Clinical trial NCT02696031
Conditions: Non-radiographic Spondyloarthritis
Keywords: non-radiographic spondyloarthritis axial spondyloarthritis Ankylosing Spondylitis
Sponsor: Novartis Pharmaceuticals
Start date: 2016-04-29; Completion date: 2021-03-11
Enrollment: 555 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to demonstrate the clinical efficacy, safety and tolerability of secukinumab compared to placebo in patients with nr-axSpA at Week 16 as well as Week 52 and long term efficacy and safety up to Week 104 (core phase) followed by an optional extension phase consisting of a 16-week randomized dose escalation treatment period and a continuous treatment period for up to Week 208

Detailed description:
Patients were randomized to one of three treatment groups (1:1:1) in the core phase:

* Secukinumab 150 mg Load: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-filled syringe (PFS) at baseline, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4
* Secukinumab 150 mg No Load: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS at baseline, placebo at Weeks 1, 2, and 3, followed by secukinumab 150 mg PFS administration every four weeks starting at Week 4
* Placebo: placebo (1 mL) s.c. PFS at baseline, Weeks 1, 2, 3, followed by administration every four weeks starting at Week 4.

All patients received secukinumab 150 mg as open-label treatment from Week 52 up to Week 100, unless they had discontinued study treatment.

At Week 104, all patients who finished the core phase according to the protocol were asked to continue in an optional, exploratory extension phase. Patients who achieved ASAS20 response at Week 104 (Core Phase Responders) were randomized to the following treatment groups (blinded) in the extension phase:

* Core Phase Responder 150 mg: secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS and placebo (1 mL) s.c. PFS every four weeks;
* Core Phase Responder 300 mg: 2 injections with secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS every four weeks.

Core Phase Non-Responders (not achieving ASAS20 at Week 104) were escalated to secukinumab 300 mg in an open-label manner.

\- Core Phase Non-Responder 300 mg: 2 injections with secukinumab 150 mg (1 mL, 150 mg/mL) s.c. PFS every four weeks open-label.

Starting from Week 156 onward, a patient could switch to secukinumab 300 mg open-label based on the clinical judgment of disease activity by the investigator.

Arms: arm 1: Secukinumab 150 mg s.c., pre-filled syringe (PFS) at baseline, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4, Load, Core phase arm 2: Secukinumab 150 mg s.c. PFS at baseline, placebo at Weeks 1, 2, and 3, followed by secukinumab 150 mg PFS administration every four weeks starting at Week 4, No Load, Core phase arm 3: Placebo s.c., PFS at baseline, Weeks 1, 2, 3, followed by administration every four weeks starting at Week 4, Core phase arm 4: Core Phase Responder 150 mg blinded: secukinumab 150 mg s.c. PFS and placebo (1 mL) s.c. PFS every four weeks, in the Extension phase arm 5: Core Phase Responder 300 mg blinded: 2 injections with secukinumab 150 mg s.c. PFS every four weeks, in the Extension phase arm 6: Core Phase Non-Responder 300 mg: 2 injections with secukinumab 150 mg s.c. PFS every four weeks open-label, in the Extension phase
Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Induction: 4x 150 mg Secukinumab s.c. weekly Maintenance: 150 mg Secukinumab s.c. monthly intervention 2: Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly

Protocol documents:
SAP_002.pdf: 
Clinical Development 
Secukinumab (AIN457) 
CAIN457H2315 / NCT02696031
A randomized, double-blind, placebo-controlled multicenter 
study of secukinumab 150 mg in patients with active non-
radiographic axial spondyloarthritis to evaluate the safety, 
tolerability and efficacy up to 2 years, followed by an 
optional phase of either 150 mg or 300 mg randomized 
dose escalation for up to another 2 years 
Statistical Analysis Plan (SAP) – Amendment 2 
Author: 
, Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
Feb 5, 2019 
Number of pages: 
81 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous version of SAP. 
Version 
Date 
Changes 
Amendment 1 
Jan 23, 2019 
-Divided efficacy section 11 for plan A and section 12 for plan B  
-Changed statistical hierarchy to follow protocol amendment 1 and 2 
- Added details on estimand definition for each hypothesis in the 
testing hierarchy 
-Added interim analysis details for US testing hierarchy 
-Added description of group sequential testing for US hierarchy 
-Added full analysis set 2 for week 52 endpoints interim analysis 
-Corrected treatment arm description 
-Changed switch treatment labeling 
- Added instruction that AEs with onset after switching to standard of 
care, e.g., TNFα blocker, will still be reported under original 
treatment according to treatment emergent definition 
- Modified presentation of cDMARD to follow protocol specification 
-Changed analysis methodology for week 52 continuous endpoints 
 
 
- Added a stepwise approach to handle cases of model convergence 
issues for logistic regression 
- Added approaches to cases where MI cannot be performed as 
planned 
 
-Updated visit windows for MRI and X-ray 
Amendment 2 
Feb 5, 2019 
 
 
 
-Corrected typos and added minor clarifications 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
2 
Study objectives ................................................................................................................... 7 
3 
Data presentation ............................................................................................................... 11 
4 
Subjects and treatments ..................................................................................................... 12 
4.1 
Analysis sets .......................................................................................................... 12 
4.2 
Treatment groups ................................................................................................... 12 
5 
Subgroup definitions ......................................................................................................... 13 
6 
Assessment windows, baseline and post baseline definitions, missing data handling ...... 13 
7 
Subject disposition, background and demographic characteristics ................................... 13 
7.1 
Subject disposition ................................................................................................. 13 
7.2 
Background and demographic characteristics ....................................................... 14 
8 
Medical history .................................................................................................................. 14 
9 
Study treatment .................................................................................................................. 15 
10 Concomitant medication .................................................................................................... 15 
11 Efficacy evaluation for analysis plan A ............................................................................. 16 
11.1 
Description of efficacy variables ........................................................................... 16 
11.2 
Description of health-related quality of life variables ........................................... 22 
11.3 
Handling of missing data ....................................................................................... 24 
11.4 
Analysis of primary variable ................................................................................. 24 
11.5 
Analysis of secondary variables ............................................................................ 26 
 
 31 
11.7 
Analysis of health-related quality of life endpoints ............................................... 34 
12 Efficacy evaluation for analysis plan B ............................................................................. 35 
12.1 
Description of efficacy variables ........................................................................... 35 
12.2 
Description of health-related quality of life variables ........................................... 36 
12.3 
Handling of missing data ....................................................................................... 36 
12.4 
Analysis of primary variable ................................................................................. 37 
12.5 
Analysis of secondary variables ............................................................................ 39 
 
 47 
12.7 
Analysis of health-related quality of life endpoints ............................................... 50 
 51 
 
 51 
 
 52 


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 52 
 
 52 
14 Safety evaluation ............................................................................................................... 52 
14.1 
Adverse events ....................................................................................................... 53 
14.2 
Laboratory data ...................................................................................................... 54 
14.3 
Vital signs .............................................................................................................. 56 
14.4 
Electrocardiogram (ECG) ...................................................................................... 57 
 
 57 
14.6 
Compound specific safety evaluation .................................................................... 58 
15 Interim analyses ................................................................................................................. 58 
15.1 
Analysis plan A ...................................................................................................... 58 
15.2 
Analysis plan B ...................................................................................................... 58 
15.3 
Confidentiality of week 24 interim analysis results .............................................. 60 
16 Determination of sample size ............................................................................................ 61 
Appendix .................................................................................................................................. 64 
17.1 
Visit Windows ....................................................................................................... 64 
17.2 
Statistical methodology and assumptions .............................................................. 68 
17.2.1 
Analysis of continuous data .................................................................. 68 
17.2.2 
Analysis of binary and categorical data ................................................ 69 
17.2.3 
Imputation methods ............................................................................... 71 
17.2.4 
Crude incidence and related risk estimates ........................................... 75 
17.2.5 
Exposure adjusted incidence rate and related risk estimates ................ 76 
 
 77 
17.2.7 
RANK based analysis ........................................................................... 77 
17.2.8 
Trimmed means ..................................................................................... 78 
 
 78 
17.3 
Group sequential design used in phase III studies ................................................. 78 
17.3.1 
Alpha spending function ....................................................................... 79 
18 References ......................................................................................................................... 79 


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 List of abbreviations 
ACR 
American College of Rheumatology  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase/ Glutamic Pyruvic Transaminase/ GPT 
AS 
Ankylosing Spondylitis 
ASAS 
Assessment of Spondyloarthritis International Society criteria 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
AST 
Aspartate Aminotransferase/ Glutamic Oxaloacetic Transaminase/ GOT 
ASQoL 
Ankylosing Spondylitis Quality of Life Questionnaire 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BSL 
Baseline 
 
 
cDMARD 
conventional (i.e., non-biologic) DMARD 
CPO 
Country Pharma Organization 
CRP (hsCRP) 
(high sensitivity) C-Reactive Protein 
CRP+ 
hsCRP > ULN (as defined by the central lab) 
DMARD 
Disease Modifying Antirheumatic Drug 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report/Record Form 
EMA / EMEA 
European Medicines (Evaluation) Agency 
 
 
 
  
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
HLA 
Human Leukocyte Antigen 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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IL 
Interleukin 
IRB 
Institutional Review Board 
IRT  
Interactive Response Technology 
MAR 
Missing At Random 
 
 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
 
 
MRI 
Magnetic Resonance Imaging 
MRI+ 
Positive for sacroiliitis (active inflammatory lesions) 
MTX 
Methotrexate 
nr-axSpA 
Non-radiographic axial SpondyloArthritis 
NRI 
Non-Responder Imputation 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCS 
Physical Component Summary 
 
 
 
 
 
 
PoC 
Proof of Concept 
PRN 
According to need, as required 
PRO 
Patient Reported Outcome 
PsA 
Psoriatic Arthritis 
QoL 
Quality of Life 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
s.c. 
Subcutaneous(ly) 
SCR  
Screening 
SF-36 
Medical Outcome Short Form (36) Health Survey 
SpA 
Spondyloarthritis 
TNF 
Tumor Necrosis Factor  


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TNF-IR 
TNFα Inhibitor Incomplete Responders 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
 
 
1 
Introduction 
Data will be analyzed by Novartis according to the data analysis section 9 of the study protocol. 
The statistical methodology is described below and any deviations from the protocol are 
documented. Additional detailed information regarding the analysis methodology is contained 
in the Appendix section. Separate statistical analysis plan will be prepared for the extension 
phase analysis. 
This document comprises two separate endpoint testing strategies based on regional 
regulatory precedent and feedback: 
• Analysis plan A: EU and other non-USA Regions 
• Analysis plan B: USA 
2 
Study objectives 
There are two primary objectives based on regional regulatory precedent and feedback. These 
objectives will be tested in separate analysis plans. 
Analysis plan A 
The primary objective is to demonstrate that secukinumab 150 mg (with load) at Week 16 is 
superior to placebo in TNF naïve patients with active non-radiographic axial spondyloarthritis 
(nr-axSpA) based on the proportion of patients achieving an ASAS40 (Assessment of 
Spondyloarthritis International Society criteria) response. 
The following are the secondary objectives: 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS40 response 
criteria 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS 5/6 response 
criteria 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline of high sensitivity C-Reactive 
Protein (hsCRP)  


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• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Functional Index (BASFI) 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from screening in SI joint edema on MRI 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS20 response 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in Short Form-36 Physical 
Component Summary (SF-36 PCS) 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in ASQoL 
• To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of patients achieving ASAS partial remission 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of TNF naïve patients meeting the ASAS40 
response criteria 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS40 response 
criteria 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS 5/6 response 
criteria 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline of high sensitivity C-Reactive 
Protein (hsCRP)  
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Functional Index (BASFI) 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from screening in SI joint edema on MRI 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS20 response 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in Short Form-36 Physical 
Component Summary (SF-36 PCS) 


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• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in ASQoL 
• To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of patients achieving ASAS partial remission 
Analysis plan B 
The primary objective is to demonstrate that secukinumab 150 mg without load at Week 52 is 
superior to placebo in TNF naïve patients with active non-radiographic axial spondyloarthritis 
(nr-axSpA) based on the proportion of patients achieving an ASAS40 (Assessment of 
Spondyloarthritis International Society criteria) response. 
The following are the secondary objectives: 
1. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 52 is 
superior to placebo based on the proportion of subjects achieving an ASAS40 response 
2. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS40 response  
3. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 52 is 
superior to placebo based on the proportion of TNF naïve subjects achieving an ASAS40 
response 
4. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 52 is 
superior to placebo based on the proportion of subjects achieving an ASAS40 response 
5. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS40 response 
6. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) 
7. To demonstrate that the efficacy of secukinumab 150 mg (without load), at Week 16 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
8. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 52 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
9. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline of high sensitivity C-Reactive 
Protein (hsCRP)  
10. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in Short Form-36 Physical 
Component Summary (SF-36 PCS) 
11. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in ASQoL 
12. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS 5/6 response 
criteria 
13. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS20 response 


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14. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Functional Index (BASFI) 
15. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 16 is 
superior to placebo based on the change from screening in SI joint edema on MRI  
16. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 52 is 
superior to placebo based on the proportion of patients achieving Ankylosing Spondylitis 
Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease as defined by 
ASDAS < 1.3 
17. To demonstrate that the efficacy of secukinumab 150 mg s.c., (without load), at Week 52 
is superior to placebo based on the change from baseline in Ankylosing Spondylitis 
Quality of Life (ASQoL) scores  
18. To demonstrate that the efficacy of secukinumab 150 mg (without load) at Week 52 is 
superior to placebo based on the change from screening in SI joint edema on MRI 
19. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) 
20. To demonstrate that the efficacy of secukinumab 150 mg (with load), at Week 16 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
21. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 52 is 
superior to placebo based on the proportion of patients achieving BASDAI 50 
22. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline of high sensitivity C-Reactive 
Protein (hsCRP)  
23. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in Short Form-36 Physical 
Component Summary (SF-36 PCS) 
24. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in ASQoL 
25. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of patients meeting the ASAS 5/6 response 
criteria 
26. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the proportion of subjects achieving an ASAS20 response 
27. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Functional Index (BASFI) 
28. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 16 is 
superior to placebo based on the change from screening in SI joint edema on MRI  
29. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 52 is 
superior to placebo based on the proportion of patients achieving Ankylosing Spondylitis 
Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease as defined by 
ASDAS < 1.3 


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30. To demonstrate that the efficacy of secukinumab 150 mg s.c.,with load, at Week 52 is 
superior to placebo based on the change from baseline in Ankylosing Spondylitis Quality 
of Life (ASQoL) scores  
31. To demonstrate that the efficacy of secukinumab 150 mg (with load) at Week 52 is 
superior to placebo based on the change from screening in SI joint edema on MRI 
 
3 
Data presentation 
Summary statistics for continuous variables will include N, mean, standard deviation, 
minimum, lower quartile, median, upper quartile, maximum. Summary statistics for discrete 
variables will be presented in the number and percent of subjects in each category. 
If not otherwise specified, p-values will be presented as two-sided p-values and two-sided 
confidence intervals will be displayed. 
The default level of significance will be set to 5% (two-sided, family-wise type-I-error). 
Data analyses will be presented by treatment regimen. Efficacy and safety data for the placebo-
controlled period (or the entire treatment period as appropriate) will be presented by the 
following 3 treatment groups. Subjects may be included in more than one treatment group for 
some analyses (e.g., exposure-adjusted adverse events over the entire treatment period). These 
treatment groups represent the regimens subjects will be randomized to for the first 52 weeks 
of the study. 
• Secukinumab regimen 1 (secukinumab 150 mg Load): secukinumab 150 mg (1 mL, 150 
mg/mL) s.c. PFS at BSL, Weeks 1, 2, and 3, followed by administration every four weeks 
starting at Week 4 
• Secukinumab regimen 2 (secukinumab 150 mg No Load): secukinumab 150 mg (1 mL, 
150 mg/mL) s.c. PFS at BSL, placebo at Weeks 1, 2 and 3, followed by secukinumab 150 
mg PFS administration every four weeks starting at Week 4 
• Placebo regimen: placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, followed by 
administration every four weeks starting at Week 4 
Note that the treatment groups above for a subject may differ depending on the time period of 
the analysis and whether one assesses the subject for efficacy or safety.  
Furthermore, additional aspects of efficacy, safety and tolerability of secukinumab will be 
investigated. 
Comparative efficacy data 
Comparative efficacy analyses (i.e., inferential efficacy comparisons with placebo) will focus 
on the time period when both active drug and the placebo are given in a manner suitable for 
making comparisons (e.g., double-blind). For CAIN457H2315, this is the first 52-weeks of 
treatment.  Comparative efficacy will be performed based on the FAS population using the 
randomized treatment. Also, the active secukinumab regimens will be compared using 
confidence intervals on the FAS population. 


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Efficacy data following treatment switch 
Data will also be presented after treatment switch, by a combination of the ‘original’ and 
‘switch’ treatment groups. This will represent the treatment combinations the subjects 
experience over the course of the entire trial in case of switch. 
All listings will be presented by randomized treatment but also indicating the current treatment. 
4 
Subjects and treatments  
4.1 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set.  
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized patients are treated as screen failures.   
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be evaluated according to the treatment assigned to at randomization, but actual stratum, if 
stratified randomization is used.  
Full analysis set 2(FAS2): The FAS2 will be comprised of all subjects from the randomized 
set to whom study treatment has been assigned and who have been in enrolled at least 379(upper 
limit of visit window for primary endpoint) days before date cut off. Following the intent-to-
treat principle, subjects will be evaluated according to the treatment assigned to at 
randomization, but actual stratum, if stratified randomization is used.  
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. Subjects will be evaluated according to treatment received. 
The FAS2 set will be used for analyzing the week 52 efficacy endpoints at interim analysis. 
4.2 
Treatment groups 
The summaries by treatment will primarily be performed by the randomized treatment but also 
by combination of randomized treatment and switch treatment. For some safety summaries 
(e.g., exposure-adjusted) the ‘switch’ treatment may be summarized separately. 
• Randomized treatment: 
• AIN457 150 mg Load 
• AIN457 150 mg No Load 
• Placebo     
• Treatment sequence: 
• AIN457 150 mg Load 


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• AIN457 150 mg No Load 
• Placebo – AIN457 150 mg No Load 
• Placebo – Standard of care 
• AIN457 150 mg Load – Standard of care 
• AIN457 150 mg No Load – Standard of care 
• Switch treatments (for patients who cross-over): 
• Open label AIN457 150 mg  
• Standard of care 
5 
Subgroup definitions 
The primary endpoint(s) and secondary endpoints will be evaluated within TNFα inhibitor 
status (TNF-naïve and TNF-IR) and within stratification factor levels (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+). 
6 
Assessment windows, baseline and post baseline 
definitions, missing data handling 
Baseline and post-baseline definitions 
In general, a baseline value refers to the last measurement made 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.  
Analysis visit windows 
Analysis visit windows will be used for the data that is summarized by visit; they are based on 
the study evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are protocol defined scheduled visits around which analysis visit windows 
were created to cover the complete range of days within the study. The analysis visit windows 
and rules for dealing with multiple measurements within the windows are described in 
Appendix 17.1. 
7 
Subject disposition, background and demographic 
characteristics 
7.1 
Subject disposition 
The number of subjects screened will be presented. In addition, the reasons for screen failures 
will be provided. The number and percentage of subjects in the randomized set who completed 
the study periods and who discontinued the study prematurely (including the reason for 
discontinuation) will be presented at the end of each treatment period (Week 24, Week 52, 
Week 104), if appropriate, for each treatment group and all subjects. 


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For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated. 
7.2 
Background and demographic characteristics 
The following common background and demographic variables will be summarized: 
Continuous variables: 
o Age (which is derived from date of birth and the date of informed consent) 
o Height 
o Weight 
o Body mass index (BMI) = (body weight in kilograms) / (height in meters)2 
For BMI, height and body weight, the last value prior to randomization is used. If there is no 
weight recorded prior to taking of study drug, BMI will be missing. 
Categorical variables: 
o Age categories (<65 years, 65 years and older, 75 years and older) 
o Gender 
o Race 
o Ethnicity 
o Smoking status at baseline 
Baseline disease characteristics will also be summarized for the following variables: 
• 
Patient’s global assessment of disease activity and other ASAS components, hsCRP (mg/L 
and >ULN), 
, prior use (yes/no) of TNF-alpha inhibitors, use (yes/no) and 
separate dose of MTX (mg/week), sulfasalazine (g/day) and systemic corticosteroids 
(mg/day) at randomization, time since first diagnosis of nr-axSpA (years), time since onset 
of back pain, modified New York criteria for AS, HLA-B27, 
 total back pain 
(VAS), nocturnal back pain (VAS), total BASDAI score, spinal pain (BASDAI question 
#2) and 
 presence of SIJ inflammation by 
MRI and each randomization strata level (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+). 
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total) in the randomized set.  
Unless otherwise specified, analyses will be based on the randomized set. 
8 
Medical history 
Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. They will be summarized by system organ class (SOC) 
and preferred term (PT) of the MedDRA dictionary. Summaries for cardiovascular medical 
history and nr-axSpA medical history will also be provided. 
Smoking history will be summarized by treatment group. 


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Unless otherwise specified, analyses will be based on the randomized set. 
9 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo injections will be summarized by treatment group. The duration of exposure to study 
treatment will also be summarized by treatment group. In addition, the number and percentage 
of subjects with cumulative exposure levels (e.g., any exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, 
≥ 4 weeks, ≥ 8 weeks, etc.) will be presented. 
Duration of exposure will be defined as the time from first dose of study treatment to the time 
of treatment switch (for subjects who switch treatment) or minimum of (last dose of the 
treatment + 84 days) and (last visit date). Patients who switch treatment during the study (e.g., 
from placebo to active treatment) will have exposure to both medications using the appropriate 
start and stop dates.  
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100 subject years) = duration of exposure (years) / 100 
The analyses of duration of exposure described above will be done for the entire study treatment 
period. 
10 
Concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment 
and within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
The number and percentage of subjects receiving prior nr-axSpA therapy will be presented by 
randomized treatment group and, at least for TNFα, also by the reasons for stopping their 
therapies (primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other). 
NSAID, glucocorticoid and DMARD (MTX, Leflunomide, Sulfasalazine) use during the study 
will be summarized. 
Significant prior and concomitant surgeries and procedures will be summarized by primary 
system organ class and MedDRA preferred term. 
Prior or concomitant medication will be identified by comparing recorded or imputed start and 
end dates of medication taken to the reference start date. 


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Presentation by dose 
Methotrexate, sulfasalazine and systemic corticosteroid intake at randomization will be 
presented based on the amount taken per time unit, e.g., mg/day. 
Since different steroids have different strengths the following multiplication factors will be used 
to convert a dose in mg into a prednisone equivalent dose in mg: 
Cortisone (0.20), hydrocortisone (0.25), prednisolone (1.0), triamcinolone (1.25), 
methylprednisolone (1.25), dexamethasone (6.67), betamethasone (8.33) (corticosteroid 
converter website).  
The reported dose and frequency of intake will be converted into the desired units. If the 
frequency is missing or specified as ‘per needed’, ‘unknown’, ‘once’, ‘other’ or if the dose or 
dose unit is missing, then the medication will not be part of the presentation. 
11 
Efficacy evaluation for analysis plan A 
11.1 
Description of efficacy variables 
Assessment of Spondyloarthritis International Society criteria (ASAS) response 
criteria 
The ASAS response measures consist of the following assessment domains (Sieper 2009) 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale. For ASAS response analyses, the total back pain will be 
used. 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale 
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 VAS 
scale (at least one question is needed) 
Additional assessment domains: 
5. Spinal lateral flexion, represented by one of the components of BASMI 
6. C-reactive protein (acute phase reactant) 
 ASDAS-CRP, 
, clinically important and 
major improvement 
The 
 ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) will be 
utilized to assess the disease activity status. Parameters used for the ASDAS include: total back 
pain (BASDAI question 2), the patient global assessment of disease activity (ASAS component 
1), peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI 
question 6) and high sensitivity C-Reactive Protein (hsCRP) 
 
 (Sieper 2009, Lukas 2009).  


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The ASDAS formulas are as follows: 
ASDAS-CRP = 0.121 x total back pain + 0.110 x patient global + 0.073 x peripheral 
pain/swelling + 0.058 x duration of morning stiffness + 0.579 x ln(hsCRP +1) 
 
 
hsCRP is in mg/liter, 
 the range of other variables is from 0 to 10; ln represents 
the natural logarithm; √ represents the square root. If any of the ASDAS components are 
missing ASDAS will not be calculated. 
Disease activity states: 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 > 3.5 between high disease activity and very high disease activity. 
Selected cutoffs for improvement scores were a change ≥ 1.1 unit for “minimal clinically 
important improvement” and a change ≥ 2.0 units for “major improvement” (Machado 2011). 
Separate states will be calculated for ASDAS-CRP 
. 
ASAS components 
Patient’s global assessment of disease activity (VAS) 
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question "How active was 
your disease on average during the last week?”.  
Patient’s assessment of total inflammatory back pain and nocturnal back pain 
intensity (VAS) 
The patient’s assessment of inflammatory back pain will be performed using a 100 mm VAS 
ranging from no pain to unbearable pain, after the question “Based on your assessment, please 
indicate what is the amount of back pain at any time that you experienced during the last week?” 
and “Based on your assessment, please indicate what is the amount of back pain at night that 
you experienced during the last week?”. 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those subjects with AS. The ten questions were chosen with a major input from subjects with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the subjects’ ability to cope with everyday life. A 100 mm VAS is used to answer the 
questions. The mean of the ten questions gives the BASFI score – a value between 0 and 10. In 
the case that some of the BASFI questions are missing, then the average of the non-missing 
items is used (Braun 2009, van Tubergen 2001). 


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Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The gold standard for measuring and evaluating disease activity in AS is the BASDAI. The 
BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem), 
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  
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 and is then added to the sum of the first 4 questions. 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 trials 
evaluating new drug therapies directed at AS. BASDAI is a quick and simple index taking 
between 30 secs and 2 mins to complete. At least 4 questions should be non-missing to calculate 
the BASDAI score. Otherwise, BASDAI score will be missing (Haywood 2002). If both Q5 
and Q6 are missing or one of Q1 to Q4 is missing, then the total sum should be divided by 4 
instead of 5. If two of Q1 to Q4 is missing and both Q5 and Q6 are not missing, then the sum 
should be divided by 3. 
 


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11.2 
Description of health-related quality of life variables 
Ankylosing Spondylitis Quality of Life (ASQoL)  
The ASQoL is a self-administered questionnaire designed to assess health-related quality of life 
in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a 
dichotomous yes/no response option. A single point is assigned for each "yes" response and no 
points for each "no" response resulting in overall scores that range from 0 (least severity) to 18 
(highest severity). As such, lower score indicate better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment," and the measure requires approximately 6 minutes to complete. 
At least 15 answered questions are required to be able to calculate ASQoL using mean 
imputation, (sum of answered)/(number answered)*18 (Doward 2003) 
SF-36 
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy subjects and patients with acute and 
chronic conditions. It consists of eight subscales (domains) that can be scored individually: 
Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, 
Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 
burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients. The eight domains are based on a scale from 0-100 while 
PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. 
Quality metric uses weighted maximum likelihood estimation, a modified version of item 
response theory (IRT) to estimate scale scores when a respondent is missing multiple 
items.  The PCS summary score measure requires scores for seven scales, one of which must 
be the PF scale and the MCS score also requires scores for seven scales, one of which must be 
the MH scale.  Only one item is needed for each of the multi-item domains.  


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11.3 
Handling of missing data 
Missing data for ASAS20/40 response and other binary efficacy variables (e.g., ASAS5/6, etc.) 
for data up to Week 20 will be handled as follows: 
1. Patients who drop out of the trial for any reason will be considered as non-responders 
from the time they drop out through Week 20 
2. Patients who do not have the required data to compute responses (e.g., ASAS 
components) at baseline and at the specific timepoint will be classified as non-responders 
at the specific timepoint.  
Patients who are unblinded will be considered non-responders from the time of unblinding up 
to Week 20. The primary analysis will use non-responder imputation.  
 
Continuous variables (e.g., ASAS components) with the exception of MRI endpoints, will be 
analyzed using a mixed-effects model repeated measures (MMRM) which is valid under the 
missing at random (MAR) assumption. The MMRM models will be applied  up to week 20 
when no treatment escape has occured. As such, single-point imputation of missing data will 
not be performed (e.g., LOCF). For analyses of these parameters, if all post-baseline values are 
missing then these missing values will not be imputed and this patient will be removed from 
the analysis of the corresponding variable, i.e., it might be that the number of patients providing 
data to an analysis is smaller than the number of patients in the FAS. 
For SI joint edema on MRI a multiple imputation (MI) approach under MAR assumption will 
be applied to handle missing data. The MI model will include stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+) and TNF-α inhibitor status as categorical covariates and patient 
weight as a continuous covariate. 
Imputation under MAR relies on the assumption that unbiased estimates can be obtained by 
borrowing information from patients with collected data that are similar in regards to model 
baseline covariates and measurements collected at prior visits. 
11.4 
Analysis of primary variable 
Description 
The ASAS Response Criteria (ASAS40) is defined as an improvement of ≥40% and ≥2 unit on 
a scale of 10 in at least three of the four main domains and no worsening at all in the remaining 
domain. 


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Primary endpoint for analysis plan A 
The estimand for primary endpoint is defined as follows 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving ASAS40 response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: odds ratio of response proportions between the treatment 
conditions 
 
The statistical hypothesis for ASAS40 being tested is that there is no difference in the proportion 
of TNF naïve patients fulfilling the ASAS40 criteria at Week 16 in the secukinumab 150 mg 
load regimen versus placebo regimen. 
Let pj denote the proportion of ASAS40 responders at Week 16 in TNF naïve patients for 
treatment regimens j, j=0, 1 where  
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab 150 mg with loading regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab 150 mg with load is not different to placebo regimen with respect to ASAS40 
response in TNF naïve patients at Week 16 
The primary analysis will be conducted via logistic regression with treatment and stratification 
factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) as factors and weight as a covariate. Odds 
ratios and 95% CI will be presented comparing each secukinumab regimen to placebo. 
Odds ratio and 95% CI will also be presented comparing the two secukinumab regimens. 


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11.5 
Analysis of secondary variables 
Secondary endpoints for analysis plan A 
The secondary efficacy variables include, 
• response to treatment at Week 16 according to the ASAS40 criteria 
• response to treatment at Week 16 according to the ASAS 5/6 criteria  
• change from baseline in total BASDAI score at Week 16 
• response to treatment at Week 16 according to the BASDAI50 criteria 
• change from baseline in hsCRP at Week 16 
• change from baseline in total BASFI score at Week 16 
• change from screening in MRI SI joint edema score at Week 16 
• response to treatment at Week 16 according to the ASAS20 criteria 
• change from baseline in SF-36 PCS score at Week 16 
• change from baseline in ASQoL score at Week 16 
• response to treatment at Week 16 according to the ASAS partial remission 
All analysis will be done in the FAS population. 
Testing strategy to control type I error 
The following null hypotheses will be included in the testing strategy, and type-I-error will be 
set such that a family-wise type-I-error of 5% is kept: 
Primary objective: 
H1: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
signs and symptoms (ASAS40 response) in TNF naïve patients at Week 16 
Secondary objectives: 
H2: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 response at Week 16 
H3: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS 5/6 response at Week 16 
H4: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H5: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H6: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H7: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H8: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 


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H9: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H10: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H11: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H12: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS partial remission at Week 16 
H13: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 response in TNF naïve patients at Week 16 
H14: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 response at Week 16 
H15: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS 5/6 response at Week 16 
H16: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H17: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H18: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H19: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H20: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H21: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H22: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H23: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H24: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS partial remission at Week 16 
 


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Figure 11-1 
Testing strategy for analysis plan A 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed sequential 
testing strategy as described in Figure 11-1. The primary hypothesis (H1) for the primary 
objective (ASAS40 in TNF naïve at Week 16) for secukinumab with load regimen versus 
placebo will be tested at α-level. If the hypothesis H1 is rejected then the whole α will be passed 
to the next hypothesis (H2) which will be tested at α-level. This procedure will continue 
(pending rejection of the null hypotheses) until H12 is rejected. If H12 is rejected then the full α-
level is passed on to the testing sequence of secukinumab without load which can now be tested 
at 5% level sequentially in a similar way.  
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
sequence for the test of another hypothesis if the treatment effect is in favor of secukinumab. 
The secondary efficacy variables and the method of analyses are described below. 


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Estimand definition for the secondary variables 
 
Estimand definition for the secondary binomial variables is the following 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving variable response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: odds ratio of response proportions between the treatment 
conditions 
The estimand of binary variables is (each secukinumab dose vs placebo) obtained from a logistic 
regression model at week 16 in the FAS population. In the analysis patients dropping out or 
being unblinded before week 16 or having missing response data at week 16 are considered as 
non-responders. 
 
Estimand definition for the secondary continuous variables is the following 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: change from baseline in the variable of interest 
C. Intercurrent event: had no intercurrent events occured before week 16  
D. Population-level summary: difference in variable means between the treatment conditions 
 
The estimand of continuous variables at week 16 is (each secukinumab dose vs placebo) 
obtained from a linear regression model in the FAS population assuming patients dropping out 
or having missing data at week 16 are missing-at-random (MAR). MAR imputation will be 
implemented through an MMRM or multiple imputation model. 
ASAS40 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
ASAS 5/6 at Week 16 
The proportion of patients meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and weight as a covariate. 
BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 


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TNF-α status, and analysis visit as factors and baseline BASDAI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASDAI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens will 
be determined from the pairwise comparisons performed between secukinumab regimens and 
placebo at Week 16. 
BASDAI50 at Week 16 
The proportion of patients meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and baseline weight and BASDAI score as covariates. 
hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature would suggest that the data are not 
normally distributed (Huffman et al 2006), analysis will be performed on the loge ratio of the 
treatment value vs baseline value (calculated by dividing the post-baseline value by the baseline 
value and then applying the loge transformation) to normalize the distribution of hsCRP at each 
analysis visit. Between-treatment differences in the change in hsCRP relative to baseline will 
be evaluated using MMRM with treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status, and analysis visit as factors and loge baseline hsCRP 
and weight as continuous covariates. Treatment by analysis visit and loge baseline hsCRP by 
analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the secukinumab treatment effect 
for secukinumab regimens will be determined from the pairwise comparisons performed 
between secukinumab regimens and placebo at Week 16. The estimate and the 2-sided 95% 
confidence intervals obtained from the model will be back transformed to the original scale. 
BASFI at Week 16 
Between-treatment differences in the change from baseline in BASFI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASFI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASFI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens will 
be determined from the pairwise comparisons performed between secukinumab regimens and 
placebo at Week 16. 
SI joint edema on MRI at Week 16 
The change from baseline to Week 16 in inflammation measured by SI joint total edema score 
will be evaluated using an ANCOVA model with treatment group, stratification factor 
(CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors, and weight and baseline 
inflammation score as covariates.  
 


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ASAS20 at Week 16 
The proportion of patients meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and weight as a covariate. 
SF-36 PCS at Week 16 
See Section 11.7. 
ASQoL at Week 16 
See Section 11.7. 
ASAS partial remission at Week 16 
Response at Week 16 to ASAS partial remission will be evaluated using a logistic regression 
model with treatment, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-
α status as factors and weight as a covariate. 


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11.7 
Analysis of health-related quality of life endpoints 
Ankylosing Spondylitis Quality of Life (ASQoL)  
ASQoL at week 16 
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status and analysis visit will be used as categorical factors 
and baseline ASQoL score and weight as continuous covariates. Treatment by analysis visit and 
baseline ASQoL score by analysis visit will be included as interaction terms in the model. An 
unstructured covariance structure will be assumed for the model. The significance of the 
treatment effects for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab regimens and placebo and/or 
secukinumab at the appropriate analysis visits. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100). 
• SF-36 PCS and MCS scores (norm-based scores). 
• SF-36 PCS responder (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change in SF-36 summary scores (PCS and MCS), between-treatment differences will 
be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+), TNF-α status and analysis visit will be included as categorical factors and 
baseline SF-36 score (PCS or MCS) and weight as continuous covariates. Treatment by analysis 
visit and baseline SF-36 score (PCS or MCS) by analysis visit will be included as interaction 
terms in the model. An unstructured covariance structure will be assumed for the model. 
Pairwise comparisons will be performed between secukinumab regimens and placebo and/or 
secukinumab at appropriate analysis visits. 


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In the responder analyses, treatment groups will be compared with respect to response to 
treatment using a logistic regression model with treatment, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status as factors and baseline SF-36 score (PCS or MCS) 
and weight as covariates. Odds ratios and 95% CI will be presented for appropriate treatment 
comparisons. 
The SF-36 domain scores will be summarized by treatment. 
12 
Efficacy evaluation for analysis plan B 
12.1 
Description of efficacy variables 
Please see section 11.1. 


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12.2 
Description of health-related quality of life variables 
Please see section 11.2 
12.3 
Handling of missing data 
Missing data for ASAS20/40 response and other binary efficacy variables (e.g., ASAS5/6, etc.) 
for data up to Week 20 will be handled as follows: 
1. Patients who drop out of the trial for any reason will be considered as non-responders 
from the time they drop out through Week 52 
2. Patients who do not have the required data to compute responses (e.g., ASAS 
components) at baseline and at the specific timepoint will be classified as non-responders 
at the specific timepoint.  
Patients who are unblinded will be considered non-responders from the time of unblinding up 
to Week 52. The primary analysis will use non-responder imputation.  
 
Continuous variables (e.g., ASAS components) with the exception of MRI endpoints, will be 
analyzed using a mixed-effects model repeated measures (MMRM) which is valid under the 
missing at random (MAR) assumption. The MMRM models will be applied  up to week 20 
when no treatment escape has occured. As such, single-point imputation of missing data will 
not be performed (e.g., LOCF). For analyses of these parameters, if all post-baseline values are 
missing then these missing values will not be imputed and this patient will be removed from 
the analysis of the corresponding variable, i.e., it might be that the number of patients providing 
data to an analysis is smaller than the number of patients in the FAS. 
For SI joint edema on MRI a multiple imputation (MI) approach under MAR assumption will 
be applied to handle missing data. The MI model will include stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+) and TNF-α inhibitor status as categorical covariates and patient 
weight as a continuous covariate. 
Imputation under MAR relies on the assumption that unbiased estimates can be obtained by 
borrowing information from patients with collected data that are similar in regards to model 
baseline covariates and measurements collected at prior visits 
For continuous endpoints analyzed at week 52 with composite strategy missing data will be 
handled similarly as escape (extreme unfavorable value will be assigned for any missing value). 
Data post treatment switch 
Within analysis plan B, the statistical testing hierarchy has endpoints at Week 16 and Week 52.   
In general, data for patients where a decision was made to escape to biologic treatment (on or 
after week 20) will be handled in the following fashion up to Week 52 (of note, changes in 
background medications other than biologics will not be treated as escape):   
• For binary endpoints, composite estimand strategy will be applied and patients will be 
considered non-responders after decision to stop blinded study treatment (this also 
includes secukinumab patients where switch decision was made although they will stay on 


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secukinumab). This is referred to as the ‘escape penalty’. This will be done for all 
treatment regimens in order to minimize bias for between-treatment comparisons. 
•  For continuous endpoints in the testing hierarchy(ASQoL and SI joint edema score on 
MRI), a composite estimand strategy will be applied and data after switch will be set to 
the extreme unfavorable value. Rank-based analysis will be used for hypothesis testing.  
• Difference in trimmed means estimate will be used to summarize the treatment effect 
estimate for the continuous composite endpoint 
• For binary and continuous endpoints the actual observed values after switch will be also 
summarized with descriptive statistics 
12.4 
Analysis of primary variable 
Description 
The ASAS Response Criteria (ASAS40) is defined as an improvement of ≥40% and ≥2 unit on 
a scale of 10 in at least three of the four main domains and no worsening at all in the remaining 
domain. 
Primary endpoint for analysis plan B 
The primary estimand is defined as follows 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: composite of remaining on the study and on randomized treatment through 52 
weeks and achieving ASAS40 response at 52 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: odds ratio of response proportions between the treatment 
conditions 
 
The statistical hypothesis for ASAS40 being tested is that there is no difference in the proportion 
of TNF naïve subjects fulfilling the ASAS40 criteria at Week 52 in secukinumab 150 mg 
without load regimen versus placebo regimen.  
Let pj denote the proportion of ASAS40 responders at Week 52 for treatment regimens j, j=0, 
1, where  
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab 150 mg without loading regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e., 
H1: secukinumab 150 mg without load is not different to placebo regimen with respect to 
ASAS40 response in TNF naïve patients at Week 52. 
The primary analysis will be conducted via logistic regression with treatment and stratification 
factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) as factors and weight as a covariate. Odds 
ratios and 95% CI will be presented comparing each secukinumab regimen to placebo.  


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Odds ratio and 95% CI will also be presented comparing the two secukinumab regimens. 


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12.5 
Analysis of secondary variables 
Secondary endpoints for analysis plan B 
The secondary efficacy variables include, 
• response to treatment at Week 52 according to the ASAS40 criteria 
• response to treatment at Week 16 according to the ASAS40 criteria  
• change from baseline in total BASDAI score at Week 16 
• response to treatment at Week 16 according to the BASDAI50 criteria 
• response to treatment at Week 52 according to the BASDAI50 criteria 
• change from baseline in hsCRP at Week 16 
• change from baseline in SF-36 PCS score at Week 16 
• change from baseline in ASQoL score at Week 16 
• response to treatment at Week 16 according to the ASAS5/6 criteria 
• response to treatment at Week 16 according to the ASAS20 criteria 
• change from baseline in total BASFI score at Week 16 
• change from screening in MRI SI joint edema score at Week 16 
• response to treatment at Week 52 according to the ASDAS-CRP Inactive Disease 
• change from screening in MRI SI joint edema score at Week 52 
• change from baseline in ASQoL score at Week 52 
All analysis will be done in the FAS population. 
Testing strategy to control type I error 
The following hypotheses will be included in the testing strategy, and type-I-errors will be set 
such that a family-wise type-I-error of 5% is kept: 
Primary objective: 
H1: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 in TNF naïve at Week 52 
Secondary objectives: 
H2: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 at Week 52 
H3: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 at Week 16 
H4: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 in TNF naïve at Week 52 
H5: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 at Week 52 
H6: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 at Week 16 


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H7: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H8: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H9: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 52 
H10: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H11: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H12: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H13: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS5/6 at Week 16 
H14: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H15: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H16: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H17: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASDAS-CRP ID at Week 52 
H18: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 52 
H19: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 52 
H20: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H21: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H22: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 52 
H23: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H24: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H25: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 


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H26: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS5/6 at Week 16 
H27: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H28: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H29: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H30: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASDAS-CRP ID at Week 52 
H31: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 52 
H32: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 52 
 


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Figure 12-1 
Testing strategy 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed sequential  
testing strategy as described in Figure 11-2. The primary hypothesis (H1) for the primary 
objective (ASAS40 in TNF naïve at Week 52) for secukinumab without load regimen versus 
placebo will be tested at α-level. If the hypothesis H1 is rejected then the whole α will be passed 
to the next hypothesis (H2) which will be tested at α-level. This procedure will continue 
(pending rejection of the null hypotheses) until H32 is rejected.  
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
graphical procedure for the test of another hypothesis if the treatment effect is in favor of 
secukinumab. 
Estimand definition 
Binomial variables week 16 or week 52 
Estimand definition for the secondary binomial variables at 16 (or 52) weeks is the following 


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A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: composite of remaining on the study and on randomized treatment through 16 (or 
52)  weeks and achieving variable response at 16 (or 52) weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: odds ratio of response proportions between the treatment 
conditions 
The estimand of binary variables is (each secukinumab dose vs placebo) obtained from a logistic 
regression model at week 16 in the FAS population. In the analysis patients dropping out or 
being unblinded before week 16 (or 52) or having missing response data at week 16 (or 52)  are 
considered as non-responders. 
Continuous variables week 16 
Estimand definition for the secondary continuous variables at week 16 is the following 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: change from baseline in the variable of interest 
C. Intercurrent event: had no intercurrent events occured before week 16  
D. Population-level summary: difference in variable means between the treatment conditions 
The estimand of continuous variables at week 16 is (each secukinumab dose vs placebo) 
obtained from a linear regression model in the FAS population assuming patients dropping out 
or having missing data at week 16 are missing-at-random (MAR). MAR imputation will be 
implemented through an MMRM or multiple imputation model 
Continuous variables week 52 
Estimand definition for the secondary continuous variables at week 52 is the following 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
nr-axSpA population  
B. Variable: continuous response variable, for patients experiencing an intercurrent event 
extreme unfavorable value is assigned 
C. Intercurrent event: the intercurrent event is captured through the variable definition; 
D. Population-level summary: The difference in ranks supplemented with the trimmed means 
for change from baseline 
Wilcoxon rank-sum test will be used for testing the difference in the composite variable in 
each secukinumab dose vs placebo. Trimmed means is analyzed using permutation test and 
MMRM or ANCOVA. 
 
ASAS40 at Week 16 and Week 52 
The proportion of patients meeting the response criteria at Week 16 and at Week 52 will be 
evaluated using a logistic regression model with treatment group, stratification factor 


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(CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors and weight as a 
covariate. 
BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASDAI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASDAI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens will 
be determined from the pairwise comparisons performed between secukinumab regimens and 
placebo at Week 16. 
BASDAI50 at Week 16 and Week 52 
The proportion of patients meeting the response criteria at Week 16 and at Week 52 will be 
evaluated using a logistic regression model with treatment group, stratification factor 
(CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors and baseline weight and 
BASDAI score as covariates. 
hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature would suggest that the data are not 
normally distributed (Huffman et al 2006), analysis will be performed on the loge ratio of the 
treatment value vs baseline value (calculated by dividing the post-baseline value by the baseline 
value and then applying the loge transformation) to normalize the distribution of hsCRP at each 
analysis visit. Between-treatment differences in the change in hsCRP relative to baseline will 
be evaluated using MMRM with treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status, and analysis visit as factors and loge baseline hsCRP 
and weight as continuous covariates. Treatment by analysis visit and loge baseline hsCRP by 
analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the treatment effect for 
secukinumab regimens will be determined from the pairwise comparisons performed between 
secukinumab regimens and placebo at Week 16. The estimate and the 2-sided 95% confidence 
intervals obtained from the model will be back transformed to the original scale. 
SF-36 PCS at Week 16 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100). 
• SF-36 PCS and MCS scores (norm-based scores). 
• SF-36 PCS responder (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change in SF-36 summary scores (PCS and MCS), between-treatment differences will 
be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+), TNF-α status and analysis visit will be included as categorical factors and 
baseline SF-36 score (PCS or MCS) and weight as continuous covariates. Treatment by analysis 


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visit and baseline SF-36 score (PCS or MCS) by analysis visit will be included as interaction 
terms in the model. An unstructured covariance structure will be assumed for the model. 
Pairwise comparisons will be performed between secukinumab regimens and placebo and/or 
secukinumab at appropriate analysis visits. 
In the responder analyses, treatment groups will be compared with respect to response to 
treatment using a logistic regression model with treatment, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status as factors and baseline SF-36 score (PCS or MCS) 
and weight as covariates. Odds ratios and 95% CI will be presented for appropriate treatment 
comparisons. 
The SF-36 domain scores will be summarized by treatment. 
 
ASQoL at Week 16  
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status and analysis visit will be used as categorical factors 
and baseline ASQoL score and weight as continuous covariates. Treatment by analysis visit and 
baseline ASQoL score by analysis visit will be included as interaction terms in the model. An 
unstructured covariance structure will be assumed for the model. The significance of the 
treatment effects for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab regimens and placebo and/or 
secukinumab at the appropriate analysis visits. 
 
ASQoL at Week 52 
The change from baseline to Week 52 in ASQoL score will be analyzed by composite estimand 
strategy in which data after switch is set to extreme unfavorable value. Wilcoxon rank-sum test 
will be used for testing the difference in distributions of the composite endpoint in active vs 
placebo. Treatment differences will be summarised using trimmed means and confidence 
intervals will be calculated using permutation distribution. 
 
 
ASAS 5/6 at Week 16 
The proportion of patients meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and weight as a covariate. 


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ASAS20 at Week 16 
The proportion of patients meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and weight as a covariate. 
BASFI at Week 16 
Between-treatment differences in the change from baseline in BASFI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASFI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASFI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens will 
be determined from the pairwise comparisons performed between secukinumab regimens and 
placebo at Week 16. 
SI joint edema on MRI at Week 16 
The change from screening  to Week 16 in inflammation measured by SI joint total edema score 
will be evaluated using an ANCOVA model with treatment group, stratification factor 
(CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors, and weight and baseline 
inflammation score as covariates. 
 
 
 
 
SI joint edema on MRI at Week 52 
The change from baseline to Week 52 in inflammation measured by SI joint total edema score 
will be analyzed by composite estimand strategy in which data after switch is set to extreme 
unfavorable value. Wilcoxon rank-sum test will be used for testing the difference in 
distributions of the composite endpoint in active vs placebo. Treatment differences will be 
summarised using trimmed means and confidence intervals will be calculated using permutation 
distribution. 
 
 
 
ASDAS-CRP inactive disease at Week 52 
The proportion of patients meeting the response criteria at Week 52 will be evaluated using a 
logistic regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+) and TNF-α status as factors and baseline weight and ASDAS-CRP score as 
covariates. 


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12.7 
Analysis of health-related quality of life endpoints 
Ankylosing Spondylitis Quality of Life (ASQoL)  
ASQoL up to week 20 
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status and analysis visit will be used as categorical factors 
and baseline ASQoL score and weight as continuous covariates. Treatment by analysis visit and 
baseline ASQoL score by analysis visit will be included as interaction terms in the model. An 
unstructured covariance structure will be assumed for the model. The significance of the 
treatment effects for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab regimens and placebo and/or 
secukinumab at the appropriate analysis visits. 
ASQoL at week 52 
The change from baseline to Week 52 in ASQoL score will be analyzed by composite estimand 
strategy in which data after switch is set to extreme unfavorable value. Wilcoxon rank-sum test 
will be used for testing the difference in distributions of the composite endpoint in active vs 
placebo. Treatment differences will be summarised using trimmed means and confidence 
intervals will be calculated using permutation distribution. 
 
 
 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100). 
• SF-36 PCS and MCS scores (norm-based scores). 
• SF-36 PCS responder (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change in SF-36 summary scores (PCS and MCS), between-treatment differences will 
be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+), TNF-α status and analysis visit will be included as categorical factors and 
baseline SF-36 score (PCS or MCS) and weight as continuous covariates. Treatment by analysis 
visit and baseline SF-36 score (PCS or MCS) by analysis visit will be included as interaction 
terms in the model. An unstructured covariance structure will be assumed for the model. 
Pairwise comparisons will be performed between secukinumab regimens and placebo and/or 
secukinumab at appropriate analysis visits. 
In the responder analyses, treatment groups will be compared with respect to response to 
treatment using a logistic regression model with treatment, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status as factors and baseline SF-36 score (PCS or MCS) 


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and weight as covariates. Odds ratios and 95% CI will be presented for appropriate treatment 
comparisons. 
The SF-36 domain scores will be summarized by treatment. 


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14 
Safety evaluation 
Summaries may be performed separately for initial (Week 1-20) period and entire treatment 
period (including follow-up). Week 20 is chosen due to the fact that patients may be switched 
to another treatment as this time. Use of data up to and including the last visit before first switch 
opportunity provides an unbiased comparison between AIN and placebo; data collected beyond 
Week 20 are included in analyses which summarize the entire treatment period.   
Safety analyses will be performed on treatment received or actual treatment as described below: 


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The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire study. 
For those subjects 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.  
14.1 
Adverse events 
The crude incidence of treatment emergent adverse events (i.e., events started after the first dose 
of study treatment or events present prior to the first dose of study treatment but increased in 
severity based on preferred term and on or before last dose date + 84 days) will be summarized 
by primary system organ class and preferred term. Confidence intervals for the crude rate will 
be derived. In addition, exposure time-adjusted incidence rates including 95% confidence 
intervals will be provided for the entire treatment period. A graphical display of the crude 
incidence rates and exposure-adjusted rates will be presented for all AEs and serious AEs by 
system organ class. 
Adverse events reported will be presented in descending frequency according to its incidence 
in total secukinumab group (combining all secukinumab treatment groups) starting from the 
most common event. Summaries (crude incidences only) will also be presented for AEs by 
severity and for study treatment related AEs. If a particular AE ‘severity’ is missing, this 
variable will be listed as missing and treated as missing in summaries. If a subject reported more 
than one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a subject reported more than one adverse event within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the system 
organ class level, where applicable.  
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
leading to temporary dose interruption. 
Adverse events will also be reported separately by SMQ according to MedDRA, using a narrow 
search. The MedDRA version used for reporting the study will be described in a footnote. 
Non-treatment emergent adverse events will be listed. 
AEs after wash-out period(84 days after last dose of study drug) for standard of care treatment 
will be provided in a separate listing. Events will be reported in standard AE tables under 
randomized treatment according to rule of 84 days after last dose. 
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures. 
When adjudication is required of major cardiovascular events, a summary of those types of 
events as reported by the investigator and confirmed by adjudication will be provided. 
An overview of the safety analyses which will be performed for treatment emergent AEs, on 
treatment labs, vital signs and ECG for each analysis period is described below.  


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Table 14-1 
Overview of analyses on some safety endpoints 
Analysis 
period 
AEs & SAEs 
AEs by 
severity 
Study drug 
related AEs 
AEs-SMQ 
Risk 
Notables for 
(vitals/ 
ECG), lab 
criteria 
Day 1 – 
Week 20 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
Entire 
Treatment  
 
• crude 
incidence 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
 
• crude 
incidence 
 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
 
Exposure-adjusted incidence rates will be done for the following: 
• at the PSOC for AE and SAE and Level 1 for Risks and SMQ analyses 
• at the PT level for common AEs, which is defined as at least 2% of the patients in the combined AIN457 
groups during the initial treatment period or events that had an incidence rate of at least 5.0 cases per 100 
subject-years in the combined AIN457 groups during the entire treatment period 
• at Level 1 for Risks and SMQ analyses 
If adjudication is performed, the adjudication events (myocardial infarction, stroke, and 
cardiovascular death) will be listed. 
Algorithms for date imputations will be provided in Programming Datasets Specifications. 
14.2 
 
Laboratory data 
The summary of lab data will only include on treatment data, which are defined as those lab 
assessments after the first dose of study treatment and on or before last dose + 84 days. 
Reported laboratory assessments with either a less than or greater than sign (“<” or “>”) will be 
used for analysis after removal of the sign and conversion to standard unit. These laboratory 
data will be displayed in listings using the standard unit with the reported sign (“<” or “>”). 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived and 
summarized. 
For urinalysis, frequency tables will be presented. 
Descriptive summary statistics for the change from baseline to each study visit will be 
presented. These descriptive summaries will be presented by laboratory test and treatment 
group. Change from baseline will only be summarized for subjects with both baseline and post 
baseline values and will be calculated as: 
change from baseline = post baseline value – baseline value 
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline, if appropriate for each study phase, will be analyzed analogously.  
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 


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or high. If appropriate, the shifts to the most extreme laboratory test value within a treatment 
phase (either initial or entire) will be presented as well (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. 
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades: hemoglobin, platelets, white blood 
cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), gamma-glutamyl 
transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), glucose, cholesterol, triglycerides (TG). 
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety. 
Table 14-2 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.0 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
Life-threatening 
consequences; urgent 
intervention indicated 
Platelet count 
decreased 
<LLN – 75.0 x10e9 /L 
<75.0 - 50.0 x10e9 /L 
<50.0 – 25.0 x10e9 /L 
<25.0 x 10e9 /L 
White blood cell 
decreased 
<LLN - 3.0 x 10e9 /L 
<3.0 - 2.0 x 10e9 /L 
<2.0 - 1.0 x 10e9 /L 
<1.0 x 10e9 /L 
Neutrophil count 
decreased 
<LLN - 1.5 x 10e9 /L 
<1.5 - 1.0 x 10e9 /L 
<1.0 - 0.5 x 10e9 /L 
<0.5 x 10e9 /L 
Lymphocyte count 
decreased 
<LLN - 0.8 x 10e9/L 
<0.8 - 0.5 x 10e9 /L 
 
<0.5 - 0.2 x 10e9 /L 
<0.2 x 10e9 /L 
Creatinine increased* 
 
>1 - 1.5 x baseline;  
>ULN - 1.5 x ULN 
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline;  
>3.0 - 6.0 x ULN 
>6.0 x ULN 
TBL increased 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 10.0 x ULN 
>10.0 x ULN 
GGT increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALT increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
AST increased 
>ULN - 3.0 x ULN 
>3.0 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
ALP increased 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
Glucose increased 
(Hyperglycemia )  
>ULN - 8.9 mmol/L 
>8.9 - 13.9 mmol/L 
>13.9 - 27.8 mmol/L 
>27.8 mmol/L 
Glucose decreased 
(Hypoglycemia) 
<LLN - 3.0 mmol/L 
<3.0 - 2.2 mmol/L 
<2.2 - 1.7 mmol/L 
<1.7 mmol/L 
Cholesterol high 
>ULN - 7.75 mmol/L 
>7.75 - 10.34 mmol/L 
>10.34 - 12.92 mmol/L 
>12.92 mmol/L 
Hypertriglyceridemia 
1.71 - 3.42 mmol/L 
>3.42 - 5.7mmol/L 
>5.7 - 11.4 mmol/L 
>11.4 mmol/L 
*Note: for “creatinine increased” the baseline criteria do not apply. 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire) 
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial 
treatment phase. Subjects with abnormal laboratory values will be listed and values outside the 
normal ranges will be flagged. 
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories: 
• HDL: 
• <=LLN 
• <0.8 x LLN 


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• LDL, cholesterol, triglycerides: 
• >=ULN  
• >1.5 x ULN  
• >2.5 x ULN 
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given below: 
Table 14-3 
Liver-related events 
Parameter 
Criterion 
ALT 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
TBL 
>1.5xULN, >2xULN, >3xULN, 
ALP 
>2xULN, >3xULN. >5xULN 
ALT or AST & 
TBL 
ALT or AST>3xULN & TBL >2xULN; 
ALT or AST >5xULN & TBL >2xULN; 
ALT or AST >8xULN & TBL >2xULN; 
ALT or AST >10xULN & TBL >2xULN 
ALP & TBL 
ALP >3xULN & TBL >2xULN 
ALP >5xULN & TBL >2xULN 
ALT or AST & 
TBL & ALP 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law laboratory 
criteria) 
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result 
in severe DILI. 
Notes: 
In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased above 
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality 
criteria 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN. 
Individual subject data listings will be provided for subjects with abnormal laboratory data. 
Data of subjects with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing. 
Boxplots over time will be presented for selected laboratory parameters (neutrophils, liver and 
lipid parameters). 
14.3 
Vital signs 
The summary of vital signs will only include on treatment data, which are defined as those vital 
sign measurements after the first dose of study treatment and on or before last dose + 84 days. 


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Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as: 
change from baseline = post-baseline value – baseline value 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided below: 
Table 14-4 
Criteria for notable vital sign abnormalities 
Vital sign (unit) 
Notable abnormalities 
Systolic blood pressure (mmHg) 
>= 140 mmHg or < 90 mmHg 
Diastolic blood pressure (mmHg) 
>=90 mmHg or <60 mmHg 
Pulse (bpm) 
> 100 bpm or <60 bpm 
14.4 
 
Electrocardiogram (ECG) 
The summary of ECG will only include on treatment data, which are defined as those ECG 
measurements after the first dose of study treatment and on or before last dose + 84 days. 
The following quantitative variables will be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Both Bazett (QTcB) and 
Fridericia (QTcF) corrections will be presented for QTc.  
QTc will summarized by computing the number and percentage of subjects (including 95% 
confidence intervals for pooled analyses, e.g., DMC or SCS) with: 
• QTc > 500 msec  
• QTc > 480 msec 
• QTc > 450 msec 
• QTc changes from baseline > 30 msec 
• QTc changes from baseline > 60 msec 
• PR > 250 msec 
Summary statistics will be presented for ECG variables by visit and treatment group. 
In addition, shift tables comparing baseline ECG interpretation (normal, abnormal, not 
available, total) with the worst on-study interpretation (normal, abnormal, not available, total) 
will be provided. 
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
subject listing of all quantitative ECG parameters.   


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14.6 
  
Compound specific safety evaluation 
Safety topics of interest, such as risks defined in the Safety Profiling Plan (SPP), Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are defined 
in the Program Case Retrieval Sheet that is stored in CREDI at the path Cabinets/CREDI 
Projects/A/AIN457A/Integrated Medical Safety. 
The crude incidence and exposure-adjusted incidence rates for SPP risks will be summarized. 
In addition, listings will be provided presenting which subjects experienced which risk.   
Important note: For the evaluation of SPP risks primary and secondary system organ classes of 
the MedDRA dictionary will be considered. 
15 
Interim analyses 
15.1 
Analysis plan A 
No formal interim analyses will be performed. The primary efficacy analyses will be performed 
after all patients complete the treatment period 1 of the study (Week 24 for analysis plan A to 
be used for e.g., EU file).  
15.2 
Analysis plan B  
For analysis plan B week 52 endpoints will be tested at time of week 24 database lock.  
It is estimated that at the time of Week 24 database lock approximately 70% of the subjects 
will have reached their Week 52 visit. The data needed to calculate the primary endpoint and 
the secondary endpoints (as outlined Analysis Plan B) will have been generated with the 
exception of SI joint edema on MRI (Week 52 MRI reading campaign will not be completed 
until all patients have completed Week 52). The primary endpoint is analyzed in the TNF-
naive population which comprises at least 80% of the total population. Considering this, at 
least 105 subjects per treatment arm will have their primary endpoint evaluable at the time of 
Week 24 database lock. The expected sample size for the proposed Week 24 interim analysis 
of Analysis Plan B is provided in Table 15-1 Expected sample sizes per treatment arm and 
cumulative power for primary endpoint ASAS40. It is estimated that at the time of Week 24 
interim analysis, 131 patients per treatment arm will have data available for the majority of 
Week 52 endpoints. Of the 131 patients, at least 105 are expected to be TNF-naive. 
Table 15-1 
Expected sample sizes per treatment arm and cumulative power for 
primary endpoint ASAS40 
 
Population 
 
TNF naive 
All 
Analysis 
Sample 
size 
Cumulative power 
for ASAS40 
Sample 
size 
Cumulative power 
for ASAS40 
Interim analysis 
105 
78% 
131 
91% 
Final analysis 
148 
91% 
185 
99% 
 


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A Lan-De Mets alpha spending function with O’Brien Fleming type stopping boundary (as 
implemented in the software East 6.3) will be used to maintain the overall type-I error rate for 
the primary and secondary endpoints at week 52.  
Based on the choice of α-spending function described above, the efficacy boundary in terms of 
p-value scale at the interim analysis is calculated as p=0.016 for a two-sided test.  The observed 
(i.e., nominal) p-value has to be smaller than 0.016 to conclude superior efficacy at the interim 
analysis. If a hypothesis is not rejected at the interim analysis, it will be tested again at the Week 
52 analysis after the Week 52 database lock, when the full Week 52 data are available. The 
efficacy boundary for the final analysis in terms of p-value scale is p=0.046. 
The exact rejecting boundaries will be calculated after the exact number of patients in each 
treatment arm is available. 
A sequential testing hierarchy will be used to test the secondary hypotheses. The secondary 
hypotheses will be tested at the interim analysis only if the primary hypothesis is rejected. This 
guarantees the 5% overall level significance for the primary and secondary hypotheses (Glimm 
2010). For Week 52 endpoints, the same rejecting boundaries will be used as for the primary 
endpoint. For Week 16 endpoints, the full data will be available at the time of the interim 
analysis, and they will be tested with full alpha at the Week 24 interim analysis.  
Table 15-2 shows all hypothesis tested at interim analysis and the expected rejection boundaries 
for each hypothesis. 
Table 15-2 
Group sequential testing boundaries for each hypothesis 
Hypothesis 
Dose 
Endpoint 
Proportion of data 
available at 
interim analysis 
Efficacy boundaries on 
p-value scale1 
Interim 
analysis 
Final 
analysis 
H1 
secukinumab 150 mg 
(without load) 
ASAS40 in TNF naïve at 
Week 52 
71% 
0.016 
0.046 
H2 
secukinumab 150 mg 
(without load) 
ASAS40 at Week 52 
71% 
0.016 
0.046 
H3 
secukinumab 150 mg 
(without load) 
ASAS40 at Week 16 
100% 
0.052 
0.052 
H4 
secukinumab 150 mg 
(with load) 
ASAS40 in TNF naïve at 
Week 52 
71% 
0.016 
0.046 
H5 
secukinumab 150 mg 
(with load) 
ASAS40 at Week 52 
71% 
0.016 
0.046 
H6 
secukinumab 150 mg 
(with load) 
ASAS40 at Week 16 
100% 
0.052 
0.052 
H7 
secukinumab 150 mg 
(without load) 
change from baseline in 
total BASDAI at Week 16 
100% 
0.052 
0.052 
H8 
secukinumab 150 mg 
(without load) 
BASDAI50 at Week 16 
100% 
0.052 
0.052 
H9 
secukinumab 150 mg 
(without load) 
BASDAI50 at Week 52 
71% 
0.016 
0.046 
H10 
secukinumab 150 mg 
(without load) 
change from baseline in 
hsCRP at Week 16 
100% 
0.052 
0.052 


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H11 
secukinumab 150 mg 
(without load) 
change from baseline in 
SF-36 PCS at Week 16 
100% 
0.052 
0.052 
H12 
secukinumab 150 mg 
(without load) 
change from baseline in 
ASQoL at Week 16 
100% 
0.052 
0.052 
H13 
secukinumab 150 mg 
(without load) 
ASAS5/6 at Week 16 
100% 
0.052 
0.052 
H14 
secukinumab 150 mg 
(without load) 
ASAS20 at Week 16 
100% 
0.052 
0.052 
H15 
secukinumab 150 mg 
(without load) 
change from baseline in 
BASFI at Week 16 
100% 
0.052 
0.052 
H16 
secukinumab 150 mg 
(without load) 
change from screening in 
SI joint edema on MRI at 
Week 16 
100% 
0.052 
0.052 
H17 
secukinumab 150 mg 
(without load) 
ASDAS-CRP ID at Week 
52 
71% 
0.016 
0.046 
H18 
secukinumab 150 mg 
(without load) 
change from baseline in 
ASQoL at Week 52 
71% 
0.016 
0.046 
H19 
secukinumab 150 mg 
(without load) 
change from screening in 
SI joint edema on MRI at 
Week 52 
0% 
NA 
0.05 
H20 to H32 
These hypotheses appear after after H19 in the 
testing hierarchy and will not be tested at interim 
analysis 
NA 
NA 
0.05 
1These are estimated rejection boundaries based on expected sample sizes on each analysis. The rejection 
boundaries will be updated after exact number of observation is available. 
2Week 16 endpoints have full data available at interim analysis and therefore they are tested with full alpha 
at both analysis. They will be tested at interim analysis if all week 52 hypotheses higher in the hierarchy have 
been rejected, otherwise they will be tested at the final analysis. 
 
15.3 
Confidentiality of week 24 interim analysis results 
Although unblinding will occur after the Week 24 database lock, the original randomization to 
active treatment vs placebo will continue to remain blinded to all investigators, site personnel 
and patients until all patients have completed the treatment period 2 (Week 52) and the Week 
52 database lock has occurred. A separate study team will conduct the 24 Week interim analysis 
and no access to the interim results or individual treatment assignments will be given to the 
study team conducting the ongoing trial until the Week 52 database lock. 
To ensure consistent efficacy result from the first 24 weeks, efficacy analyses up to Week 20 
related to the primary and secondary endpoints will not be re-analyzed for the next lock at Week 
52 as part of the statistical hierarchy. 
Example of how this will be handled in practice: 
• For  ASAS40 analysis at Week 16 (which is part of both statistical testing hierarchies) the 
result will be made consistent across analysis plans by using the value from the Week 24 
lock even if the data slightly changes for the Week 52 lock.  Re-analyzed values related to 


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the primary endpoint may be presented in the statistical appendix for comparative 
purposes. 
16 
Determination of sample size 
In a study on the same indication of similar design (Landewé et al 2014) an ASAS40 response 
rate of 47.1% for active treatment and 16% for placebo was observed at Week 12, however this 
trial had a limited number of TNFα-IR patients and a meta-analysis (MA) from unpublished 
studies with secukinumab in AS indicates that the placebo rates observed in recent AS studies 
may be higher. Hence, assumptions are based on the result of active treatment from this TNF-
inhibitor study in nr-axSpA (but adjusted for the expected inclusion of TNF-IR patients) and 
with placebo response rates taken from the secukinumab MA. This MA included approximately 
25% TNF-IR patients, and the ASAS40 response rate in the 150 mg dose for TNF-IR was 76% 
of the response in the TNF naïve group. Assuming 20% of randomized patients will be TNF-
IR and have the same TNF-IR vs TNF naïve response ratio as seen in the MA (76%), the 
estimate for the entire population is 44.8% (i.e., 47.1%*0.8 + 47.1%*0.2*0.76) for secukinumab 
and 25.9% for placebo. ASAS40 in TNF naïve patients only is assumed to be 47.1% for 
secukinumab and 27.9% for placebo. 
At Week 16, response rates for the secukinumab 150 mg s.c. regimens with loading and without 
loading are assumed to be the same. 
Primary endpoint for analysis plan A 
An overall type I error (2-sided) 5% will be used to control type I error. Since the hierarchy is 
sequential starting with secukinumab with load tested versus placebo the full type I error will 
be utilized for each comparison. 
Table 16-1 
Summary of power for binary primary endpoint 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with SC Loading 
Secukinumab without SC 
Loading 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 TNF 
naïve at Week 
16 
27.9% 
47.1% 
91% 
47.1% 
91% 
Based on these assumptions including 185 patients per arm would give 91% power to reject a 
hypothesis of equal response rate based on Fisher’s exact test. Note that the power of 91% is 
for the subgroup of TNF naïve (185*0.8=148), but to achieve 90% power for important 
secondary endpoints 185 patients will be included per arm. 
Primary endpoint for analysis plan B 
An overall type I error (2-sided) 5% will be used to control type I error. Since the hierarchy is 
sequential starting with secukinumab without load tested versus placebo the full type I error 
will be utilized for each comparison. 


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Based on an assumption that the ASAS40 TNF naïve response rate at Week 16 will be 47.1% 
for secukinumab and 27.9% for placebo, that 80% of secukinumab patients and 65% of placebo 
patients will retain their response status from Week 16, and that 10% of secukinumab patients 
and 5% of placebo patients will be new responders at Week 52, the ASAS40 response rate at 
Week 52 based on non-responder imputation can be estimated as 43.0% and 21.7%, 
respectively, resulting in a power of 97% to reject an hypothesis of equal response rate at the 
5% level. 
Table 16-2 
Summary of power for binary primary endpoint 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with SC Loading 
Secukinumab without SC 
Loading 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 TNF 
naïve at Week 
52 
21.7% 
43.0% 
97% 
43.0% 
97% 
Secondary endpoints for analysis plan A 
In Table 15-3 the power for rejecting each of the binary secondary hypotheses at Week 16 is 
presented based on Fisher’s exact test with a 2-sided 5% type I error rate and 185 patients per 
group assuming the response rates without SC loading are the same as for with load. 
Table 16-3 
Power for binary secondary variables at Week 16 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with SC Loading 
Secukinumab without SC 
Loading 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 
25.9% 
44.8% 
96% 
44.8% 
96% 
ASAS5/6 
24.3% 
45.0% 
98% 
45.0% 
98% 
BASDAI50 
19.4% 
45.4% 
99% 
45.4% 
99% 
ASAS20 
43.7% 
61.1% 
90% 
61.1% 
90% 
ASAS PR1 
8.7% 
21.9% 
93% 
21.9% 
93% 
Source: Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-
analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). Calculations based on Fisher’s exact test 
(nQuery 7.0 PTT2-1) 
1Week 16 response for TNF naïve patients assumed 25% for secukinumab and 10% for placebo which were then adjusted for 
20% TNF-IR. 
In Table 15-4 the power for rejecting each of the secondary hypotheses at Week 16 based on 
continuous variables are presented with assumed change from baseline and standard deviation 
(SD). Following the assumption for response variables the change from baseline was adjusted 
for inclusion of TNFα-IR patients but with unchanged SD. The change from baseline without 
SC loading is assumed the same as for with load. 
Table 16-4 
Power for continuous secondary variables at Week 16 
Endpoint 
Common 
SD 
Placebo 
Mean 
Secukinumab              
with SC Loading 
Secukinumab                
without SC Loading 


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Mean 
Power 
N=185/arm 
Mean 
Power 
N=185/arm 
BASDAI1 
2.3 
-1.75 
-3.30 
99% 
-3.30 
99% 
hsCRP2 
0.867 
0.095 
-0.544 
99% 
-0.544 
99% 
BASFI1 
2.1 
-1.37 
-2.20 
96% 
-2.20 
96% 
MRI SI joint 
edema3 
2.17 
-0.17 
-1.30 
99% 
-1.30 
99% 
SF-36 PCS4 
7.15 
3.67 
6.32 
94% 
6.32 
94% 
ASQoL4 
4.55 
-2.32 
-4.10 
96% 
-4.10 
96% 
SD=standard deviation. Result is mean change from baseline with CRP in log scale. 
1 Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-analysis of 
unpublished AS studies (CAIN457F2314 and CAIN457F2320). 
2 Meta-analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320) 
3 Novartis AS study (AIN457F2305) 
4 Meta-analysis of Novartis AS studies (CAIN457F2310 and CAIN457F2320) 
Calculations based on two-sample t-test (nQuery 7.0 MTT0-1) 
Secondary endpoints for analysis plan B 
 Response rates for load and without load at weeks 16 and 52 are assumed to be the same. 
Table 16-5 
Power for binary secondary variables 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with SC Loading 
Secukinumab without SC 
Loading 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 wk52 
20.5% 
41.4% 
99% 
41.4% 
99% 
ASAS40 wk16 
25.9% 
44.8% 
96% 
44.8% 
96% 
BASDAI50 wk16 
19.4% 
45.4% 
99% 
45.4% 
99% 
BASDAI50 wk52 
16.6% 
41.8% 
99% 
41.8% 
99% 
ASAS5/6 wk16 
24.3% 
45.0% 
98% 
45.0% 
98% 
ASAS20 wk16 
43.7% 
61.1% 
90% 
61.1% 
90% 
ASDAS ID wk521 
10.2% 
25.3% 
96% 
25.3% 
96% 
Week 16 
Source: Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-
analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). 
Week 52 
Estimates from Week 16 were adjusted for assumed response retention. 
1 Week 16 response for TNF naïve patients assumed 25% for secukinumab and 10% for placebo which were then adjusted for 
20% TNF-IR and assumed response retention. 
ASDAS ID = ASDAS CRP Inactive Disease (ASDAS-CRP score < 1.3) 
Calculations based on Fisher’s exact test (nQuery 7.0 PTT2-1) 
Table 16-6 
Power for continuous secondary variables 
Endpoint 
Common 
SD 
Placebo 
Mean 
Secukinumab with SC 
Loading 
Secukinumab without 
SC Loading 
Mean 
Power 
N=185/arm 
Mean 
Power 
N=185/arm 
BASDAI wk161 
2.30 
-1.75 
-3.30 
99% 
-3.30 
99% 
hsCRP wk162 
0.867 
0.095 
-0.544 
99% 
-0.544 
99% 
SF-36 PCS wk163 
7.15 
3.67 
6.32 
94% 
6.32 
94% 


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Endpoint 
Common 
SD 
Placebo 
Mean 
Secukinumab with SC 
Loading 
Secukinumab without 
SC Loading 
Mean 
Power 
N=185/arm 
Mean 
Power 
N=185/arm 
BASFI wk161 
2.10 
-1.37 
-2.20 
96% 
-2.20 
96% 
MRI SI joint edema wk164 
2.17 
-0.17 
-1.30 
99% 
-1.30 
99% 
ASQoL wk163 
4.55 
-2.32 
-4.10 
96% 
-4.10 
96% 
SD=standard deviation. Result is mean change from baseline with CRP in log scale. 
Week 16 
1Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-analysis of 
unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). 
2Meta-analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320) 
3Meta-analysis of Novartis AS studies (CAIN457F2310 and CAIN457F2320) 
4Novartis AS study (CAIN457F2305). 
Power for continuous composite estimands depends on the difference in continuous endpoint 
and difference in treatment escape rates. Assuming the change from baseline being the same at 
Week 52 as at Week 16 and no escape, the power for Wilcoxon rank sum test would be similar 
to power of two-sample t-test (ASQoL 96% and MRI SI joint edema 99%). If escape rates are 
similar in both treatment arms the power will decrease if overall escape rate is increasing, 
whereas the power will remain the same or increase if escape rates are different between 
treatment arms.  
Appendix 
17.1 
Visit Windows 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, 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 below.  
For lab/ECG/vital signs, follow-up (F/U) visit is excluded from analysis visit mapping window. 
Only assessments that come as F/U nominal visit will be directly assigned as analysis F/U visit. 
Other assessments that are beyond the last on-treatment visit window (W104) or after nominal 
F/U visit date won't be mapped to any analysis visit. F/U visit will not be included in the 
summary tables by visit. 
Of note, subjects are allowed to have gaps in visits. All data collected will be displayed in 
listings.  


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Table 17-1   
Analysis visit windows 
Analysis 
Visit 
 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 6 
Group 7 
 
Group 8 
Baseline 
 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 7 
Week 1 
 
8 
2-11 
2-11 
2-11 
2-11 
 
 
 
 
Week 2 
 
15 
12-18 
12-18 
12-18 
12-22 
 
 
 
 
Week 3 
 
22 
19-25 
19-25 
19-25 
 
 
 
 
 
Week 4 
 
29 
26-43 
26-43 
26-43 
23-43 
 
 
 
 
Week 8 
 
57 
44-71 
44-71 
44-71 
44-71 
2-85 
2-85 
 
 
Week 12 
 
85 
72-99 
72-99 
72-99 
72-99 
 
 
 
 
Week 16 
 
113 
100-127 
100-127 
100-127 
100-141 
86-141 
86-239 
2-239 
8-239 
Week 20 
 
141 
128-155 
128-155 
128-155 
 
 
 
 
 
Week 24 
 
169 
156-183 
156-183 
156-183 
142-183 
142-267 
 
 
 
Week 28 
 
197 
184-211 
184-211 
184-239 
184-239 
 
 
 
 
Week 32 
 
225 
212-239 
212-239 
 
 
 
 
 
 
Week 36 
 
253 
240-267 
240-267 
 
 
 
 
 
 
Week 40 
 
281 
268-295 
268-295 
240-323 
240-323 
 
 
 
 
Week 44 
 
309 
296-323 
296-323 
 
 
 
 
 
 
Week 48 
 
337 
324-351 
324-351 
 
 
 
 
 
 
Week 52 
 
365 
352-379 
352-407 
324-407 
324-407 
268-449 
240-547 
240-547 
240-547 
Week 56 
 
393 
380-407 
 
 
 
 
 
 
 
Week 60 
 
421 
408-435 
 
 
 
 
 
 
 
Week 64 
 
449 
436-463 
408-491 
408-491 
408-491 
 
 
 
 
Week 68 
 
477 
464-491 
 
 
 
 
 
 
 
Week 72 
 
505 
492-519 
 
 
 
 
 
 
 


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Analysis 
Visit 
 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 6 
Group 7 
 
Group 8 
Week 76 
 
533 
520-547 
492-575 
492-575 
492-575 
450-631 
 
 
 
Week 80 
 
561 
548-575 
 
 
 
 
 
 
 
Week 84 
 
589 
576-603 
 
 
 
 
 
 
 
Week 88 
 
617 
604-631 
576-673 
576-673 
576-673 
 
 
 
 
Week 92 
 
645 
632-659 
 
 
 
 
 
 
 
Week 96 
 
673 
660-687 
 
 
 
 
 
 
 
Week 100 
 
701 
688-715 
 
 
 
 
 
 
 
Week 104 
 
729 
716-743 
674-743 
674-743 
674-743 
632-743 
548-743 
548-743 
548-743 
 
Group 1: Patient’s global assessment of disease activity (VAS), Patient’s assessment of back pain intensity (VAS), BASFI, BASDAI, 
, 
 hsCRP 
Group 2: Vital signs 
Group 3: Hematology, blood chemistry, urinalysis 
Group 4: 
, ASQoL, SF-36, 
 
 
Group 6: Lipids 
Group 7: Weight, ECG 
Group 8: MRI 
 


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The following rules are used to determine the window for an applicable visit post baseline: 
“Lower limit” = “upper limit of prior applicable visit” + 1. “Upper limit” = “target day of current 
visit” + integer part of (“target day of next applicable visit” – “target day of current visit”)/2. 
Lower limit of the first applicable visit is always Day 2. 
The mapping described above applies to all visits (not just scheduled visits).  Repeat and/or 
unscheduled visits (which will be numbered in the database according to new NCDS standards) 
will be mapped for analysis purposes in the same way as scheduled visits. This leaves the 
possibility, then, for multiple measurements within an analysis window. The following 
conventions will be used to determine the appropriate measurement to be summarized in the 
event of multiple measurements within a visit window. 
Table 17-2 
Rules for flagging variables 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
Baseline is defined as the last available measurement recorded on or before 
the reference start date (only date part)/Day 1. If there are multiple 
assessments on Day 1, the following rules apply: 
1. If assessment time exists:  
• 
select the last available measurement prior to reference start date/time 
considering time 
• 
if no measurement prior to reference start date/time considering time, 
select the earliest measurement post reference start date/time 
considering time   
2. If assessment time does not exist: 
select the available measurement from the lowest CRF visit number 
Post-baseline efficacy 
All data 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g. 1 day before target date and 1 
day after) the first one will be used. 
If the patient switches treatment (e.g. from placebo to AIN) within the window 
the following rules apply: 
• 
If available, the closest measurement to the target date which is on 
or before the switch date will be used 
• 
If there are no data on or before the switch date then the closest 
measurement after the switch to target will be used 
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be used 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
Post-baseline safety 
Summary visit 
information (e.g. 
lab, ECG, etc.) 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g. 1 day before target date and 1 
day after) the first one will be used. 
If the patient switches treatment (e.g. from placebo to AIN) within the window 
the following rules apply: 
• 
If available, the closest measurement to the target date which is on 
or before the switch date will be used 
• 
If there are no data on or before the switch date then the closest 
measurement after the switch to target will be used 
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be used 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
Post-baseline safety  
Notable 
abnormalities (e.g. 
lab) 
The most extreme measurement in the window will be used. Note this means 
a patient can have a notably high and notably low measurement within a 
window 


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17.2 
Statistical methodology and assumptions 
17.2.1 
Analysis of continuous data 
17.2.1.1 Summary statistics for continuous data 
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group.  
17.2.1.2 Analysis of covariance 
Univariate model 
An analysis of covariance (ANCOVA) model will be used to analyze some endpoints. The 
model will include factors and covariates as specified for respective analysis. The SAS code 
below outlines a template for the analysis where covariates can be added or removed as 
required: 
ods output diffs=lsm_diff lsmeans=lsm_est; 
proc mixed data=; 
by visit; 
class treatment strata tnf_status; 
model outcome = treatment strata tnf_status baseline weight; 
lsmeans treatment / diff cl; 
run; 
Least-square-mean (LSM) estimates for each treatment group and LSM difference, confidence 
intervals and p-value for the difference between each dose of secukinumab and placebo, and 
between secukinumab doses if relevant, can be obtained. 
Repeated measures analysis 
Some endpoints will be analyzed using a longitudinal model that comprises several visits. The 
model used will be mixed model repeated measures (MMRM) with factors, covariates, 
interactions and covariance structure as specified for respective analysis. The SAS code below 
outlines a template for the analysis where covariates and interaction terms can be added or 
removed as required: 
ods output diffs=lsm_diff lsmeans=lsm_est; 
proc mixed data=; 
class treatment strata visit tnf_status; 
model outcome = treatment strata visit tnf_status baseline weight treatment*visit 
baseline*visit / ddfm=kr; 
repeated visit / type=un subject=; 
lsmeans treatment*visit / diff cl; 


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run; 
Least-square-mean (LSM) estimates for each treatment group and LSM difference, confidence 
intervals and p-value for the difference between each dose of secukinumab and placebo, and 
between secukinumab doses if relevant, will be calculated at appropriate analysis visits. 
In case the MMRM model does not converge the following sequential steps will be used: 
1. change to ddfm=bw. If still no convergence, perform step 2. 
2. change to type=cs. If still no convergence, perform step 3. 
3. remove covariates in the following order until convergence: weight, baseline*visit, TNF-α 
inhibitor status, strata.  
17.2.2 
Analysis of binary and categorical data 
17.2.2.1 Summary statistics for binary and categorical data 
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be derived 
as well based on the score method including continuity correction (Newcombe 1998): 


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With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=probit(1-α/2), n as total 
number of subjects (i.e., number of subjects in the denominator), p as estimated crude incidence 
(number of subjects with event / n) and q = 1-p 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
Note: if p < L then L = p and if p > U then U = p. 
17.2.2.2 Logistic regression 
Certain binary outcome variables, e.g., response outcomes, will be evaluated using a logistic 
regression model. The model will include factors and covariates as specified for respective 
analysis. The SAS code below outlines a template for the analysis where covariates can be 
added or removed as required: 
ods output diffs=lsm_diff convergencestatus=conv_status; 
proc logistic data=; 
by visit; 
class treatment strata tnf_status / param=glm; 
model response = treatment strata tnf_status weight; 
lsmeans treatment / diff cl exp; 
run; 
For cases where the convergence status indicates that the model did not reach appropriate 
convergence (conv_status is not 0), no odds ratio or p-value will be presented from that model. 
However, if the issue relates to the primary timepoint of Week 16 or Week 52 then the following 
steps will be followed: 
1. Remove TNF status from the model. If there are still issues perform step 2 
2. Run an exact logistic model as described below 
In cases where separation is a concern for the primary timepoint Week 16 or Week 52, e.g., 0% 
or 100% response for some treatment and covariate level combination, an exact logistic 
regression model may be applied to all visits. To help with convergence, this model will not 
include any continuous covariates. The SAS code below outlines a template for the analysis 
where covariates can be added or removed as required: 


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ods output exactoddsratio=exact_or; 
proc logistic data=data exactonly; 
by visit; 
class treatment strata tnf_status / param=ref; 
model response = treatment strata tnf_status; 
exact treatment / estimate=odds; 
run; 
When exact logistic regression is unable to be implemented (due to computational complexity 
as the procedure can lead to extremely long run times), then Fisher’s exact test will be applied. 
In this case, only a p-value for a test of equal response in the two groups can be obtained (no 
odds ratios or confidence intervals can be estimated.) 
ods output fishersexact=fisher; 
proc freq data=; 
by visit; 
table treatment*response / fisher; 
run; 
Input dataset should only contain data from the two treatment groups to be compared. 
17.2.3 
Imputation methods 


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17.2.3.2 Multiple Imputation 
Under MAR assumption 
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. 
The SAS code below outlines a template for the analysis where covariates and visits can be 
added or removed as required. To ensure that results can be replicated the data should be sorted 
by subject number before running the model (the data should be in horizontal format with one 
subject per dataset row). 
proc mi data= seed=4572315 nimpute=100 out=mi_out; 
by treatment; 
class strata tnf_status; 
fcs reg (/details); 
var strata tnf_status weight value1 value2 value3; 
run; 
Where in the template code the continuous variable to be imputed is value (e.g., value1 could 
be the baseline value and value2 the first post-treatment measurement of the variable to be 
imputed.) Normally, all data collection visits during the analysis period of interest would be 
included in the model. Including variables using a CLASS statement instead of a BY statement 


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should help facilitate model convergence also when the number of non-missing data points are 
low for some specific covariate level and visit combination. The FCS option is used to ensure 
that also non-monotone missing data can be handled in an appropriate way. 
If convergence is not obtained the following sequential steps will be used: 
1. remove weight. If still no convergence, perform step 2 
2. remove TNF-α inhibitor status. 
For a situation where several variables need to be imputed using separate models (e.g., using 
independent models to impute each component needed to derive a response variable V) a step-
wise process needs to be implemented as outlined below: 
1. Run the SAS code as described above for the first variable to be imputed 
2. Run the SAS code as described above for the next variable to be imputed (but with the 
following changes: “data=mi_out”, “out=mi_out2”, “by treatment _imputation_”, 
“nimpute=1”) 
3. Repeat step 2, but with input dataset equal to the output dataset from the prior step, until 
all j variables have been imputed resulting in a dataset named mi_outj 
4. Derive the variable V from within mi_outj 
The required analysis (e.g., ANCOVA) is then performed separately within each imputation 
dataset (as identified by variable _imputation_). To obtain the final result of the imputation 
process the analysis result from each imputation dataset needs to be combined according to 
Rubin’s rules as outlined below: 
ods output parameterestimates=mi_result; 
proc mianalyze data=; 
modeleffects estimate; 
stderr estimate_se; 
run; 
The estimate and estimate_se parameters come from the analysis model used to analyze the 
imputed variable within each imputation dataset (e.g., from the lsmean estimate of the treatment 
difference and its standard error obtained from PROC LOGISTIC or PROC MIXED.) 
To obtain binary response rates and confidence intervals for individual treatment groups the 
following process should be followed (exemplified for one visit): 
ods output binomialprop=bin_est; 
proc freq data=; 
by treatment _imputation_; 
table response / binomial (cl=wilson correct); 
run; 
Then apply a logit transformation on the saved proportions and derive its standard error:  


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data bin_est; set bin_est; 
estimate=log(_bin_/(1-_bin_)); 
estimate_se=e_bin/(_bin_*(1-_bin_)); 
run; 
The transformed binomial proportion estimates and its standard errors are then combined by 
applying Rubin’s rules as described above using PROC MIANALYZE. Before presenting the 
combined data it needs to be transformed back as follows: 
data mi_result; set mi_result; 
prop_est=1/(1+exp(-estimate)); 
prop_lower=1/(1+exp(-lclmean)); 
prop_upper=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 or subgroup would be presented as seen in any of the 
imputed datasets together with 95% CI from Wilson’s method (as obtained from PROC FREQ). 
The following steps will be performed to handle special cases: 
• If after imputation all responses (observed+imputed) are the same either 0 or 1 for all 
imputation datasets for a specific treatment or subgroup 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) 


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17.2.4 
Crude incidence and related risk estimates  


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17.2.4.2 Odds ratio and 100*(1-α)% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event with probability π1 and π0 respectively, the odds ratio is estimated as 
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p
−
−
 with p1= x1/n1 and p0=x0/n0. A conditional exact 100*(1-α)% confidence interval 
can be obtained by using the SAS procedure PROC FREQ with statement EXACT OR. 
However, to be able to adjust for covariates odds ratios will primarily be obtained from PROC 
LOGISTIC. 
17.2.5 
Exposure adjusted incidence rate and related risk estimates 
17.2.5.1 Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 
∑
=
=
n
j
jt
T
1
 and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood 1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai 
1993; Ulm 1990): 
Lower confidence limit   
T
c
L
D
2
,2
/
5.0
α
=
 for D>0, 0 otherwise, 
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0
+
−
=
α
 
Where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom. 
The example below shows how this should be handled for cases where subjects switch 
treatment. In particular for summarizing ‘Any AIN’ as a group, one should take into 
consideration the sequence of treatments while calculating exposure time for subjects. 


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Table 17-4 
Examples for calculating exposure time for incidence rates (IR) 
1st treatment / total 
exposure time 
2nd treatment / total 
exposure time 
AE event onset (in days 
from study start) 
Exposure for IR 
Placebo / 100 days 
AIN457 150 mg / 200 days 
Day 50 (during 1st 
treatment) 
Day 110 (10 days into 2nd 
treatment) 
Placebo:  50 days 
AIN457 150 mg: 10 days 
Any AIN: 10 days 
17.2.7 
RANK based analysis 
Rank based test using Wilcoxon rank sum test will be used for composite continuous estimands. 
A SAS code template for hypothesis testing for treatment1 vs treatment2 is given below: 
proc npar1way data= wilcoxon; 
where treatment in ("treatment1", "treatment2"); 
class treatment; 
var rankvariable; 
run; 


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The analysis variable rankvariable will either be the based on the observed value or extreme 
unfavorable value, if patient has discontinued, has missing data or has switched treatment. 
17.2.8 
Trimmed means 
Trimmed means will be calculated using methodology presented in (Permutt 2017). Trimming 
is compatible with a wide range of analytical methods. The trimming will be combined with the 
appropriate analytical method(e.g. MMRM or ANCOVA). The general algorithm can be stated 
simply:  
1. Order the data and trim equal fractions, always trimming all dropouts. 
2. Compute a summary measure on the trimmed data. 
3. Repeat steps 1 and 2 on permuted data to construct a reference distribution for testing 
and interval estimation 
The fraction trimmed will be chosen adaptively as the greatest of the proportions of dropouts in 
the treatment groups to be compared.  
17.3 
Group sequential design used in phase III studies 
The statistical methodology for the interim analyses of week 52 endpoints will be based on 
group sequential methodology with efficacy stopping boundaries defined by type I error 
spending functions. 
This approach is flexible in dealing with any deviations from the targeted sample sizes, or 
unexpected changes to the plan. 
If the exact number of subjects observed at the interim and final analyses deviates from the 
target numbers described in the statistical analysis plan, the actual critical boundaries will be 
derived using the prespecified 
error spending functions and the actual numbers of subjects observed. 
• At interim analysis, information fractions will be computed as the ratio of the number of 
observations at the interim analysis relative to the number targeted for the final analysis, 
as described in the sample size section of the protocol. 
• At the final analysis, the critical value will be calculated using the exact number of 
observations at the final analysis, considering the α-levels spent at interim analyses and 
considering the actual correlation among the test statistics, in order to achieve a 
cumulative type I error smaller than the desired significance level (i.e., smaller than 2.5% 
for a one-sided test and smaller than 5% for a two-sided test). 


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17.3.1 
Alpha spending function 
The stopping boundaries to be used for week 52 tests will be calculated using the α-spending 
function approach described in Lan and DeMets (Lan and DeMets, 1983). The spending 
function for one-sided test has the following functional form: 
𝛼𝛼(𝑡𝑡) = 2 −2Φ( Z𝛼𝛼2  
⁄
√𝑡𝑡
⁄
 ) 
This function generates stopping boundaries that closely resemble the O’Brien-Fleming 
boundaries (O’Brien and Fleming, 1979). 
18 
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35(3):549-56. 
 
Permutt T, Li F(2017). Trimmed means for symptom trials with dropouts. Pharmaceutical 
statistics.;16(1):20-8. 
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. (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis.; 
68 Suppl 2:ii1-44. 
Sieper J, et al. (2013) Efficacy and safety of adalimumab in patients with non-radiographic 
axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann 
Rheum Dis 2013;72:815–822. 
Ulm, K. (1990) A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology; 131(2): 373-375. 
van der Heijde D, Dijkmans B, et al. (2005) Efficacy and safety of infliximab in patients with 
ankylosing spondylitis: Results of a randomized, placebo-controlled trial (ASSERT). Arthritis 
Rheum; 52(2):582-591. 


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van der Heijde D, Kivitz A, Schiff MH, et al. (2006) Efficacy and safety of adalimumab in 
patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, 
placebo-controlled trial. Arthritis Rheum; 54(7):2136-46. 
 
 
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 
Yellen SB, Cella DF, Webster K, 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. 
 


Clinical Development
Secukinumab (AIN457)
CAIN457H2315 / NCT02696031
A randomized, double-blind, placebo-controlled multicenter 
study of secukinumab 150 mg in patients with active non-
radiographic axial spondyloarthritis to evaluate the safety, 
tolerability and efficacy up to 2 years, followed by an 
optional phase of either 150 mg or 300 mg randomized 
dose escalation for up to another 2 years
Statistical Analysis Plan (SAP) – Extension Phase 
Amendment 1
Author:
, Trial Statistician
Document type:
SAP Documentation
Document status:
Final
Release date:
09-Apr-2021
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of SAP.
Version
Date
Changes
1
19-Jan-2021
Initial version
Amendment 1
08-April-2021
-
Add clarification about analysis set, since there are subjects who 
were randomized before ASAS20 response status at Week 104 
was confirmed.
-
Update the wording about COVID-19 related PDs.
-
Remove the subgroup analysis on TNF-α inhibitor status and 
stratification factor, since it is not planned for the final CSR.
-
Remove the paragraphs about prior nr-axSpA therapy, since it is 
not of interest for the extension phase.
-
Remove the paragraphs about lipids, since it is not of interest for 
the extension phase.
-
Add clarification about analysis visit.
-
Update the sample code of MI to solve the convergence issue.


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................9
2
Study objectives...................................................................................................................9
2.1
Primary objectives ...................................................................................................9
2.2
Secondary objectives ...............................................................................................9
3
Data presentation...............................................................................................................10
4
Subjects and treatments .....................................................................................................11
4.1
Analysis sets ..........................................................................................................11
4.2
Treatment groups...................................................................................................11
5
Subgroup definitions .........................................................................................................12
6
Assessment windows, baseline and post baseline definitions, missing data handling......12
7
Subject disposition, background and demographic characteristics ...................................12
7.1
Subject disposition.................................................................................................12
7.2
Background and demographic characteristics .......................................................12
8
Medical history..................................................................................................................13
9
Study treatment..................................................................................................................13
10 Concomitant medication....................................................................................................14
14
14
19
20
21
22
23
 
24
25
25
26
26
26
13 Safety evaluation ...............................................................................................................26
13.1
Adverse events.......................................................................................................26


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13.2
Laboratory data......................................................................................................27
13.3
Vital signs..............................................................................................................29
13.4
Electrocardiogram (ECG)......................................................................................30
.30
13.6
Compound specific safety evaluation....................................................................30
14 Determination of sample size............................................................................................30
15 Appendix ...........................................................................................................................30
15.1
Visit Windows .......................................................................................................30
15.2
Statistical methodology and assumptions..............................................................31
15.2.1
Analysis of continuous data ..................................................................31
15.2.2
Analysis of binary and categorical data ................................................31
15.2.3
Crude incidence and related risk estimates...........................................34
15.2.4
Exposure adjusted incidence rate and related risk estimates ................35
16 References .........................................................................................................................35


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List of tables
Document History – Changes compared to previous version of SAP........................................2
Table 11-1
Equations for the conversion of the assessments A into scores S for 
the five components of the BASMI linear ............................................17
Table 11-2
NSAID Score by dose and medication..................................................18
Table 11-3
Mapping of dosing frequency to NSAID score.....................................18
Table 13-1
Overview of analyses on some safety endpoints...................................27
Table 13-2
CTCAE grades for laboratory parameters to be analyzed ....................28
Table 13-3
Liver-related events...............................................................................29
Table 13-4
Criteria for notable vital sign abnormalities..........................................30
Table 15-1
Examples for calculating exposure time for incidence rates (IR).........35


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List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AS
Ankylosing Spondylitis
ASAS
Assessment of Spondyloarthritis International Society criteria
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASQoL
Ankylosing Spondylitis Quality of Life Questionnaire
AST
Aspartate Aminotransferase
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BMI
Body Mass Index
BSL
Baseline
CRF
Case Report/Record Form (paper or electronic)
CRP (hsCRP)
(high sensitivity) C-Reactive Protein
CRP+
hsCRP > ULN (as defined by the central lab)
CTCAE 
Common Criteria for Adverse Events
DMARD
Disease Modifying Antirheumatic Drug
DMC
Data Monitoring Committee
EAS
Extension Phase Full Analysis Set
ECG
Electrocardiogram
ESR
Erythrocyte Sedimentation Rate
FACIT-Fatigue Functional Assessment of Chronic Illness Therapy – Fatigue 
FDA
Food and Drug Administration
GGT
Gamma Glutamyl Transferase
HDL
High Density Lipoprotein
HLA
Human Leukocyte Antigen
IRT 
Interactive Response Technology
ITT 
Intent-to-Treat
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal


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LOCF
Last Observation Carried Forward
LSM
Least-Square-Mean
MAR
Missing At Random
MASES
Maastricht Ankylosing Spondylitis Enthesis Score
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram(s)
MI
Multiple Imputation
MMRM
Mixed effect Model for Repeated Measurements
MRI
Magnetic Resonance Imaging
MRI+
Positive for sacroiliitis (active inflammatory lesions)
MTX
Methotrexate
nr-axSpA
Non-radiographic axial SpondyloArthritis
NSAID
Non-Steroidal Anti-Inflammatory Drug
PCS
Physical Component Summary
PD
Pharmacodynamic
PRN
According to need, as required
PRO
Patient Reported Outcome
QoL
Quality of Life
RAN2
Extension Phase Randomized Set
SAE
Serious Adverse Event
SAF
Safety Set
SAF2
Extension Phase Safety Set
s.c.
Subcutaneous(ly)
SD
Standard Deviation
SE
Standard Error
SF-36
Medical Outcome Short Form (36) Health Survey
SPP
Safety Profiling Plan
TNF/TNF-α
Tumor Necrosis Factor 
TNF-IR
TNF-α Inhibitor Incomplete Responders
ULN
Upper Limit of Normal
VAS
Visual Analog Scale


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vs
Versus


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1
Introduction
Data will be analyzed by Novartis according to the data analysis Section 9 of the study protocol. 
The statistical methodology for the final database lock of the AINH2315 trial is described below 
and any deviations from the protocol are documented. Additional detailed information 
regarding the analysis methodology is contained in the Appendix section. 
2
Study objectives
There are two sets of primary and secondary objectives based on the regional regulatory 
precedent and feedback. These objectives were tested in separate analysis plans during the core 
phase and will not be repeated. For the purpose of the final database lock of the extension phase, 
only the exploratory objectives will be analyzed.
2.1
Primary objectives
Not applicable for the extension phase. Refer to [AIN457H2315 SAP] for details.
2.2
Secondary objectives
Not applicable for the extension phase. Refer to [AIN457H2315 SAP] for details.
 
 
 
 
 
 
 
 
 
 
 


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3
Data presentation
The analysis of the extension phase data will be exploratory in nature and mainly reported by 
descriptive statistics, applying the same principles as in core phase data analysis.
Statistical models may be applied to produce confidence intervals for treatment summaries, but 
no formal statistical inference will be done.
Summary statistics for continuous variables will include N, mean, standard deviation (SD), 
minimum, lower quartile, median, upper quartile and maximum. Summary statistics for discrete 
variables will be presented in the number and percent of subjects in each category.
Efficacy data of the extension phase will be presented by the following 3 treatment groups:

Core Phase Responders – Randomized AIN457 150 mg

Core Phase Responders – Randomized AIN457 300 mg 

Core Phase Non-Responders – AIN457 300 mg Open-Label
Safety data will be summarized as follows for the entire treatment period depending on the 
timing of event:


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
Any AIN457 150 mg

Any AIN457 300 mg

Any AIN457

Placebo
Note that the treatment groups above for a subject may differ depending on the time period of 
the analysis. 
Data will also be presented after patient up-titrated to secukinumab 300 mg open-label after 
Week 156, by a combination of the ‘original’ and ‘current’ treatment groups. This will represent 
the treatment combinations the subjects experience over the course of the entire trial in case of 
up-titration.
All listings will be presented by randomized treatments (Core Phase Responders) and 
Secukinumab 300 mg open-label but also indicating the current treatment.
4
Subjects and treatments 
4.1
Analysis sets
The following analysis sets will be used in this trial:
Extension phase randomized set (RAN2): The RAN2 will be defined as all Core Phase 
Responders who were randomized. Unless otherwise specified, mis-randomized subjects (mis-
randomized in IRT) will be excluded from the randomized set. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given for the extension phase. Mis-randomized subjects are treated as screen 
failures.  
Subjects who have been randomized with an incorrect ASAS20 response status or prior to the 
availability of the ASAS20 criteria will be analyzed as randomized. 
Extension phase full analysis set (EAS): The EAS will be comprised of all subjects enrolled 
in the extension phase (subjects from the randomized set plus the open label subjects) and study 
treatment has been assigned. Following the intent-to-treat principle, subjects will be evaluated 
according to the treatment assigned to at Week 104. 
Safety set (SAF): The SAF includes all subjects who took at least one dose of study treatment 
during the treatment period in core study. Subjects will be evaluated according to treatment 
received.
Extension phase safety set (SAF2): The SAF2 includes all subjects enrolled in the extension 
phase and who took at least one dose of study treatment during the extension phase.
4.2
Treatment groups
Treatment groups for core phase responders are as follows:

Secukinumab 150 mg 


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
Secukinumab 300 mg 
and for core phase non-responders:

Secukinumab 300 mg open-label 
5
Subgroup definitions
Additional subgroup analysis may be conducted if deemed necessary.
6
Assessment windows, baseline and post baseline 
definitions, missing data handling
Baseline and post-baseline definitions
In general, a baseline value refers to the last measurement made 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. 
Analysis visit windows
No analysis visit windows will be employed during the extension phase. Instead the nominal 
visits will be used. However, analysis visit window will be used for Week 104 to keep consistent 
with analyses in the core phase.
7
Subject disposition, background and demographic 
characteristics
7.1
Subject disposition
The number of subjects entered the extension will be presented. The number and percentage of 
subjects who completed the study periods and who discontinued the study prematurely 
(including the reason for discontinuation) will be presented at the end of the study, if appropriate, 
for each treatment group and all subjects.
For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated for the entire study period. Protocol deviations due to COVID-19 will 
be reported in separate categories.
Additional analysis due to COVID-19 might be provided, e.g., summary of patients completed 
Week 120 prior to 1-Mar-2020 and patients missed visit and/or treatment in the extension phase 
due to COVID-19.
7.2
Background and demographic characteristics
The following common background and demographic variables will be summarized for patients 
entered the extension phase.
Continuous variables:

Age (which is derived from date of birth and the date of informed consent)


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
Height

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2
For BMI, height and body weight, the last value prior to randomization is used. If there is no 
weight recorded prior to taking of study drug, BMI will be missing.
Categorical variables:

Age categories (<65 years, 65 years and older, 75 years and older)

Gender

Race

Ethnicity

Smoking status at baseline
Baseline disease characteristics will also be summarized for the following variables:

Patient’s global assessment of disease activity and other ASAS components, hsCRP 
(mg/L and >ULN), ESR (mm/h), prior use (yes/no) of TNF-α inhibitors, use (yes/no) 
and separate dose of MTX (mg/week), sulfasalazine (g/day) and systemic 
corticosteroids (mg/day) at randomization, time since first diagnosis of nr-axSpA 
(years), time since onset of back pain, modified New York criteria for AS, HLA-B27, 
MASES, total back pain (VAS), nocturnal back pain (VAS), total BASDAI score, 
spinal pain (BASDAI question #2) and BASMI components (all seven in original 
units), presence of SIJ inflammation by MRI and each randomization strata level of 
the core phase (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+).
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the EAS. The number and percentage of 
subjects in each category will be presented for categorical variables for each treatment group 
and all subjects (total) in the EAS. 
8
Medical history
The evaluation of medical history was subject to prior interim analysis and will not be repeated. 
Refer to [AIN457H2315 SAP] for details.
9
Study treatment
The analysis of study treatment data will be based on SAF and SAF2. The number of active and 
placebo injections will be summarized by treatment group. The duration of exposure to study 
treatment will also be summarized by treatment group. In addition, the number and percentage
of subjects with cumulative exposure levels (e.g., any exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, 
≥ 4 weeks, ≥ 8 weeks, etc.) during the extension phase will be presented.
Duration of exposure will be defined as the time from first dose of study treatment to the time 
of treatment switch (for subjects who switch treatment) or minimum of (last dose of the 
treatment + 84 days) and (last visit date). Patients who switch treatment during the study (e.g., 


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from placebo to active treatment) will have exposure to both medications using the appropriate 
start and stop dates. 
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100
The analyses of duration of exposure described above will be done for the entire study treatment 
period.
10
Concomitant medication
Concomitant medications will be summarized in separate tables by treatment group.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment 
and within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group.
Significant concomitant surgeries and procedures will be summarized by primary system organ 
class and MedDRA preferred term.
Prior or concomitant medication will be identified by comparing recorded or imputed start and 
end dates of medication taken to the reference start date.
 
 
 
 
 
 


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13
Safety evaluation
Summaries may be performed for the entire treatment period (including follow-up). 
Safety analyses will be performed on treatment received or actual treatment as described below:
The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire study.
For those subjects 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. 
13.1
Adverse events
The crude incidence of treatment emergent adverse events (i.e., events started after the first dose 
of study treatment or events present prior to the first dose of study treatment but increased in 
severity based on preferred term and on or before last dose date + 84 days) will be summarized 
by primary system organ class and preferred term. Confidence intervals for the crude rate will 
be derived. In addition, exposure time-adjusted incidence rates including 95% confidence 
intervals will be provided for the entire treatment period. 
Adverse events reported will be presented in descending frequency according to its incidence 
in total secukinumab group (combining all secukinumab treatment groups) starting from the 
most common event. Summaries (crude incidences only) will also be presented for AEs by 
severity and for study treatment related AEs. If a particular AE ‘severity’ is missing, this 
variable will be listed as missing and treated as missing in summaries. If a subject reported more 
than one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a subject reported more than one adverse event within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the system 
organ class level, where applicable. 
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
leading to temporary dose interruption.


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Adverse events will also be reported separately by SMQ according to MedDRA, using a narrow 
search. The MedDRA version used for reporting the study will be described in a footnote.
When adjudication is required of major cardiovascular events, a summary of those types of 
events as reported by the investigator and confirmed by adjudication will be provided.
An overview of the safety analyses which will be performed for treatment emergent AEs, on 
treatment labs and vital signs for each analysis period is described below. 
Table 13-1
Overview of analyses on some safety endpoints
Analysis 
period
AEs & SAEs
AEs by 
severity
Study drug 
related AEs
AEs-SMQ
Risk
Notables for 
(vitals), lab 
criteria
Entire 
Treatment 
• crude incidence
• exposure time 
adjusted 
incidence
• crude 
incidence
• crude 
incidence
• exposure time 
adjusted 
incidence
• crude incidence
• exposure time 
adjusted 
incidence
• crude 
incidence
Exposure-adjusted incidence rates will be done for the following:
• at the PSOC for AE and SAE and Level 1 for Risks and SMQ analyses
• at the PT level for common AEs, which is defined as at least 2% of the patients in the combined AIN457 
groups during the initial treatment period or events that had an incidence rate of at least 5.0 cases per 100 
subject-years in the combined AIN457 groups during the entire treatment period
• at Level 1 for Risks and SMQ analyses
If adjudication is performed, the adjudication events (myocardial infarction, stroke, and 
cardiovascular death) will be listed.
Algorithms for date imputations will be provided in Programming Datasets Specifications.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on-
treatment/treatment emergent> adverse events which are not serious adverse events with an 
frequency greater than 5% and on <on-treatment/treatment emergent> serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the SAF and SAF2 population.
13.2
Laboratory data
The summary of lab data will only include on treatment data, which are defined as those lab 
assessments after the first dose of study treatment and on or before last dose + 84 days.
Reported laboratory assessments (hematology, chemistry and urinalysis) with either a less than 
or greater than sign (“<” or “>”) will be used for analysis after removal of the sign and 
conversion to standard unit. These laboratory data will be displayed in listings using the 
standard unit with the reported sign (“<” or “>”).
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 
ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived and 
summarized.
For urinalysis, frequency tables will be presented.


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Descriptive summary statistics for the change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test and treatment group. Change 
from baseline will only be summarized for subjects with both baseline and post baseline values 
and will be calculated as:
change from baseline = post baseline value – baseline value
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline, if appropriate for each study phase, will be analyzed analogously. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. If appropriate, the shifts to the most extreme laboratory test value within a treatment 
phase (either initial or entire) will be presented as well (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group.
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 13-2: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG).
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety.
Table 13-2
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.0 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased 
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Life-threatening
consequences; urgent
intervention indicated
Platelet count
decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell 
decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count 
decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased*
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN
>3.0 baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Glucose increased 
(Hyperglycemia ) 
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose decreased 
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 mmol/L
>10.34 - 12.92 mmol/L
>12.92 mmol/L
Hypertriglyceridemia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L


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*Note: for “creatinine increased” the baseline criteria do not apply.
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire) 
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial 
treatment phase. Subjects with abnormal laboratory values will be listed and values outside the 
normal ranges will be flagged.
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given below:
Table 13-3
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
TBL
>1.5xULN, >2xULN, >3xULN,
ALP
>2xULN, >3xULN. >5xULN
ALT or AST & 
TBL
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST & 
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law laboratory criteria)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or bile 
duct disease; ALP may also be increased in malignancy. FDA therefore terms Hy’s 
Law cases as indicators of pure hepatocellular injury. This does not mean that cases 
of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result in severe DILI.
Notes: In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased 
above ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the 
abnormality criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN.
13.3
Vital signs
The summary of vital signs will only include on treatment data, which are defined as those vital 
sign measurements after the first dose of study treatment and on or before last dose + 84 days.
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. The respective listing will be provided.
Criteria for notable vital sign abnormalities are provided below:


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Table 13-4
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm
13.4
Electrocardiogram (ECG)
Not applicable.
13.6
Compound specific safety evaluation
Safety topics of interest, such as risks defined in the Safety Profiling Plan (SPP), Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are defined 
in the Program Case Retrieval Sheet that is stored in CREDI at the path Cabinets/CREDI 
Projects/A/AIN457A/Integrated Medical Safety.
The crude incidence and exposure-adjusted incidence rates for SPP risks will be summarized. 
In addition, listings will be provided presenting which subjects experienced which risk.  
Important note: For the evaluation of SPP risks primary and secondary system organ classes of 
the MedDRA dictionary will be considered.
14
Determination of sample size
Please see [AIN457H2315 SAP] for the sample size calculation of the core phase.
The total sample size for extension phase is not pre-specified. It is estimated that approximately 
70% of subjects enrolled in the core phase will enter the extension phase, which is equivalent 
to about 380 subjects. Around 305 subjects are estimated to be core phase responders and will 
be in the randomized group and around 75 subjects are expected to be core phase non-
responders and will enter the open-label treatment group.
15
Appendix
15.1
Visit Windows
No analysis visit windows will be employed in the analysis, except for Week 104. Refer to 
[AIN457H2315 SAP_Week104 Amendment 1] for details about the analysis visit window of 
Week 104.
All data collected will be displayed in listings. 


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15.2
Statistical methodology and assumptions
15.2.1
Analysis of continuous data
15.2.1.1 Summary statistics for continuous data
Summary statistics (including N, mean, SD, minimum, lower quartile, median, upper quartile 
and maximum) will be provided for continuous data by visit and treatment group. 
15.2.1.2 Analysis of covariance
Endpoints with continuous data type expected to be normally distributed (e.g., change from 
baseline in BASDAI) will be analyzed using a mixed-effects repeated measures model (MMRM) 
with factors, covariates, interactions and covariance structure as specified for respective 
analysis. The SAS code below outlines a template for the analysis where covariates and 
interaction terms can be added or removed as required:
ods output diffs=lsm_diff lsmeans=lsm_est;
proc mixed data=mydata;
        class treatment strata tnf_status visit;
        model outcome = treatment strata tnf_status visit baseline_score baseline_weight      
             treatment*visit  baseline_score *visit / ddfm=kr;
        repeated visit / type=un subject=;
        lsmeans treatment*visit / diff cl;
run;
Least-square-mean (LSM) estimates and the standard error (SE) for each treatment groupwill 
be calculated at appropriate analysis visits, i.e., Week 104, Week 112 and Week 120.
In case the MMRM model does not converge the following sequential steps will be used:
1. change to ddfm=bw. If still no convergence, perform step 2.
2. change to type=cs. If still no convergence, perform step 3.
3. remove covariates in the following order until convergence: baseline_weight, 
baseline_score*visit, tnf_status, strata. 
15.2.2
Analysis of binary and categorical data
15.2.2.1 Summary statistics for binary and categorical data
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be derived 
as well 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-α/2), n as total 
number of subjects (i.e., number of subjects in the denominator), p as estimated crude incidence 
(number of subjects with event / n) and q = 1-p


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Then the lower limit is
























2
2
2
2
1
4
1
2
1
2
,0
max
100
z
n
nq
p
n
z
z
z
np
L
and the upper limit is
























2
2
2
2
1
4
1
2
1
2
,1
min
100
z
n
nq
p
n
z
z
z
np
U
.
In addition, if L > p then L = p and if U < p then U = p.
For binary response variables the placebo-adjusted response rates including 95% confidence
interval will be derived.
SAS code for risk difference:
proc freq data=;
        tables response* treatment / riskdiff;
run;
Note the response value should be sorted with ‘1’ ahead of ‘0’.
15.2.2.2 Multiple Imputation
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.
The SAS code below outlines a template for the analysis where covariates and visits can be 
added or removed as required. To ensure that results can be replicated the data should be sorted 
by treatment group and unique subject ID before running the model (the data should be in 
horizontal format with one subject per dataset row).
proc mi data=mydata seed=4572315 nimpute=100 out=mi_out;
        by treatment;
        class strata tnf_status;
        fcs reg (/details);
        var strata tnf_status baseline_weight value1 value2 value3 value4;
run;


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In the template code, the continuous variable to be imputed is value (e.g., value1 could be the 
baseline value and value2 the first post-treatment measurement of the variable to be imputed.) 
Normally, all data collection visits during the analysis period of interest (i.e., Week 104, Week 
112 and Week 120) would be included in the model. Including variables using a CLASS 
statement instead of a BY statement should help facilitate model convergence also when the 
number of non-missing data points are low for some specific covariate level and visit 
combination. The FCS option is used to ensure that also non-monotone missing data can be 
handled in an appropriate way.
If convergence is not obtained the following sequential steps will be used:
1. remove baseline_weight. If still no convergence, perform step 2.
2. remove tnf_status. If still no convergence, perform step 3.
3. remove status.
For a situation where several variables need to be imputed using separate models (e.g., using 
independent models to impute each component needed to derive a response variable V) a step-
wise process needs to be implemented as outlined below:
1. Run the SAS code as described above for the first variable to be imputed
2. Run the SAS code as described above for the next variable to be imputed (but with the 
following changes: “data=mi_out”, “out=mi_out2”, “by treatment _imputation_”, 
“nimpute=1”)
3. Repeat step 2, but with input dataset equal to the output dataset from the prior step, until 
all j variables have been imputed resulting in a dataset named mi_outj
4. Derive the variable V from within mi_outj
To obtain binary response rates and confidence intervals for individual treatment groups the 
following process should be followed (exemplified for one visit):
ods output binomialprop=bin_est;
proc freq data=;
        by treatment _imputation_;
        table response / binomial (cl=wilson correct);
run;
Then apply a logit transformation on the saved proportions and derive its standard error: 
data bin_est; 
        set bin_est;
        estimate=log(_bin_/(1-_bin_));
        estimate_se=e_bin/(_bin_*(1-_bin_));
run;
The transformed binomial proportion estimates and its standard errors are then combined by 
applying Rubin’s rules as described above using PROC MIANALYZE. Before presenting the 
combined data it needs to be transformed back as follows:


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data mi_result; 
        set mi_result;
        prop_est=1/(1+exp(-estimate));
        prop_lower=1/(1+exp(-lclmean));
        prop_upper=1/(1+exp(-uclmean));
run;
If all responses are imputed as 0 (or 1) for all imputation datasets for a specific treatment group 
then the between-imputation-variation will be zero. The combined final response rate would be 
presented as seen in any of the imputed datasets but the 95% CI will be undefined.
If after imputation all responses are either 0 or 1 for a combination of treatment group and 
imputation dataset it will not be possible to perform a logit transformation and the response rate 
(0% or 100%) will be presented without 95% CI.
15.2.3
Crude incidence and related risk estimates 
15.2.3.1 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-α/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























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
In addition, if L > p then L = p and if U < p then U = p.
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson, 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 


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However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses.
15.2.4
Exposure adjusted incidence rate and related risk estimates
15.2.4.1 Exposure adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 



n
j
jt
T
1
and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood 1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai 
1993; Ulm 1990):
Lower confidence limit 
T
c
L
D
2,2
/
5.0


for D>0, 0 otherwise,
Upper confidence limit 
T
c
U
D 2
2,2
/
1
5.0




Where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom.
The example below shows how this should be handled for cases where subjects switch treatment. 
In particular for summarizing ‘Any AIN’ as a group, one should take into consideration the 
sequence of treatments while calculating exposure time for subjects.
Table 15-1
Examples for calculating exposure time for incidence rates (IR)
1st treatment / total 
exposure time
2nd treatment / total 
exposure time
AE event onset (in days from study 
start)
Exposure for IR
Placebo / 100 days
AIN457 150 mg / 200 days
Day 50 (during 1st treatment)
Day 110 (10 days into 2nd treatment)
Placebo: 50 days
AIN457 150 mg: 10 days
Any AIN: 10 days
16
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 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):570-579.


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Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413.
Dougados M, Paternotte S, et al. (2010) ASAS recommendations for collecting, analysing and 
reporting NSAID intake in clinical trials/epidemiological studied in axial spondyloarthritis. 
Ann Rheum Dis; 70:249-251
Doward LC, Spoorenberg A, Cook SA, et al. (2003) Development of the ASQoL: a quality of 
life instrument specific to ankylosing spondylitis. Ann Rheum Dis; 62(1):20-26.
Garwood, F. (1936) Fiducial limits for the Poisson distribution. Biometrika; 46: 441-453. 
Haywood KL, et al. (2002) Disease-specific, patient-assessed measures of health outcome in 
ankylosing spondylitis: reliability, validity and responsiveness. Rheumatology; 41:1295-1302.
Lubeck, DP. (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis.  Pharmacoeconomics 22(1): 27-38.
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):1502-1506.
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. (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis.; 
68 Suppl 2:ii1-44.
Ulm, K. (1990) A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology; 131(2): 373-375.
van der Heijde D, Dijkmans B, et al. (2005) Efficacy and safety of infliximab in patients with 
ankylosing spondylitis: Results of a randomized, placebo-controlled trial (ASSERT). Arthritis 
Rheum; 52(2):582-591.
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

Prot_000.pdf: 
Global Clinical Development - General Medicine 
AIN457/Secukinumab 
Clinical Trial Protocol CAIN457H2315 / NCT02696031
A randomized, double-blind, placebo-controlled multicenter 
study of secukinumab 150 mg in patients with active non-
radiographic axial spondyloarthritis to evaluate the safety, 
tolerability and efficacy up to 2 years, followed by an 
optional phase of either 150 mg or 300 mg randomized 
dose escalation for up to another 2 years 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2015-001106-33 
Version number: 
v02 Clean 
Development phase: 
III 
Release date: 
11-Jul-2018
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed  
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0, November, 2013 


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Amended Protocol Version v02 Clean 
Protocol No. CAIN457H2315 
 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 23 
2 
Study objectives ................................................................................................................. 24 
2.1 
Primary objective(s) ............................................................................................... 24 
2.2 
Secondary objectives ............................................................................................. 24 
 
 26 
3 
Investigational plan ........................................................................................................... 28 
3.1 
Study design........................................................................................................... 28 
3.2 
Rationale of study design ....................................................................................... 31 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 32 
3.4 
Rationale for choice of comparator ....................................................................... 33 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 33 
3.6 
Risks and benefits .................................................................................................. 34 
4 
Population .......................................................................................................................... 34 
4.1 
Inclusion criteria .................................................................................................... 35 
4.2 
Exclusion criteria ................................................................................................... 36 
5 
Treatment ........................................................................................................................... 39 
5.1 
Protocol requested treatment ................................................................................. 39 
5.1.1 
Investigational treatment ....................................................................... 39 
5.1.2 
Additional study treatment .................................................................... 40 
5.2 
Treatment arms ...................................................................................................... 40 
5.3 
Treatment assignment, randomization ................................................................... 41 
5.4 
Treatment blinding ................................................................................................. 42 
5.5 
Treating the patient ................................................................................................ 43 
5.5.1 
Patient numbering ................................................................................. 43 
5.5.2 
Dispensing the investigational treatment .............................................. 43 
5.5.3 
Handling of study treatment .................................................................. 44 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 44 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 45 


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Protocol No. CAIN457H2315 
 
 
5.5.6 
Allowed treatment modifications and escape treatment ....................... 46 
5.5.7 
Concomitant treatment .......................................................................... 47 
5.5.8 
Prohibited Treatment ............................................................................. 48 
5.5.9 
Discontinuation of study treatment and premature withdrawal ............ 49 
5.5.10 
Withdrawal of consent .......................................................................... 51 
5.5.11 
Loss to follow-up .................................................................................. 51 
5.5.12 
Emergency breaking of assigned treatment code .................................. 51 
5.5.13 
Study completion and post-study treatment .......................................... 52 
5.5.14 
Early study termination ......................................................................... 52 
6 
Visit schedule and assessments ......................................................................................... 53 
6.1 
Information to be collected on screening failures .................................................. 61 
6.2 
Patient demographics/other baseline characteristics ............................................. 61 
6.3 
Treatment exposure and compliance ..................................................................... 61 
6.4 
Efficacy .................................................................................................................. 61 
6.4.1 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................. 62 
6.4.2 
Patient’s global assessment of disease activity (VAS) ......................... 63 
6.4.3 
Patient’s assessment of back pain intensity (VAS) ............................... 63 
6.4.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 63 
6.4.5 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 63 
 
 64 
 
 64 
6.4.8 
High sensitivity C-reactive protein (hsCRP) ......................................... 64 
 
 64 
6.4.10 
, ASDAS-CRP 
 response categories ............ 64 
 
 65 
6.4.12 
MRI ....................................................................................................... 65 
6.4.13 
X-ray ..................................................................................................... 66 
6.4.14 
Appropriateness of efficacy assessments .............................................. 66 
6.5 
Safety ..................................................................................................................... 66 
6.5.1 
QuantiFERON TB-Gold test or PPD skin test ...................................... 67 
6.5.2 
Chest X-ray or MRI .............................................................................. 67 
6.5.3 
Physical examination ............................................................................ 67 
6.5.4 
Vital signs.............................................................................................. 68 
6.5.5 
Height and weight ................................................................................. 68 
6.5.6 
Laboratory evaluations .......................................................................... 68 


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Protocol No. CAIN457H2315 
 
 
 
 69 
6.5.8 
Electrocardiogram (ECG) ..................................................................... 69 
6.5.9 
Pregnancy and assessments of fertility ................................................. 69 
6.5.10 
Local tolerability (Injection site reactions) ........................................... 70 
6.5.11 
Tolerability of secukinumab ................................................................. 70 
6.5.12 
Appropriateness of safety measurements .............................................. 70 
6.6 
Other assessments .................................................................................................. 70 
6.6.1 
Health-related Quality of Life and Patient Reported Outcome ............. 70 
 
 73 
6.6.3 
HLA-B27............................................................................................... 73 
 
 73 
 
 74 
 
 74 
7 
Safety monitoring .............................................................................................................. 75 
7.1 
Adverse events ....................................................................................................... 75 
7.2 
Serious adverse events ........................................................................................... 77 
7.2.1 
Definition of SAE ................................................................................. 77 
7.2.2 
SAE reporting........................................................................................ 78 
7.3 
Liver safety monitoring ......................................................................................... 79 
7.4 
Renal safety monitoring ......................................................................................... 79 
7.5 
Pregnancy reporting ............................................................................................... 79 
8 
Data review and database management ............................................................................. 79 
8.1 
Site monitoring ...................................................................................................... 80 
8.2 
Data collection ....................................................................................................... 80 
8.3 
Database management and quality control ............................................................ 80 
8.4 
Data Monitoring Committee .................................................................................. 81 
8.5 
Adjudication Committee ........................................................................................ 81 
9 
Data analysis ...................................................................................................................... 82 
9.1 
Analysis sets .......................................................................................................... 82 
9.2 
Patient demographics and other baseline characteristics ....................................... 82 
9.3 
Treatments ............................................................................................................. 83 
9.4 
Analysis of the primary variable(s) ....................................................................... 84 
9.4.1 
Variable(s) ............................................................................................. 84 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 84 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 85 
9.4.4 
Supportive analyses ............................................................................... 86 


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9.5 
Analysis of secondary variables ............................................................................ 86 
9.5.1 
Secondary efficacy variables ................................................................. 86 
 
 96 
9.5.3 
Safety variables ..................................................................................... 98 
 
 99 
 
 101 
 
 101 
 
 102 
 
 102 
9.6 
Interim analyses ................................................................................................... 102 
9.7 
Sample size calculation ........................................................................................ 102 
9.8 
Power for analysis of secondary variables ........................................................... 104 
9.9 
Analysis of extension phase................................................................................. 106 
10 Ethical considerations ...................................................................................................... 106 
10.1 
Regulatory and ethical compliance ...................................................................... 106 
10.2 
Informed consent procedures ............................................................................... 107 
10.3 
Responsibilities of the investigator and IRB/IEC ................................................ 107 
10.4 
Publication of study protocol and results............................................................. 108 
11 Protocol adherence .......................................................................................................... 108 
11.1 
Protocol Amendments ......................................................................................... 108 
12 References ....................................................................................................................... 108 
13 Appendices ...................................................................................................................... 111 
13.1 
Appendix 1: Clinically notable laboratory values ............................................... 111 
 
 112 
13.3 
Appendix 3: Modified New York criteria ........................................................... 114 
13.4 
Appendix 4: ASAS Classification Criteria for Axial Spondyloarthritis 
(axSpA) ................................................................................................................ 115 
13.5 
Appendix 5: Assessment of SpondyloArthritis International Society criteria 
(ASAS) ................................................................................................................ 115 
13.5.1 
Bath Ankylosing Spondylitis Functional Index (BASFI) ................... 115 
13.5.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ...... 116 
 
 116 
13.6 
Appendix 6: Definition of Sacroiliitis on MRI .................................................... 117 
 
 118 
13.8 
Appendix 8: Guidelines for administering the questionnaires for patient 
reported outcomes ................................................................................................ 118 
 


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List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 49 
Table 6-1 
Assessment schedule: Core phase ......................................................... 54 
Table 6-2 
Assessment schedule: Extension phase ................................................. 59 
Table 9-1 
Summary of power for binary primary endpoint ................................ 103 
Table 9-2 
Summary of power for binary primary endpoint ................................ 104 
Table 9-3 
Power for binary secondary variables at Week 16 .............................. 104 
Table 9-4 
Power for continuous secondary variables at Week 16 ...................... 104 
Table 9-5 
Power for binary secondary variables ................................................. 105 
Table 9-6 
Power for continuous secondary variables .......................................... 105 
Table 13-1 
Safety Analyses: Expanded Limits and Notable Criteria .................... 112 
 
 112 
 
 112 
 
 113 
 
 113 
 
 113 
 
 114 
 
List of figures 
Figure 3-1 
Study design Core Phase ....................................................................... 30 
Figure 3-2 
Study design Extension Phase ............................................................... 31 
Figure 9-1 
Testing strategy for analysis plan A ...................................................... 90 
Figure 9-2 
Testing strategy for analysis plan B ...................................................... 95 
 


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List of abbreviations 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic pyruvic transaminase 
ANCOVA 
analysis of covariance  
AS 
Ankylosing Spondylitis 
ASAS 
Ankylosing SpondyloArthritis International Society 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
ASQoL 
Ankylosing Spondylitis Quality of Life 
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
axSpA 
Axial Spondyloarthritis 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index  
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
BSL 
baseline 
BOCF 
Baseline observation carried forward 
CFR 
Code of Federal Regulation 
COX 
Cyclooxygenase 
CPO 
country pharma organization 
(e)CRF 
electronic case report form 
CRO 
contract research organization 
CRP (hsCRP) 
(high sensitivity) C-reactive protein 
CRP+ 
Patient with a CRP value above the ULN at screening 
DMARD 
disease modifying anti-rheumatic drug 
DNA 
deoxyribonucleic acid 
DS&E 
Drug Safety and Epidemiology 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EDTA 
ethylenediamine-tetraacetic acid 
EEA 
European Economic Area 
ELISA 
enzyme-linked immuno sorbent assay 
EMA/EMEA 
European Medical Agency 
 
 


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EU 
European Union 
eSource 
electronic Source Data Capturing Tool 
 
 
 
 
FDA 
Food and Drug Administration 
FAS 
full analysis set 
GCP 
good clinical practice 
GDPR 
General Data Protection Regulation 
GGT 
gamma-glutamyl-transferase 
hCG 
human chorionic gonadotropin 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC/EC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IQS 
Integrated Quantitive Sciences 
IL 
interleukin 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
i.v. 
intravenous(ly) 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
MAR 
missing at random 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed-effects model repeated measures 
MRI 
magnetic resonance imaging 


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MRI+ 
Patient with a MRI considered positive for sacroiliitis at screening 
 
 
MTX 
methotrexate 
nr-axSpA 
non-radiographic axial spondyloarthritis 
NSAID 
non-steroidal anti-inflammatory drug 
PCS 
Physical Component Summary  
 
 
PFS 
pre-filled syringe 
 
 
 
 
PoC 
proof of concept 
PPD 
purified protein derivative 
PRN 
pro re nata  
PRO 
patient reported outcome 
PsA 
psoriatic arthritis 
OC/RDC 
Oracle clinical/remote data capture 
QoL 
quality of life 
RA 
rheumatoid arthritis 
RoW 
Rest of World 
SAE 
serious adverse event 
SCR 
screening 
s.c. 
subcutaneous(ly) 
SD 
Standard Deviation 
SF-36 
Short Form-36 
SIJ/SI Joint 
Sacroiliac Joint 
SpA 
Spondyloarthritis 
STIR 
Short tau inversion recovery 
SUSAR 
suspected unexpected serious adverse reaction  
t.i.d. 
ter in die, three times a day 
TB 
Tuberculosis 
TNF/TNFα 
Tumor Necrosis Factor 
TNF-IR 
TNFα inhibitor inadequate responder 


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ULN 
upper limit of normal 
USA 
United States of America 
VAS 
visual analog scale  
WBC 
White Blood Cell 
 
 


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Glossary of terms 
 
Assessment 
A procedure used to generate data required by the study 
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) 
Epoch  
A portion of the study which serves a specific purpose. Typical 
Epochs are: screening / wash-out, treatment, and follow-up 
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. 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study 
are: a single dose part and a multiple dose part, or a part in patients 
with established disease and in those with newly-diagnosed 
disease. 
Period 
A subdivision of a cross-over study 
Premature subject/patient 
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 


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Amendment 1  
Amendment rationale 
This protocol amendment is issued for the following reasons: 
Based on a meta-analysis from unpublished studies with secukinumab, the powering of the 
study was re-evaluated. This new evaluation triggered a changed order in the testing hierarchy 
as well as adjustments of the population for the primary endpoint to TNF naïve patients only. 
These changes ensure that the placebo population will remain the same size and the 
randomization will continue to be 2:1 for the active to placebo ratio, while maintaining adequate 
power for primary and secondary analyses.  
After the study was initiated, feedback from the FDA requested a focus on the no-load dosing 
regimen, which is reflected in the changes to Analysis Plan B. In alignment with that, Analysis 
Plan A evaluates the dosing regimen approved in countries outside of the US, which is reflected 
in its focus on the load regimen. 
The test for HLA-B27 is moved from the baseline visit to screening visit 2 to facilitate the 
screening process for the sites. 
The maximally allowed proportion of TNF-IR patients was changed from 30% to 20%, based 
on the aforementioned meta-analysis from unpublished studies with secukinumab and due to 
the changes in the statistical hierarchy, as well as the unavailability of response rates for 
biologics in TNF-IR patients to validate power calculation assumptions. Additionally, due to 
the long wash out required for some TNF-IR patients, enrolment of TNF-IR patients will end 
two months prior to the projected end of the screening period. 
Historic MRI will be accepted, if taken within 3 months of baseline and in alignment of the 
imaging criteria to facilitate the re-screening process for patients and sites.  
The wording in the SAE reporting section was updated to be aligned with current and future 
SAE reporting processes. 
A decision was taken to replace the eSource system and collect the data for the study in 
OC/RDC in all countries. This process change will be reflected in the respective sections where 
eSource is mentioned.  
None of the changes made are due to evidence-based safety concerns. 
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 deletions and red underlined for insertions. 
The wording of various sub-sections to “Study objectives” (Section 2), “Investigational Plan” 
(Section 3), “Population” (Section 4), “Treatment” (Section 5), “Visit schedule and 
assessments” (Section 6), “Safety Monitoring” (Section 7), “Data review and database 
management” (Section 8), and “Data analysis” (Section 9) have been amended to reflect the 
rationale given above. 


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Additionally, this protocol amendment includes the correction of typographical and formatting 
errors and minor editorial changes for increased clarity of the text. Consequently, a small 
number of changes were implemented throughout the protocol. 
None of the changes described in this amended protocol are made due to newly emerged safety 
considerations.  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
 
 


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Amendment 2  
Amendment rationale 
This protocol amendment is issued to add an extension phase to the current core protocol. This 
extension phase will consist of two treatment periods, a 16-week blinded dose escalation 
treatment period followed by a blinded treatment period lasting until the last patient has reached 
the end of the 16-week dose escalation treatment period. Before a patient will be able to 
participate in this additional 16-week treatment escalation period, a new informed consent form 
(ICF) has to be signed.  
The order of the secondary endpoints of the analysis plan B in the hierarchy was updated to 
elevate several Load regimen endpoints to reflect their clinical relevance.  
The wording for the Withdrawal of Consent section was updated to align with the European 
Economic Area (EEA) General Data Protection Regulation (GDPR) requirements.  
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 deletions and red underlined for insertions. 
The wording of various sub-sections to “Introduction” (Section 1),  “Study objectives” (Section 
2), “Investigational Plan” (Section 3), “Population” (Section 4), “Treatment” (Section 5), “Visit 
schedule and assessments” (Section 6), “Data analysis” (Section 9), “References” (Section 12), 
and “Appendices” (Section 13) have been amended to reflect the rationale given above. 
Additionally, this protocol amendment includes the correction of typographical and formatting 
errors and minor editorial changes for increased clarity of the text. Consequently, a small 
number of changes were implemented throughout the protocol. 
None of the changes described in this amended protocol are made due to newly emerged safety 
considerations.  
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Protocol summary 
Protocol number 
CAIN457H2315 
Title 
A randomized, double-blind, placebo-controlled multicenter study of 
secukinumab 150 mg in patients with active non-radiographic axial 
spondyloarthritis to evaluate the safety, tolerability and efficacy up to 2 
years, followed by an optional phase of either 150 mg or 300 mg 
randomized dose escalation for up to another 2 years 
Brief title 
 
Study of efficacy and safety of secukinumab in patients with non-
radiographic axial spondyloarthritis  
Sponsor and Clinical 
Phase 
Novartis 
Phase III 
Investigation type 
Drug; Biologic 
Study type 
Interventional  
Purpose and rationale 
To demonstrate the clinical efficacy, safety and tolerability of 
secukinumab compared to placebo in patients with nr-axSpA at Week 
16 as well as Week 52 and long term efficacy and safety up to Week 
104 followed by an optional 16-week randomized dose escalation 
treatment period and a continuous treatment period for up to Week 208. 
Primary Objective(s)  
ANALYSIS PLAN A - EU and other non- USA Regions 
To demonstrate superiority of secukinumab 150 mg s.c. with loading 
over placebo at Week 16, based on the proportion of TNF naïve patients 
achieving an ASAS40 response (Assessment of SpondyloArthritis 
International Society criteria). 
ANALYSIS PLAN B - USA 
To demonstrate superiority of secukinumab 150 mg s.c. without loading 
over placebo at Week 52, based on the proportion of TNF naïve patients 
achieving an ASAS40 response (Assessment of SpondyloArthritis 
International Society criteria) 
Secondary Objectives 
 
ANALYSIS PLAN A 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
proportion of all patients achieving an ASAS40 response 
2. To demonstrate that the efficacy of secukinumab 150 mg s.c., 
without loading, at Week 16 is superior to placebo based on the 
proportion of TNF naive patients achieving an ASAS40 response 
3. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
proportion of patients meeting the ASAS 5/6 response criteria 
4. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
change from baseline in total Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) 
5. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
proportion of patients achieving BASDAI 50 


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6. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
change from baseline of high sensitivity C-Reactive Protein (hsCRP)  
7. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
change from baseline in total Bath Ankylosing Spondylitis Functional 
Index (BASFI) 
8. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
change from screening in sacroiliac (SI) joint edema on MRI  
9. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
proportion of subjects achieving an ASAS20 response 
10. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
change from baseline in Short Form-36 Physical Component 
Summary (SF-36 PCS) 
11. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
change from baseline in Ankylosing Spondylitis Quality of Life 
(ASQoL) scores  
12. To demonstrate that the efficacy of secukinumab 150 mg s.c. with or 
without loading at Week 16 is superior to placebo based on the 
proportion of patients achieving ASAS partial remission 
13. Overall safety and tolerability of secukinumab 
 
ANALYSIS PLAN B 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 52 is superior to placebo based on the 
proportion of all patients achieving an ASAS40 response 
2. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
loading, at Week 52 is superior to placebo based on the proportion 
of TNF naive patients achieving an ASAS40 response 
3. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
proportion of subjects achieving an ASAS40 response 
4. 
To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 
change from baseline in total Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) 
5. 
To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 
proportion of patients achieving BASDAI 50 
6. 
To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 52 is superior to placebo based on the 
proportion of patients achieving BASDAI 50 
7. 
To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
change from baseline of high sensitivity C-Reactive Protein 
(hsCRP)  
8. 
To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 


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change from baseline in Short Form-36 Physical Component 
Summary (SF-36 PCS) 
To demonstrate that the efficacy of secukinumab 150 mg s.c., with or 
without loading, at Week 16 is superior to placebo based on the change 
from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) scores  
9. 
To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 
proportion of patients meeting the ASAS 5/6 response criteria 
10. To demonstrate that the efficacy of secukinumab 150 mg s.c., with 
or without loading, at Week 16 is superior to placebo based on the 
proportion of subjects achieving an ASAS20 response 
11. To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 
change from baseline in total Bath Ankylosing Spondylitis 
Functional Index (BASFI) 
12. To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 16 is superior to placebo based on the 
change from screening in SI joint edema on MRI  
13. To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 52 is superior to placebo based on the 
proportion of patients achieving Ankylosing Spondylitis Disease 
Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease 
as defined by ASDAS < 1.3 
14. To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 52 is superior to placebo based on the 
change from screening in SI joint edema on MRI 
15. To demonstrate that the efficacy of secukinumab 150 mg s.c. with 
or without loading at Week 52 is superior to placebo based on the 
change from baseline in Ankylosing Spondylitis Quality of Life 
(ASQoL) scores  
16. Overall safety and tolerability of secukinumab 
Study design 
This is a randomized, double-blind, placebo-controlled study 
Population 
The study population will consist of 555 male and female patients (≥ 18 
years old at the time of consent) fulfilling the ASAS classification criteria 
for axSpA, with no radiographic evidence of changes in the sacroiliac 
joints that would meet the modified New York criteria for AS. 
Inclusion criteria 
• 
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 
• 
Male or non-pregnant, non-nursing female patients at least 18 
years of age 
• 
Diagnosis of axSpA according to ASAS axSpA criteria: 
• 
Inflammatory back pain for at least 6 months 
• 
Onset before 45 years of age 
• 
Sacroiliitis on MRI with ≥ 1 SpA feature OR HLA-B-27 
positive with ≥2 SpA features 
• 
Objective signs of inflammation at screening, evident by  
Either MRI with Sacroiliac Joint inflammation 
OR hsCRP > ULN (as defined by the central lab) 


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• 
Active axSpA as assessed by total BASDAI ≥ 4 cm (0-10 cm) 
at baseline 
• 
Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 
cm) at baseline 
• 
Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at 
baseline 
• 
Patients should have been on at least 2 different NSAIDs at the 
highest recommended dose for at least 4 weeks in total prior to 
randomization with an inadequate response or failure to 
respond, or less if therapy had to be withdrawn due to 
intolerance, toxicity or contraindications  
• 
Patients who are regularly taking NSAIDs (including  COX-2 
inhibitors) as part of their axSpA therapy are required to be on 
a stable dose for at least 2 weeks before randomization 
• 
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 randomization or have been intolerant to 
at least one administration of an anti-TNFα agent 
• 
Patients who have previously been on a TNFα inhibitor will be 
allowed entry into study after an appropriate wash-out period 
prior to randomization: 
• 
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) 
• 
10 weeks for Humira® (adalimumab) – with a terminal 
half-life of 10-20 days (average 2 weeks) (s.c. route) 
• 
10 weeks for Simponi® (golimumab) – with a terminal half-
life of 11-14 days 
• 
10 weeks for Cimzia® (certolizumab) – with a terminal 
half-life of 14 days  
• 
Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 
g/day) are allowed to continue their medication and must have 
taken it for at least 3 months and have to be on a stable dose 
for at least 4 weeks prior to randomization 
• 
Patients on MTX must be on stable folic acid supplementation 
before randomization 
• 
Patients who are on a DMARD other than MTX or sulfasalazine 
must discontinue the DMARD 4 weeks prior to randomization, 
except for leflunomide, which has to be discontinued for 8 
weeks prior to randomization unless a cholestyramine washout 
has been performed 
• 
Patients taking systemic corticosteroids have to be on a stable 
dose of ≤ 10 mg/day prednisone or equivalent for at least 2 
weeks before randomization 
For extension phase: 
• 
Written informed consent must be obtained before any 
assessment is performed.  
• 
Patients who have completed the full study treatment period 
(104 weeks) in the core phase on study treatment. 


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Exclusion criteria 
• 
Patients with radiographic evidence for sacroiliitis, grade  ≥ 2  
bilaterally or grade ≥ 3 unilaterally (radiological criterion 
according to the modified New York diagnostic criteria for AS) 
as assessed by central reader 
• 
Inability or unwillingness to undergo MRI (e.g., patients with 
pacemakers, aneurysm clips or metal fragments / foreign 
objects in the eyes, skin or body) 
• 
Chest X-ray or MRI with evidence of ongoing infectious or 
malignant process, obtained within 3 months of screening and 
evaluated by a qualified physician 
• 
Patients taking high potency opioid analgesics (e.g., 
methadone, hydromorphone, morphine) 
• 
Previous exposure to secukinumab or any other biologic drug 
directly targeting IL-17 or IL-17 receptor 
• 
Use of any investigational drug and/or devices within 4 weeks 
of randomization, or a period of 5 half-lives of the 
investigational drug, whichever is longer 
• 
History of hypersensitivity to the study drug or its excipients or 
to drugs of similar chemical classes 
• 
Any therapy by intra-articular injections (e.g., corticosteroid) 
within 4 weeks before randomization 
• 
Any intramuscular corticosteroid injection within 2 weeks before 
randomization 
• 
Patients previously treated with any biological 
immunomodulating agents, except those targeting TNFα 
• 
Patients who have taken more than one anti-TNFα agent 
• 
Previous treatment with any cell-depleting therapies including 
but not limited to anti-CD20 or investigational agents (e.g., 
CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19) 
• 
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  
• 
Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are 
using effective methods of contraception during entire study  or 
longer if required by locally approved prescribing information.  
• 
Active ongoing inflammatory diseases other than axSpA that 
might confound the evaluation of the benefit of secukinumab 
therapy, including inflammatory bowel disease or uveitis 
• 
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 
• 
Significant medical problems or diseases, including but not 
limited to the following: uncontrolled hypertension (≥ 160/95 
mmHg), congestive heart failure (New York Heart Association 


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status of class III or IV), uncontrolled diabetes, or very poor 
functional status unable to perform self-care 
• 
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.  
• 
History of renal trauma, glomerulonephritis, or patients with one 
kidney only, or a serum creatinine level exceeding 1.5 mg/dL 
(132.6 µmol/L) 
• 
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) 
• 
Active systemic infections during the last two weeks prior to 
randomization (exception: common cold) 
• 
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 QuantiFERON TB-Gold. 
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 
• 
Known infection with human immunodeficiency virus (HIV), 
hepatitis B or hepatitis C at screening or randomization 
• 
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) 
• 
Current severe progressive or uncontrolled disease which in 
the judgment of the clinical investigator renders the patient 
unsuitable for the trial 
• 
Inability or unwillingness to undergo repeated venipuncture 
(e.g., because of poor tolerability or lack of access to veins) 
• 
Inability or unwillingness to receive injections with PFS 
• 
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 
• 
Donation or loss of 400 mL or more of blood within 8 weeks 
before dosing 
• 
History or evidence of ongoing alcohol or drug abuse, within the 
last six months before randomization 
• 
Plans for administration of live vaccines during the study period 
or 6 weeks prior to randomization 
Investigational and 
reference therapy 
Secukinumab 150 mg s.c. 
Matching placebo 


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Efficacy assessments 
• 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) 
• 
Patient’s global assessment of disease activity (VAS) 
• 
Patient’s assessment of back pain intensity (VAS) 
• 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
• 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
 
 
 
 
• 
hsCRP 
 
• 
, ASDAS-CRP 
 response categories 
 
 
• 
MRI of spine and sacroiliac joints 
 
 
• 
X-ray of the sacroiliac joints 
Safety assessments 
• 
QuantiFERON TB-Gold test or PPD skin test 
• 
Chest X-ray or MRI 
• 
Physical examination 
• 
Vital signs 
• 
Height and weight 
• 
Laboratory evaluations 
 
 
• 
Electrocardiogram 
• 
Pregnancy and assessment of fertility 
• 
Local tolerability (Injection site reactions) 
• 
Tolerability of secukinumab 
Other assessments 
• 
Health-related Quality of Life 
SF-36 
ASQoL 
 
 
 
 
 
• 
HLA-B27 
 
 
 
 
 
 
Data analysis 
The statistical hypothesis for ASAS40 being tested is that there is no 
difference in the proportion of patients fulfilling the ASAS40 criteria at 
Week 16 (analysis plan A) or 52 (analysis plan B), respectively in the 
secukinumab regimens versus placebo regimen 
Key words 
Non-radiographic spondyloarthritis, chronic inflammatory disease, 
inflammatory back pain, secukinumab, AIN457 


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1 
Introduction 
1.1 
Background 
Axial Spondyloarthritis (axSpA) is a group of rheumatic disorders with spinal inflammation 
and inflammatory back pain as common denominator. axSpA is among the most common 
chronic inflammatory joint disorders, with recent estimates of prevalence in Caucasian 
populations in the range of 1–2% (Baraliakos and Braun 2011). Patients with chronic back pain 
(onset before 45 years of age) are classified according to the Assessment of Spondyloarthritis 
international Society (ASAS) classification criteria (Rudwaleit et al 2009) for axSpA if they 
fulfill either the clinical arm or the imaging arm of the criteria.  
Based on the presence or absence of sacroiliitis on conventional X-ray radiographs, axSpA 
patients are sub-grouped into non-radiographic axSpA (nr-axSpA) and ankylosing spondylitis 
(AS). Patients with evidence for sacroiliitis on X-ray fulfilling the 1984 modified New York 
diagnostic criteria (van der Linden et al 1984) are classified AS whereas patients who do not 
show sacroiliitis on X-ray but may show evidence of sacroiliitis on magnetic resonance imaging  
(MRI) are classified as having nr-axSpA. 
The 2009 ASAS classification criteria for axSpA were introduced to establish standards that 
apply to patients with or without radiographic sacroiliitis by including both X-ray and MRI as 
imaging modalities. The diagnosis of nr-axSpA based on imaging can achieve up to 88% 
specificity and 67% sensitivity whilst diagnosis based on clinical parameters only achieve 
approximately 83% specificity and 57% sensitivity when based on clinical parameters only 
(Sieper and van der Heijde 2013). In addition to the differential identification of AS and nr-
axSpA patients, the ASAS criteria allow for the implementation of clinical trials in the treatment 
of nr-axSpA, a disease entity for which there is an unmet medical need (Sieper 2012). 
Studies and registry data have shown that nr-axSpA patients have similar levels of disease 
activity, pain, and health-related quality of life impairment as do AS patients (Wallis et al 2013). 
Commonality of etiopathogenic characteristics and natural history of AS and nr-axSpA is the 
subject of ongoing research. Disease parameters and response rates to treatment with tumor 
necrosis factor (TNF) antagonists are similar in patients with AS and nr-axSpA, supporting the 
concept that axSpA is a disease with distinct stages (Song et al 2013). Progression from nr-
axSpA to AS was observed in about 12% of nr-axSpA patients over the course of 2 years 
(Poddubnyy et al 2011). However, it is estimated that 10-15% of nr-axSpA patients do not 
develop radiographic sacroiliitis (Sieper and van der Heijde 2013). 
Non-steroidal anti-inflammatory drugs (NSAIDs) are considered first-line therapy for all 
patients with axSpA. Traditional disease-modifying antirheumatic drugs (DMARDs) such as 
methotrexate and sulfasalazine are not effective in the treatment of axSpA. Anti-TNF agents 
are approved therapies for patients with AS who continue to have active disease despite 
NSAIDs. In Europe, several anti-TNF agents are also approved for nr-axSpA. However, more 
than 60% of nr-axSpA patients treated with adalimumab or etanercept did not achieve an 
ASAS40 response in randomized clinical trials (Sieper et al 2013, Dougados et al 2014). 
Moreover, TNF blockade does not result in long term remission in AS and responders usually 
relapse within a few weeks after interruption of treatment (Baraliakos et al 2005). Whilst 
effective in treating the inflammatory symptoms, TNF antagonists do not prevent structural 


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damage of the joints in AS (van der Heijde et al 2008a, van der Heijde et al 2008b). Currently, 
there is no experimental evidence that early therapy with approved treatment options in patients 
with nr-axSpA can prevent or delay the occurrence of structural alterations of the axial skeleton, 
which usually develop over a period of up to 10 years (Robinson et al 2013). 
Secukinumab (AIN457) is a high-affinity recombinant, fully human monoclonal anti-human 
Interleukin-17A antibody of the IgG1/κ-class. Secukinumab binds to human IL-17A and 
neutralizes the bioactivity of this cytokine. IL-17A is the central lymphokine of a newly defined 
subset of inflammatory T cells (Th17) which appear to be pivotal in several autoimmune and 
inflammatory processes in some animal models. IL-17A is mainly produced by memory CD4+ 
and CD8+ T lymphocytes and is being recognized as one of the principal pro-inflammatory 
cytokines in immune mediated inflammatory diseases. Assuming a potential role of Th17 cells 
in the inflammatory infiltrate in spondyloarthritides, it can be speculated that the activity of 
inflammation in early disease stages, such as nr-axSpA and the ensuing structural changes in 
axial joints over the longer term, characteristic of axSpA may be amenable to modulation via 
IL-17 antagonism. 
AS (one of the Radiographic axial SpAs) Phase III studies showed an ASAS40 response rate of 
36.1% at Week 16 to secukinumab (150 mg s.c. at Weeks 0, 1, 2, and 3, followed by the same 
dose every 4 weeks). A statistically significant difference in ASAS40 response between the 
secukinumab 150 mg group and placebo was evident as early as at Week 2. In the Phase II study 
in AS, MRI imaging performed at baseline and at Weeks 6 and 28 showed a reduction of 
inflammation after 6 weeks which was maintained up to Week 28. Early improvements were 
especially noted in patients with higher baseline MRI scores (Baraliakos et al 2011). 
As of 12-Jul-2015, approximately 12000 healthy subjects and patients have been enrolled into 
clinical trials with secukinumab, of which approximately 9600 have received at least one dose 
of secukinumab. Overall, secukinumab trials have included various indications (Rheumatoid 
Arthritis (RA), AS, Psoriatic Arthritis (PsA), psoriasis, multiple sclerosis, uveitis, Crohn’s 
disease, dry eye syndrome, polymyalgia rheumatica) at doses ranging from single and multiple 
doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg subcutaneous(ly) (s.c.). As of March 
2015, Secukinumab is now approved for the treatment of psoriasis in the European Union (EU), 
the US, and Japan. Full safety results from completed studies for PsA, AS and psoriasis show 
that secukinumab generally is safe and well tolerated. Please refer to the 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 nr-axSpA patients with secukinumab. 
As most studies for currently marketed biologic treatments for axSpA (with and without 
radiologic evidence) have failed to show evidence of slowing-down or even stopping the 
structural progression of the disease, there is an unmet medical need for new therapies being 
able to stop this structural damage. 
1.2 
Purpose 
The purpose of this study is to demonstrate the clinical efficacy, safety and tolerability of two 
different regimens of secukinumab, with loading and without loading, compared to placebo in 
patients with nr-axSpA at Week 16 as well as Week 52. Additionally, 1 year progression of 
structural changes as evidenced by MRI will be assessed at Week 52. This study will also 
observe the long-term efficacy, safety, and tolerability of secukinumab and the evolution of 


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radiographic correlates of inflammation and structural progression based on the MRI and X-ray 
results up to Week 104. 
At the end of the core phase, an optional 16-week randomized dose escalation treatment period 
will assess if a treatment escalation from 150 mg to 300 mg secukinumab is of further benefit 
to patients, as compared to continuous treatment with 150 mg secukinumab. Additionally, long-
term efficacy, safety and tolerability of the 300 mg dose will be assessed in a treatment follow-
up phase.  
2 
Study objectives 
2.1 
Primary objective(s) 
There are two primary objectives based on regional regulatory precedent and feedback. These 
objectives will be tested in separate analysis plans. 
ANALYSIS PLAN A - EU and other non-United States of America (USA) Regions 
To demonstrate superiority of secukinumab 150 mg s.c. with loading over placebo at Week 16, 
based on the proportion of TNF naïve patients achieving an ASAS40 response (Assessment of 
SpondyloArthritis International Society criteria). 
ANALYSIS PLAN B - USA 
To demonstrate superiority of secukinumab 150 mg s.c. without loading over placebo at Week 
52, based on the proportion of TNF naïve patients achieving an ASAS40 response (Assessment 
of SpondyloArthritis International Society criteria) 
2.2 
Secondary objectives 
ANALYSIS PLAN A 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of all patients achieving an 
ASAS40 response 
2. To demonstrate that the efficacy of secukinumab 150 mg s.c., without loading, at Week 16 
is superior to placebo based on the proportion of TNF naïve patients achieving an 
ASAS40 response 
3. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of patients meeting the ASAS 5/6 
response criteria 
4. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in total Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI) 
5. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of patients achieving BASDAI 50 
6. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline of high sensitivity C-
Reactive Protein (hsCRP)  


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7. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in total Bath 
Ankylosing Spondylitis Functional Index (BASFI) 
8. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from screening in SI joint edema on 
MRI  
9. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of subjects achieving an ASAS20 
response 
10. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in Short Form-36 
Physical Component Summary (SF-36 PCS) 
11. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in Ankylosing 
Spondylitis Quality of Life (ASQoL) scores  
12. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of patients achieving ASAS partial 
remission 
13. Overall safety and tolerability of secukinumab 
ANALYSIS PLAN B 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 52 is superior to placebo based on the proportion of all patients achieving an 
ASAS40 response 
2. To demonstrate that the efficacy of secukinumab 150 mg s.c., with loading, at Week 52 is 
superior to placebo based on the proportion of TNF naïve patients achieving an ASAS40 
response 
3. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of subjects achieving an ASAS40 
response 
4. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in total Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI) 
5. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of patients achieving BASDAI 50 
6. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 52 is superior to placebo based on the proportion of patients achieving BASDAI 50 
7. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline of high sensitivity C-
Reactive Protein (hsCRP)  
8. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in Short Form-36 
Physical Component Summary (SF-36 PCS) 


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9. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in Ankylosing 
Spondylitis Quality of Life (ASQoL) scores  
10. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of patients meeting the ASAS 5/6 
response criteria 
11. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the proportion of subjects achieving an ASAS20 
response 
12. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from baseline in total Bath 
Ankylosing Spondylitis Functional Index (BASFI) 
13. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 16 is superior to placebo based on the change from screening in SI joint edema on 
MRI  
14. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 52 is superior to placebo based on the proportion of patients achieving Ankylosing 
Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive disease 
as defined by ASDAS < 1.3 
15. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 52 is superior to placebo based on the change from screening in SI joint edema on 
MRI 
16. To demonstrate that the efficacy of secukinumab 150 mg s.c., with or without loading, at 
Week 52 is superior to placebo based on the change from baseline in Ankylosing 
Spondylitis Quality of Life (ASQoL) scores  
17. Overall safety and tolerability of secukinumab 


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3 
Investigational plan 
3.1 
Study design 
This is a randomized, double-blind, placebo-controlled study. Approximately 555 analyzable 
patients will be randomized to one of three treatment groups (secukinumab 150 mg Load, 
secukinumab 150 mg No Load or placebo in a ratio of 1:1:1): 
• Group 1 (secukinumab 150 mg Load): secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-
filled syringe (PFS) at baseline (BSL), Weeks 1, 2 and 3, followed by administration every 
four weeks starting at Week 4 
• Group 2 (secukinumab 150 mg No Load): secukinumab 150 mg (1 mL, 150 mg/mL) s.c. 
PFS at BSL, placebo at Weeks 1, 2 and 3, followed by secukinumab 150 mg PFS 
administration every four weeks starting at Week 4 
• Group 3 (placebo): placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, followed by 
administration every four weeks starting at Week 4 
At Week 104, patients can continue in an optional randomized dose escalation treatment 
extension phase. The patients will be assessed based on their ASAS20 response at Week 104. 
Secukinumab 150 mg responders at Week 104 (Core Phase Responders) will be randomized to 
the following treatment groups in a blinded manner: 
• Group 4 (Core Phase Responder 150 mg): secukinumab 150 mg (1 mL, 150 mg/mL) s.c. 
pre-filled syringe (PFS) and placebo (1 mL) s.c. PFS every four weeks 


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• Group 5 (Core Phase Responder 300 mg): 2 injections with secukinumab 150 mg (1 mL, 
150 mg/mL) s.c. PFS every four weeks 
Secukinumab 150 mg incomplete-responders at Week 104 (Core Phase Non-Responders) will 
be escalated to secukinumab 300 mg in an open-label manner 
• Group 6 (Core Phase Non-Responder 300 mg): 2 injections with secukinumab 150 mg (1 
mL, 150 mg/mL) s.c. PFS every four weeks open-label 
Based on the clinical judgment of disease activity by the investigator and the patient, 
background medications, such as NSAIDs and DMARDs, may be modified or added to treat 
signs and symptoms of nr-axSpA from Week 16 on. Furthermore, patients who are repeatedly 
(e.g. at two or more consecutive visits) considered to be inadequate responders based on the 
clinical judgment of disease activity by the investigator and the patient, may receive 
secukinumab 150 mg s.c. or other biologics as standard of care treatment as outlined in Section 
5.5.6 from Week 20 on.  
Changes in concomitant medications used to treat nr-axSpA will not be allowed before the 
completion of all Week 16 assessments (see Section 5.5.6). Efficacy will be assessed in detail 
at every study visit, and patients who are deemed not to be benefiting from the study treatment 
based upon safety and efficacy assessments as defined in Section 5.5.9 or for any reason of their 
own accord will be free to discontinue participation in the study at any time. 
Patients will be stratified at randomization according to the subgroup of objective signs of 
inflammation they belong to (based on their CRP and MRI status at screening). The only 
condition that will be placed on enrollment is that no less than 15% of patients should belong 
to either of the three subgroups of objective signs of inflammation: CRP+ and MRI+, CRP+ 
and MRI-, CRP- and MRI+. 
Additionally, it is planned to enroll no more than approximately 20% TNF-IR patients in the 
study. Due to the long wash out required for some TNF-IR patients, enrolment of TNF-IR 
patients will end two months prior to the projected end of screening period.   
Starting at Week 52, all patients will be assigned to receive secukinumab 150 mg s.c. in an 
open-label fashion except for those patients who discontinued blinded study treatment 
(secukinumab 150 mg or placebo) during the initial 52 weeks of the study.  
The originally randomized treatment assignment (secukinumab 150 mg or placebo) will remain 
blinded until all patients have completed the Week 52 visit. After all patients have completed 
the Treatment Period 2 (Week 52) and the Week 52 database lock has occurred, site personnel 
and patients may be unblinded to the original randomized treatment assignment at baseline. All 
patients will continue to receive secukinumab as open-label treatment up to Week 100, unless 
they have discontinued study treatment. 
Starting at Week 104, all patients who finish the core phase according to the protocol on study 
medication will be asked to continue in an additional extension phase. A new Informed Consent 
form has to be signed before proceeding into the extension phase. The patients will be assessed 
as having been Core Phase Responders (i.e., achieving ASAS20 at Week 104) or Core Phase 
Non-Responders (i.e., not achieving ASAS20 at Week 104). Core Phase Responders will be 
randomized 1:1 to continue on secukinumab 150 mg or escalated to 300 mg treatment. Core 
Phase Non-Responders will receive 300 mg treatment open-label.  


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At the end of the 16-week dose escalation treatment period, all patients will continue on their 
current treatment until the last patient has finished the 16-week dose escalation treatment period 
(i.e., continuous treatment period).  
Starting from Week 156 onward, a patient can be up-titrated to secukinumab 300 mg open-label 
based on the clinical judgment of disease activity by the investigator. The original dose of the 
extension phase will only be unblinded on an individual patient level at the end of the extension 
phase for each patient to enable continuous treatment on the same dose, if available. 
A follow-up visit is to be done 12 weeks after last administration of study treatment for all 
patients, regardless of whether they complete the entire study (either core or extension phase) 
as planned or discontinue prematurely. 
Subjects who complete the 2- year Core Phase are eligible to enter the extension phase. 
Figure 3-1 
Study design Core Phase 
 
Week
4
20
8
12
16*
24
28
32
36
40
44
48
52*
56
60
-10 to BSL
104
100
F112
Group 2: No Load
Secukinumab 150 mg s.c. 
N=185
Group 3: Placebo
Placebo s.c.
N=185
Randomization 
Secukinumab 150 mg administration s.c.
Placebo to secukinumab administration s.c.
Primary Endpoint at Week 16 (Analysis Plan A) 
and Week 52 (Analysis Plan B)
*
Escape treatment for 
inadequate responders
Secukinumab 150 mg s.c
Group 1: Load
Secukinumab 150 mg s.c. 
N=185


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Figure 3-2 
Study design Extension Phase 
 
3.2 
Rationale of study design 
This phase III trial utilizes a double-blind, randomized, placebo-controlled design with two 
different loading regimens. The treatment duration of the placebo group will be 52 weeks. 
Starting at Week 20, all patients who are repeatedly (e.g. two or more consecutive visits) 
considered to be inadequate responders based on the clinical judgment of disease activity by 
the investigator and /or the patient will receive secukinumab 150 mg s.c. or can switch to 
standard of care after observing the required wash out period as described in Section 5.5.6. This 
is in compliance with the EMA/EMEA (European Medicines Agency) guidelines for AS (EMA 
2009), considered relevant for trials in nr-axSpA and in line with guidance provided by the 
FDA. All other patients will continue their original randomly assigned treatment. From Week 
52 on, all patients will receive secukinumab 150 mg every 4 weeks up to Week 100 unless they 
have discontinued study treatment.  
All patients can join the extension phase upon completing the core phase of the study. During 
the first 16 weeks of the extension phase, it will be assessed if a higher dose of treatment 
(secukinumab 300 mg) will provide further benefit to patients. The 300 mg dose is an approved 
dose for secukinumab in psoriasis as well as psoriatic arthritis. At the end of the 16-week 
randomized escalation treatment phase, the patients will continue on their current treatment for 
a maximum duration of an additional 2 years after the end of the core phase. However, the study 
will end once the last patient has finished the 16-week dose escalation treatment phase.  
After the first year of the extension phase, the study medication can be escalated to 300 mg s.c. 
every 4 weeks open-label for patients whose overall therapeutic response is not fully achieved 
with the current dose and may improve with a higher dose, as judged by the investigator. The 
decision to escalate the study medication may be determined at any site visit after the first year 
of the extension phase. For patients escalated to 300 mg open-label, no dose reduction can be 
performed at a later time point. 


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Regular assessments of disease activity ensure that patients who are experiencing worsening of 
disease in any of the treatment groups can be discontinued from the study as described in 
Section 5.5.9.1. Data up to 216 weeks (204 weeks of treatment plus 12 weeks of safety follow-
up) is being generated to evaluate the safety and the duration of response in this population. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dosing regimen in this study is based upon dose-efficacy relationships observed in a proof 
of concept (PoC) trial (CAIN457A2209) and two phase III trials (CAIN457F2305, 
CAIN457F2310) in AS. The Phase III trials in AS, CAIN457F2305 and CAIN457F2310, 
assessed the efficacy of both 75 mg and 150 mg s.c. maintenance doses with loading regimens 
consisting of either intravenous doses (CAIN457F2305: 3 doses of 10 mg/kg given every 2 
weeks at BSL, Weeks 2 and 4) or subcutaneous doses (CAIN457F2310: 4 weekly doses 
matching the maintenance dose of either 75 mg or 150 mg given at BSL, Weeks 1, 2, and 3). 
Given the similarity of the ASAS20 and ASAS 40 response at the Week 16 primary endpoint 
for the 150 mg dose in each of these studies, regardless of whether the loading dosing was i.v. 
(CAIN457F2305: 60.8% for IV-150 mg vs 28.7% for placebo for ASAS20 and 41.6% for IV-
150 mg vs 13.1% for placebo for ASAS 40) or s.c. (CAIN457F2310: 61.1% for SC-150 mg vs 
27.0% for placebo for ASAS20 and 36.1% for SC-150 mg vs 10.8% for placebo for ASAS 40), 
secukinumab 150 mg s.c. is a sufficient dose to provide clinically and statistically significant 
efficacy, whereas higher loading doses of secukinumab do not appear to confer greater efficacy 
in AS. Of note, the 75 mg s.c. loading and maintenance regimen tested in CAIN457F2310 did 
not achieve statistically significant improvements in any of the efficacy endpoints tested in a 
pre-defined testing hierarchy, including ASAS20, ASAS 40, hsCRP, ASAS5/6, BASDAI, SF-
36 PCS and ASQoL. Therefore, there are currently no plans to further pursue the 75 mg dose 
in future studies. Furthermore, a meta-analysis of trials examining TNF-α inhibitors, 
demonstrated that nr-axSpA patients respond similarly well to biologic anti-TNF treatments as 
AS patients (Callhoff et al 2014). There was no evidence that different axSpA populations (e.g. 
AS and nr-axSpA) could require different dose regimens (Callhoff et al 2014, Landewe et al 
2014). As other phase III trials of TNF-α inhibitors in nr-axSpA also evaluated dosages that 
already proved to be efficacious in AS, this trial will use the secukinumab dose of 150 mg s.c. 
In addition to evaluating the 150 mg s.c. loading and maintenance regimen for efficacy 
compared with placebo, this study will also assess the impact of the s.c. loading regimen itself 
on efficacy by including a treatment arm of 150 mg maintenance dosing without a s.c. loading 
regimen. Thus, the loading regimen (150 mg Load) will assess initial weekly administration of 
150 mg for 4 weeks (BSL, Weeks 1, 2, and 3) followed by maintenance dosing every 4 weeks 
at the same dose starting at Week 4, whereas the No Load regimen will assess dosing of 150 
mg given every 4 weeks from BSL onward, with placebo dosing given during the loading phase 
to mask the two active treatment regimens. Both secukinumab regimens will be compared to a 
placebo arm whose dosing simulates the loading regimen, in order to blind placebo treatment 
compared to either active treatment arm.  
Notably, 300 mg s.c. administered monthly is an approved dose for secukinumab in both 
psoriasis and in PsA, and the safety profile for 300 mg s.c. every 4 weeks is comparable to 150 
mg s.c. every 4 weeks (Langley et al, 2014, McInnes et al, 2015). The higher dose of 


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secukinumab confers an additional benefit in other disease conditions (e.g., psoriasis and PsA). 
This study will evaluate whether a higher dose of secukinumab will have an effect on subjects 
with nr-axSpA with respect to treatment response. The dose escalation will be done in a 
randomized and blinded manner for responding patients who achieve an ASAS20 response at 
the end of the core phase, whereas non-responders will all be escalated during the extension 
phase in open-label fashion to the 300 mg dose. This will allow an assessment of the effect of 
150 mg and 300 mg in an unbiased manner, as no study has yet assessed both 150 mg or 300 
mg s.c. in nr-axSpA. 
After the first year of randomized treatment in the extension phase, patients whose overall 
therapeutic response is not fully achieved with the current dose and may improve with a higher 
dose, as judged by the investigator, can escape to the open-label 300 mg dose. 
3.4 
Rationale for choice of comparator 
A placebo arm up to Week 52 is included in this study. Due to the nature of the disease and the 
outcome measures used (e.g., ASAS response criteria, MRI for inflammation), a placebo arm 
is necessary to obtain reliable efficacy measurements. As there is currently conflicting evidence 
as to whether biologic treatments for axSpA are able to slow down or halt the structural 
progression of the disease, there is a need to study whether secukinumab as a new treatment 
option targeting IL-17A has a positive effect on correlates of structural damage evident on MRI 
of the sacroiliac joint (SIJ) and the spine as compared to placebo. A placebo controlled period 
of one year is considered the shortest possible timeframe to assess differences in effects on signs 
of structural damage (assessed by MRI) between both treatment groups. In a similar population, 
the anti-TNF α agent etanercept failed to show a reduction or a stop in progression of fatty 
lesions over 1 year of treatment compared to sulfasalazine (Song et al 2011). The continuation 
of the placebo group up to Week 52 can be supported from an ethical standpoint, as patients 
continue their treatment with NSAIDs and other concomitant treatments including MTX and 
sulfasalazine. If the patient or investigator feels the level of disease activity requires an 
escalation in therapy, background medications such as NSAIDs and DMARDs may be modified 
or added after Week 16, and all patients repeatedly (e.g. two or more consecutive visits) 
considered to be not responding to treatment can be re-assigned to secukinumab 150 mg or 
standard of care from Week 20 on as described in Section 3.2. Moreover, the inclusion of a 
placebo group is in accordance with previously implemented methodology and in compliance 
with the EMA/EMEA (European Medicines Agency) guidelines for AS (EMA 2009), 
considered relevant for trials in nr-axSpA and recommended by the FDA. 
3.5 
Purpose and timing of interim analyses/design adaptations 
The first primary endpoint analysis will be performed after all patients complete the treatment 
period 1 of the study (Week 24 for analysis plan A) and again after all patients complete the 
treatment period 2 of the study (Week 52 for analysis plan B).  
Depending on health authority advice, group sequential testing, as described in the statistical 
analysis plan, might be done at the Week 24 interim analysis for the Week 52 timepoint. The 
final analysis of the core phase will be conducted after all patients complete the Week 104 study 
visit. 


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The final analysis of the treatment escalation phase will be conducted after the last patient has 
completed the 16-week dose escalation treatment period and the required follow-up period of 
12 weeks after the last study dose.  
Although unblinding will occur after the Week 24 database lock, the original randomization to 
active treatment vs placebo will continue to remain blinded to all investigators, site personnel 
and patients until all patients have completed the treatment period 2 (Week 52) and the Week 
52 database lock has occurred. If required by health authorities, a separate study team will 
conduct the 24 Week interim analysis and no access to the interim results or individual treatment 
assignments will be given to the study team conducting the ongoing trial until the Week 52 
database lock. 
3.6 
Risks and benefits 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure. 
As of July 2015, approximately 12000 subjects have been enrolled in both completed and 
ongoing studies with secukinumab, with over 9600 having received active drug at doses ranging 
from single and/or multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c. across 
various indications (including psoriasis, RA, AS, PsA, multiple sclerosis and uveitis).  
The risk profile of secukinumab in nr-axSpA is informed by the safety experience from psoriasis 
and arthritides trials. Secukinumab has been studied most extensively in psoriasis, and side 
effects seen in psoriasis patients treated with secukinumab include upper respiratory tract 
infections (nasopharyngitis, rhinitis) (very common: in more than 1 in 10 patients); oral herpes, 
rhinorrhea, diarrhea and urticaria (common: in more than 1 in 100 but fewer than 1 in 10 
patients); oral candidiasis, tinea pedis, neutropenia, and conjunctivitis (uncommon: in more 
than 1 in 1,000 but fewer than 1 in 100 patients). Additionally, worsening of Crohn’s disease, 
in some cases serious, was seen in studies of Crohn’s disease and psoriasis, in patients receiving 
secukinumab or placebo.  
In the phase III AS studies CAIN457F2305 and CAIN457F2310 in 590 patients the most 
common side effects in the 52-week dataset were upper respiratory tract infection, 
nasopharyngitis, pharyngitis and oral herpes as secukinumab treatment-related adverse events 
which generally were mild to moderate in severity and did not lead to study drug 
discontinuation. 
Immunogenicity was low with secukinumab and did not correlate with hypersensitivity-related 
adverse event or loss of efficacy in all indications studied up to date. 
From the standpoint of the overall risk benefit assessment, the current trial with secukinumab 
is justified. 
4 
Population 
The study population will consist of male and female patients (≥ 18 years old at the time of 
consent) fulfilling the ASAS classification criteria for axSpA plus an abnormal CRP and/or 


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MRI, with no radiographic evidence of changes in the sacroiliac joints that would meet the 
modified New York criteria for AS (described in Appendix 3).  
Patients included must report active disease despite current or previous NSAID, non-biologic 
DMARD, and/or anti-TNFα therapy. Patients should have been on NSAIDs at the highest 
recommended dose for at least 4 weeks in total prior to randomization with an inadequate 
response or failure to respond, or less than 4 weeks if therapy had to be withdrawn due to 
intolerance, toxicity or contraindications. Patients who have been on a TNFα inhibitor (not more 
than one) must have experienced an inadequate response to treatment given at an approved dose 
for at least 3 months prior to randomization or have been intolerant to at least one administration 
of an anti-TNFα agent. It is planned to limit the inclusion of patients that are TNF inadequate 
responders (TNF-IR) to no more than 20% of the overall randomized population. Due to the 
long wash out required for some TNF-IR patients, enrolment of TNF-IR patients will end two 
months prior to the projected end of screening period.   
The study aims to randomize approximately 555 analyzable patients worldwide. Enrollment 
will stop as soon as the target number of randomized analyzable patients is reached.  
Patients can be re-screened only once, and no study-related re-screening procedure should be 
performed prior to written re-consent by the patient. Mis-randomization occurs when a patient 
who does not meet all eligibility criteria receives a randomization number nevertheless; mis-
randomized patients will not be re-screened. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to 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-nursing female patients at least 18 years of age 
3. Diagnosis of axSpA according to ASAS axSpA criteria (Appendix 4): 
a. Inflammatory back pain for at least 6 months 
b. Onset before 45 years of age 
c. Sacroiliitis on MRI with ≥ 1 SpA feature OR HLA-B-27 positive with ≥2 SpA 
features 
4. Objective signs of inflammation at screening, evident by either 
• MRI with Sacroiliac Joint inflammation (Appendix 6) 
AND / OR 
•  hsCRP > ULN (as defined by the central lab) 
5. Active axSpA as assessed by total BASDAI ≥ 4 cm (0-10 cm) at baseline 
6. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at baseline 
7. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at baseline 
8. Patients should have been on at least 2 different NSAIDs at the highest recommended 
dose for at least 4 weeks in total prior to randomization with an inadequate response or 
failure to respond, or less if therapy had to be withdrawn due to intolerance, toxicity or 
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9. Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their axSpA therapy are required to be on a stable dose for at least 2 weeks before 
randomization 
10. 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 randomization or have been intolerant to at least one administration 
of an anti-TNFα agent 
11. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after an appropriate wash-out period prior to randomization: 
• 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) 
• 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) (s.c. route) 
• 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
• 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days  
12. Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 g/day) are allowed to continue 
their medication and must have taken it for at least 3 months and have to be on a stable 
dose for at least 4 weeks prior to randomization 
13. Patients on MTX must be on stable folic acid supplementation before randomization 
14. Patients who are on a DMARD other than MTX or sulfasalazine must discontinue the 
DMARD 4 weeks prior to randomization, except for leflunomide, which has to be 
discontinued for 8 weeks prior to randomization unless a cholestyramine washout has 
been performed 
15. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization. 
Inclusion criteria for extension phase: 
1. Written informed consent must be obtained before any assessment is performed.  
2. Patients who have completed the full study treatment period (104 weeks) in the core 
phase on study treatment. 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. 
Patients with radiographic evidence for sacroiliitis, grade  ≥ 2  bilaterally or grade ≥ 3 
unilaterally (radiological criterion according to the modified New York diagnostic 
criteria for AS; Appendix 3) as assessed by central reader 
2. 
Inability or unwillingness to undergo MRI (e.g., patients with pacemakers, aneurysm 
clips or metal fragments / foreign objects in the eyes, skin or body that are not MRI 
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3. 
Chest X-ray or MRI with evidence of ongoing infectious or malignant process, obtained 
within 3 months of screening and evaluated by a qualified physician 
4. 
Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, 
morphine) 
5. 
Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or 
IL-17 receptor 
6. 
Use of any investigational drug and/or devices within 4 weeks of randomization, or a 
period of 5 half-lives of the investigational drug, whichever is longer 
7. 
History of hypersensitivity to the study drug or its excipients or to drugs of similar 
chemical classes 
8. 
Any therapy by intra-articular injections (e.g., corticosteroid) within 4 weeks before 
randomization 
9. 
Any intramuscular corticosteroid injection within 2 weeks before randomization 
10. Patients previously treated with any biological immunomodulating agents, except those 
targeting TNFα 
11. Patients who have taken more than one anti-TNFα agent 
12. Previous treatment with any cell-depleting therapies including but not limited to anti-
CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19) 
13. 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  
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
entire study or longer if required by locally approved prescribing information (e.g. 20 
weeks in EU). Effective contraception methods include: 
• Total abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception  
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment  
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient  
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository  
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
• Placement of an intrauterine device or intrauterine system 
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 treatment. 


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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential.  
15. Active ongoing inflammatory diseases other than axSpA that might confound the 
evaluation of the benefit of secukinumab therapy, including inflammatory bowel disease 
or uveitis 
16. 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 
17. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or very poor functional 
status unable to perform self-care 
18. 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/randomization, to rule 
out lab error. 
• If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. 
19. History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum 
creatinine level exceeding 1.5 mg/dL (132.6 µmol/L) 
20. 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) 
21. Active systemic infections during the last two weeks prior to randomization (exception: 
common cold) 
22. 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 
QuantiFERON TB-Gold 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 
23. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
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24. 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) 
25. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial 
26. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
27. Inability or unwillingness to receive injections with PFS 
28. 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 
29. Donation or loss of 400 mL or more of blood within 8 weeks before dosing 
30. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization 
31. Plans for administration of live vaccines during the study period or 6 weeks prior to 
randomization  
Exclusion criteria for extension phase: 
No additional exclusion criteria apply for the extension phase 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Novartis/CRO will supply the following study treatments: 
• Investigational Treatment: 
• Secukinumab 150 mg provided in a 1 mL PFS (one PFS for 150 mg dose) 
• Reference Therapy:  
• Secukinumab placebo (Placebo) provided in a 1 mL PFS 
After the Week 24 database lock, the Sponsor will be unblinded to treatment assignment in 
order to perform the first primary efficacy analysis. Although unblinding will occur after the 
Week 24 database lock, the original randomization to active treatment vs placebo will continue 
to remain blinded to all investigators, site personnel and patients until all patients have 
completed the treatment period 2 (Week 52) and the week 52 database lock has occurred. If 
required by health authorities a separate study team will conduct the 24 week interim analysis 
and no access to the interim data will be given to the study team conducting the ongoing trial 
until Week 52. After the treatment period 2 (Week 52) has been completed for all patients and 
the Week 52 database lock has occurred, the site personnel, patients and study team directly 
involved with the conduct of the trial may be unblinded to the randomized treatment assignment 


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at baseline. From Week 52 onwards, all patients regardless of efficacy response will receive 
open-label secukinumab 150 mg s.c. unless they have discontinued study treatment. 
After the core phase of the study, patients can join the extension phase and will receive either 
double-blinded or open-label treatment consisting of two injections per treatment.  
Patients will be instructed by site staff on how to self-administer the s.c. injection using the PFS 
containing the liquid formulation of secukinumab/placebo, based on the Instructions for Use 
(IFU). The s.c. investigational drug will be administered by the patient into the appropriate 
injection site of the body under the supervision of the site staff.  
Note: The Secukinumab/Placebo PFSs are packaged in double-blinded fashion until Week 52 
when open-label treatment is started and, therefore, do not need to be prepared by the study site. 
Starting at Week 52, open-label medication will be supplied until the last dose is given at Week 
100.  
In the extension phase, the study medication will again be provided in a double-blinded fashion 
to mask the 150 mg and 300 mg doses. 
The core phase medication will be labeled as follows: 
• Double-blind Secukinumab and Placebo PFS will be labeled as AIN457 
150mg/1mL/Placebo. 
• Open-label Secukinumab PFS will be labeled as AIN457 150mg/1mL 
The extension study medication will be labeled as follows: 
• Double-blind Secukinumab and Placebo PFS will be labeled as AIN457 
150mg/1mL/Placebo. 
• Open-label Secukinumab PFS will be labeled as AIN457 150mg/1mL 
For detailed instructions on storage of the investigational treatments, please refer to 
Section 5.5.3. 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is required for this trial. 
5.2 
Treatment arms 
Patients will be assigned to one of the following three treatment arms in a 1:1:1 ratio, with 
approximately 185 analyzable patients each in the following arms: 
• Group 1: Secukinumab 150 mg Load 
• Group 2: Secukinumab 150 mg No Load 
• Group 3: Placebo 
Patients will receive study treatment at BSL, Weeks 1, 2, 3, and 4 followed by treatment every 
4 weeks through Week 100. Patients who are repeatedly (e.g. two or more consecutive visits) 
considered to be inadequate responders based on the clinical judgement of disease activity from 
Week 20 on, can receive secukinumab 150 mg s.c. or standard of care treatment as outlined in 
Section 5.5.6. In case the chosen standard of care is a TNFα inhibitor, a 12-week wash-out 
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After Week 52 database lock, all patients will receive secukinumab 150 mg s.c. in open-label 
fashion, without a loading regimen for patients switching from placebo, unless they have 
discontinued study treatment. Blinding to the original treatment assignment will be maintained 
until the treatment period 2 (Week 52) is completed by all patients. Patients will self-administer 
all secukinumab and placebo doses as described in Section 3.1 at the study site or at home, 
according to the assessment schedule in Table 6-1.  
Patients in the extension phase will be assigned to one of the following three treatment arms:  
Core Phase Responders:  
• Group 4: Secukinumab 150 mg blinded 
• Group 5: Secukinumab 300 mg blinded 
Core Phase Non-Responders:  
• Group 6: Secukinumab 300 mg open-label 
At Week 104, patients will be assessed as being Core Phase Responders or Core Phase Non-
Responders. Core Phase Responders will be randomized to treatment group 4 or 5; Core Phase 
Non-Responders will receive treatment according to group 6. Patients will self-administer all 
secukinumab and placebo doses as described in Section 3.1 at the study site or at home, 
according to the assessment schedule in Table 6-2. After the first year in the extension phase 
(Week 156), patients whose overall therapeutic response is not fully achieved with the current 
dose and may improve with a higher dose, as judged by the investigator, can escape to open-
label secukinumab 300 mg. The study will remain blinded until the randomized 16-week 
extension period for the last patient is completed and the database is locked after the completion 
of all follow-up visits.  
5.3 
Treatment assignment, randomization 
At baseline, all eligible patients will be randomized to one of the treatment arms via Interactive 
Response Technology (IRT). The investigator or delegate will contact the IRT system after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of investigational treatment 
to be dispensed to the patient.   
From Week 20 on, the patient’s responder status (responder / inadequate responder) which 
should be based on the clinical judgment of disease activity should be entered into IRT. Patients 
repeatedly (e.g. two or more consecutive visits) considered to be inadequate responders may 
receive secukinumab 150 mg or standard of care as outlined in Section 5.5.6. Starting at Week 
52, all patients will receive secukinumab 150 mg up to Week 104 with last study treatment 
administered at Week 100, unless they have discontinued study 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 patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 


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Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).  
Patients will be stratified at randomization according to the subgroup of objective signs of 
inflammation they belong to (based on their CRP and MRI status at screening). The only 
condition that will be placed on enrollment is that no less than 15% of patients should belong 
to either of the three subgroups of objective signs of inflammation: CRP+ and MRI+, CRP+ 
and MRI-, CRP- and MRI+. 
Additionally, it is planned to enroll no more than 20% TNF-IR patients in the study.   
At the beginning of the extension phase, patients will be assessed as being Core Phase 
Responders or Core Phase Non-Responders at Week 104 based on ASAS20 response. Core 
Phase Responders will be randomized via IRT. The investigator or delegate will contact the 
IRT system after confirming that the patient fulfills the inclusion criteria for the extension 
phase. The randomization number of the patient will remain the same as assigned in the core 
phase, which will be used to link the patient to a treatment arm and will specify a unique 
medication number for the first package of investigational treatment to be dispensed to the 
patient in the extension phase. Core Phase Non-Responders will be recorded in IRT as a non-
responder and will receive open-label treatment with secukinumab 300 mg s.c. 
From Week 156 onward, patients whose overall therapeutic response is not fully achieved with 
the current dose and may improve with a higher dose, as judged by the investigator, can escape 
to open-label secukinumab 300 mg. 
The randomization scheme for patients will be reviewed and approved by a member of the IQS 
Randomization Group. 
5.4 
Treatment blinding 
This is a double-blind randomized treatment trial. Although unblinding will occur after the 
Week 24 database lock, the original randomization to active treatment vs placebo will continue 
to remain blinded to all investigators, site personnel and patients until all patients have 
completed the treatment period 2 (Week 52) and the Week 52 database lock has occurred. If 
required by health authorities, a separate study team will conduct the 24 Week interim analysis 
and no access to the interim data will be given to the study team conducting the ongoing trial 
until Week 52. The blind is kept by using the following methods: (1) Randomization data are 
kept strictly confidential until the time of unblinding and will not be accessible by anyone else 
involved in the study except the bioanalyst; (2) The identity of the original randomized 
treatments administered through Week 52 will be concealed up to the Week 52 by the use of 
study treatments in the form of PFS for s.c. injection, filled with secukinumab or placebo that 
are identical in appearance during the double-blind treatment period. Analysis results for any 
interim study reports generated prior to unblinding that would reveal subject-level data will be 
kept in a secured area. 
 
 
 
 


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The hsCRP results from samples collected during the treatment period will be revealed only 
after all patients have completed the treatment period 2 (Week 52). For details regarding the 
planned Interim Analyses, refer to Section 3.5. 
The reading of MRI and X-ray will be performed in a blinded fashion by independent readers 
and post screening results will only be provided to the sites after full unblinding of the study. 
Other unblinding of original randomized treatment assignment before Week 52 will only occur 
in the case of patient emergencies (see Section 5.5.12) and at the conclusion of the study.  
The extension phase will be conducted in double-blinded fashion (for Core Phase Responders) 
and will remain blinded for the duration of each individual patient’s participation in the study. 
At the end of the extension treatment phase, which may last up to 2 years for any individual 
patient, investigators can request single-patient unblinding to support continuous treatment of 
the respective patient at their study-provided dose of secukinumab, if available.  
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified by a Subject Number which is composed of the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Subject Number will not be reused.  
Upon signing the informed consent form, the patient is assigned the next sequential number by 
the investigator. The investigator or his/her staff will contact the IRT and provide the requested 
identifying information for the patient to register them into the IRT. The site should select the 
CRF book with a matching Subject Number from the electronic data capture tool (EDC) system 
to enter data.  
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening Epoch 
Study Disposition eCRF. 
All patients will continue in the extension phase with their original subject number assigned for 
the core phase.  
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with investigational treatment in packaging of 
identical appearance. 
The investigational treatment packaging has a 2-part label. A unique randomization number is 
printed on each part of this label which corresponds to placebo or active treatment. Investigator 
staff will identify the investigational treatment package(s) to dispense to the patient by 
contacting the IRT and obtaining the medication number(s). Immediately before dispensing the 
package to the patient, investigator staff will detach the outer part of the label from the 
packaging and affix it to the source document (Drug Label Form) for that patient’s unique 
subject number.  


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After Week 52, if the patient opts for home administration (at protocol specified time points, 
see Table 6-1 and Table 6-2) the investigator will dispense, via IRT, an appropriate number of 
investigational treatment packages for home administrations. The investigator will detach the 
outer part of the label and affix it to the source documentation (Drug Label Form). Detailed 
instructions on the self-administration of the study treatment will be described in the IFU 
provided to each patient and made available to the site staff and investigator. These instructions 
should be reviewed in detail by the patient and the site personnel.  
5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designees have access. Upon receipt, all investigational treatment should be stored according 
to the instructions specified on the labels. Clinical supplies are to be dispensed only in 
accordance with the protocol. The investigator should educate the patient on how to properly 
store the study treatment if the patient is self-administering at home. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the investigational treatment but no 
information about the patient except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by the field monitor during site visits and at the completion of the trial. Patients 
will be asked to return all unused investigational treatment and packaging throughout the study 
or at the time of discontinuation of investigational treatment.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Study treatment (150 mg secukinumab and placebo) will be administered s.c. by 1 mL PFS 
throughout the study as 150 mg / 1 mL secukinumab or 1 mL placebo, respectively. 
Administration of study treatment will occur via self-injection at the study site through Week 
52. Administration of study treatment must occur after the study assessments for the visit have 
been completed. The PFS with the ready-to-use study treatment solution will be provided by 
the site staff to the patient. Detailed instructions on the self-administration of the study treatment 
will be described in the IFU for secukinumab and provided to each patient. After Week 52, 
patients will be allowed to self-administer the study treatment at home during the optional visits 
in which there are no scheduled assessments at the site (see Table 6-1 and Table 6-2 below). If 


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the patient is not comfortable self-injecting the study treatment, then the site staff or caregiver 
can administer it for the patient. 
At the BSL visit, patients will be instructed by the site staff, utilizing the IFU, on how to self-
inject using a PFS. Patients will be asked to raise any questions and then to proceed with self-
injection. At the Week 1 visit, patients will be asked to refer to the IFU and to proceed directly 
with self-injection of the study drug (i.e., no prior retraining) for the remainder of the trial. 
However, if the patient is not comfortable self-injecting the study treatment, then the site staff 
may administer it for the patient. 
All study treatment kits assigned to the patient during the study will be recorded in the IRT. 
 
The investigator should promote compliance by instructing the patient to attend the study visits 
as scheduled and by stating that compliance is necessary for the patient’s safety and the validity 
of the study. The patient 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. 
Home administration 
Up to Week 52, all doses of study treatment will be self-administered by the patient at the study 
site, after the study assessments for the visit have been completed. After Week 52, the patients 
will be allowed to self-administer the study treatment at home during the optional visits in which 
there are no scheduled site assessments. Optional site visits are included in the assessment table 
of the study (Table 6-1), between visits in which trial-related procedures are to be conducted. 
Patients will be allowed to self-administer the study treatment by PFS at home or to visit the 
site during the optional visits to self-administer study treatment under the supervision of the site 
staff. If the patient opts for home administration of study treatment and is unable or unwilling 
to self-administer the treatment via PFS, a caregiver may administer the study treatment after 
Week 52. Caregivers should be trained on the IFU prior to administering the study treatment to 
the patient. It should be recorded on the Dose Administration Record eCRF(s) whether the 
patient self-administered the study treatment at home or at the site and if a caregiver 
administered the treatment. In the extension phase of the study, the optional site visits for drug 
administration will continue to be possible, but will only be recorded in the source documents 
at the site. 
Prior to self-administration at home, patients should contact the investigator/site staff in case 
they are experiencing any AE/SAEs, or have any concerns. 
All dates and times of self-administrations by the patient during the study must be recorded on 
the Dosage Administration Record eCRF. Immediately before dispensing the package to the 
patient, site staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that patient’s unique subject number. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Study treatment interruption is also not 
permitted with the following exceptions: 


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Study treatment interruption is only permitted if, in the opinion of the investigator, a patient is 
deemed to be at a significant safety risk unless administration of investigational treatment 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, study treatment should be interrupted for 12 weeks. 
Any study treatment interruption must be recorded on the corresponding eCRF page. 
5.5.6 
Allowed treatment modifications and escape treatment 
Treatment modifications as new therapeutic interventions or a significant change to ongoing 
therapy must not be made before completion of Week 16 assessments.  
From Week 16 on, if the patient or investigator feels the level of disease activity requires an 
escalation in therapy, background medications such as NSAIDs and DMARDs may be modified 
or added to treat signs and symptoms of nr-axSpA as outlined in Section 5.5.7. All medication 
changes must be recorded in the eCRF page. 
From Week 20 on, based on the clinical judgment of disease activity by the investigator and 
the patient, patients may be considered as inadequate responders. Patients who are repeatedly 
(e.g. two or more consecutive visits) considered to be inadequate responders will have the 
option to enter escape. Upon entering “escape”, patients have the option (at investigator/patient 
discretion) to continue to receive blinded study treatment or switch to open-label locally 
applicable standard of care. Patients continuing with blinded study treatment will be assigned 
to receive secukinumab 150 mg s.c. (patients originally assigned to placebo) or continue to 
receive secukinumab 150 mg s.c. (patients originally assigned to secukinumab). While the 
standard of care will be open-label, the originally randomized treatment assignment 
(secukinumab 150 mg or placebo) will remain blinded. If the standard of care includes the use 
of a biologic such as a TNFα inhibitor, it should be prescribed in accordance with investigator 
practice and local treatment guidelines. Patients switching to a biologic therapy (e.g. anti-TNF) 
other than secukinumab must not receive any further study medication and will have to observe 
a 12 week wash out period after the last application of study treatment prior to starting any other 
biologic treatment. The earliest time point for a patient to receive a biologic as standard of care 
would thus be at Week 28. All other patients will continue their original randomly assigned 
treatment. 
From Week 156 onward, patients whose overall therapeutic response is not fully achieved 
with the current dose and may improve with a higher dose, as judged by the investigator, can 
escape to open-label secukinumab 300 mg. 
While nr-axSpA is a multifaceted disease and the assessment of responder status should be 
based on the global clinical picture and not on a single efficacy parameter; repeatedly (e.g. at 
two or more consecutive visits) not achieving a clinically meaningful improvement in the 
BASDAI of ≥ 20% or ≥ 1 unit (0 – 10 scale) (Pavy et al. 2005) may be considered as a general 
guidance for considering a patient inadequate responder to study treatment. 


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Although no patient will be restricted from receiving necessary medications for lack of benefit 
or worsening of disease, if treatment with prohibited biologics (as described in Section 5.5.8) 
occurs, patients may remain in the trial but must discontinue study treatment. Efficacy will be 
assessed in detail at every study visit, and patients who are deemed not to be benefiting from 
the study treatment based on safety and efficacy assessments (see Section 5.5.9) or for any 
reason on their own accord will be free to discontinue participation in the study at any time. 
Changes in NSAID, non-biologic DMARDs and corticosteroid concomitant therapy are 
permitted as per investigator’s and patient’s clinical judgment after all Week 16 assessments 
are completed. Please see Section 5.5.7, Section 5.5.8 and Section 5.5.9 for details. 
Any treatment modifications or new therapeutic interventions must be recorded in the 
Prior/Concomitant medications eCRF page. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was 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. 
Guidelines for the use of specific medications are provided below: 
Methotrexate 
Patients taking MTX (≤ 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 16. Any changes in dose or initiation after 
Week 16 must be recorded in the Prior/Concomitant medications eCRF page. 
Folic acid 
Patients on MTX must be taking folic acid supplementation before randomization and during 
the trial to minimize the likelihood of MTX associated toxicity.  
Sulfasalazine 
Patients taking sulfasalazine (≤ 3 g/day) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 16. Any changes in dose or initiation after 
Week 16 must be recorded in the Prior/Concomitant medications eCRF page. 
Leflunomide wash-out with cholestyramine 
In case of leflunomide treatment, a drug wash-out of 8 weeks has to be performed. However, 
another wash-out procedure might be considered. Cholestyramine could be given orally to 
wash-out the drug at a dose of 8 g t.i.d. Cholestyramine reduced plasma levels of the active 
leflunomide metabolite by approximately 40% in 24 hours and by 49 % to 65 % in 48 hours in 
three healthy volunteers. The administration of cholestyramine is recommended in patients who 
require a drug elimination procedure. If a patient receives the dose of 8 g t.i.d. for 11 days, 
he/she could be safely randomized 4 weeks after the beginning of the 11 days treatment period. 
After all Week 16 assessments are completed, leflunomide therapy may be initiated as a 
background medication. Any initiation or changes in dose after Week 16 must be recorded in 
the Prior/Concomitant medications eCRF page. 


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Systemic corticosteroids 
Treatment with systemic corticosteroids is permitted if the dose was stable within the 2 weeks 
preceding randomization, up to a maximum daily dosage of 10 mg prednisone equivalent. After 
Week 16, the dose and regimen of systemic corticosteroids may be modified as per 
investigator’s judgment and patient’s need, although the corticosteroid dose should not be 
reduced rapidly. Any change in the dose of systemic corticosteroids during the trial must be 
recorded on the corresponding eCRF page. 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 16. No single injection should exceed 40 mg of triamcinolone (or equivalent) 
and the total dose of intra-articular corticosteroid may not exceed 80 mg of triamcinolone (or 
equivalent) during any 52-week period. Injection of intra-articular steroids is not permitted 
within 8 weeks prior to Week 52. 
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 inhibitors) 
and acetaminophen/paracetamol 
Patients on regular use of NSAIDs or paracetamol/acetaminophen should be on stable dose for 
at least 2 weeks before randomization to allow inclusion in the study. 
NSAIDs, low strength opioids or paracetamol/acetaminophen PRN can be taken during the 
study; however, patients should refrain from any intake during at least the 24 hours before a 
visit with disease activity assessment. 
After the Week 16 assessments are completed, a change in the NSAID intake regimen is 
permitted. Any change of the NSAID/paracetamol/acetaminophen treatment during the trial 
should be recorded on the corresponding eCRF page. 
TNFα inhibitors 
If TNFα inhibitors are chosen as escape treatment for patients considered as inadequate 
responders, a 12 weeks wash out period has to be observed after administration of the last dose 
of blinded study treatment for safety reasons. Thus, the earliest time for the patient to receive 
the TNFα inhibitor will be at Week 28. Initiation of TNFα inhibitors must be recorded on the 
corresponding eCRF page. 
TNFα inhibitors prescribed in accordance with investigator practice, treatment guidelines or 
locally approved uses will not be considered study medication and will not be supplied by the 
sponsor. 
5.5.8 
Prohibited Treatment  
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of the washout 
period unless otherwise specified below. Treatment continuation with secukinumab at the end 
of the treatment phase is acceptable. 
Live vaccines should not be given until 12 weeks after last study treatment administration. 


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Table 5-1 
Prohibited treatment 
Prohibited treatments 
Washout period  
(before randomization) 
Etanercept* (until Week 28, if used as escape treatment) 
4 weeks 
Infliximab* (until Week 28, if used as escape treatment) 
8 weeks 
Adalimumab, golimumab, certolizumab* (until Week 28, if used as 
escape treatment) 
10 weeks 
Unstable dose of MTX or sulfasalazine 
(until Week 16) 
4 weeks 
Other DMARD (except MTX or sulfasalazine) 
(until Week 16) 
4 weeks  
Leflunomide 
(until Week 16) 
8 weeks  
Leflunomide with Cholestyramine washout 
4 weeks 
Unstable dose of NSAIDs (COX1 or COX2 inhibitors)  
(until Week 16) 
2 weeks 
Systemic corticosteroids > 10 mg prednisone equivalent** 
(until Week 16) 
2 weeks  
Intra-articular steroid injections  
(until Week 16) 
4 weeks 
Any biological immunomodulating agents, except those targeting 
TNFα* 
No prior exposure 
Any cell-depleting therapies including but not limited to anti-CD20 or 
investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-
CD3, anti-CD19) 
No prior exposure 
Any investigational treatment or participation in any interventional 
trial 
4 weeks or 5 half-lives 
(whichever is longer)  
Analgesics other than paracetamol/acetaminophen or low strength 
opioids PRN 
4 weeks 
Live vaccinations  
6 weeks 
* These agents fall under the category of biologic immunomodulators and are prohibited medications. 
Administration of these agents requires study treatment discontinuation (see Section 5.5.9). 
** See details about corticosteroid management in Section 5.5.7 
5.5.9 
Discontinuation of study treatment and premature withdrawal 
Patients may voluntarily discontinue from the study for any reason at any time. They may be 
considered discontinued if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any other reason. 
If premature discontinuation occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature discontinuation from the study and 
record this information on the appropriate Study Phase Completion eCRF.  


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Patients who discontinue study should undergo an end of treatment visit (corresponding to the 
last visit for the patient’s current period of treatment: e.g., Week 24, Week 52, Week 104, Week 
208) at 4 weeks after last study treatment and then also return after an additional 8 weeks for a 
final follow-up visit, corresponding to Week F112 or Week F216, respectively (12 weeks after 
last study treatment; see Table 6-1 and Table 6-2). The final follow-up visit should be performed 
before any new treatment other than secukinumab is initiated. Study treatment discontinuation 
must also be recorded in IRT. 
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 from the study), the 
investigator should show "due diligence" by documenting in the source documents steps taken 
to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
Patients who are prematurely discontinued from the study will not be replaced. 
5.5.9.1 
Discontinuation of study treatment 
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment would result in a significant safety risk for a patient. The following circumstances 
require study treatment discontinuation: 
• Withdrawal of informed consent 
• Emergence of the following adverse events: 
a. Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with prohibited co-
medication 
b. Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed 
c. Life-threatening infection 
d. Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the patient at a safety risk for continuation in the 
study (A general guidance on clinically notable laboratory values is provided in 
Appendix 1.) 
e. Pregnancy 
f. Use of  any biologic immunomodulating agent except secukinumab (see Section 5.5.6 
for washout periods) 
g. Any protocol deviation that results in a significant risk to the patient’s safety 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given patient if on balance, he/she thinks that continuation 
would be detrimental to the patient’s well-being. For patients who were considered inadequate 
responders as outlined in Section 5.5.6, the investigator should consider discontinuing patients 
from study treatment who experience a clinically important worsening of disease activity 
compared to baseline at two consecutive visits after inadequate responder status was confirmed. 
A clinically important worsening will be defined as a worsening of BASDAI ≥ 20% AND ≥ 1 


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unit (0-10 scale), which represents the minimum clinically important difference (Pavy et al. 
2005). 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject: 
• 
Does not want to participate in the study anymore, and 
• 
Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.  
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.  
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
For US and Japan: All biological samples not yet analyzed at the time of study withdrawal may 
still be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.  
For EU and RoW: All biological samples not yet analyzed at the time of study withdrawal will 
no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements. 
 
5.5.11 
Loss to follow-up 
For 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 trying to contact the 
patient and by documenting in the source documents steps taken to contact the patient, e.g., 
dates of telephone calls, registered letters, etc. A patient should not be formally considered lost 
to follow-up until his/her scheduled end of study visit would have occurred. 
5.5.12 
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, investigational 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 


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the IRT. When the investigator contacts the 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 fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of 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, subject number, and instructions for 
contacting the local Novartis CPO (or any entity to which it has delegated responsibility for 
emergency code breaks) to the patient in case an emergency treatment code break is  required 
at a time when the investigator and backup are unavailable. 
Study medication must be discontinued after emergency unblinding. 
In the case of accidental unblinding, patients will not be replaced by an equal number of newly 
enrolled patients. 
5.5.13 
Study completion and post-study treatment 
A patient will be considered to have completed the core phase if he/she received a maximum of 
100 weeks of study treatment and upon completion of the scheduled study assessments and 
procedures up to and including Visit F112 or continuation into the extension phase. 
A patient will be considered to have completed the extension phase if he/she has received an 
additional 16 weeks of study treatment and has completed the scheduled study assessments and 
procedures up to and including Visit F216. 
Information on the patient’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion eCRF 
page. 
In any case, the investigator or site staff must contact the IRT as soon as possible to record the 
patient’s study completion (Visit F112 for the core phase/Visit F216 for the extension phase) 
and/or discontinuation. 
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. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic DMARD. In case of a biologic treatment, 
a waiting period of 3 months before initiating the treatment is recommended. 
5.5.14 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated as a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 


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will be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
6 
Visit schedule and assessments 
Table 6-1 and Table 6-2 list all of the assessments and indicates with an “x” when the visits are 
performed. 
Patients should be seen for all visits on the designated day or as close to it as possible. 
Patients who prematurely discontinue during a specific treatment period should return for the 
final visit within that treatment period (4 weeks after the last study treatment administration), 
as well as return for the follow-up visit 12 weeks after the last study treatment administration. 
If they refuse to return for these assessments or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine the reason. 
Screening will be flexible in duration based on the time required to washout prior anti-rheumatic 
and other medications and will have a duration of up to 10 weeks, during which time the patient 
will sign the informed consent form (ICF), be evaluated for eligibility and sufficient time is 
allowed for potential medication washout, in addition to all other assessments indicated in Table 
6-1.  
Screening will consist of two consecutive visits. During Screening visit 1, initial assessments 
will be performed as outlined in Table 6-1. At that visit, the duration of the washout period will 
be determined and Screening visit 2 will be performed as follows: 
• If the washout period is ≤ 4 weeks the investigator should proceed directly to Screening 
visit 2 on the same day and complete all assessments in the next 4 weeks prior to 
randomization.  
• If the washout period is more than 4 weeks, the patient will be instructed to initiate the 
necessary washout regimen and return for Screening visit 2 at 4 weeks prior to 
randomization. 
The rationale is that in all cases Screening visit 2 must occur within the 4 weeks prior to 
randomization. 
All patients evaluated at Screening visits 1 and 2 for eligibility should not be screen failed on 
the basis of a medication requiring washout, unless the patient will be unable to complete the 
washout in the appropriate time frame before randomization 
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit, however preferably for a follow up visit F112 for the core phase/Visit F216 
for the extension phase, 12 weeks after last study treatment. Attempts to contact the patient 
should be recorded in the source documentation. 


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Table 6-1 
Assessment schedule: Core phase 
 
Screening1 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Follow 
up 
Week 
SV1     
-10 to 
-4 
SV2   
≤ -4 
BSL
1 
2 
3 
4 
8 
12 
16 
20 
24* 
28
32 
36 
40 
44 
48 
52* 
 56 & 60 
 64 
 68 & 72 
 76 
 80 & 84 
 88 
 92, 96&100 
 104* 
 F112* 
Optional site visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Inclusion/Exclusion criteria2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history/ current 
medical condition2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
nr-axSpA assessment and history 
of extra-axial involvement3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI (spine and sacroiliac joints)  
X11 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X-Ray of sacroiliac joints 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cardiovascular medical history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
S 
 
S 
 
S 
 
S 
S 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening1 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Follow 
up 
Week 
SV1     
-10 to 
-4 
SV2   
≤ -4 
BSL
1 
2 
3 
4 
8 
12 
16 
20 
24* 
28
32 
36 
40 
44 
48 
52* 
 56 & 60 
 64 
 68 & 72 
 76 
 80 & 84 
 88 
 92, 96&100 
 104* 
 F112* 
Weight 
 
X 
X 
 
 
 
 
  
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
PPD skin test5 or QuantiFERON 
TB-Gold test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or MRI6 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, blood chemistry, 
urinalysis 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B, C or HIV serology 
(only in countries where 
required)** 
 
S 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
X 
 
  
X  
 
X  
X  
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
ECG 
 
 
X 
 
 
 
 
  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Randomization via IRT 
 
 
X 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Responder assessment via IRT 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X  
 
 
 
 
 
On-site administration of s.c. 
study treatment by PFS7 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
X 
X7 
X 
X7 
X 
X7 
 
 
Concomitant medication / non-
drug therapy 
X 
Updated as necessary 


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Screening1 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Follow 
up 
Week 
SV1     
-10 to 
-4 
SV2   
≤ -4 
BSL
1 
2 
3 
4 
8 
12 
16 
20 
24* 
28
32 
36 
40 
44 
48 
52* 
 56 & 60 
 64 
 68 & 72 
 76 
 80 & 84 
 88 
 92, 96&100 
 104* 
 F112* 
Adverse events/SAEs (including 
injection site reactions)8 
X 
Update as necessary 
Patient’s global assessment of 
disease activity (VAS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Patient’s assessment of back pain 
intensity (VAS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
BASFI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
BASDAI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
ASQoL 
 
 
X 
 
  
 
X 
 
X  
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
SF-36 v2 
 
 
X 
 
  
 
X 
 
X  
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 


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Screening1 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Follow 
up 
Week 
SV1     
-10 to 
-4 
SV2   
≤ -4 
BSL
1 
2 
3 
4 
8 
12 
16 
20 
24* 
28
32 
36 
40 
44 
48 
52* 
 56 & 60 
 64 
 68 & 72 
 76 
 80 & 84 
 88 
 92, 96&100 
 104* 
 F112* 
High sensitivity C-Reactive 
protein (hsCRP) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
HLA-B27 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipids9 
 
 
X 
 
 
  
X  
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Treatment period 1 completion 
form 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment period 2 completion 
form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Treatment period 3 completion 
form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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S Source data only 
1 If the patient’s washout period ≤ 4 weeks, Screening visit 1 (SV1) and Screening visit 2 (SV2) can be performed on the same day.  
2 Eligibility and relevant medical history assessments are conducted at SV1, SV2 and BSL. The data for all three visits should be recorded on the 
corresponding eCRF available at SV1 
3 Extra-axial involvement such as uveitis, psoriasis, inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis 
4 Unless X-ray according to the imaging criteria was taken within the past 3 months prior Screening  
5 The PPD skin test can be performed at any time during the screening period, but it must be read within 72 hours and before randomization. 
6 A chest X-ray or MRI is required if it was not performed and evaluated within 3 months prior to screening. The X-ray should be performed after it is 
certain the patient meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The X-ray may be replaced by an MRI 
assessment. 
7 After Week 52, patients able to self-administer can do so at home and don’t have to attend the site at these specified visits 
8 AEs/SAEs occurring after the patient has signed the informed consent must be captured on the appropriate eCRF page. 
9 Sample must be obtained fasting. 
 
11Unless MRI according to the imaging criteria was taken within the past 3 months prior to targeted Baseline 
* For all patients who discontinue the study prematurely, the investigator should ensure that the patient completes an end of treatment visit (corresponds 
to the last visit for the patient’s current treatment period) 4 weeks after last study treatment to complete assessments shown for Week 104, and also 
returns after an additional 8 weeks for a final follow-up visit, F112 (12 weeks after last study treatment). The final visit should be performed before any 
new treatment other than secukinumab is initiated.  
All patients that continue into the extension phase will have their first extension phase visit at the last treatment period visit of the core phase (week 104) 
and will skip the follow-up visit F112. 
** Hepatitis B and/or hepatitis C and/or HIV serology testing to be performed during screening period only if required as per local medical practice or local 
regulations prior to initiation of therapy. These assessments will be documented in source records only and will not be entered into the eCRF 
 


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Table 6-2 
Assessment schedule: Extension phase 
Period /Visit name 
16-week dose escalation treatment 
period 
Continuous treatment period14 
EoT
* 
Follow 
up* 
Week 
10412 
108 
112 
116 
120 
124/128/132 
136 
140/144/148 
152 
156/160/164 
168 
172/176/180 
184 
188/192/196 
200 
204 
208 
216 
Optional site visit 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Obtain informed consent13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Randomization in IRT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient’s global assessment of 
disease activity (VAS) 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Patient’s assessment of back pain 
intensity (VAS) 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
BASFI 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
BASDAI 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
ASQoL 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
SF-36 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 


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Period /Visit name 
16-week dose escalation treatment 
period 
Continuous treatment period14 
EoT
* 
Follow 
up* 
Week 
10412 
108 
112 
116 
120 
124/128/132 
136 
140/144/148 
152 
156/160/164 
168 
172/176/180 
184 
188/192/196 
200 
204 
208 
216 
High sensitivity C-Reactive 
Protein (hsCRP) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hematology, blood chemistry, 
urinalysis 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Serum pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Urine pregnancy test 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
On-site administration of s.c. 
study treatment by PFS15 
X 
X15 
X 
X15 
X 
X15 
X 
X15 
X 
X15 
X 
X15 
X 
X15 
X 
X15 
 
 
Concomitant medication / non-
drug therapy 
X 
Update as necessary 
Adverse events/SAEs (including 
injection site reactions)8 
X 
Update as necessary 
8 AEs/SAEs occurring after the patient has signed the informed consent must be captured on the appropriate eCRF page. 
12 The Week 104 visit of the core phase will be the first visit in the extension phase  
13  Patients have to sign a new ICF for participation in the extension phase 
14 Depending on the timing for each patient, some of these visits might not be conducted and the patient will go directly to the EoT (End of Treatment) 
visit 
15 Patients able to self-administer can do so at home and don’t have to come to the site at these specified visits 
* For all patients who discontinue the study prematurely, the investigator should ensure that the patient completes an end of treatment visit Week 208, 4 
weeks after last study treatment to complete assessments shown for Week 208, and also returns after an additional 8 weeks for a final follow-up visit, 
F216 (12 weeks after last study treatment). The final visit should be performed before any new treatment other than secukinumab is initiated. 
 


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6.1 
Information to be collected on screening failures 
Patients may discontinue from the study prior to randomization. These patients are considered 
screening failures.  
If a patient discontinues before entering the double-blind treatment period at baseline, IRT must 
be notified within 2 days and the reason for not being randomized will be entered on the 
Screening Phase Disposition eCRF page. In addition, only the following eCRFs should be 
completed: Demography eCRF, Informed Consent eCRF, Inclusion/Exclusion eCRF, and the 
Adverse event (AE) eCRF should be completed for any Serious Adverse Events (SAEs) that 
occurred during the screening period. Adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data. 
All patients who have signed informed consent and are randomized into the Treatment period 
1 of the study will have all adverse events occurring after informed consent is signed 
recorded on the Adverse Event eCRF and as SAE if applicable, i.e. when SAE criteria are met. 
Investigators will have the discretion to record abnormal test findings on the medical history 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristics data to be collected on all patients and to be 
recorded in the eCRF include: 
• Date of birth, age, sex, race, ethnicity and source of patient referral 
• Relevant nr-axSpA and general medical history/current medical condition data until the 
start of study treatment, history of extra-axial involvement (uveitis, psoriasis, 
inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis), date of onset of 
inflammatory back pain, number of previous DMARDs used, date of diagnosis of nr-
axSpA, previous nr-axSpA therapies, cardiovascular medical history and smoking history 
Whenever possible, diagnoses and not symptoms will be recorded here. 
6.3 
Treatment exposure and compliance 
All dates and times of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page. 
Drugs administered prior to start of treatment and other drugs continuing or started during the 
study treatment period will be entered in the Prior/Concomitant medications or Significant non-
drug therapies eCRF page.  
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in Section 5.5.5. Compliance will also be assessed by a Novartis/CRO monitor 
using information provided by the authorized site personnel. 
6.4 
Efficacy 
• Assessment of SpondyloArthritis International Society criteria (ASAS) 


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•
Patient’s global assessment of disease activity (VAS)
•
Patient’s assessment of back pain intensity (VAS)
•
Bath Ankylosing Spondylitis Functional Index (BASFI)
•
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
•
hsCRP 
•
, ASDAS-CRP 
 response categories
•
MRI of spine and sacroiliac joints
•
X-ray of the sacroiliac joints
6.4.1 
Assessment of SpondyloArthritis International Society criteria (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper et al 2009). 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores,
both measured on a VAS scale
3. Function represented by BASFI average of 10 questions regarding ability to perform
specific tasks as measured by VAS scale
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 VAS
scale
Additional assessment domains: 
5. Spinal mobility represented by the BASMI lateral spinal flexion assessment
6. C-reactive protein (acute phase reactant)
6.4.1.1 
ASAS Response Criteria-20% (ASAS20) 
ASAS20 response is defined as an improvement of ≥20% and ≥1 unit on a scale of 10 in at least 
three of the four main domains and no worsening of ≥20% and ≥1 unit on a scale of 10 in the 
remaining domain. 
6.4.1.2 
ASAS Response Criteria-40% (ASAS 40) 
ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at 
least three of the four main domains and no worsening at all in the remaining domain. 
6.4.1.3 
ASAS 5/6 improvement criteria 
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six 
domains. 


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6.4.1.4 
ASAS partial remission criteria 
The ASAS partial remission criteria are defined as a value not above 2 units in each of the four 
main domains on a scale of 10. 
6.4.2 
Patient’s global assessment of disease activity (VAS) 
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question, "How active was 
your disease on average during the last week?”  
6.4.3 
Patient’s assessment of back pain intensity (VAS) 
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from no 
pain to unbearable pain, after the question “Based on your assessment, please indicate what is 
the amount of back pain at any time that you experienced during the last week?” and “Based 
on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?” 
6.4.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. The ten questions were chosen with major input from patients with AS. 
The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the patients’ ability to cope with everyday life. A 0 through 10 scale (captured by a 
continuous VAS) is used to answer the questions. The mean of the ten scales gives the BASFI 
score – a value between 0 and 10. 
6.4.5 
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 as a continuous VAS), 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 duration  
6. Morning stiffness severity  
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken (questions 5 and 6). The resulting 0 to 10 score 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 patients with scores of 
4 or greater are usually good candidates for either a change in their medical therapy or for 
enrollment in clinical trials evaluating new drug therapies directed at AS. BASDAI is a quick 
and simple index taking between 30 seconds and 2 minutes to complete. 


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6.4.5.1 
BASDAI 50 
The BASDAI 50 is defined as an improvement of at least 50% in the BASDAI compared to 
baseline.  
6.4.8 
High sensitivity C-reactive protein (hsCRP) 
This assessment will be performed in order to identify the presence of inflammation, to 
determine its severity, and to monitor response to treatment. 
Since the results of this test may unblind study personnel, results from the central lab will be 
provided for screening and baseline only. The hsCRP results from samples collected during the 
treatment period will be revealed following database lock only. 
6.4.10 
 ASDAS-CRP 
 response categories 
The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess 
disease activity in AS.  


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The 
 ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) will be 
utilized to assess the disease activity status. Parameters used for the ASDAS include spinal pain 
(BASDAI question 2), the patient 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 et al 2009, 
Lukas et al 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 < 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 “minimal clinically 
important improvement” and a change ≥ 2.0 units for “major improvement” (Machado et al 
2011). 
6.4.12 
MRI 
MRIs will be obtained as defined in the schedule of assessments (Table 6-1) and according to 
the imaging acquisition guidelines provided by the central imaging lab. The MRI for each 


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patient will include T1 and STIR sequences of the sagittal spine (cervical, thoracic and lumbar) 
and oblique coronal of the pelvis including both sacroiliac joints. These MRI images should be 
transferred as anonymized electronic files to the central imaging lab following acquisition. The 
central imaging lab will conduct independent review for all spine and sacroiliac MR imaging 
in this trial. 
6.4.13 
X-ray 
X-rays will be obtained as defined in the schedule of assessments (Table 6-1) and according to 
the imaging acquisition guidelines provided by the central imaging lab. The X-ray requirements 
include
 
anterio-posterior view of the pelvis including 
visibility of both sacroiliac joints for modified New York AS determination. These images 
should be transferred to the central imaging lab following acquisition. Some X-rays may need 
to be repeated if deemed unevaluable by central review. In case of insufficient quality, the center 
will be advised and trained on any quality issues prior to the repeat X-ray, to keep any repeat 
X-rays to a minimum.  
The central imaging lab will conduct independent review for all spine and sacroiliac X-rays in 
this trial. 
6.4.14 
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are the standard measures used across all AS 
and nr-axSpA trials and are considered to be required for filing. 
This study involves exposure to radiation from a possible chest X-ray, as well as X-rays of part 
of the thoracic, the cervical and lumbar spine and the SIJs. The radiation exposure from these 
procedures is not necessary for medical care but is intended for research purposes only. 
The amount of cumulative annual radiation in this study is about 3.4 mSv for the combined X-
ray procedures and is based on effective doses for various diagnostic radiological procedures 
reported in literature (Mettler et al 2008). This exposure is comparable to the natural radiation 
an average person receives in one year. The radiation dose between 3 mSv and 50 mSv is 
considered ‘minimal’ (Stabin et al 2009). Therefore, the radiation exposure in this study 
involves minimal risk and is necessary to obtain the research information desired. 
6.5 
Safety 
• QuantiFERON TB-Gold test or PPD skin test 
• Chest X-ray or MRI 
• Physical examination 
• Vital signs 
• Height and weight 
• Laboratory evaluations 
 
 
• Electrocardiogram 
• Pregnancy and assessment of fertility 


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• Local tolerability (Injection site reactions) 
• Tolerability of secukinumab 
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. 
6.5.1 
QuantiFERON TB-Gold test or PPD skin test 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at screening. 
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, or if presence of latent tuberculosis is established then treatment according to local 
guidelines must have been initiated. 
QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test is to be performed at the second screening visit and the results 
to be available prior to randomization to determine the patient’s eligibility. The test will be used 
to screen the patient population for latent tuberculosis infection.  
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
PPD skin test 
A PPD skin test is to be performed at screening and read before randomization to determine the 
patient’s eligibility for the trial. The test dose is bioequivalent to 5 tuberculin units of standard 
PPD injected intradermally, usually into the volar surface of the forearm. The site is cleaned 
and the PPD extract is then injected into the most superficial layer under the skin. If given 
correctly, the injection should raise a small wheal of about 5 mm, which resolves within 10-15 
minutes. 
Since the reaction (induration) will take 48-72 hours to develop, the patients must return to the 
investigators’ site within that time for a proper evaluation of the injection site. This will 
determine whether the patient has had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration ≥5 mm 
(or according to local practice/guidelines) is interpreted as a positive result. 
6.5.2 
Chest X-ray or MRI 
A chest X-ray or MRI 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. 
6.5.3 
Physical examination 
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. 


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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 that meet the 
definition of an AE must be recorded in the Adverse Event eCRF and if SAE criteria are met, 
also reported as a SAE.  
6.5.4 
Vital signs 
This will include blood pressure and pulse rate measurements after 5 minutes rest in sitting 
position. 
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study. 
6.5.5 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing) 
(both without shoes) will be measured. 
If possible, body weight assessments should be performed by the same study site staff member 
using the same scale throughout the study. 
6.5.6 
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 Appendix 1. 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. 
6.5.6.1 
Hematology 
Hemoglobin, platelet, red blood cell, white blood cell (WBC) and differential white blood cell 
counts will be measured at scheduled visits.  
6.5.6.2 
Clinical chemistry 
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorus, 
total protein, albumin, and uric acid. 
6.5.6.3 
Lipid panel 
A lipid profile including High Density Lipoprotein, Low Density Lipoprotein, cholesterol and 
triglycerides will be measured from a fasting blood sample. 
A cardiovascular profile including lipoprotein (a), apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be measured from a fasting blood sample. 


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6.5.6.4 
Urinalysis 
Dipsticks will be provided by the central laboratory to the sites for local urinalysis assessments. 
The urinalysis results for standard parameters such as protein, glucose, blood and WBCs will 
be recorded in the appropriate eCRF page. 
 
 
 
  
 
 
 
 
6.5.8 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as indicated in Table 6-1.  
All ECGs must be performed on the ECG machines provided for the study. 
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual. 
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 
(Section 7.1). 
6.5.9 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed at the second screening visit and local urine pregnancy tests as 
indicated in Table 6-1 and Table 6-2. A positive urine pregnancy test requires immediate 
interruption of study drug until serum β-hCG is performed and found to be negative. 


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6.5.10 
Local tolerability (Injection site reactions) 
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 Adverse Events eCRF, including the 
severity (mild, moderate, severe) and the duration. 
6.5.11 
Tolerability of secukinumab 
Tolerability will be assessed by adverse events, laboratory values, injection site reaction 
 
 
6.5.12 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
The safety measures used in this study are reliable and relevant standard measures for a biologic 
in nr-axSpA.  
The safety assessments selected are standard and adequate for this indication/patient population. 
6.6 
Other assessments 
• Health-related Quality of Life 
• 
 
• HLA-B27 
• 
 
• 
 
• 
 
6.6.1 
Health-related Quality of Life and Patient Reported Outcome 
The impact of nr-axSpA on various aspects of patient's health-related quality of life (QoL) will 
be assessed by the following instruments: 
• SF-36 
• ASQoL 
 
 
 
 
 
 
All questionnaires will be available, where possible, in the local languages of the participating 
countries. 
All questionnaires will be completed at the scheduled study visit prior to the patient seeing the 
investigator for any other clinical assessment or evaluation. The patient should be given 
sufficient instruction, space, time and privacy to complete the questionnaires. The study 
coordinator should check each questionnaire for completeness and encourage the patient to 
complete any missing responses. Guidelines for administering the PRO questionnaires can be 


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found in Appendix 8. A detailed training manual relating to the administrative procedures of 
the questionnaires will be provided to the sites. 
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires but also for any unsolicited comments written by the patient. If AEs or SAEs are 
confirmed, then the physician must record the events as per instructions given in Appendix 8 of 
the protocol. Investigators should not encourage the patients to change the responses reported 
in the completed questionnaires. 
The language in which each of the questionnaires to be completed will also be captured the first 
time a questionnaire is administered. 
6.6.1.1 
Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute 
Form) 
The SF-36 is a widely used and extensively studied instrument to measure health-related quality 
of life among healthy patients and patients with acute and chronic conditions. It consists of eight 
subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, 
General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health (Ware and 
Sherbourne 1992). Two overall summary scores, the Physical Component Summary and the 
Mental Component Summary also can be computed (McHorney et al 1993). The SF-36 has 
proven useful in monitoring general and specific populations, comparing the relative burden of 
different disease, differentiating the health benefits produced by different treatments, and in 
screening individual patients. 
The purpose of the SF-36 in this study is to assess the health-related QoL of patients. Given the 
acute nature of this disease, version 2, with a 1-week recall period, will be used in this study.  
The use of the SF-36, especially the SF-36 physical component summary (PCS), in patients 
with nr-axSpA can be supported. While SF-36 was widely used to assess the health related 
quality of life in AS patients, a recent study investigated the questionnaire in both, AS and nr-
axSpA patients, within one trial. Specifically for the SF-36 PCS which will be included as a 
secondary objective in this trial, van Tubergen et al. 2015 found good test-retest reliability, good 
construct and known-groups validity as well as good correlations with clinical outcomes in nr-
axSpA. 
6.6.1.2 
Ankylosing Spondylitis Quality of Life (ASQoL) 
The ASQoL is a self-administered questionnaire designed to assess health-related quality of life 
in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a 
dichotomous yes/no response option. A single point is assigned for each "yes" response and no 
points for each "no" response resulting in overall scores that range from 0 (least severity) to 18 
(highest severity). As such, lower score indicate better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment," and the measure requires approximately 6 minutes to complete. 
The purpose of the ASQoL is to assess the disease specific QoL of patients in this study.  


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6.6.3 
HLA-B27 
A blood sample to analyze Human Leukocyte Antigen-B27 (HLA-B27) will be obtained from 
all patients at screening. 
Details on the collection, handling and shipment of the sample to the central laboratory will be 
provided to investigators in the laboratory manual. 


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7 
Safety monitoring 
7.1 
Adverse events 
An AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory 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,  


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• 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. Alert ranges for labs and other test abnormalities are 
included in Appendix 1. 
Adverse events should be recorded in the AE eCRF under the signs, symptoms, or diagnosis 
associated with them, accompanied by the following information. 
• the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study treatment (no/yes) 
• its duration (start and end dates), or if the event is ongoing, an outcome of not 
recovered/not resolved should be reported. 
• whether it constitutes a serious adverse event (SAE) 
• action taken regarding study treatment 
• whether other medication or therapies have been taken (concomitant medication/non- drug 
therapy) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
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 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. 


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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  
• 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 
• 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 eCRF, SAEs also require individual 
reporting to Drug Safety and Epidemiology (DS&E) as per Section 7.2.2. 


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7.2.2 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks after last administered dose of study treatment 
must be reported to Novartis/CRO within 24 hours of learning of its occurrence. 
Any SAEs experienced after this period should only be reported to Novartis/CRO if the 
investigator suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
Information about all SAEs (either initial or follow-up information) is collected and recorded 
in English on the paper Serious Adverse Event Report Form or the electronic Serious Adverse 
Event Form within the EDC system (where available). The Investigator must assess the 
relationship to each specific component of the study treatment (if the study treatment consists 
of several components). 
SAEs (initial and follow-up) that are recorded on the paper SAE form should be faxed within 
24 hours of awareness of the SAE to the local Novartis/CRO Drug Safety and Epidemiology 
Department. The telephone and fax number of the contact persons in the local department of 
DS&E, specific to the site, are listed in the investigator folder provided to each site. The original 
copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. Follow-up information should be provided using a new 
paper SAE Report Form stating that this is a follow-up to a previously reported SAE. 
SAEs (initial and follow-up) that are recorded electronically in the EDC system should be 
submitted within 24 hours of awareness of the SAE or changes to an existing SAE. 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 provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the patient 
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the investigational treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for Health 
Authority reporting. Novartis/CRO may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same investigational treatment that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
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7.3 
Liver safety monitoring 
There has been no safety signal for liver toxicity with secukinumab to date in over 9600 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 Appendix 1. 
7.4 
Renal safety monitoring 
There has been no safety signal for nephrotoxicity with secukinumab to date in over 9600 
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 patients with laboratory tests containing 
clinically significant abnormal values (see Appendix 1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined. Standard renal function tests (blood urea nitrogen, serum creatinine) will 
be obtained at regular intervals, but special measures for renal safety monitoring are not 
planned. 
7.5 
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 in a patient on study drug must be reported to 
Novartis/CRO 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. The study drug must be discontinued, though the patient may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during pregnancy 
must not be performed. The patient may continue all other protocol assessments. 
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis/CRO 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 Novartis/CRO study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
8 
Data review and database management 
The study originally used two data collection systems, eSource and OC/RDC. The systems were 
chosen according to the countries and only one system was in place in each site. Due to the 
discontinuation of the eSource system, all sites using eSource will switch to OC/RDC and this 
will be the only data capture system in the study moving forward. All collected data from 
eSource will be provided to the sites for documentation and will be included in OC/RDC. 


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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 data capture tools 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 eCRFs, the adherence 
to the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis Clinical Teams to assist 
with trial oversight. 
The investigator must maintain source documents for each 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 in the eCRF must be traceable to the source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source records.  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.  No information in source documents about the identity of the patients will 
be disclosed.  
8.2 
Data collection 
This study originally incorporated technology (eSource) to capture source documents and 
source data electronically, consistent with FDA guidance (CDER 2013) regarding electronic 
source and regulations related to the maintenance of adequate patient case histories (21CFR 
312.62 (b)), but this was discontinued during the conduct of the study.   
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the 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 
Novartis/CRO staff 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 


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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.  
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 
Novartis /CRO. 
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis/CRO. 
Randomization codes and data about all study drug(s) dispensed to the patient will be tracked 
using an IRT. The system will be supplied by a vendor, who will also manage the database. The 
database will be sent electronically to Novartis /CRO. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis.  
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 
changes to the database after that time can only be made after written agreement by Novartis 
Development management. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
An independent adjudication committee may be used to monitor specific safety events, 
including, but potentially not limited to clinically significant cardio- and cerebrovascular 
events. The events will be blindly reviewed and adjudicated as they occur during the conduct 
of the trial as applicable. 
Details regarding the adjudication process will be available in the relevant secukinumab 
Adjudication Committee charter. 


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9 
Data analysis 
Summary statistics for continuous variables will generally include the number of patients (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of patients in each category will be presented. P-values 
presented will be two-sided unless otherwise specified. 
Data analyses will be presented by treatment group. Efficacy and safety data for Treatment 
Period 1 and Treatment Period 2 will be presented by the following three treatment groups. 
Patients may be included in more than one treatment group for some analyses (e.g., exposure-
adjusted adverse events over the entire treatment period). 
• Secukinumab 150 mg with loading regimen 
• Secukinumab 150 mg with no loading regimen 
• Placebo 
Note that the treatment groups above for a patient may differ depending on the time period of 
the analysis and whether one assesses the patient for efficacy or safety (see Section 9.1 for 
details). Data may be presented by a combination of the ‘original’ and ‘switch’ treatment 
groups. These treatment groups represent the treatment combinations the patients experience 
over the course of the entire trial (e.g., placebo patients who are reassigned to 150 mg 
secukinumab). 
9.1 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all patients who were randomized. 
Unless otherwise specified, mis-randomized patients (mis-randomized in IRT) will be excluded 
from the randomized set.  
Full analysis set (FAS): The FAS will be comprised of all analyzable patients from the 
randomized set to whom study treatment has been assigned. Following the intent-to-treat 
principle, patients will be evaluated according to the treatment assigned to at randomization, 
but actual stratum. 
Safety set: The safety set includes all patients who took at least one dose of study treatment 
during the treatment period. Patients will be evaluated according to treatment received. 
9.2 
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics 
The following common background and demographic variables will be summarized:  
• Gender, age, race, ethnicity, weight, height, and BMI. 
Baseline disease characteristics will also be summarized for the following variables: 
• Patient’s global assessment of disease activity and other ASAS components, hsCRP (mg/L 
and >ULN), 
 prior use (yes/no) of TNF-alpha inhibitors, use (yes/no) and 
separate dose of MTX (mg/week), sulfasalazine (g/day) and systemic corticosteroids 
(mg/day) at randomization, time since first diagnosis of inflammatory back pain and nr-


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axSpA (years), modified New York criteria for AS, HLA-B27, 
 total back pain 
(VAS), nocturnal back pain (VAS), total BASDAI score, spinal pain (BASDAI question 
#2) and BASMI components (all seven in original units), presence of SIJ inflammation by 
MRI and each randomization strata level (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+). 
Medical history 
A history of nr-axSpA with focus on previous extra-articular involvement and past therapies 
for nr-axSpA will be obtained and summarized by treatment group. Any other significant prior 
or active medical condition at the time of signing informed consent will be recorded and coded 
using the MedDRA dictionary. These medical conditions will be summarized by primary 
system organ class and preferred term. 
To establish a baseline level of cardiovascular risk, the number and percentage of patients with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each patient has will also be summarized by treatment group. 
If it is unknown whether or not a patient currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not occur for 
that patient. 
9.3 
Treatments 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of visits with 
active and placebo injections received will be presented by treatment group.  
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g., any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented. 
Prior and concomitant medication 
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment 
and within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of patients receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term. 
The number and percentage of patients receiving prior and concomitant nr-axSpA therapy will 
be presented by treatment group as well as the reasons for stopping their therapies (primary lack 
of efficacy, secondary lack of efficacy, lack of tolerability, other) and the total duration of 


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exposure to nr-axSpA therapies previously. 
 
 use will be summarized. 
9.4 
Analysis of the primary variable(s) 
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 9.5. 
9.4.1 
Variable(s) 
Primary endpoint for analysis plan A 
The primary efficacy variable is response to treatment according to the ASAS40 criteria at 
Week 16 in TNF naïve patients. The analysis of the primary variable will be based on the FAS 
patients. 
Primary endpoint for analysis plan B 
The primary efficacy variable is response to treatment according to the ASAS40 criteria at 
Week 52 in TNF naïve patients. The analysis of the primary variable will be based on the FAS 
patients. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Primary endpoint for analysis plan A 
The statistical hypothesis for ASAS40 being tested is that there is no difference in the proportion 
of TNF naïve patients fulfilling the ASAS40 criteria at Week 16 in secukinumab with loading 
regimen versus placebo regimen. 
Let pj denote the proportion of ASAS40 responders at Week 16 in TNF naïve patients for 
treatment regimens j, j=0, 1, where  
• 0 corresponds to placebo regimen, 
• 1 corresponds to secukinumab 150 mg with loading regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e. 
H1: secukinumab 150 mg with load is not different to placebo regimen with respect to ASAS40 
response in TNF naïve patients at Week 16 
The primary analysis will be conducted via logistic regression with treatment and stratification 
factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) as factors and weight as a covariate. Odds 
ratios and 95% CI will be presented comparing secukinumab regimen to placebo. 
Primary endpoint for analysis plan B 
The statistical hypothesis for ASAS40 being tested is that there is no difference in the proportion 
of TNF naïve patients fulfilling the ASAS40 criteria (and did not escape) at Week 52 in 
secukinumab without loading regimen versus placebo regimen. 
Let pj denote the proportion of ASAS40 responders at Week 52 in TNF naïve patients for 
treatment regimens j, j=0, 1, where  
• 0 corresponds to placebo regimen, 


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• 1 corresponds to secukinumab 150 mg without loading regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e. 
H1: secukinumab 150 mg without load is not different to placebo regimen with respect to 
ASAS40 response in TNF naïve patients at Week 52 
The primary analysis will be conducted via logistic regression with treatment and stratification 
factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) as factors and weight as a covariate. Odds 
ratios and 95% CI will be presented comparing secukinumab regimen to placebo. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Missing data for ASAS20/40 response and other binary efficacy variables (e.g., ASAS5/6, etc.) 
for data up to Week 52 will be handled as follows: 
1. Patients who drop out of the trial for any reason will be considered as non-responders 
from the time they drop out through Week 52 
2. Patients who do not have the required data to compute responses (e.g., ASAS 
components) at baseline and at the specific time point will be classified as non-responders 
at the specific time point.  
Patients who are unblinded will be considered non-responders from the time of unblinding up 
to Week 52. The primary analysis will use non-responder imputation.  
Continuous variables (e.g., ASAS components) with the exception of MRI endpoints, will be 
analyzed using a mixed-effects model repeated measures (MMRM) which is valid under the 
missing at random (MAR) assumption. As such, single-point imputation of missing data will 
not be performed (e.g., LOCF). For analyses of these parameters, if all post-baseline values are 
missing then these missing values will not be imputed and this patient will be removed from 
the analysis of the corresponding variable, i.e., it might be that the number of patients providing 
data to an analysis is smaller than the number of patients in the FAS. 
For SI joint edema on MRI a multiple imputation approach will be applied to handle missing 
data. 
Data post treatment switch decision (see Section 5.5.6) 
In general, data for patients where a decision was made to switch treatment will be handled in 
the following fashion up to Week 52:   
• For binary endpoints, patients will be considered non-responders after switching. This will 
be done for all treatment regimens in order to minimize bias for between-treatment 
comparisons. However, the actual response rates will also be summarized without 
considering the patients as non-responders as they provide insight into the long-term 
response profile within each treatment regimen.  
• For continuous endpoints (ASQoL and SI joint edema score on MRI), a composite 
estimand strategy will be applied and data after switch will be set to the worst possible 
outcome. Rank-based analysis will be used for hypothesis testing.  
• If applicable, difference in trimmed means estimate will be used to summarize the 
treatment effect estimate for the continuous composite endpoint 


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• For continuous endpoints the actual observed values after switch will be also summarized 
with descriptive statistics 
• A supplementary estimand principal stratum strategy might be used to quantify treatment 
effect in population of subjects who would adhere in case randomized to secukinumab 
•  
9.4.4 
Supportive analyses 
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, ASAS40 response in TNF naïve patients at Week 16 and Week 52 will also be 
evaluated using a non-parametric regression (Koch et al 1998) model with the same independent 
variables as the logistic regression model. 
The impact of missing data on the analysis results of ASAS40 in TNF naïve patients will be 
assessed as well by repeating the logistic regression model using different ways to handle 
missing data. These may include, but are not limited to: 
• Multiple imputation 
• Observed based on randomized treatment (based on patients providing data at a specific 
visit regardless of current treatment, i.e. also using data collected after switch decision 
point).  
• Tipping point analysis 
9.5 
Analysis of secondary variables 
9.5.1 
Secondary efficacy variables 
Secondary endpoints for analysis plan A 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below. Secondary efficacy variables will be analyzed using the FAS population. 
ASAS40 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
ASAS 5/6 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 


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BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASDAI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASDAI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
secukinumab regimens and placebo at the appropriate analysis visits. 
BASDAI50 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and baseline weight and BASDAI score as covariates. 
hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature would suggest that the data are not 
normally distributed (Huffman et al 2006), analysis will be performed on the loge ratio of the 
treatment value vs baseline value (calculated by dividing the post-baseline value by the baseline 
value and then applying the loge transformation) to normalize the distribution of hsCRP at each 
analysis visit. Between-treatment differences in the change in hsCRP relative to baseline will 
be evaluated using MMRM with treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status, and analysis visit as factors and loge baseline hsCRP 
and weight as continuous covariates. Treatment by analysis visit and loge baseline hsCRP by 
analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the secukinumab treatment effect 
for secukinumab regimens at different analysis visits will be determined from the pairwise 
comparisons performed between secukinumab regimens and placebo at the appropriate analysis 
visits. The estimate and the 2-sided 95% confidence intervals obtained from the model will be 
back transformed to the original scale. 
SF-36 PCS at Week 16 
See Section 9.5.4. 
ASQoL at Week 16 
See Section 9.5.4. 
ASAS20 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 


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BASFI at Week 16 
Between-treatment differences in the change from baseline in BASFI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASFI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASFI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
secukinumab regimens and placebo at the appropriate analysis visits. 
SI joint edema on MRI at Week 16 
The change from baseline to Week 16 in inflammation measured by SI joint total edema score 
will be evaluated using an analysis of covariance (ANCOVA) model with treatment group, 
stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors, and 
weight and baseline inflammation score as covariates.  
Supportive analysis for SI joint edema on MRI will be performed as follows: 
• Using a non-parametric ANCOVA model on multiple imputation data 
• Using an ANCOVA model where instead of multiple imputation missing data is handled 
by Baseline observation carried forward (BOCF) 
ASAS partial remission at Week 16 
Response at Week 16 to ASAS partial remission will be evaluated using a logistic regression 
model with treatment, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-
α status as factors and weight as a covariate. 
Testing strategy for analysis plan A 
The following null hypotheses will be included in the testing strategy, and type-I-error will be 
set such that a family-wise type-I-error of 5% is kept: 
Primary objective: 
H1: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 response in TNF naïve patients at Week 16 
Secondary objectives: 
H2: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 response at Week 16 
H3: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS 5/6 response at Week 16 
H4: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H5: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 


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H6: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H7: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H8: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H9: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H10: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H11: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H12: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS partial remission at Week 16 
H13: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 response in TNF naïve patients at Week 16 
H14: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 response at Week 16 
H15: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS 5/6 response at Week 16 
H16: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H17: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H18: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H19: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H20: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H21: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H22: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H23: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H24: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS partial remission at Week 16 


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Figure 9-1 
Testing strategy for analysis plan A 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed sequential 
testing strategy as described in Figure 9-1. The primary hypothesis (H1) for the primary 
objective (ASAS40 in TNF naïve at Week 16) for secukinumab with load regimen versus 
placebo will be tested at α-level. If the hypothesis H1 is rejected then the whole α will be passed 
to the next hypothesis (H2) which will be tested at α-level. This procedure will continue 
(pending rejection of the null hypotheses) until H12 is rejected. If H12 is rejected then the full α-
level is passed on to the testing sequence of secukinumab without load which can now be tested 
at 5% level sequentially in a similar way. 
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
sequence for the test of another hypothesis if the treatment effect is in favor of secukinumab. 
Secondary endpoints for analysis plan B 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below. Secondary efficacy variables will be analyzed using the FAS population. 


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ASAS40 at Week 52 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
ASAS40 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
ASAS 5/6 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
ASAS20 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and weight as a covariate. 
BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASDAI score and weight as continuous 
covariates. Treatment by analysis visit and baseline BASDAI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
secukinumab regimens and placebo at the appropriate analysis visits.   
SF-36 PCS at Week 16 
See Section 9.5.4. 
ASQoL at Week 16  
See Section 9.5.4. 
ASQoL at Week 52 
The change from baseline to Week 52 in ASQoL score will be analyzed by composite estimand 
strategy in which data after switch is set to worst possible value. Wilcoxon rank-sum test will 
be used for testing the difference in distributions of the composite endpoint in active vs placebo. 
If observed switching rate allows, treatment differences will be summarised using trimmed 
means and confidence intervals will be calculated using bootstrap. 


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Total direct effect (principal stratum) estimand may be presented as supplementary estimand 
for treatment effect in population adhering to treatment in case of randomized to secukinumab. 
SI joint edema on MRI at Week 16 
The change from baseline to Week 16 in inflammation measured by SI joint total edema score 
will be evaluated using an ANCOVA model with treatment group, stratification factor 
(CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-α status as factors, and weight and baseline 
inflammation score as covariates.  
Supportive analysis for SI joint edema on MRI will be performed as follows: 
• Using a non-parametric ANCOVA model on multiple imputation data 
• Using an ANCOVA model where instead of multiple imputation missing data is handled 
by BOCF 
SI joint edema on MRI at Week 52 
The change from baseline to Week 52 in inflammation measured by SI joint total edema score 
will be analyzed by composite estimand strategy in which data after switch is set to worst 
possible value. Wilcoxon rank-sum test will be used for testing the difference in distributions 
of the composite endpoint in active vs placebo. If observed switching rate allows, treatment 
differences will be summarized using trimmed means and confidence intervals will be 
calculated using bootstrap. 
Total direct effect (principal stratum) estimand may be presented as supplementary estimand 
for treatment effect in population adhering to treatment in case of randomized to secukinumab. 
hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature would suggest that the data are not 
normally distributed (Huffman et al 2006), analysis will be performed on the loge ratio of the 
treatment value vs baseline value (calculated by dividing the post-baseline value by the baseline 
value and then applying the loge transformation) to normalize the distribution of hsCRP at each 
analysis visit. Between-treatment differences in the change in hsCRP relative to baseline will 
be evaluated using MMRM with treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status, and analysis visit as factors and loge baseline hsCRP 
and weight as continuous covariates. Treatment by analysis visit and loge baseline hsCRP by 
analysis visit will be included as interaction terms in the model. An unstructured covariance 
structure will be assumed for the model. The significance of the secukinumab treatment effect 
for secukinumab regimens at different analysis visits will be determined from the pairwise 
comparisons performed between secukinumab regimens and placebo at the appropriate analysis 
visits. The estimate and the 2-sided 95% confidence intervals obtained from the model will be 
back transformed to the original scale. 
BASFI at Week 16 
Between-treatment differences in the change from baseline in BASFI will be evaluated using 
MMRM with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+), 
TNF-α status, and analysis visit as factors and baseline BASFI score and weight as continuous 


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covariates. Treatment by analysis visit and baseline BASFI score by analysis visit will be 
included as interaction terms in the model. An unstructured covariance structure will be 
assumed for the model. The significance of the treatment effect for secukinumab regimens at 
different analysis visits will be determined from the pairwise comparisons performed between 
secukinumab regimens and placebo at the appropriate analysis visits. 
BASDAI50 at Week 16 and Week 52 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-
/MRI+) and TNF-α status as factors and baseline weight and BASDAI score as covariates. 
ASDAS-CRP inactive disease at Week 52 
Response at Week 52 to ASAS partial remission will be evaluated using a logistic regression 
model with treatment, stratification factor (CRP+/MRI+, CRP+/MRI-, CRP-/MRI+) and TNF-
α status as factors and baseline weight and ASDAS-CRP score as covariates. 
Testing strategy for analysis plan B 
The following null hypotheses will be included in the testing strategy, and type-I-error will be 
set such that a family-wise type-I-error of 5% is kept: 
Primary objective: 
H1: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 in TNF naïve at Week 52 
Secondary objectives: 
H2: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 at Week 52 
H3: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS40 at Week 16 
H4: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 in TNF naïve at Week 52 
H5: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 at Week 52 
H6: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS40 at Week 16 
H7: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H8: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H9: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
BASDAI50 at Week 52 


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H10: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H11: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H12: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H13: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS5/6 at Week 16 
H14: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H15: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 
H16: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H17: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
ASDAS-CRP ID at Week 52 
H18: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 52 
H19: 
secukinumab 150 mg (without load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 52 
H20: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in total BASDAI at Week 16 
H21: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 16 
H22: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
BASDAI50 at Week 52 
H23: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in hsCRP at Week 16 
H24: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in SF-36 PCS at Week 16 
H25: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 16 
H26: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS5/6 at Week 16 
H27: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASAS20 at Week 16 
H28: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in BASFI at Week 16 


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H29: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 16 
H30: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
ASDAS-CRP ID at Week 52 
H31: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from baseline in ASQoL at Week 52 
H32: 
secukinumab 150 mg (with load) is not different to placebo regimen with respect to 
change from screening in SI joint edema on MRI at Week 52 
Figure 9-2 
Testing strategy for analysis plan B 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed sequential 
testing strategy as described in Figure 9-2. The primary hypothesis (H1) for the primary 
objective (ASAS40 in TNF naïve at Week 52) for secukinumab without load regimen versus 
placebo will be tested at α-level. If the hypothesis H1 is rejected then the whole α will be passed 


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to the next hypothesis (H2) which will be tested at α-level. This procedure will continue 
(pending rejection of the null hypotheses) until H32 is rejected.  
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
graphical procedure for the test of another hypothesis if the treatment effect is in favor of 
secukinumab. 


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9.5.3 
Safety variables 
Adverse events 
Treatment emergent adverse events (i.e. events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term and on or before last dose + 84 days) will be summarized.  
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any AE, having an AE in each primary system organ class and 
having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a patient reported more than one adverse event 
with the same preferred term, the adverse event with the greatest severity will be presented. If 
a patient reported more than one adverse event within the same primary system organ class, the 
patient will be counted only once with the greatest severity at the system organ class level, 
where applicable.  
These summaries may be presented separately by different study periods, e.g., Week 1-20 and 
entire treatment period. 
As appropriate, the incidence of AEs will be presented per 100 patient years of exposure.  
Separate summaries will be provided for death, serious adverse event, adverse events leading 
to discontinuation and adverse events leading to dose adjustment. 
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
When adjudication is required of major cardiovascular events, a listing of those types of events 
as reported by the investigator and confirmed by adjudication will be provided. 
Non-treatment emergent AEs will be provided in listings. 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for patients with both baseline and post baseline.  
For each parameter, the maximum change from baseline within each study period will be 
evaluated analogously.  


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In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented by visit as well as for most extreme values post-baseline. 
 
 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for patients 
with both baseline and post-baseline values. 
ECG 
Summary statistics will be presented for ECG variables by visit and treatment group. Qualitative 
changes will be summarized. 
9.5.4 
Health-related Quality of Life 
Health-related Quality of Life assessments will be evaluated based on FAS unless otherwise 
specified. 
SF-36 
The following variables will be evaluated:  
• SF-36 domain scores (based on a scale of 0-100). 
• SF-36 PCS and MCS scores (norm-based scores). 
• SF-36 PCS and MCS responder (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change in SF-36 summary scores (PCS and MCS), between-treatment differences will 
be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, CRP+/MRI-, 
CRP-/MRI+), TNF-α status and analysis visit will be included as categorical factors and 
baseline SF-36 score (PCS or MCS) and weight as continuous covariates. Treatment by analysis 
visit and baseline SF-36 score (PCS or MCS) by analysis visit will be included as interaction 
terms in the model. An unstructured covariance structure will be assumed for the model. 
Pairwise comparisons will be performed between secukinumab regimens and placebo and/or 
secukinumab at appropriate analysis visits. 
In the responder analyses, treatment groups will be compared with respect to response to 
treatment using a logistic regression model with treatment, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status as factors and baseline SF-36 score (PCS or MCS) 
and weight as covariates. Odds ratios and 95% CI will be presented for appropriate treatment 
comparisons. 


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The SF-36 domain scores will be summarized by treatment. 
ASQoL 
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using MMRM. Treatment group, stratification factor (CRP+/MRI+, 
CRP+/MRI-, CRP-/MRI+), TNF-α status and analysis visit be used as categorical factors and 
baseline ASQoL score and weight as continuous covariates. Treatment by analysis visit and 
baseline ASQoL score by analysis visit will be included as interaction terms in the model. An 
unstructured covariance structure will be assumed for the model. The significance of the 
treatment effects for secukinumab regimens at different analysis visits will be determined from 
the pairwise comparisons performed between secukinumab regimens and placebo and/or 
secukinumab at the appropriate analysis visits. 


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9.5.8 
PK/PD 
Not applicable. 
9.6 
Interim analyses 
For analysis plan A 
The primary endpoint analysis will be performed after all patients complete Week 24 in order 
to support regulatory filing. As all patients will have completed the assessments associated with 
the primary endpoint (Week 16), no adjustment will be made to the type I error rate for this 
analysis.  
Subsequent to the primary endpoint analysis, an analysis of the full double-blind treatment 
period (up to Week 52) will also be performed after all patients have completed the Week 52 
visit. 
For analysis plan B 
The primary endpoint analysis will be performed after all patients complete Week 52 in order 
to support regulatory filing. As all patients will have completed the assessments associated with 
the primary endpoint (Week 52), no adjustment will be made to the type I error rate for this 
analysis. Based on enrollment, it is estimated that approximately 70% of patients will have 
completed the Week 52 assessments at the time of the database lock for Week 24 (analysis plan 
A). An interim analysis may be conducted at that time for analysis plan B using an Obrien-
Fleming spending function to control the type I error. The results of the interim analysis will 
not affect the study conduct; i.e., all patients will continue to be treated according to the current 
study design and a blinded study team will oversee the trial conduct to prevent bias until the 
Week 52 database lock. Performing the interim analysis is dependent on health authority 
feedback and further details will be included in the statistical analysis plan, which will be 
finalized before Week 24 database lock. 
9.7 
Sample size calculation 
In a study of an anti-TNF agent in the same indication of similar design (Landewé et al 2014) 
an ASAS40 response rate of 47.1% for active treatment and 16% for placebo was observed at 
Week 12; however, this trial had a limited number of TNF-IR patients and a meta-analysis (MA) 
from unpublished studies with secukinumab in AS indicates that the placebo rates observed in 
recent AS studies may be higher. Hence, assumptions are based on the result of active treatment 


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from this TNF-inhibitor study in nr-axSpA (but adjusted for the expected inclusion of TNF-IR 
patients) and with placebo response rates taken from the secukinumab MA. This MA included 
approximately 25% TNF-IR patients, and the ASAS40 response rate in the 150 mg dose for 
TNF-IR was 76% of the response in the TNF naïve group. Assuming 20% of randomized 
patients will be TNF-IR and have the same TNF-IR vs. TNF naïve response ratio as seen in the 
MA (76%), the estimate for the entire population is 44.8% (i.e. 47.1%*0.8 + 47.1%*0.2*0.76) 
for secukinumab and 25.9% for placebo. ASAS40 in TNF naïve patients only is assumed to be 
47.1% for secukinumab and 27.9% for placebo. 
At Week 16, response rates for the secukinumab 150 mg s.c. regimens with loading and without 
loading are assumed to be the same. 
Primary endpoint for analysis plan A 
An overall type I error (2-sided) 5% will be used to control type I error. Since the hierarchy is 
sequential starting with secukinumab with load tested versus placebo the full type I error will 
be utilized for each comparison. 
Table 9-1 
Summary of power for binary primary endpoint 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with load 
Secukinumab without load 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 TNF 
naïve at Week 
16 
27.9% 
47.1% 
91% 
47.1% 
91% 
Based on these assumptions including 185 patients per arm would give 91% power to reject a 
hypothesis of equal response rate based on Fisher’s exact test. 
Primary endpoint for analysis plan B 
An overall type I error (2-sided) 5% will be used to control type I error. Since the hierarchy is 
sequential starting with secukinumab without load tested versus placebo the full type I error 
will be utilized for each comparison. 
Based on an assumption that the ASAS40 TNF naïve response rate at Week 16 will be 47.1% 
for secukinumab and 27.9% for placebo, that 80% of secukinumab patients and 65% of placebo 
patients will retain their response status from Week 16, and that 10% of secukinumab patients 
and 5% of placebo patients will be new responders at Week 52, the ASAS40 response rate at 
Week 52 based on non-responder imputation can be estimated as 43.0% and 21.7%, 
respectively, resulting in a power of 97% to reject an hypothesis of equal response rate at the 
5% level.  


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Table 9-2 
Summary of power for binary primary endpoint 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with load 
Secukinumab without Loading 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 TNF 
naïve at Week 
52 
21.7% 
43.0% 
97% 
43.0% 
97% 
9.8 
Power for analysis of secondary variables 
Secondary endpoints for analysis plan A 
In Table 9-3 the power for rejecting each of the binary secondary hypotheses at Week 16 is 
presented based on Fisher’s exact test with a 2-sided 5% type I error rate and 185 patients per 
group assuming the response rates without load are the same as for with load. 
Table 9-3 
Power for binary secondary variables at Week 16 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with load 
Secukinumab without load 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 
25.9% 
44.8% 
96% 
44.8% 
96% 
ASAS5/6 
24.3% 
45.0% 
98% 
45.0% 
98% 
BASDAI50 
19.4% 
45.4% 
99% 
45.4% 
99% 
ASAS20 
43.7% 
61.1% 
90% 
61.1% 
90% 
ASAS PR1 
8.7% 
21.9% 
93% 
21.9% 
93% 
Source: Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-
analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). Calculations based on Fisher’s exact test 
(nQuery 7.0 PTT2-1) 
1Week 16 response for TNF naïve patients assumed 25% for secukinumab and 10% for placebo which were then adjusted for 
20% TNF-IR. 
In Table 9-4 the power for rejecting each of the secondary hypotheses at Week 16 based on 
continuous variables are presented with assumed change from baseline and standard deviation 
(SD). Following the assumption for response variables the change from baseline was adjusted 
for inclusion of TNF-IR patients but with unchanged SD. The change from baseline without 
load is assumed the same as for with load. 
Table 9-4 
Power for continuous secondary variables at Week 16 
Endpoint 
Common 
SD 
Placebo 
Mean 
Secukinumab              
with load 
Secukinumab                
without load 
Mean 
Power 
N=185/arm 
Mean 
Power 
N=185/arm 
BASDAI1 
2.3 
-1.75 
-3.30 
99% 
-3.30 
99% 
hsCRP2 
0.867 
0.095 
-0.544 
99% 
-0.544 
99% 
BASFI1 
2.1 
-1.37 
-2.20 
96% 
-2.20 
96% 
MRI SI joint 
edema3 
2.17 
-0.17 
-1.30 
99% 
-1.30 
99% 
SF-36 PCS4 
7.15 
3.67 
6.32 
94% 
6.32 
94% 
ASQoL4 
4.55 
-2.32 
-4.10 
96% 
-4.10 
96% 
SD=standard deviation. Result is mean change from baseline with CRP in log scale. 


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1 Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-analysis of 
unpublished AS studies (CAIN457F2314 and CAIN457F2320). 
2 Meta-analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320) 
3 Novartis AS study (AIN457F2305) 
4 Meta-analysis of Novartis AS studies (CAIN457F2310 and CAIN457F2320) 
Calculations based on two-sample t-test (nQuery 7.0 MTT0-1) 
Secondary endpoints for analysis plan B 
Response rates for load and without load at Weeks 16 and 52 are assumed to be the same. 
Table 9-5 
Power for binary secondary variables 
Endpoint 
Placebo 
Response  
Rate 
Secukinumab with load 
Secukinumab without load 
Response   
Rate 
Power 
N=185/arm 
Response  
Rate 
Power 
N=185/arm 
ASAS40 wk52 
20.5% 
41.4% 
99% 
41.4% 
99% 
ASAS40 wk16 
25.9% 
44.8% 
96% 
44.8% 
96% 
BASDAI50 wk16 
19.4% 
45.4% 
99% 
45.4% 
99% 
BASDAI50 wk52 
16.6% 
41.8% 
99% 
41.8% 
99% 
ASAS5/6 wk16 
24.3% 
45.0% 
98% 
45.0% 
98% 
ASAS20 wk16 
43.7% 
61.1% 
90% 
61.1% 
90% 
ASDAS ID wk521 
10.2% 
25.3% 
96% 
25.3% 
96% 
Week 16 
Source: Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-
analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). 
Week 52 
Estimates from Week 16 were adjusted for assumed response retention. 
1 Week 16 response for TNF naïve patients assumed 25% for secukinumab and 10% for placebo which were then adjusted for 
20% TNF-IR and assumed response retention. 
ASDAS ID = ASDAS CRP Inactive Disease (ASDAS-CRP score < 1.3) 
Calculations based on Fisher’s exact test (nQuery 7.0 PTT2-1) 
Table 9-6 
Power for continuous secondary variables 
Endpoint 
Common 
SD 
Placebo 
Mean 
Secukinumab with 
load 
Secukinumab without 
load 
Mean 
Power 
N=185/arm 
Mean 
Power 
N=185/arm 
BASDAI wk161 
2.30 
-1.75 
-3.30 
99% 
-3.30 
99% 
hsCRP wk162 
0.867 
0.095 
-0.544 
99% 
-0.544 
99% 
SF-36 PCS wk163 
7.15 
3.67 
6.32 
94% 
6.32 
94% 
BASFI wk161 
2.10 
-1.37 
-2.20 
96% 
-2.20 
96% 
MRI SI joint edema wk164 
2.17 
-0.17 
-1.30 
99% 
-1.30 
99% 
ASQoL wk163 
4.55 
-2.32 
-4.10 
96% 
-4.10 
96% 
SD=standard deviation. Result is mean change from baseline with CRP in log scale. 
Week 16 
1Active from R Landewé et al 2014 (Week 12 result, 400 mg Q4W) adjusted for TNF-IR and Placebo from a meta-analysis of 
unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320). 
2Meta-analysis of unpublished Novartis AS studies (CAIN457F2314 and CAIN457F2320) 
3Meta-analysis of Novartis AS studies (CAIN457F2310 and CAIN457F2320) 
4Novartis AS study (CAIN457F2305). 
Calculations based on two-sample t-test (nQuery 7.0 MTT0-1) 


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Power for continuous composite estimands depends on the difference in continuous endpoint 
and difference in treatment escape rates. Assuming the change from baseline being the same at 
Week 52 as at Week 16 and no escape, the power for Wilcoxon rank sum test would be similar 
to power of two-sample t-test (ASQoL 96% and MRI SI joint edema 99%). If escape rates are 
similar in both treatment arms the power will decrease if overall escape rate is increasing, 
whereas the power will remain the same or increase if escape rates are different between 
treatment arms.  
9.9 
Analysis of extension phase 
The analysis extension phase data will be exploratory in nature and mainly reported by 
descriptive statistics, applying the same principles as in core phase data analysis.  
Statistical models may be applied to produce confidence intervals for treatment summaries, but 
no formal statistical inference will be done. 
Data analyses will be presented by treatment groups. Treatment groups for core phase 
responders are as follows: 
• Secukinumab 150 mg blinded 
• Secukinumab 300 mg blinded 
and for core phase non-responders: 
• Secukinumab 300 mg open-label 
The following analysis sets will be used in the extension phase: 
Full analysis set (FAS): The FAS will be comprised of all subjects enrolled in the extension 
phase. 
Safety set: The safety set includes all subjects enrolled in the extension phase and who took at 
least 1 dose of study treatment during the extension phase 
Total sample size for extension phase is not pre-specified. It is estimated that approximately 
70% of subjects enrolled in the core phase will enter the extension phase, which is equivalent 
to about 380 subjects. Around 305 subjects are estimated to be core phase responders and will 
be in the randomized group and around 75 subjects are expected to be core phase non-
responders and will enter the open-label treatment group. 
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. 


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10.2 
Informed consent procedures  
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 
entire study or longer if required by locally approved prescribing information (e.g. 20 weeks in 
EU). If there is any question that the patient will not reliably comply, they should not be entered 
in the study. 
 
 
 
 
 
 
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 
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, patient 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. 


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10.4 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
11 
Protocol adherence 
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. 
12 
References 
References are available upon request 
Baraliakos X and Braun J (2011) Spondyloarthritides. Best Pract Res Clin Rheumatol; 
25:825-42. 
Baraliakos X, Braun J, Laurent D, et al (2011) Interleukin-17A blockade with secukinumab 
reduces spinal inflammation in patients with ankylosing spondylitis as early as Week 6, as 
detected by Magnetic Resonance Imaging. Arthritis Rheum; 63:S972. 
Baraliakos X, Listing J, Brandt J, et al (2005) Clinical response to discontinuation of anti-
TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with 
infliximab. Arthritis Res Ther; 7: R439-R444. 
 


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Callhoff J, Sieper J, Weib A,et al (2014) Efficacy of TNFα blockers in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann 
Rheum Dis; 0:1-8 
 
 
 
 
Dougados M, van der Heijde D, Sieper J, et al (2013) Safety and Efficacy Of Etanercept In 
Early Non-Radiographic Axial Spondyloarthritis: A Randomized, Double-Blind, Placebo-
Controlled Trial At 24 Weeks. Abstract Number 1516. ACR 2013 
Dougados M, van der Heijde D, Sieper J, et al (2014) Symptomatic efficacy of etanercept and 
its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis 
– a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum; 
66:2091-2102. 
EMA guidance document: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC5
00003424.pdf 
 
 
 
Huffman KM, Samsa GP, Slentz CA, et al (2006) Response of high-sensitivity C-reactive 
protein to exercise training in an at-risk population. Am Heart J; 152:793-800. 
Koch GG, Tangen CM, Jung JW, et al (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statist Med; 17:1863-92. 
Landewé R, Braun J, Deodhar A, et al (2014) Efficacy of certolizumab pegol on signs and 
symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a 
double-blind randomized placebo-controlled Phase 3 study. Ann Rheum Dis; 73:39-47. 
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. 
Lubeck DP (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis. Pharmacoeconomics; 22 Suppl 1:27-38. 
Lukas C, Landewé R, Sieper J, et al (2009) Development of an ASAS-endorsed disease 
activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis; 68:18-24. 
Machado P, Landewé R, Lie E, et al (2011) Ankylosing Spondylitis Disease Activity Score 
(ASDAS): defining cut-off values for disease activity states and improvement scores. Ann 
Rheum Dis; 70:47-53. 
McHorney CA, Ware JE and Raczek AE C (1992) The MOS 36-Item Short-Form Health 
Survey (SF-36). Medical Care; 31: 247-263. 


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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. 
Mettler FA, Huda W, Yoshizumi TT, et al (2008) Effective doses in Radiology and 
Diagnostic Nuclear Medicine – A catalog. Radiology; 248:254-63. 
Pavy S, Brophy S, Calin A (2005) Establishment of the minimum clinically important 
difference for the Bath Ankylosing Spondylitis Indices- A prospective study. J Rheumatol; 
32:80-5. 
Poddubnyy D, Rudwaleit M, Haibel H, et al (2011) Rates and predictors of radiographic 
sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis; 
70:1369-74. 
Robinson PC, Wordsworth BP, Reveille JD, et al (2013) Axial spondyloarthritis: a new 
disease entity, not necessarily early ankylosing spondylitis. Ann Rheum Dis; 72:162-4. 
Rudwaleit M, Landewé R, van der Heijde D, et al (2009) The development of Assessment of 
SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part 
I): classification of paper patients by expert opinion including uncertainty appraisal. Ann 
Rheum Dis; 68:770-76. 
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 2:1-44. 
Sieper J (2012) Developments in therapies for spondyloarthritis. Nat Rev Rheumatol; 8:280-
87. 
Sieper J, Kivitz AJ, Van Tubergen AM, et al. (2012) Rapid improvements in patient reported 
outcomes with certolizumab pegol in patients with axial spondyloarthritis, including 
ankylosing spondylitis and non-radiographic axial spondyloarthritis: 24 week results of a 
phase 3 double blind randomized placebo-controlled study. Abstract Number 558. ACR 2012 
Sieper J and van der Heijde D (2013) Nonradiographic Axial Spondyloarthritis - New 
Definition of an Old Disease? Arthritis Rheum; 65:543-51. 
Sieper J, van der Heijde D, Dougados M, et al (2013) Efficacy and safety of adalimumab in 
patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-
controlled trial (ABILITY-1). Ann Rheum Dis; 72:815-22. 
Song IH, Hermann KG, Haibel H, et al (2011) Effects of etanercept versus sulfasalazine in 
early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI 
(ESTHER): a 48-week randomized controlled trial. Ann Rheum Dis; 70:590-96. 
Song IH, Weib A, Hermann KG, et al (2013) Similar response rates in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis after 1 year of treatment 
with etanercept: results from the ESTHER trial. Ann Rheum Dis; 72:823-25. 
Stabin M, Marcus C, Siegel J (2009) New tool for nuclear medicine patient release 
calculations. J Nucl Med; 50:14N. 
US Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER) (2013) Guidance for Industry – Electronic Source 
Data in Clinical Investigations. 


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van der Heijde D, Landewé R, Baraliakos X, et al (2008a) Radiographic findings following 
two years of infliximab therapy in patients with Ankylosing Spondylitis. Arthritis Rheum; 
58:3063-70. 
van der Heijde D, Landewé R, Einstein S, et al (2008b) Radiographic progression of 
Ankylosing Spondylitis after up to two years of treatment with etanercept. Arthritis Rheum; 
58:1324-31. 
van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of the diagnostic criteria for 
ankylosing spondylitis - A proposal for modification of the New York criteria. Arthritis 
Rheum; 27:361-8. 
van Tubergen A, Black PM, Coteur G (2015) Are patient-reported outcome instruments for 
ankylosing spondylitis fit for purpose for the axial spondyloarthritis patient? A qualitative and 
psychometric analysis. Rheumatology; EPub  
Wallis D, Haroon N, Ayearst R, et al (2013) Ankylosing Spondylitis and Nonradiographic 
Axial Spondyloarthritis: Part of a Common Spectrum or Distinct Diseases? J Rheumatol; 
40:2038-41. 
Ware JE and Donald Sherbourne C (1992) The MOS 36-Item Short-Form Health Survey (SF-
36). Medical Care; 30: 473-483. 
 
13 
Appendices 
13.1 
Appendix 1: Clinically notable laboratory values  
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Clinically notable values will be forwarded to Novartis/CRO at the same time that they are sent 
to investigators. Any action based on these laboratory values should be discussed with 
Novartis/CRO personnel. 


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Table 13-1 
Safety Analyses: Expanded Limits and Notable Criteria 
 
Final Harmonization 
Laboratory Variable 
Notable Criteria 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
>3 x ULN 
>3 x ULN 
SGPT (ALT) 
>3 x ULN 
>3 x ULN 
Bilirubin 
>2 x ULN 
>2 x ULN 
Alkaline phosphatase 
>2.5 x ULN 
>2.5 x ULN 
RENAL FUNCTION, METABOLIC AND ELECTROLYTE VARIABLES 
Creatinine (serum) 
>2 x ULN 
>2 x ULN 
HEMATOLOGY VARIABLES 
Hemoglobin 
20 g/L decrease from baseline 
Platelet Count 
<100x10E9/L 
White blood cell count 
<0.8 x LLN 
Neutrophils 
<0.9 x LLN 
 


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13.3 
Appendix 3: Modified New York criteria 
According to Exclusion Criteria 1, patients must not have below described radiological changes 
Clinical criteria: 
• Low back pain and stiffness for more than 3 months that improves with exercise, but is not 
relieved by rest. 
• Limitation of motion of the lumbar spine in the sagittal and frontal planes. 
• Limitation of chest expansion relative to normal values correlated for age and sex. 
Radiological criterion: 
• Sacroiliitis grade ≥2 bilaterally or grade 3–4 unilaterally. 
Definite AS if the radiological criterion is associated with at least one clinical criterion. 


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13.4 
Appendix 4: ASAS Classification Criteria for Axial 
Spondyloarthritis (axSpA) 
In patients with ≥ 3 months back pain and age at onset <45 years: 
 
Sacroiliitis on imaging*  
plus 
 ≥ 1 SpA feature 
OR 
HLA-B27  
plus  
≥ 2 other SpA features 
*Sacroiliitis on imaging: 
• Active (acute) inflammation 
on MRI highly suggestive of 
sacroiliitis associated with 
SpA 
• Definite radiographic 
sacroiliitis according to the 
modified NY criteria 
SpA features: 
• Inflammatory back pain 
• Arthritis 
• Enthesitis (heel) 
• Uveitis 
• Dactylitis 
• Psoriasis 
• Crohn’s / colitis 
• Good respons to NSAIDs 
• Family history for SpA 
• HLA-B27 
• Elevated CRP 
 
13.5 
Appendix 5: Assessment of SpondyloArthritis International 
Society criteria (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper et al 2009). 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale 
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 VAS 
scale 
Additional assessment domains: 
5. Spinal mobility represented by the BASMI lateral spinal flexion assessment 
6. C-reactive protein (acute phase reactant) 
13.5.1 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. The ten questions were chosen with a major input from patients with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions 


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assess the patients’ ability to cope with everyday life. A 10 cm visual analog scale is used to 
answer the questions. The mean of the ten scales gives the BASFI score – a value between 0 
and 10. 
13.5.2 
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 as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS: 
1. How would you describe the overall level of fatigue/tiredness you have experienced? 
2. How would you describe the overall level of AS neck, back or hip pain you have had? 
3. How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had? 
4. How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure? 
5. How would you describe the overall level of morning stiffness you have had 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 patients with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical trials evaluating new drug therapies directed at Ankylosing 
Spondylitis. BASDAI is a quick and simple index (taking between 30 seconds and 2 minutes to 
complete). 


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13.6 
Appendix 6: Definition of Sacroiliitis on MRI 
An MRI will be considered positive for sacroiliitis (active inflammatory lesions, “positive 
MRI”, MRI+) if the following characteristics are evident (Sieper et al 2009): 
• The presence of definite subchondral bone marrow oedema/osteitis highly suggestive of 
sacroiliitis is mandatory. 
• The presence of synovitis, capsulitis, or enthesitis only without concomitant subchondral 
bone marrow oedema/osteitis is compatible with sacroliitis but not sufficient for making a 
diagnosis of active sacroliitis. 
• Amount of signal required: if there is one signal (lesion) only, this should be present on at 
least two slices. If there is more than one signal on a single slice, one slice may be enough. 


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13.8 
Appendix 8: Guidelines for administering the questionnaires for 
patient reported outcomes 
Before trial start 
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-36 asks ‘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. 
Before completion 
1. Patients should be provided with the correct questionnaire at the appropriate visits and in 
the appropriate language 
2. Patients should have adequate space and time to complete the forms 
3. Questionnaire should be administered before the clinical examination 


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During completion 
1. Administrator may clarify the questions but should not influence the response 
2. Only one response for each question 
3. Also see “Addressing Problems and Concerns” 
After completion 
1. Check for completeness and not for content* 
2. Check for multiple responses that were made in error 
*However, any response which may directly impact or reflect the patient’s medical condition 
(e.g., noting of depression) should be communicated by the study coordinator to the 
investigator). 
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 voluntary. The goal is to better 
understand the physical, mental and social health problems of patients. Emphasize that such 
information is as important as any other medical information and that the questionnaire(s) is 
simple to complete. Suggest that the questionnaire(s) may be different from anything the 
respondent has filled in the past. If the patient still declines, retrieve the questionnaires. Record 
the reason for the decline and thank the patient. 
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-report. 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, accept it as 
incomplete. Thank the patient. 


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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 
forms are not routinely shared with treating staff and that their responses will only be seen by 
you (to check for completeness) and by the investigator. Any response which may directly 
impact on or reflect their medical condition (e.g., noting of severe depression) will be 
communicated by the coordinator to the physician. 
The patient asks the meaning of a question/item 
While completing the questionnaire, some patients might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the patient by rereading the 
question for them verbatim. If the patient asks to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question. Patients should 
answer the questions based on what they think the questions mean. 
General information about all questionnaire(s): 
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. 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 and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be accepted 
without first encouraging the patient to complete unanswered questions. 
The investigator must complete the patient/visit information on the electronic device and ensure 
that the center number, patient’s number and initials are identical to the Case Record Form. As 
there are no source data for this questionnaire, the data queries will be restricted to patient/visit 
information.