Conditions: Ankylosing Spondylitis
Keywords: Ankylosing spondylitis ASDAS inactive disease secukinumab ASDAS
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 322
Healthy volunteers: no

Brief summary:
This was a study estimating the clinical difference between 300 mg and 150 mg of secukinumab following dose escalation to 300 mg in patients with ankylosing spondylitis

Detailed description:
The study used a multicenter design which included an initial 16 week open-label period (Treatment Period 1) followed by a randomized, double-blind, parallel-group period (Treatment Period 2),

1. Screening: A Screening Period took place over 2 separate visits, with the first visit used to assess eligibility and to washout prohibited medications (up to 11 weeks). The second Screening Visit, which occurred at a minimum of 2 weeks prior to the Baseline Visit for all patients, was used to further assess eligibility and to initiate patients on the sensor actigraphy device and morning sleep questionnaires which collected data over the 2-week Screening Period to establish Baseline data. Note: Patients who did not require a washout, and who satisfied all inclusion and none of the exclusion criteria at the first Screening Visit, could initiate the second Screening Visit 1 (SV1) week after their first Screening Visit.
2. Treatment Period 1: Patients who met all of the inclusion criteria and none of the exclusion criteria had a Baseline Visit performed to start Treatment Period 1. During this 16-week period, all patients received open-label secukinumab 150 mg (1 x 1.0mL subcutaneously \[s.c.\]) at Baseline, Weeks 1, 2, 3, 4, 8, and 12.

At Week 16, patients were placed into 1 of the following groups:

1. Responders (Rs): Patients who achieved ASDAS inactive disease (total score \< 1.3) at both Week 12 and Week 16 and who achieved a decrease (improvement) from Baseline in total ASDAS score at both Week 12 and Week 16.
2. Inadequate responders (IRs): Patients who had active disease, defined as an ASDAS total score of ≥ 1.3 at either Week 12 or Week 16, and who achieved a decrease (improvement) from Baseline in total ASDAS score at both Week 12 and Week 16.
3. Nonresponders: Patients who exhibited 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 was 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.

1\. Treatment Period 2: Upon completion of the Week 16 visit,

1. Responders entered Treatment Period 2 and continued to receive secukinumab 150 mg every 4 weeks through Week 48 as well as 1 matched placebo dose (s.c. injection) to maintain the integrity of the blind for the randomized IR group.
2. Inadequate responders entered Treatment Period 2 and were randomized (1:1, double blinded) to secukinumab 300 mg or secukinumab 150 mg every 4 weeks through Week 48. Patients knew that they were on secukinumab, but were blinded to dose, so they did not know whether they were receiving 150 mg or 300 mg.
3. Nonresponders were discontinued from the study at Week 16. The only condition that was placed on enrollment targets was that no less than 60% of patients (162 patients) were tumor necrosis factor alpha (TNFα) inhibitor naive (or, no more than 40% of patients were TNF-IR). In theory the percentage of TNFα inhibitor naive patients could have reached 100%, although that was not anticipated.

Patients could discontinue the study at any time. If rescue treatment with prohibited medications (as described in Section 9.4.7) occurred, patients were discontinued from the study and were to return for an End of Study Visit. The End of Study Visit was scheduled approximately 4 weeks after the last study treatment and was performed before any new treatment was initiated. After the End of Study Visit, any serious adverse events (SAEs) that occurred in the following 30 days were required to be reported.

Arms:
arm 1: Patients who achieved an Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (total score \<1.3) at both Week 12 and Week 16. arm 2: Patients who have active disease, defined as an Ankylosing Spondylitis Disease Activity Score (ASDAS) total score of \>1.3 at both Week 12 and Week 16, and who achieved a decrease (improvement) from baseline in total ASDAS score at both Week 12 and Week 16. arm 3: Patients who exhibit no change or an increase (worsening) from baseline in total Ankylosing Spondylitis Disease Activity Score (ASDAS) score at either Week 12 or Week 16.

Non-responders were not entered Treatment Period 2. Non-responders were discontinued from the study at Week 16.

Interventions: intervention 1: 150 mg open-label secukinumab intervention 2: 150 mg double-blinded secukinumab intervention 3: 300 mg double-blinded secukinumab
Intervention descriptions: intervention 1: All patients in Treatment Period 1 received 150 mg s.c. injection open-label secukinumab. intervention 2: Treatment Period 2 Patients who achieved responder status entered Treatment Period 2 and continued to receive 150 mg s.c. (1 s.c. injection of secukinumab 150 mg) intervention 3: Treatment Period 2 300 mg (2 s.c. injections of the 150 mg dose)

Protocol document:
Prot_000.pdf: 
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. 

SAP_001.pdf: 
US Clinical Development and Medical Affairs
AIN457/Secukinumab
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)  
Statistical Analysis Plan (SAP)
Author:
Trial Statisticians:
Document type:
SAP Documentation
Document status:
Addendum v1.0
Release date:
08-Jul-2021
Number of pages:
62
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
CAIN457FUS06
Document History - Changes compared to previous final version
Date
Time 
point
Reason 
for 
update
Outcome for update
Section 
and title 
impacted 
(Current)
14-Aug-2018
Prior 
to 
DB 
lock
As 
advised 
in 
the 
RAP 
meeting
Nonresponder Set definition 
added.
Section 
2.2
Subgroup efficacy analyses 
based on two subgroups 
defined by the TNF-alpha 
inhibitor status are added.
Section 
2.2.1
Information on
additional 
analyses are added.
Additional 
analysis 
of 
change from Week 16 in total 
BASDAI 
using 
mixed-
effects 
model 
repeated 
measures (MMRM) is added.
Multiple 
imputation 
is
removed for secondary 
 
 
efficacy 
variables.
 
              
Section 
2.5.2 and 
2.7.2
Section 
2.7.2
Section 
2.7.3
 
Information on calculation of 
95% confidence interval is 
added.
SAS 
code 
for 
MMRM 
analysis added
Section 
5.4.4
and 
5.4.5
Section 
5.4.3


Novartis
For business use only
Page 3
SAP
CAIN457FUS06
Date
Time 
point
Reason 
for 
update
Outcome for update
Section 
and title 
impacted 
(Current)
01-Apr-2021
Prior 
to 
DB 
Lock
Visit window for baseline
and Week 52 assessments
Section 
2.1.2
Removed 
reference 
to 
PASI75 and mNAPSI
Section 
2.1.3
Defined Enrolled Set for 
safety analyses and removed 
Randomized Set
Section 
2.2
Medical history details added
Section 
2.3.3
Duration of exposure defined 
and compliance added
Section 
2.4.1
Elaborated 
non-responder 
imputation and removed the 
wording 
“post-
randomization” 
for 
non-
responder imputation
Section 
2.5.3
Removed ANCOVA model 
for 
analysis 
of 
some 
secondary efficacy variables
Section 
2.7.2
Removed the wording “post-
randomization” 
for 
non-
responder imputation and 
removed LOCF for handling 
missing data 
Section 
2.7.3
Defined 
Treatment-
Emergent Adverse Events 
separately 
for 
Treatment 
Periods 1 and 2 and entire 
treatment period
Section 
2.8.1
Described legal requirements
of ClinicalTrials.gov
Described 
analyses 
for 
laboratory data
Section 
2.8.3
Updated analysis for ECG 
data
Section 
2.8.4.1


Novartis
For business use only
Page 4
SAP
CAIN457FUS06
Date
Time 
point
Reason 
for 
update
Outcome for update
Section 
and title 
impacted 
(Current)
Updated analysis for vital 
signs
Section 
2.8.4.2
Replaced VAS with NRS and 
updated with more details
Section 
2.11
 
 
 
 
 
 
 
 
 
Statements about not using 
multiple 
imputation 
for 
continuous 
secondary 
efficacy 
variables, 
using 
MMRM, not using LOCF for 
handling missing data and
definition of Enrolled Set for 
safety analyses, are added
Section 4
Medical history date of 
diagnosis imputation rules 
added
Section 
5.1.4
Formatting update
Section 
5.2
Added 
more 
details 
on 
multiple imputation
Section 
5.4.1
Described rules for protocol 
deviations with their severity 
codes for excluding patients 
from analysis sets
Section 
5.5
08-Jul-2021
Post 
DB 
Lock
Added details on duration of 
exposure for entire treatment 
period
Section 
2.4.1
Added details on figures for 
entire treatment period
Section 
2.5.2
Added details on analyses 
considering 
baseline 
for 
Treatment Period 2 and 
figures for entire treatment 
period
Section 
2.7.2


Novartis
For business use only
Page 5
SAP
CAIN457FUS06
Date
Time 
point
Reason 
for 
update
Outcome for update
Section 
and title 
impacted 
(Current)
Added details on analyses 
considering 
baseline 
for 
Treatment Period 2 and 
figures for entire treatment 
period
Section 
2.13


Novartis
For business use only
Page 6
SAP
CAIN457FUS06
Table of contents
Table of contents .................................................................................................................6
List of abbreviations............................................................................................................9
1
Introduction .......................................................................................................................10
1.1
Study design...........................................................................................................11
1.2
Study objectives and endpoints .............................................................................13
2
Statistical methods.............................................................................................................16
2.1
Data analysis general information .........................................................................16
2.1.1
General definitions................................................................................17
2.1.2
Visits windows......................................................................................18
2.1.3
Multiple assessments within visit windows..........................................19
2.2
Analysis sets ..........................................................................................................20
2.2.1
Subgroup of interest ..............................................................................21
2.3
Patient disposition, demographics and other baseline characteristics ...................21
2.3.1
Patient disposition.................................................................................21
2.3.2
Patient demographic and other baseline characteristics........................21
2.3.3
Medical History.....................................................................................22
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies...................................................23
2.5
Analysis of the primary objective..........................................................................24
2.5.1
Primary endpoint...................................................................................24
2.5.2
Statistical hypothesis, model, and method of analysis..........................24
2.5.3
Handling of missing values/censoring/discontinuations.......................25
2.5.4
Supportive analyses...............................................................................25
2.6
Analysis of the key secondary objective ...............................................................25
2.6.1
Key secondary endpoint........................................................................25
2.6.2
Statistical hypothesis, model, and method of analysis..........................25
2.6.3
Handling of missing values/censoring/discontinuations.......................25
2.7
Analysis of secondary efficacy objective(s)..........................................................25
2.7.1
Secondary endpoints .............................................................................25
2.7.2
Statistical hypothesis, model, and method of analysis..........................26
2.7.3
Handling of missing values/censoring/discontinuations.......................27
2.8
Safety analyses.......................................................................................................27
2.8.1
Adverse events (AEs)............................................................................28
2.8.2
Deaths....................................................................................................29


Novartis
For business use only
Page 7
SAP
CAIN457FUS06
2.8.3
Laboratory data .....................................................................................30
2.8.4
Other safety data ...................................................................................32
2.9
Pharmacokinetic endpoints....................................................................................33
2.10
PD and PK/PD analyses.........................................................................................33
2.11
Patient-reported outcomes .....................................................................................33
2.11.1
ASDAS and ASDAS response categories.............................................33
2.11.2
Assessment of Spondylo-Arthritis International Society criteria 
(ASAS)..................................................................................................34
34
35
35
2.11.6
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........35
2.11.7
ASAS Health Index (ASAS-HI) ...........................................................36
36
2.12
Biomarkers.............................................................................................................38
2.13
Other Exploratory analyses....................................................................................38
39
2.13.2
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue) ...................................................................................39
39
40
2.14
Interim analysis......................................................................................................42
3
Sample size calculation .....................................................................................................42
4
Change to protocol specified analyses ..............................................................................42
5
Appendix ...........................................................................................................................42
5.1
Imputation rules.....................................................................................................43
5.1.1
Study drug.............................................................................................43
5.1.2
AE date imputation ...............................................................................43
5.1.3
Concomitant medication date imputation .............................................45
5.1.4
Medical history date of diagnosis imputation.......................................46
5.2
AEs coding/grading ...............................................................................................46
5.3
Laboratory parameters derivations ........................................................................47
5.4
Statistical models...................................................................................................47
5.4.1
Primary analysis....................................................................................47
5.4.2
Key secondary analysis.........................................................................50
5.4.3
Secondary analysis................................................................................50


Novartis
For business use only
Page 8
SAP
CAIN457FUS06
51
5.4.5
Exposure-adjusted incidence rate and 100*(1-α)% confidence 
interval...................................................................................................51
5.4.6
Crude incidence and 100*(1-α)% confidence interval..........................52
5.5
Rule of exclusion criteria of analysis sets..............................................................53
5.6
Evaluation algorithm for ASDAS inactive disease status .....................................59
6
References .........................................................................................................................61


Novartis
For business use only
Page 9
SAP
CAIN457FUS06
List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
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 
AST/SGOT
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATC
Anatomical Therapeutic Chemical
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index 
BMI
Body mass index
BSL
Baseline
CI
Confidence interval
COX
Cyclooxygenase
CRF
Case Report/Record Form (paper or electronic)
CRP
C-reactive protein
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
DMARD
Disease Modifying Anti-rheumatic Drug
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
FACIT-Fatigue©
Functional Assessment of Chronic Illness Therapy – Fatigue
FCS
Fully conditional specification
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
hCG
Human chorionic gonadotropin
HGB
Hemoglobin
HIV
Human immunodeficiency virus
HLA-B27
Human leukocyte antigen B27
ICH
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IR
Inadequate responder
IRT
Interactive Response Technology
MAR
Missing at random
MedDRA
Medical dictionary for regulatory activities


Novartis
For business use only
Page 10
SAP
CAIN457FUS06
mg
milligram
MMRM
Mixed-effects model repeated measures
MRI
Magnetic resonance imaging/image 
MTX
Methotrexate
NRS
Numeric rating scale
NSAID
Non-steroidal anti-inflammatory drug
PFS
Prefilled syringe
PPD
Purified protein derivative
PRO
Patient Reported Outcome
PsA
Psoriatic arthritis 
PT
Preferred term
RBC
Red blood cell
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
s.c.
Subcutaneous(ly)
SE
Sleep efficiency 
SOC
System Organ Class
SpA
Spondyloarthritis
SV
Subject visit
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TFL
Tables, Figures, Listings
TNF
Tumour Necrosis Factor
WBC
White blood cell
1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses 
which will be performed in the Phase 4 clinical trial AIN457FUS06. 
This document describes the planned statistical analysis methodologies which will be 
performed 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 in the Phase 4 Clinical Trial AIN457FUS06.
Analysis plans in this document refer to the related statistical analysis sections in Clinical 
Study Report (CSR).
Data will be analyzed by NBS CONEXTs (formerly known as Novartis Product Lifecycle
Services) using Statistical Analysis Software (SAS®, version 9.4), according to Section 9 
(Data Analysis) of the study protocol which is available in Appendix 16.1.1 of the CSR. 


Novartis
For business use only
Page 11
SAP
CAIN457FUS06
Additional detailed information regarding the analysis methodology will be contained in the
Appendix Section 16.1.9 of CSR.
Please refer to the following document:
Clinical Protocol CAIN457FUS06
1.1
Study design
This study will use a randomized, double-blind, parallel-group, 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, 


Novartis
For business use only
Page 12
SAP
CAIN457FUS06
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.
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 will return for an End of Study Visit. 
The End of Study Visit will be scheduled approximately four weeks after the last study 
treatment, and will be performed before any new treatment is initiated. After the End of Study 
Visit, any SAEs that occur in the following 30 days will be reported. 
Figure 1       Study design


Novartis
For business use only
Page 13
SAP
CAIN457FUS06
1.2
Study objectives and endpoints
Objective
Endpoint
Primary objective
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.
ASDAS inactive disease response (yes, no) at 
Week 52.
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)
Reduction in ASDAS ≥1.1 from Week 16 
(yes, no)
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)
Change from Week 16 in total 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 
BASDAI50 response (yes, no) 
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 
ASAS20 response (yes, no) 


Novartis
For business use only
Page 14
SAP
CAIN457FUS06
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
ASAS40 response (yes, no) 
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)  
ASAS partial remission (yes, no) 
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)  
Change from Week 16 in ASAS-Health 
Index
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 
Change from Week 16 in FACIT-Fatigue
The overall safety and tolerability of 
secukinumab


Novartis
For business use only
Page 15
SAP
CAIN457FUS06


Novartis
For business use only
Page 16
SAP
CAIN457FUS06
2
Statistical methods
2.1
Data analysis general information
Data will be analyzed by NBS CONEXTs (formerly known as Novartis Product Life-Cycle 
Services).
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. 
Analysis datasets and statistical outputs will be produced using the most recent SAS® Version 
9.4 (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global programming & 
statistical environment (GPS).
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, standard 
error, 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.


Novartis
For business use only
Page 17
SAP
CAIN457FUS06
2.1.1
General definitions
Study Treatment
  
The following are the investigational treatments:

Secukinumab 150 mg provided in 1.0 mL in PFS for s.c. injection. 

Secukinumab 300mg provided in 1.0 mL PFS for s.c. injection.
Study treatment start and end date
Study treatment start date is defined as the first date when a non-zero dose of study drug is 
administered and recorded on the Drug Administration Record (DAR) CRF page. 
Study treatment end date is defined as the last date when a non-zero dose of study drug is 
administered and recorded on the DAR CRF page of the core study.
Study day
Study day will be calculated as (event date – study drug start date + 1 day) for events that 
occurred on or after study drug start date (e.g. visit, lab samples, AEs). For events prior to study 
drug start date (e.g., time of diagnosis), study day will be negative and calculated as (event date 
– study drug start date). Note that study drug start date is study day 1 and the day before study 
drug start date is study day -1 (i.e. no study day 0).
Due to the study drug dosing schedule, one month will be considered as 28 days. However, 
for ”time since event” data (e.g., medical history), one month will be considered as 365.25/12 
days for events that occurred prior to study Day 1. 
Baseline and post-baseline definitions
In general, a baseline value refers to the last measurement available prior to administration of 
the first dose of study treatment. A post-baseline value refers to a measurement taken after the 
first dose of study treatment.
For Treatment Period 2, Week 16 assessments will be considered the baseline for all analyses 
performed during this period.
Treatment Period
There are 2 treatment periods for this study defined as:
Treatment Period 1 is defined as the 16-week open-label treatment period starting from baseline 
until Week 16.
Treatment Period 2 is a 36-week, double-blind treatment period starting from Week 16 until
Week 52.
Lost to follow up
Patients whose study completion status is unclear because they fail to appear for study visits 
without stating an intention to withdraw.
On-treatment period


Novartis
For business use only
Page 18
SAP
CAIN457FUS06
The period where the patients are exposed to the study treatment. For this study the treatment 
phase consists of 52 weeks.
2.1.2
Visits windows
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows were created to 
cover the complete range of days within the study. The visit windows are shown in
These apply to measurements taken at every visit. 
For assessments collected less often different visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into 
one of the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on 
Day 46 instead of on Day 29, say, it will be re-aligned to visit window Week 8. In the 
case of major deviations from the visit schedule, or due to unscheduled visits, several 
assessments of a subject may fall in a particular visit window (either scheduled or 
unscheduled). Statistical approaches to handle multiple assessments in a given visit 
window are specified in 
Of note, subjects are allowed to have gaps in visits.


Novartis
For business use only
Page 19
SAP
CAIN457FUS06
For data which are not collected at every visit (e.g., ASAS-HI,
, visit windows defined 
in 
will be combined. For example, if an assessment is at Week 12 and Week 24 only, 
Week 12 visit window will extend from Day 2 to Day 99 (combining Week 1 to Week 12 visit 
windows), Week 24 will extend from Day 100 to Day 183 (combining Week 16 to Week 24). 
If more than one assessment falls into the interval, the rules defined in Section 2.1.3 below are 
applied.
2.1.3
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (See 
 
For baseline assessment definition see Section 2.1.1. For post-baseline visit windows the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined.

in cases where qualitative variables are derived from quantitative variables (e.g., ASDAS, 
BASDAI50, ASAS20, ASAS40, ASAS partial remission, and reduction in ASDAS>=1.1 
from Week 16), the visit will be assigned to the quantitative variable, and this visit will be 
used for the derived qualitative variable. 


Novartis
For business use only
Page 20
SAP
CAIN457FUS06
2.2
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.
Note: For safety analyses, the Enrolled Set will consist of enrolled patients for the initial 16-
week, Treatment Period 1 who received at least one dose of the open-label treatment,
secukinumab 150 mg.
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.
  
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. According to the intent-to-treat principle, patients will be 
analyzed according to the treatment they have been assigned to during the randomization 
procedure.
Non-responder Set: The Non responder Set consists of all patients who are labeled as non-
responders at the end of Treatment Period 1 and do not enter Treatment Period 2.


Novartis
For business use only
Page 21
SAP
CAIN457FUS06
2.2.1
Subgroup of interest
Subgroup analyses will be performed for all the efficacy variables based on the TNF-alpha 
inhibitor status (naive, inadequate responder).
2.3
Patient disposition, demographics and other baseline 
characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics
and the number and percentage of patients in each category will be presented for categorical 
variables for each treatment group. The summaries will be reported for Enrolled Set, 
Responder Set, Safety Set, Full Analysis Set (FAS), and Nonresponder Set.
2.3.1
Patient disposition
The number and percentage of patients screened, completed Treatment period 1 and 2,  
discontinued Treatment Period 1 or 2 including a summary of reasons for discontinuations will 
be presented for Enrolled Set and Full Analysis Set. In addition, the reasons for screen failures 
will be provided. 
All patient disposition data will be listed.
Number and percentage of patients with pandemic related protocol deviations will be tabulated
for each treatment period. The pandemic period is considered to be a period starting from 1st
March 2020 onwards.
2.3.2
Patient demographic and other baseline characteristics
Demographic and other baseline data, including disease characteristics will be listed and 
summarized descriptively for the Enrolled Set, Responder Set, and by treatment group for Full 
Analysis Set, Safety Set and Nonresponder Set.
The following demographic and baseline variables, if collected, will be summarized:
Continuous variables:

Age (which is derived from date of birth and the screening assessment date)

Height (cm)

Weight (kg)

BMI (kg/m2)
Categorical variables:

Sex

Race

Ethnicity

Child-bearing status (for females only)Age (<65 and >=65)
Smoking status at Baseline will be summarized.


Novartis
For business use only
Page 22
SAP
CAIN457FUS06
In addition to this, data for tuberculosis risk assessment, ECG evaluation and chest X-ray or 
MRI, as collected from respective CRF pages at Screening Visit 2, will be summarized.
2.3.3
Medical History
Any condition entered on the Medical History CRF will be coded
using the MedDRA 
dictionary. These will be summarized by system organ class (SOC) and preferred term (PT) of 
the MedDRA dictionary for the Enrolled Set, the Responder Set, the Nonresponder Set and by 
treatment group for the Safety Set. Summaries for cardiovascular medical history as collected 
on Cardiovascular Medical History CRF will be provided as well.
Ankylosing Spondylitis disease background including time (years) since axial symptom onset, 
time (years) since diagnosis of ankylosing spondylitis, TNF-alpha exposure, inhibitor 
treatment and response status along with history of extra-axial involvement, will be 
summarized at Screening Visit 1 for the Enrolled Set, the Responder Set, and by treatment 
group for the Full Analysis Set and Safety Set.
Smoking history and alcohol history as collected at baseline, will be summarized for the 
Enrolled Set, the Responder Set, and by treatment group for the Full Analysis Set and Safety 
Set.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Study Treatment
The summaries by treatment group will be performed by the actual treatment received (as 
follows) for every visit until Week 16. 
Treatment groups in Treatment Period 1:

Secukinumab 150 mg
In Treatment Period 2, the summaries by treatment group will be performed by the actual 
treatment received (as follows) for every visit up to Week 52, including patients who switched 
at Weeks 16. 
Treatment groups in Treatment Period 2:

Secukinumab 150 mg - 300 mg (IR)

Secukinumab 150 mg - 150 mg (IR)

Secukinumab 150 mg – 150 mg (R)
where, R: Responders and IR: Inadequate Responders
Treatment groups in entire treatment period:

Secukinumab 150 mg


Novartis
For business use only
Page 23
SAP
CAIN457FUS06

Secukinumab 300 mg
Duration of exposure
The duration of exposure (in days) will be summarized by means of descriptive statistics for the 
Enrolled Set, the Responder Set, and each treatment group for the Safety Set. In addition, the 
number of subjects with exposure of at least certain time thresholds will be displayed (e.g. any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.).
For Treatment Period 1, the end date for the calculation of duration of exposure will be the 
earlier of:

Date of last injection in Treatment Period 1 + 84 days, and

Date of first injection in Treatment Period 2
For Treatment Period 2, the end date for the calculation of duration of exposure will be the date 
of last injection in Treatment Period 2 + 84 days.
For entire treatment period, the end date for the calculation of duration of exposure will be the 
date of last injection + 84 days.
For patients with death as an event, end date for calculation of duration of exposure will be the 
date of death if it is earlier than the date of last injection + 84 days.
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 patient years) = duration of exposure (years) / 100
Compliance
Compliance will be calculated based on documented study drug administrations and syringe 
counts and displayed by treatment group. It is calculated as follows:
Compliance (%) = 100*(total no. of injections administered) / (no. of injections prescribed). 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons.
The analyses of duration of exposure and compliance described above will be done for 
Treatment Period 1 and Treatment Period 2.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant therapies
Prior medications are defined as treatments taken and stopped prior to first dose of study
treatment. Any medication given at least once between the day of first dose of study treatment 
and the date of the last study visit will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered.
Summaries will be presented for the Enrolled Set, the Responder Set, and each treatment group 
for the Safety Set.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Chemical 
(ATC) classification codes and grouped by anatomical main group. Tables will show the overall 
number and percentage of patients receiving at least one treatment of a particular ATC code 
and at least one treatment in a particular anatomical main group.


Novartis
For business use only
Page 24
SAP
CAIN457FUS06
Significant prior and concomitant surgeries and procedures will be summarized by primary
system organ class and MedDRA preferred term.
In addition, prior and concomitant medication data will be listed.
Rescue medication
Rescue medication is not permitted during the study. 
2.5
Analysis of the primary objective
The primary objective is 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.
2.5.1
Primary endpoint
The primary efficacy variable is ASDAS inactive disease response (yes, no) and the primary 
analysis time point will be at Week 52.
The primary analysis will be done on Full Analysis Set (FAS).
2.5.2
Statistical hypothesis, model, 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 until Week 52 using a logistic 
regression model with treatment, TNF-alpha inhibitor status (naive, inadequate responder), and 
Week 16 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. 
Number and percentages for ASDAS inactive disease response will also be reported for each 
treatment group, by TNF-alpha inhibitor status (naive, inadequate responder) by visit.   A line 
plot for ASDAS inactive disease responders (%) from Week 16 to Week 52 will be presented.
A similar line plot will be presented by TNF-alpha inhibitor status.
A line plot for ASDAS inactive disease responders (%) over entire treatment period (from Week 
1 to Week 52) will be presented. A similar line plot will be presented by TNF-alpha inhibitor 
status.
Also, number and percentages for the patients with ASDAS inactive disease response in 
Treatment Period 1 who entered Treatment Period 2 will be provided based on the below criteria:

Patients receiving 150mg (open label) (Enrolled Set)

Patients receiving randomized 300mg and 150mg (Randomized Set)

Patients who are responders (Responder Set)

Patients who are nonresponders (Nonresponder Set)


Novartis
For business use only
Page 25
SAP
CAIN457FUS06
In addition, the above analysis will be done by TNF-alpha inhibitor status and by visit.
2.5.3
Handling of missing values/censoring/discontinuations
Patients who discontinue prematurely for any reason will be considered nonresponders from 
the time they discontinued through Week 52. Also, patients who do not have the required data 
to compute response (ASDAS components) at the specific time point will be classified as 
nonresponders.
In an additional analysis, missing data for ASDAS inactive disease response will be imputed 
using multiple imputation. Details for multiple imputation is presented in Appendix Section 5.4.
2.5.4
Supportive analyses
A 95% confidence interval for the difference between the two treatment groups in the proportion 
of patients who have ASDAS inactive disease response will be calculated using the normal 
approximation to the binomial distribution for the Full Analysis Set.
The analysis will be performed at each time point in Treatment Period 2.
2.6
Analysis of the key secondary objective
Not applicable.
2.6.1
Key secondary endpoint
Not applicable.
2.6.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.6.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
Refer to Section 1.2 for the list of secondary objectives.
2.7.1
Secondary endpoints
The secondary efficacy variables are the following (see Section 2.11 for details of the 
assessments from which the efficacy variables are derived): 
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
For business use only
Page 26
SAP
CAIN457FUS06
8. Change from Week 16 in FACIT-Fatigue
2.7.2
Statistical hypothesis, model, and method of analysis
Analyses of the secondary efficacy variables will be based on the Full Analysis Set.
Reduction in ASDAS ≥1.1 from Week 16
Reduction in ASDAS ≥1.1 from Week 16 (yes, no) will be analyzed at each time point in 
Treatment Period 2 until Week 52 using a logistic regression model with treatment, TNF-alpha 
inhibitor status (naive, inadequate responder), and Week 16 body weight as explanatory 
variables.  The odds ratios and 95% confidence intervals for the odds ratios will be reported, 
based on the fitted model. Similar analysis will be performed for the subgroups defined by TNF-
alpha inhibitor status.  
A 95% confidence interval for the difference, at each time point in Treatment Period 2 until
Week 52, between the two treatment groups in the proportion of patients who have reduction 
in ASDAS≥1.1 from Week 16 will be calculated using the normal approximation to the 
binomial distribution for the Full Analysis Set.
Number and percentages of patients with reduction in ASDAS≥1.1 from Week 16 will also be 
reported for each treatment group in each treatment period by visit and similarly by TNF-alpha 
inhibitor status (naive, inadequate responder).
Change from Week 16 in total BASDAI
Analysis of change from Week 16 in total BASDAI score will be performed using mixed-effects 
model repeated measures (MMRM) with treatment, visit, and TNF-alpha inhibitor status (naive, 
inadequate responder) as factors, Week 16 score and Week 16 weight as covariates, and 
treatment-by-visit and Week 16-by-visit as interaction terms (Diggle, Heagerty, and Liang KY,
2002).  The least-squares (LS) mean difference between secukinumab 150 mg - 300mg (IR)
and secukinumab 150 mg - 150mg (IR) will be presented along with the corresponding 95% CI.
Similar analysis will be performed for the subgroups defined by TNF-alpha inhibitor status.  
Descriptive summary statistics for change from baseline in Treatment Period 1 and change from 
Week 16 in Treatment Period 2, for total BASDAI score for each visit will be provided. 
Similarly, descriptive summary statistics will also be provided by TNF-alpha inhibitor status.
Analysis of change from Week 16 in ASAS-Health Index and change from Week 16 in 
FACIT-Fatigue will be similar to analyses as described for change from Week 16 in total 
BASDAI.
Analysis of BASDAI50 response, ASAS20 response, ASAS40 response, and ASAS partial 
remission will be similar to the analyses as described for reduction in ASDAS ≥1.1 from Week 
16.
Also summary statistics for secondary efficacy variables 1, 2, 4 and 5 for the patients in
Treatment Period 1 who entered Treatment Period 2 will be provided based on the below 
criteria :

Patients receiving 150mg (open label) (Enrolled Set)

Patients receiving randomized 300mg and 150mg (Randomized Set)


Novartis
For business use only
Page 27
SAP
CAIN457FUS06

Patients who are responders (Responder Set)

Patients who are nonresponders (Nonresponder Set)
In addition, the above analysis will be done by TNF-alpha inhibitor status and by visit.
As additional analyses, following will be performed on Full Analysis Set:
1. Descripive summary statistics for change from baseline (Week 0) to all visits in 
Treatment Period 2 for secondary efficacy variables - total BASDAI, ASAS-Health 
Index and FACIT-Fatigue, will be provided.
2. Number and percentages of patients for secondary efficacy variables 3 - 6 will also be 
reported for each treatment group considering baseline (Week 0) to derive the 
response for Treatment Period 2 and similarly by TNF-alpha inhibitor status only for 
ASAS20 and ASAS40 response.
3. Line plots of mean change from baseline for secondary efficacy variables – total 
BASDAI, ASAS-Health Index and FACIT-Fatigue, and line plots displaying 
responder percentage for secondary efficacy variables 3 – 6, for entire treatment period 
will be presented from Week 1 to Week 52, considering baseline as Week 0.
4. Descriptive summary statistics for change from baseline (Week 0) in all 6 components 
of BASDAI will be provided in Treatment Period 1 and 2. Line plots of mean change
from baseline (Week 0) for these components will also be presented over entire 
treatment period (from Week 1 to Week 52). 
2.7.3
Handling of missing values/censoring/discontinuations
For secondary efficacy variables 1 and 3 – 6, patients who discontinue prematurely for any 
reason will be considered nonresponders from the time they discontinued through to Week 52. 
Also, patients who do not have the required data to compute response (e.g., ASAS components) 
at the specific time point will be classified as nonresponders.
Secondary efficacy variables 2, 7, and 8, will be analyzed using a mixed-effects model
repeated measures (MMRM) which is valid under the missing at random (MAR) assumption.
For analyses of these variables, if all post-baseline values are missing then these missing values 
will not be imputed and the patient will be removed from the analysis of the corresponding 
variable, i.e., it may be that the number of patients providing data to an analysis is smaller than 
the number of patients in the FAS.
2.8
Safety analyses
The safety analysis will be performed on Enrolled Set for Treatment Period 1 and on Safety Set 
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.


Novartis
For business use only
Page 28
SAP
CAIN457FUS06
The analyses for treatment-emergent adverse events, serious adverse events and risk based on 
adverse events will be summarized. Safety analyses will be performed on treatment received or 
actual treatment as described below:

The actual treatment or treatment received for summaries of safety data will differ from
the treatment assigned at randomization only if a subject received the wrong treatment 
during the entire study.

For those patients who received not the treatment randomized, i.e., who received 
erroneously the wrong treatment at least once, an additional AE listing will be prepared 
displaying which events occurred after the treatment errors.
2.8.1
Adverse events (AEs)
The crude incidence of treatment emergent adverse events (TEAEs)  will be summarized by 
primary system organ class (SOC) and preferred term (PT) for Treatment Period 1 and 
Treatment Period 2.
Treatment-emergent adverse events (TEAEs) are defined as follows:

For Treatment Period 1, TEAEs are those AEs that started on or after the first dose date
of study treatment, or events present prior to the first dose date of study treatment but 
increased in severity based on preferred term and the earlier of the last dose date in 
Treatment Period 1 + 84 days or prior to the first dose date in Treatment Period 2.

For Treatment Period 2, TEAEs are those AEs that started on or after the first dose date
of study treatment in Treatment Period 2 and on or before the last dose date + 84 days.
In addition, exposure time-adjusted rates (incidence rate) including 95% confidence intervals
will be provided for entire treatment period to adjust for differences in exposure. For the entire 
treatment period, TEAEs are those AEs that started on or after the first dose of study treatment,
or events present prior to the first dose of study treatment but increased in severity based on 
preferred term and on or before last dose date + 84 days. For summaries over the entire treatment 
period, patients who switched from secukinumab 150 mg to secukinumab 300 mg will appear 
in both treatment groups.
Crude incidence rates and exposure-adjusted incidence rates will be graphically presented for 
all TEAEs and serious TEAEs along with 95% confidence intervals, by system organ class.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries (crude incidences only) will also 
be presented for AEs by severity and for study treatment related AEs. If a particular AE 
‘severity’ is missing, this variable will be listed as missing and treated as missing in summaries. 
If a subject reported more than one adverse event with the same preferred term, the adverse 
event with the greatest severity will be presented. If a subject reported more than one adverse 


Novartis
For business use only
Page 29
SAP
CAIN457FUS06
event within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable.
Separate summaries will be provided for 

adverse events suspected to be related to study drug by the investigator

deaths

serious adverse events

adverse events leading to discontinuation
A listing of non-treatment emergent adverse events will be provided. These adverse events 
occurred before the first dose of the study treatment. The crude incidence rate will be
provided without treatment information.
Algorithms for date imputations will be provided in Programming Specifications.
For SAEs that occur during screening, a listing will be prepared for all patients screened
including screening failures.
A listing of suspected or confirmed SARS-CoV-2 infections will be provided.
For legal requirements of ClinicalTrials.gov, two required tables on TEAEs which are not SAEs
with an incidence greater than or equal to 5% and on treatment-emergent SAEs and SAEs
suspected to be related to study treatment will be provided by SOC and PT for entire treatment 
period.
If, for the same patient, several consecutive TEAEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

A single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE.

More than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block, e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
Not applicable.
2.8.2
Deaths
Separate summaries and listings will be provided for deaths in each treatment period.


Novartis
For business use only
Page 30
SAP
CAIN457FUS06
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests
(hematology, chemistry and urinalysis).
Descriptive summary statistics for the change from baseline in Treatment Period 1 and change 
from Week 16 in Treatment Period 2 to each study visit in respective treatment periods will be
presented. These descriptive summaries will be presented by laboratory test and treatment
group. Change from baseline (or Week 16) will only be summarized for patients with both 
baseline (or Week 16) and post-baseline (or post-Week 16) values and will be calculated as:
change from baseline = post-baseline value – baseline value
change from Week 16 = post-Week 16 value – Week 16 value
For urinalysis and urine pregnancy test, data will be listed by treatment and patient.
QuantiFERON TB-Gold test, serum pregnancy test results and HLA-B27 results will be listed 
at Screening Visit 2, by treatment and patient.
Shift table will be provided for all laboratory variables to compare a patient’s baseline
laboratory evaluation relative to observed post-baseline values in Treatment Period 1. The 
reference laboratory ranges will be used to evaluate whether a particular laboratory test value 
was within reference range, low, or high for each visit value relative to whether or not the 
baseline value was within reference range, low, or high. The shifts to the most extreme 
laboratory test value within the treatment period will be presented (including category “high 
and low”). These summaries will be presented by laboratory test and treatment group. Similar 
shift tables will be provided for all laboratory variables to compare a patient’s Week 16 
laboratory evaluation relative to observed post-Week 16 values in Treatment Period 2.
The following laboratory variables will be analyzed with respect to numerical 
commonterminology criteria for adverse events (CTCAE) grades, given in Table 2-3: 
hemoglobin (HGB), platelets, white blood cell (WBC) count, neutrophils, lymphocytes, 
creatinine, total bilirubin (TBL), gamma-glutamyl transferase (GGT), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), 
glucose.
Table 2-3
CTCAE grades for laboratory variables to be analyzed
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
HGB decreased
(Anemia)
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
Platelet count
decreased
< LLN – 75.0 x
10e9 /L
< 75.0 - 50.0 
x 10e9 /L
< 50.0 – 25.0 
x 10e9 /L
< 25.0 
x 10e9 /L
WBC
decreased
< LLN - 3.0 
x 10e9 /L
< 3.0 - 2.0 
x 10e9 /L
< 2.0 - 1.0 
x 10e9 /L
<1.0 
x 10e9 /L
Neutrophil count
decreased
< LLN - 1.5
x 10e9 /L
< 1.5 - 1.0 
x 10e9 /L
< 1.0 - 0.5 
x 10e9 /L
< 0.5 
x 10e9 /L
Lymphocyte count
decreased
< LLN - 0.8 
x 10e9/L
< 0.8 - 0.5 
x 10e9 /L
< 0.5 - 0.2 
x 10e9 /L
< 0.2 
x 10e9 /L


Novartis
For business use only
Page 31
SAP
CAIN457FUS06
Creatinine 
increased*
> 1 - 1.5 
x baseline;
> ULN - 1.5 x ULN
> 1.5 - 3.0 
x baseline;
> 1.5 - 3.0 xULN
> 3.0 
x baseline;
> 3.0 - 6.0 x 
ULN
> 6.0 x ULN
TBL increased
> ULN - 1.5 x ULN
> 1.5 - 3.0 x 
ULN
> 3.0 - 10.0 x 
ULN
> 10.0 x ULN
GGT increased
> ULN - 2.5 x ULN
> 2.5 - 5.0 x 
ULN
> 5.0 - 20.0 x 
ULN
> 20.0 x ULN
ALT increased
> ULN - 3.0 x ULN
> 3.0 - 5.0 x 
ULN
> 5.0 - 20.0 x 
ULN
> 20.0 x ULN
AST increased
> ULN - 3.0 x ULN
> 3.0 - 5.0 x 
ULN
> 5.0 - 20.0 x 
ULN
> 20.0 x ULN
ALP increased
> ULN - 2.5 x ULN
> 2.5 - 5.0 x 
ULN
> 5.0 - 20.0 x 
ULN
> 20.0 x ULN
Glucose increased
(Hyperglycemia )
> ULN - 8.9 
mmol/L
> 8.9 - 13.9 
mmol/L
> 13.9 - 27.8 
mmol/L
> 27.8 
mmol/L
Glucose decreased
(Hypoglycemia)
< LLN - 3.0 
mmol/L
< 3.0 - 2.2 
mmol/L
< 2.2 - 1.7 
mmol/L
< 1.7 
mmol/L
LLN = lower limit of normal, ULN = upper limit of normal
*Note: for “creatinine increased” the baseline criteria do not apply
These summaries will be split into hematology and chemistry for study level reports and the
pooled summary of clinical safety.
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the
worst results (expressed in CTCAE grade) during the treatment period analyzed.
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on
the event criteria given in Table 2-4 below:
Table 2-4
Liver-related events
Assessment
Criterion
ALT
AST
ALT or AST
TBL
ALP
ALT or AST and
TBL
> 3 x ULN; > 5 x ULN; > 8 x ULN; > 10 x ULN, > 20 x ULN
> 3 x ULN; > 5 x ULN; > 8 x ULN; > 10 x ULN; > 20 x ULN
> 3 x ULN; > 5 x ULN; > 8 x ULN; > 10 x ULN; > 20 x ULN
> 1.5 x ULN; > 2 x ULN; > 3 x ULN
> 2 x ULN; > 3 x ULN; > 5 x ULN
ALT or AST > 3 x ULN and TBL > 2 x ULN
ALT or AST > 5 x ULN and TBL > 2 x ULN
ALT or AST > 8 x ULN and TBL > 2 x ULN
ALT or AST > 10 x ULN and TBL > 2 x ULN
ALP and TBL
ALP > 3 x ULN and TBL > 2 x ULN
ALP > 5 x ULN and TBL > 2 x ULN
ALT or AST and
TBL and ALP
ALT or AST > 3 x ULN and TBL > 2 x ULN and ALP < 2 x ULN (Hy’s 
Law)


Novartis
For business use only
Page 32
SAP
CAIN457FUS06
Note: elevated ALP may suggest obstruction as a consequence of gall 
bladder or bile duct disease; ALP may also be increased in 
malignancy. FDA therefore terms Hy’s Law cases as indicators of pure 
hepatocellular injury. This does not mean that cases of ALT or AST > 3
x ULN and TBL > 2 x ULN and ALP ≥2 x ULN may not result
in severe DILI.
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit.
The criteria are not mutually exclusive, e.g. a subject with ALT = 6.42 × ULN is counted for
ALT > 3 × ULN and ALT > 5 × ULN.
Individual subject data listings will be provided for subjects with abnormal laboratory data.
2.8.3.1
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.
2.8.3.2
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. 
2.8.3.3
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. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
All ECG data at Screening Visit 2 will be listed by treatment group and patient, and 
abnormalities will be flagged.  
2.8.4.2
Vital signs
All vital signs data will be listed by treatment group, patient, and visit. Descriptive summary 
statistics will be provided by treatment and visit.
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-5 below.


Novartis
For business use only
Page 33
SAP
CAIN457FUS06
Table 2-5
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg (hypertension) or < 90 mmHg 
(hypotension)
Diastolic blood pressure (mmHg)
>=90 mmHg (hypertension) or <60 mmHg 
(hypotension)
Pulse (bpm)
> 100 bpm (tachycardia) or <60 bpm 
(bradycardia)
Vital signs will be assessed at Screening Visit 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,  
17, 18 and 19 and will include systolic and diastolic blood pressure, pulse rate and body 
temperature measurements. 
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
In this section, the details of each PRO is provided. The analysis of the PROs are presented in 
Section 2.7.
2.11.1
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 spinal pain (BASDAI question 2), the patient’s global assessment of disease activity, 
peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI 
question 6) and C-reactive protein (CRP) in mg/L (Sieper 2009, Lukas 2009). 
ASDAS-CRP is calculated in the following way:
ASDAS-CRP = 0.12*Back pain + 0.06*Duration of Morning Stiffness + 0.11*Patient   
Global + 0.07*Peripheral Pain/Swelling + 0.58*Ln(CRP+1)
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:

< 1.3 between inactive disease and moderate disease activity, 

< 2.1 between moderate disease activity and high disease activity, and 


Novartis
For business use only
Page 34
SAP
CAIN457FUS06

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).
2.11.2
Assessment of Spondylo-Arthritis 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 numeric rating scale (NRS)
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a NRS (for derivation of response “back pain at any time” will be 
used from data)
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
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. 
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.
ASAS partial remission
The ASAS partial remission criteria is defined as a value not above 2 units in each of the 
domains 1 to 4 on a scale of 10.
 
 
 
 


Novartis
For business use only
Page 35
SAP
CAIN457FUS06
 
 
 
 
 
 
 
 
 
 
 
 
 
2.11.6
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 as 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.
At least 4 questions should be non-missing to calculate the BASDAI score. Otherwise, BASDAI 
score will be missing (Haywood et al., 2002). If both Q5 and Q6 are missing or one of Q1 to 


Novartis
For business use only
Page 36
SAP
CAIN457FUS06
Q4 is missing, the total sum should be divided by 4 instead of 5. If two of Q1 to Q4 are missing 
and both Q5 and Q6 are not missing, the sum should be divided by 3.
BASDAI50 response is defined as at least a 50% improvement (decrease) in total BASDAI 
score, as compared to the baseline total BASDAI score.
Note: BASDAI is only assessed at Screening Visit 1 for TNF inhibitor inadequate responders 
currently on a TNF inhibitor and prior to discontinuation/washout.
2.11.7
ASAS Health Index (ASAS-HI)
The ASAS health index is a linear composite measure and contains 17 items (dichotomous 
response option: “I agree” and “I do not agree”). 
Each statement on the ASAS health index is given a score of 1 = I agree OR 0 = I do not agree. 
All item scores are summed up to give a total score that ranges from 0 (good functioning) to 17 
(poor functioning). Items No 7 and 8 are not applicable for all patients. For those patients who 
ticked the response “not applicable”, the sum score is analyzed based on n=16 or n=15, 
respectively.
A total score can be analyzed if no more than 20% of the data are missing. The total score is
calculated as follows for respondents with one to a maximum of 3 missing responses:
Cases with more than 3 missing responses cannot be allocated a total score.
 


Novartis
For business use only
Page 37
SAP
CAIN457FUS06
 
 
 
 
 
 


Novartis
For business use only
Page 38
SAP
CAIN457FUS06
2.12
Biomarkers
Not Applicable.


Novartis
For business use only
Page 39
SAP
CAIN457FUS06
2.13.2
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-
Fatigue)
The FACIT-Fatigue© is a 13-item questionnaire that assesses self-reported fatigue and its 
impact upon daily activities and function. The purpose of FACIT-Fatigue in this study is to 
assess the impact of fatigue on patients with AS. Subjects respond to each item on a 5-point 
Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much) 
based on their experience of fatigue during the past 2 weeks. The scale score is computed by 
summing the item scores, after reversing those items that are worded in the negative direction. 
Numbering the questions from 1 to 13, it is evident that questions 7 and 8 are worded in the 
positive direction (4 indicates a desirable response) and all other questions are worded in the 
negative directions (4 indicates an undesirable response). Thus, it is necessary to reverse the 
responses for all questions except questions 7 and 8 (i.e. original response of 0 gets mapped to 
4, 1=3, 2=2, 3=1, and 4=0) for scoring purposes. 
When there are missing item scores, the scale score will be computed by summing the non-
missing item scores, multiplying by 13 (the total number of items in the scale) and dividing by 
the number of non-missing items (i.e., normalizing the results). The latter rule will be applied 
only when at least half of the items (seven or more) are non-missing.
FACIT-Fatigue scale score range from 0 to 52, where higher scores represent less fatigue (Cella 
et al., 2004).
 
 
 
 
 
 
 


Novartis
For business use only
Page 40
SAP
CAIN457FUS06
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis
For business use only
Page 41
SAP
CAIN457FUS06
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
e.


Novartis
For business use only
Page 42
SAP
CAIN457FUS06
 
 
2.14
Interim analysis
No interim analysis is planned.
3
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.
4
Change to protocol specified analyses
For (continuous) secondary efficacy variables 2, 7, and 8 (Section 2.7.1), multiple imputation 
will not be performed as an additional analysis
For secondary efficacy variables 2, 7, and 8 MMRM will be used for analysis instead of 
ANCOVA. LOCF will not be used to handle missing data for these variables.
For safety analyses in Treatment Period 1, definition of Enrolled Set will be updated to include 
patients who received the open-label secukinumab 150 mg.
Randomized Set was deleted.
5
Appendix
This section will be used later for drafting CSR Appendix 16.1.9.


Novartis
For business use only
Page 43
SAP
CAIN457FUS06
5.1
Imputation rules
5.1.1
Study drug
Not applicable.
5.1.2
AE date imputation
The following table explains the notation used in the logic matrix. Please note that
missing start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSTD)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON 
MISSIN
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSIN
NC
Uncertain
N
C
N
C
N
C
YYYY < TRTY
( D )
Before Treatment Start
( C
)
( C
)
( C
)
YYYY = TRTY
(B)
Uncertain
( C
)
Before Treatment
(A
)
Uncertai
(A
)
After Treatment
YYYY > TRTY
(E)
After Treatment Start
(A
)
After Treatment
(A
)
After Treatment
(A
)
After Treatment
The following table is the legend to the logic matrix.
If AE end date is complete and AE end date < Treatment start date or AE end date
is partial and AE imputed end date < Treatment start date, then AE start reference 
= min (informed consent date, earliest visit date from SV) Else if AE end date is
partial,AE end date > = Treatment start date or AE is ongoing , then AE start
reference = treatment start date.
Relationship
Time imputation
Before AE start reference
Partial date indicates AE start 
date prior to AE start
After AE start reference
Partial date indicates AE
start date after AE start
f
Uncertain
Partial date insufficient to 
determine relationship of AE 
start date to AE start
f
Imputation Calculation


Novartis
For business use only
Page 44
SAP
CAIN457FUS06
NC/Blank
No convention
(A)
MAX( 01MONYYYY, AE
start reference+1 day)
(B)
AE start reference+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
Complete date
No date imputation
If time is captured for the study
Case1: if AE start date is not 
equal to AE start reference
then do the following:
Relationship                                                                 Time imputation
If minutes missing then AESTMF = M
and time is imputed to hh:00
If minutes missing then AESTMF = H 
and time is imputed to 00:00
Case2: if AE start date = AE start
reference then AESTMF = H and time is 
imputed to treatment start time + 1 hour
Adverse Event End Date Imputation
Imputed date = date part of original date, if complete date
Imputed date = min (completion/discontinuation visit date, DEC 31, date of death), if 
month is missing
Imputed date = min (completion/discontinuation visit date, last day of the month, date 
of death), if day is missing
Adverse Event End Time Imputation
If the AE end date is complete and time is captured in the study then:
Case 1. if AE end date is not equal to Treatment end date, then do the following:
if minutes missing then time is imputed to hh:00 if time missing then time is imputed to
00:00
Case 2: if AE end date = Treatment end date then time is imputed to treatment end time
If the AE end date is partial then end time is imputed to 00:00.
Imputed Date Flag
If year of the imputed date is not equal to YYYY then date flag = Y
else if month of the imputed date is not equal to MON then date flag = M
else if day of the imputed date is not equal to day of original date then date_flag = D
else date flag = null
Imputed Time Flag


Novartis
For business use only
Page 45
SAP
CAIN457FUS06
If hours of the imputed time is not equal to hours of original time then time flag = H
else if minutes of the imputed time is not equal to minutes of original time then time flag =
M
else time flag = null.
5.1.3
Concomitant medication date imputation
This algorithm is used when event is the partial start date of the concomitant
medication. The following table explains the notation used in the logic matrix. Please
note that missing start dates will not be imputed.
Day 
                    
Year
Partial CM Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY 
MISSING
(C2)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
(C1)
Uncertain
YYYY < TRTY
(D)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
(A)
Before Treatment Start
YYYY = TRTY
(C2)
Uncertain
(A)
Before Treatment Start
(C1)
Uncertain
(B)
After Treatment Start
YYYY > TRTY
(E)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
(B)
After Treatment Start
The following table is the legend to the logic matrix.
Relationship
Before Treatment Start
Partial date indicates CMD start date prior to Treatment Start Date
After Treatment Start
Partial date indicates CMD start date after Treatment Start Date
Uncertain
Partial date insufficient to determine relationship of CMD start date relative to Treatment
Start Date
Imputation Calculation
(A)
15MONYYYY
(B)
01MONYYYY
(C1 or C2)
IF         relative reference start = before treatment start THEN TRTSDT-1
ELSE IF relative reference start = ‘ ’ THEN TRTSDT+1
(D)
01JULYYYY
(E)
01JANYYYY


Novartis
For business use only
Page 46
SAP
CAIN457FUS06
Concomitant Medication End Date Imputation
If not ongoing then -
Imputed date = date part of CMENDTC,  if complete date
Imputed date = min(completion/discontinuation visit date,  DEC 31) , if month is
missing, (C2, D, E)
Imputed date = min(completion/discontinuation visit date, last day of the Month) , if
day is missing. (A, B, C1)
Concomitant Medication Date Flag
If not a complete date then
Y - If year of the imputed date is not equal to YYYY else M – If month of the imputed
date is not equal to MON else D.
5.1.3.1
Prior therapies date imputation
Same as  above.
5.1.3.2
Post therapies date imputation
Same as above.
5.1.3.3
Other imputations
Same as above.
5.1.4
Medical history date of diagnosis imputation
Completely missing dates and partially missing end dates will not be imputed. Partial dates of 
diagnosis will be compared to the treatment start date.

If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY).

Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY).

If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG 
month is equal to study treatment start month), the imputed DIAG date is set to one day 
before study treatment start date.
5.2
AEs coding/grading
Not applicable.


Novartis
For business use only
Page 47
SAP
CAIN457FUS06
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Primary analysis
The primary analysis will be performed comparing treatments with respect to the primary
efficacy variable in a logistic regression model with treatment, TNF-alpha inhibitor (naive, 
inadequate responder) and baseline body weight as explanatory variables.
Proc logistic data=aaa;
Class TRT TNF/ param=glm;
Model AVAL= TRT TNF base_weight;
Lsmeans TRT / diff cl exp;
Ods output diffs=lsm_diff;
Run;
Where TRT = treatment group
TNF = TNF-alpha inhibitor (naive, inadequate responder)
Base_weight = baseline body weight
Logistic regression will be applied to response variables at each visit.
In cases where separation is a concern, e.g., 0% response in one treatment group, an exact
logistic regression model will be applied. 
Proc logistic data=aaa exactonly;
Class TRT TNF / param=glm;
Model AVAL = TRT TNF base_weight;
Exact TRT / estimate;
Ods output exactoddsratio=exactoddsratio;
Run;
Multiple Imputation for Primary Efficacy Variable (ASDAS inactive disease response)
A linear regression model will be used to perform multiple imputation (MI) under a missing at 
random (MAR) assumption. To help preserve the relationship between outcome and covariates 
within each treatment, a separate model will be run for each treatment. This will also help ensure 
that the imputation model does not make stronger assumptions on data relations than the 
analysis model.


Novartis
For business use only
Page 48
SAP
CAIN457FUS06
To ensure that results can be replicated, the data should be sorted by treatment group, TNF-
alpha inhibitor status (naive, inadequate responder), and unique subject ID before running the 
model. The data should be in horizontal format with one subject per dataset row and should 
only include one component of the composite variable. Only dataset rows with a non-missing 
baseline assessment and at least one non-missing post-baseline assessment will be included.
Impute the missing values 500 times (NIMPUTE) with a seed=45706 as shown below:
proc mi data= min= max= out=imp minmaxiter=10000000 nimpute=500 seed=45706;
           by trt TNF;
           var weight_Week16 var1_Week16 var1_week20-var1_week52;
           mcmc chain=multiple initial=em;  
run;
Depending on the component to be imputed, the list of visits in the VAR statement will be 
adjusted. It will only contain visits where the respective component was planned to be assessed.
<min of scale> and <max of scale> refer to minimum and maximum imputed values and 
depends on the component:

All scores measured on NRS: minval=0, maxval=10; 

hs-CRP: minval=0, maxval=  (no maximum value)
The imputation of hs-CRP will be based on log(value+1).
If issues with convergence arise:
1. Change Markov Chain Monte Carlo (MCMC) to Fully Conditional Specification (FCS), and 
check whether it is converged; 
2. If both MCMC and FCS do not converge, TNF-alpha inhibitor status should be removed 
from PROC MI.
This procedure should be repeated separately for each component of the composite variable.
The score as well as ASDAS response can now be calculated based on the complete data. The 
response rate will be calculated for each imputation and then combined using Rubin’s rules.
In order to calculate the response rate for each imputation, PROC FREQ will be used as follows.
Calculate binomial proportion and standard error for each imputation.
proc freq data=<ASDAS>;
by treat visit _imputation_ ;
tables <response> / binomial (level=2 cl=wilson correct) ;
ods output BinomialProp=imp_bpr;
run;
Transpose the dataset for subsequent use with PROC MIANALYZE.


Novartis
For business use only
Page 49
SAP
CAIN457FUS06
proc transpose data=imp_bpr out=imp_trs(drop=_name_) ;
by treat visit _imputation_ ;
var nvalue1; id name1; idlabel label1;
run;
Apply LOGIT transformation: y=log(p/(1-p)) and std. err. transformation: <new se> = se/(p*(1-
p)) 
data logit;
set imp_trs(rename=(_bin_=p e_bin=se));
by treat visit _imputation_ ;
lmean=log(p/(1-p));
lse=se/(p*(1-p));
run;
The transformed binomial proportion estimates and standard errors are combined by applying 
Rubin’s rules for multiple imputed data sets.
proc mianalyze data=logit;
by treat visit ;
modeleffects lmean;
stderr lse;
ods output ParameterEstimates=logitres;
run;
The combined data should be transformed back using the following formula: p=1/(1+exp(-y))
data miexpres;
set logitres;
by treat visit ;
resti = 1/(1+exp(-estimate));
rlow = 1/(1+exp(-lclmean));
rupp = 1/(1+exp(-uclmean));
run;
If all responses are imputed the same as 0 (or 1) for all imputation datasets for a specific 
treatment or subgroup, then the between-imputation-variation will be zero. The combined final 
response rate for the specific treatment would be presented as seen in any of the imputed 
datasets together with 95% confidence interval from Wilson’s method (as obtained from PROC 
FREQ).
The following steps will be performed to handle special cases:


Novartis
For business use only
Page 50
SAP
CAIN457FUS06

If after imputation all responses (observed + imputed) are the same either 0 or 1 for all 
imputation datasets for a specific treatment, it will not be possible to perform a logit 
transformation and the response rate (0% or 100%) for these cases will be presented together 
with the 95% CI from Wilson’s method (as obtained from PROC FREQ).

If after imputation the average response rate is the same across all imputed datasets (but not 
0 or 1), there is no between-dataset variation and Rubin’s rules cannot be applied. Instead 
the average response will be used with 95% CI from Wilson’s method (as obtained from 
PROC FREQ).  
The odds ratio will be derived using GENMOD for each imputation, then combined using 
Rubin’s rules again.
proc genmod data = acr20_mi descending;
  
by avisitn _imputation_;
   
class trt_ TNFRESN ;
  
model aval = trt_ TNFRESN  weight  / link=logit dist=bin;
  
lsmeans trt_ / diff;
  
estimate 'AIN457 150 mg vs AIN457 300 mg' trt_ 1 -1;
  
estimate 'AIN457 150mg mg vs Placebo' trt_ 0 1 -1;
  
ods output Estimates=imp_est;
run;
proc mianalyze data=imp_est;
by avisitn trt_ ;
           modeleffects LBetaEstimate;
  
stderr StdErr;
  
ods output ParameterEstimates=_res;
run;
5.4.2
Key secondary analysis
Not applicable.
5.4.3
Secondary analysis
Binary variables will be analyzed using the logistic model; code is described above (Section 
5.4.1).
For continuous secondary 
 efficacy variables, MMRM approch will be used 
with treatment, visit, and TNF-alpha inhibitor status as factors, Week 16 score and Week 16 
weight as covariates, and treatment-by-visit and Week 16 score-by-visit as interaction terms.


Novartis
For business use only
Page 51
SAP
CAIN457FUS06
The following SAS code will be applied :
Proc mixed data=<dataset> order=internal method = reml;
class visit TNF-alpha ;
model Change_score = Wk16_score TNF-alpha Wk16_weight avisit trt*avisit 
Wk16_score*avisit / s ddfm=kr;
repeated visit / type=un subject=USUBJID;
lsmeans visit / cl;
run;
where;
Wk16_score = Week 16 score
avisit = Analysis visit (Week 20, 24,28, 32, 36, 40, 44, 48 and 52)
TNF-alpha = TNF-alpha status
weight = subject weight
USUBJID= Subject ID
Change_score = Change in score of specified variable from Week 16 to each post-
baseline visit
In case the MMRM model does not converge the following sequential steps will be used:
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2.
2. change type=un to type=cs. If still no convergence, perform step 3.
3. remove covariates in the following order until convergence is achieved: weight, 
blscore*visit, TNF-alpha.
5.4.5
Exposure-adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The total exposure time will be the total number of 
days with an actual dose greater than zero summed up over all patients, and then divided by 
365.25 days. Incidence rate will be calculated per 100 patient years.


Novartis
For business use only
Page 52
SAP
CAIN457FUS06
The sequence of first occurrences of an event will be modeled to follow approximately a 
Poisson process with constant intensity θ. The rate parameter θ will be estimated as λ
=D/T, where T = ∑tj, (j=1,...,n)and D is the number of subjectswith at least one event. 
Conditionally on T, an exact 100*(1-α)% confidence interval for aPoisson variable with 
parameter θT and observed value D can be obtained based on (Garwood,1936), from which 
an exact 100*(1-α)% confidence interval for D/T will be derived asfollows (Sahai and 
Anwer, 1993; Ulm, 1990):
Lower confidence limit:
Upper confidence limit : 
where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.4.6
Crude incidence and 100*(1-α)% confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude
incidence is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 
1998).
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/2), 
n as total number of subjects (i.e. number of subjects in the denominator), and p as estimated 
crude incidence (number of subjects with event / n ) it is q 1p .
Then the lower limit is:
In addition, if L > p x 100 then L = p x 100 and if U < p x 100 then U = p x 100.


Novartis
For business use only
Page 53
SAP
CAIN457FUS06
5.5
Rule of exclusion criteria of analysis sets 
Table 5-1
Protocol deviations that cause subjects to be excluded
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
D01
Patient met one or more of the 
Discontinuation of Study Drug criteria but 
study drug was not discontinued 
Include in everything
0
D02
Patient voluntarily withdrew consent. 
However, still continuing in the study. 
Exclude from 
everything
9
E01
Patient enrolled with total ankylosis of 
the spine
Include in everything
0
E02
Patient used other investigational drugs 
within 5 half-lives of enrollment, or within 
4 weeks before the Baseline Visit, 
whichever is longer
Include in everything
0
E03
Patient 
enrolled 
with 
history 
of 
hypersensitivity to any of the study drugs 
or its excipients or to drugs of similar 
chemical classes
Include in everything
0
E04
Patient enrolled with 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
Include in everything
0
E05
Patient enrolled with 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 TNF α
Include in everything
0
E06
Patient who took more than one anti-TNF 
α agent
Include in everything
0
E07
Patient 
took 
any 
intramuscular 
or 
intravenous 
corticosteroid 
injection 
within 2 weeks before baseline
Include in everything
0
E08
Patient took any therapy by intra-articular 
injections (e.g. corticosteroid) within 4 
weeks before baseline
Include in everything
0
E09
Patient 
enrolled 
whose
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)
Include in everything
0
E10
Patient 
using 
high 
potency 
opioid 
analgesics 
(e.g., 
methadone, 
hydromorphone, morphine)
Include in everything
0
E11
Patient enrolled with active systemic 
infections during the last two weeks 
Include in everything
0


Novartis
For business use only
Page 54
SAP
CAIN457FUS06
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
(exception: common cold) prior to 
baseline
E12
Patient enrolled with active ongoing 
inflammatory diseases other than AS 
that might confound the evaluation of the 
benefit 
of 
secukinumab 
therapy, 
including inflammatory bowel disease or 
uveitis
Include in everything
0
E13
Patient 
enrolled 
with 
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
Include in everything
0
E14
Patient has 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
Include in everything
0
E15
Patient enrolled with 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 
rechecked once more as soon as 
possible, and in all cases, at least prior to 
enrollment/baseline, to rule out lab error
Include in everything
0
E16
Patient enrolled with serum creatinine 
level 
exceeding 2.0 mg/dL (176.8 
umol/L ) at screening
Include in everything
0
E17
Patient enrolled with Screening total 
WBC count < 3,000/uL, or platelets < 
100,000/uL or neutrophils <1,500/uL or 
hemoglobin < 8.5 g/dL (85 g/L)
Include in everything
0
E18
Patient enrolled with Known infection 
with human immunodeficiency virus 
(HIV), hepatitis B or hepatitis C at 
screening
Include in everything
0


Novartis
For business use only
Page 55
SAP
CAIN457FUS06
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
E19
Patient 
enrolled 
with 
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)
Include in everything
0
E20
Patient enrolled 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 patient at increased 
risk
Include in everything
0
E21
Patient 
enrolled 
with 
inability 
or 
unwillingness 
to 
undergo 
repeated 
venipuncture (e.g., because of poor 
tolerability or lack of access to veins)
Include in everything
0
E22
Patient 
enrolled 
with 
inability 
or 
unwillingness to receive injections with 
the PFS
Include in everything
0
E23
Patient enrolled with any medical or 
psychiatric condition which, in the 
Investigators opinion, would preclude the 
participant from adhering to the protocol 
or completing the study per protocol
Include in everything
0
E24
patient enrolled, and had donated or loss 
of 400 mL or more of blood within 8 
weeks before baseline
Include in everything
0
E25
patients enrolled and had a history or 
evidence of ongoing alcohol or drug 
abuse, within the last 6 months before 
baseline
Include in everything
0
E26
Patient enrolled and knew he/she will be 
unable to complete 1 year of study 
treatment period
Include in everything
0
E27
Patient enrolled and has received
Administration of live vaccines during the
study period or 6 weeks prior to baseline
Include in everything
0
E28
Patient enrolled and has 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
Include in everything
0


Novartis
For business use only
Page 56
SAP
CAIN457FUS06
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
E28A
Patient enrolled with a positive central 
laboratory TB blood screening test and 
did not have further work up (according 
to local practice/guidelines) establishing 
conclusively that the patient has no 
evidence of active tuberculosis.
Include in everything
0
E28B
Patient 
had 
latent 
tuberculosis 
established, and then treatment was not 
initiated according to local country 
guidelines.
Include in everything
0
E29
Patient is enrolled and 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
Include in everything
0
E30
Patient was enrolled and Women of 
child-bearing potential, defined as all 
women 
physiologically 
capable 
of 
becoming pregnant, and did not use 
highly effective methods of contraception 
during dosing and for 16 weeks after 
stopping of study medication.
Include in everything
0
I01
Patient was not 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
Include in everything
0
I02
Patient was not male or non-pregnant, 
non-lactating female patients at least 18 
years of age
Include in everything
0
I03
Patient did not have a 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
Include in everything
0
I04
Patient did not have active AS assessed 
by total BASDAI of >= 4 (NRS of 0-10) at 
baseline
Include in everything
0
I05
Patient did not have spinal pain as 
measured by BASDAI question #2 of >= 
4 (NRS of 0-10) at baseline
Include in everything
0
I06
Patient did not have total back pain of >= 
4 on a NRS of 0-10 at baseline
Include in everything
0
I07
Patient was not taking NSAIDs at the 
maximum tolerated dose for at least 4 
weeks prior to their Baseline Visit, with 
an inadequate response or for less than 
Include in everything
0


Novartis
For business use only
Page 57
SAP
CAIN457FUS06
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
4 weeks if withdrawn for intolerance, 
toxicity or contraindications
I08
Patient was regularly taking NSAIDs 
(including COX-1 or COX-2 inhibitors) as 
part of their AS therapy was not on a 
stable dose for at least 2 weeks before 
their Baseline Visit
Include in everything
0
I09
Patient was on a TNFα inhibitor (not 
more than one) but did not experience an 
inadequate response to previous or 
current treatment given at an approved 
dose for at least 3 months prior to 
baseline 
or 
did 
not 
experience 
intolerance upon administration of an
anti-TNFα agent
Include in everything
0
I10
Patient has been previously on a TNFα 
inhibitor and did not have appropriate 
wash-out period prior to a week before 
their Baseline Visit
Include in everything
0
I11
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.
Include in everything
0
I12
Patients on MTX must be on a stable 
folic acid supplementation before their 
Baseline Visit.
Include in everything
0
I13
Patient was on a DMARD other than 
MTX, sulfasalazine or leflunomide and 
did not discontinue the DMARD 4 weeks 
prior to baseline
Include in everything
0
I14
Patient took systemic corticosteroids and 
was not on a stable dose of <= 10 
mg/day prednisone or equivalent for at 
least 2 weeks before baseline
Include in everything
0
M01
Patient had concomitant intake of a 
prohibited medication as outlined in
protocol 
after 
randomization 
and 
remained on study treatment
Include in everything
0
M02
Patient has used live virus vaccines 
during the study after the baseline visit. 
However still patient is part of study.
Include in everything
0
M03
Failure to initiate / modify concomitant 
medication doses according to protocol
Include in everything
0
O01
Site is not compliant to ICH GCP at any 
time in the study
Include in everything
0
O02
Deficient informed consent or any other 
process documentation at any time in the 
study.
Include in everything
0


Novartis
For business use only
Page 58
SAP
CAIN457FUS06
Deviation ID
Description of deviation
Exclusion in 
analyses
Severity 
code
O03
Failure to perform key study efficacy 
procedures 
for 
example, 
ASDAS, 
BASDAI,
ASAS20, ASAS40, ASAS 
partial remission, ADAS-Health Index, or 
FACIT
Include in everything
0
O04
Failure to perform safety procedure such 
as vitals, central labs, ECG, and 
pregnancy.
Include in everything
0
O06
Any 
other 
protocol 
deviation 
or 
observation not specified in the protocol 
deviations list.
Include in everything
0
O07
Missed visit due to COVID-19
Include in everything
0
O08
Visit done outside of study site due to 
COVID-19
Include in everything
0
O09
Assessment / procedure changed due to 
COVID-19
Include in everything
0
O10
Visit conducted out of window for week 
12, week 16, or week 52 due to COVID-
19
Include in everything
0
D03
Study/Treatment Discontinuation due to 
COVID-19
Include in everything
0
S01
Failure to return or failure to follow 
sponsor/institution for returning unused 
study medication
Include in everything
0
S02
Improper storage and/or accountability 
of study medication
Include in everything
0
S03
Incorrect 
study 
medication 
stock 
used/dispensed
Include in everything
0
S04
Improper 
procedure 
followed 
for 
Emergency 
Breaking 
of 
Assigned 
Treatment Code 
Include in everything
0
S05
Any incorrect route of administration of 
study drug at any time during the study, 
per protocol
Include in everything
0
S06
Missed study drug administration at any 
time in the study.
Include in everything
0
S07
Patient received more injections than 
prescribed by protocol.
Include in everything
0
S08
Incorrect ASDAS domain 
 
result entered into IRT at Baseline, Week 
12 or Week 16
Include in everything
0
S09
Drug supply method changed due to 
COVID-19
Include in everything
0


Novartis
For business use only
Page 59
SAP
CAIN457FUS06
Table 5-2
Analysis set exclusions based on codes
Analysis set 
Codes that cause a subject to be excluded
SAF 
5, 7, 9
FAS 
4, 7, 8, 9
ENR
1, 9
Responder Set
2, 8, 9
Non-Responder Set
6, 8, 9
Table 5-3
Code text
Code
Code text
0
Include in everything
1
Exclude from Enrolled Set
2
Exclude from Responder Set
3
Exclude from Randomized Set (RAN)
4
Exclude from Full Analysis Set (FAS)
5
Exclude from Safety Set (SAF)
6
Exclude from Nonresponder Set
7
Exclude from FAS and SAF
8
Exclude from FAS, Responder Set, Randomized 
Set and Nonresponder Set
9
Exclude from everything
5.6
Evaluation algorithm for ASDAS inactive disease status
At Week 12 and Week 16, all patients will be assessed for achieving the ASDAS inactive 
disease (total score < 1.3) status, as well as for an inadequate response or a non-response.  
Patients will then be divided into three groups in the following order:

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. 

Inadequate responders: Patients not achieving ASDAS inactive disease at Week 12 
and Week 16 (i.e., not achieving total score < 1.3), but who do achieve decrease 
(improvement) from baseline in total ASDAS score at Week 12 and Week 16.

Non-responders: Patients who exhibit no change or an increase (worsening) from 
baseline in total ASDAS score at either Week 12 or Week 16.


Novartis
For business use only
Page 60
SAP
CAIN457FUS06
Patient 
Baseline 
ASDAS
Week 
12 
ASDAS 
<1.3
Week 
16 
ASDAS 
< 1.3
Week 12 
ASDAS 
< 
Baseline
Week 16 
ASDAS 
<  
Baseline
Responder 
status
Definition 
Patient 
1
Yes
Yes
Responder
1
Patient 
2
?
No
No
Yes
Yes
Inadequate
2
Patient 
3
?
Yes
No
Yes
Yes
Inadequate
2
Patient 
4
?
No
Yes
Yes
Yes
Inadequate
2
Patient 
5
?
No
No
Yes
No
Non-
responder
3
Patient 
6
?
No
No
No
Yes
Non-
responder
3
Patient 
7
?
No
No
No
No
Non-
responder
3
Patient 
8
?
Yes
No
Yes
No
Non-
responder
3
Patient 
9
?
Yes
No
No
Yes
Non-
responder
3
Patient 
10
?
Yes
No
No
No
Non-
responder
3
Patient 
11
?
No
Yes
Yes
No
Non-
responder
3
Patient
12
?
No
Yes
No
Yes
Non-
responder
3
Patient 
13
?
No
Yes
No
No
Non-
responder
3
SAS program logic:
Do;
If ASDAS12 < 1.3 and ASDAS16 <1.3 
then RESPONSE = “Responder”;
Else if ASDAS12 <ASDAS0 and ASDAS16 < ASDAS0 
then RESPONSE = “Inadequate”;


Novartis
For business use only
Page 61
SAP
CAIN457FUS06
Else RESPONSE = “Non-responder”;
End;
6
References

Braun J, McHugh N, Singh A, Wajdula JS, Sato R (2009) Improvement in patient-
reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 
mg once-weekly and 25 mg twice-weekly. Rheumatology (Oxford); 46: 999-1004.

Cella, et al. (2004) Validation of the Functional Assessment of Chronic Illness 
Therapy Fatigue Scale relative to other instrumentation in patients with rheumatoid 
arthritis. J Rheumatol; 32: 811–9.

Diggle PJ, Heagerty P, Liang KY, et al (2002) Analysis of longitudinal data, 2nd ed; 
Oxford: Oxford University Press.

Garwood F (1936). Fiducial limits for the Poisson distribution. Biometrika; 46: 441–
453.

Gladman DD (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9: 455-
60.

Haywood KL, et al. (2002) Disease-specific, patient-assessed measures of health 
outcome in ankylosing spondylitis: reliability, validity and responsiveness. 
Rheumatology; 41: 1295-1302.

Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. (2003) Assessment of 
enthesitis in ankylosing spondylitis. Ann Rheum Dis; 62: 127-32.

Julious SA, Patterson SD (2004) Sample sizes for estimation in clinical research. 
Pharmaceutical Statistics; 3: 213-215.

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.

Newcombe, RG. (1998) Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Statistics in Medicine; 17: 857-872.

Sahai H, Khurshid A (1993). Confidence intervals for the mean of a poisson 
distribution: a review. Biom J; 35(7): 857-867.

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.


Novartis
For business use only
Page 62
SAP
CAIN457FUS06

Stokes ME, Davis CS, Koch GG (2012) Categorical data analysis using the SAS system. 
3rd ed; Cary, NC: SAS Institute, Inc.

Ulm K (1990). A simple method to calculate the confidence interval of a standard   
mortality ratio. American Journal of Epidemiology; 131(2): 373-375.

van Tubergen A, Landewe R, van der Heijde D, et al. (2001) Combined spa-exercise 
therapy is effective in patients with ankylosing spondylitis: a randomized controlled 
trial. Arthritis Rheum; 45: 430–38.