking a family member or friend for 
help in completing a questionnaire. 
The patient does not want to finish completing the questionnaire(s) 
If non-completion is a result of the patient having trouble understanding particular items, ask 
the patient to explain the difficulty. Re-read the question for them verbatim, but do not rephrase 
the question. If the respondent is still unable to complete the questionnaire, that questionnaire 
will be forfeited since partial response will not be saved. Patients that refuse to complete PRO 

Novartis 
Confidential 
Page 81 
Amended Protocol Version 04 (Track Changes) 
 
Protocol No. CAIN457FUS06 
 
 
questionnaires at Baseline, Week 12 or Week 16 must be discontinued from the study per 
Section 5.6.2. 
The patient is concerned that someone will look at his/her responses 
Emphasize that all responses are to be kept confidential. Point out that their names do not appear 
anywhere on the questionnaire, so that their results will be linked with an ID number and not 
their name. Tell the patient that his/her answers will be pooled with other patients’ answers and 
that they will be analyzed as a group rather than as individuals. Tell the patient that completed 
questionnaires are not routinely shared with treating staff, and that their responses will only be 
seen by you and possibly the investigator. Any response which may directly impact on or reflect 
their medical condition (e.g. noting of severe depression) will be communicated by the 
coordinator to the physician. 
General Information about all questionnaire(s):  
All questionnaires are to be completed by the patients. The questionnaires should be completed 
by the patients in a quiet area free from disturbance, and before any visit assessments. Patients 
should receive no help from family members; if questions cannot be answered alone (due to 
problems with reading or understanding), then the doctor or nurse should read the questions 
verbatim without influencing their answers. The information provided is strictly confidential 
and will be treated as such.  
As there are no source data for the questionnaires, the data queries will be restricted to 
patient/visit information.