Clinical trial NCT02896127
Conditions: Ankylosing Spondyloarthritis
Keywords: Ankylosing Spondyloarthritis Axial spondyloarthritis
Sponsor: Novartis Pharmaceuticals
Start date: 2016-10-18; Completion date: 2019-03-19
Enrollment: 458 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to demonstrate the clinical efficacy at week 16; and to demonstrate safety and tolerability of secukinumab compared to placebo in patients with ankylosing spondylitis at week 16 and long term safety up to Week 52.

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

At baseline, subjects were randomized to one of the two treatment groups:

* Group 1: 300 subjects, secukinumab 150 mg (1 mL, 150 mg/mL) s.c. pre-filled syringes (PFS) at BSL, Weeks 1, 2, and 3, followed by administration every four weeks starting at Week 4
* Group 2: 150 subjects, placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, 4, 8, and 12, followed by secukinumab 150 mg (1 mL, 150 mg/mL) administration every four weeks starting at Week 16

The subjects were stratified at randomization according to the region (China and non-China). Approximately 70% of randomized subjects were from China (327 Chinese subjects) in order to evaluate the efficacy and safety in this subject population. No more than 30% TNFα inhibitor inadequate responders (TNF-IR) subjects were to be enrolled in the study.

Starting at Week 16, all subjects switched to open-label secukinumab 150 mg, including all placebo subjects; however, all subjects and investigators/site staff remained blinded to the original randomized treatment group assignment (150 mg vs placebo). Study treatment continued up to Week 48.

An end of treatment visit was done 4 weeks after last study treatment administration and a post treatment follow-up visit was done 12 weeks after last study treatment administration for all subjects (regardless of whether they completed the entire study as planned or discontinued prematurely).

Subjects were instructed in detail how to self-administer the s.c. injection using PFS. Each injection was administered into an appropriate injection site of the body (thighs, arms, or abdomen). All injections were performed at the study site. Site personnel administered the injections to subjects who were not able to, or felt insecure to self-administer. Rescue medication was not allowed until Week 20. However, subjects who were deemed by the investigator not to be benefiting from the study treatment based on safety and efficacy assessments or for any reason of their own accord were free to discontinue participation in the study at any time.

Arms: arm 1: Secukinumab 150 mg s.c.

Arm includes all patients who received at least 1 dose of study drug including placebo switchers at Week 16 arm 2: Placebo s.c.
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

All Subjects received blinded treatment weekly starting at baseline, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until Week 16. At Week 16, Group 1 patients continued using secukinumab 150 mg and Group 2 patients started receiving secukinumab 150 mg dosing every four weeks. Treatment was provided open-label from Week 16 onward, as all patients took 150 mg s.c. every 4 weeks; however, subjects, investigators, and site staff remained blinded to initial randomized group assignment. intervention 2: Induction: 4x placebo s.c. weekly Maintenance: placebo s.c. monthly

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
AIN457/Secukinumab
Clinical Trial Protocol CAIN457F2308 / NCT02896127
A randomized, double-blind, placebo-controlled, phase III 
multicenter study of subcutaneous secukinumab in 
prefilled syringes, to compare efficacy at 16 weeks with 
placebo and to assess safety and tolerability up to 52 
weeks in subjects with active Ankylosing Spondylitis 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2015‐005021‐39 
Version number: 
v01 Clean 
Development phase: 
III 
Release date: 
15-Jan-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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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 .................................................................................................................... 11 
Protocol summary .............................................................................................................. 12 
1 
Introduction ....................................................................................................................... 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Purpose .................................................................................................................. 18 
2 
Study objectives ................................................................................................................. 18 
2.1 
Primary objective ................................................................................................... 18 
2.2 
Secondary objectives ............................................................................................. 18 
 
 19 
3 
Investigational plan ........................................................................................................... 20 
3.1 
Study design........................................................................................................... 20 
3.2 
Rationale of study design ....................................................................................... 21 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 21 
3.4 
Rationale for choice of comparator ....................................................................... 23 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 23 
3.6 
Risks and benefits .................................................................................................. 23 
4 
Population .......................................................................................................................... 24 
4.1 
Inclusion criteria .................................................................................................... 25 
4.2 
Exclusion criteria ................................................................................................... 26 
5 
Treatment ........................................................................................................................... 29 
5.1 
Protocol requested treatment ................................................................................. 29 
5.1.1 
Investigational treatment ....................................................................... 29 
5.1.2 
Additional study treatment .................................................................... 29 
5.2 
Treatment arms ...................................................................................................... 29 
5.3 
Treatment assignment, randomization ................................................................... 29 
5.4 
Treatment blinding ................................................................................................. 30 
5.5 
Treating the patient ................................................................................................ 31 
5.5.1 
Patient numbering ................................................................................. 31 
5.5.2 
Dispensing the investigational treatment .............................................. 31 


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5.5.3 
Handling of study treatment .................................................................. 31 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 32 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 33 
5.5.6 
Escape medication ................................................................................. 33 
5.5.7 
Concomitant treatment .......................................................................... 33 
5.5.8 
Prohibited Treatment ............................................................................. 35 
5.5.9 
Discontinuation of study treatment and premature withdrawal ............ 35 
5.5.10 
Withdrawal of consent .......................................................................... 36 
5.5.11 
Loss to follow-up .................................................................................. 37 
5.5.12 
Emergency breaking of assigned treatment code .................................. 37 
5.5.13 
Study completion and post-study treatment .......................................... 37 
5.5.14 
Early study termination ......................................................................... 38 
6 
Visit schedule and assessments ......................................................................................... 38 
6.1 
Information to be collected on screening failures .................................................. 44 
6.2 
Patient demographics/other baseline characteristics ............................................. 44 
6.3 
Treatment exposure and compliance ..................................................................... 44 
6.4 
Efficacy .................................................................................................................. 44 
6.4.1 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................. 45 
6.4.2 
Patient’s global assessment of disease activity (VAS) ......................... 46 
6.4.3 
Patient’s assessment of back pain intensity (VAS) ............................... 46 
6.4.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 46 
6.4.5 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 46 
 
 46 
 
 47 
 
 47 
 
 48 
6.4.10 
High Sensitivity C-reactive protein (hsCRP) ........................................ 48 
 
 48 
 
 48 
6.4.13 
Appropriateness of efficacy assessments .............................................. 48 
6.5 
Safety ..................................................................................................................... 48 
6.5.1 
QuantiFERON TB-Gold test or PPD skin test ...................................... 49 
6.5.2 
Hepatitis and human immunodeficiency virus (HIV) screen ................ 50 
6.5.3 
Chest x-ray or MRI ............................................................................... 50 


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6.5.4 
Physical examination ............................................................................ 50 
6.5.5 
Vital signs.............................................................................................. 50 
6.5.6 
Height and weight ................................................................................. 50 
6.5.7 
Electrocardiogram (ECG) ..................................................................... 50 
6.5.8 
Local tolerability (Injection site reactions) ........................................... 51 
6.5.9 
Laboratory evaluations .......................................................................... 51 
6.5.10 
Pregnancy and assessments of fertility ................................................. 51 
6.5.11 
Tolerability of secukinumab ................................................................. 52 
 
 52 
6.5.13 
Appropriateness of safety measurements .............................................. 52 
6.6 
Other assessments .................................................................................................. 52 
6.6.1 
Quality of Life questionnaires/ Patient reported outcomes (PROs) ...... 53 
 
 55 
6.6.3 
HLA-B27............................................................................................... 55 
 
 55 
7 
Safety monitoring .............................................................................................................. 56 
7.1 
Adverse events ....................................................................................................... 56 
7.2 
Serious adverse event ............................................................................................ 57 
7.3 
Liver safety monitoring ......................................................................................... 58 
7.4 
Renal safety monitoring ......................................................................................... 59 
7.5 
Pregnancy reporting ............................................................................................... 59 
8 
Data review and database management ............................................................................. 59 
8.1 
Site monitoring ...................................................................................................... 59 
8.2 
Data collection ....................................................................................................... 60 
8.3 
Database management and quality control ............................................................ 60 
8.4 
Data Monitoring Committee .................................................................................. 60 
8.5 
Adjudication Committee ........................................................................................ 60 
9 
Data analysis ...................................................................................................................... 61 
9.1 
Analysis sets .......................................................................................................... 61 
9.2 
Patient demographics and other baseline characteristics ....................................... 61 
9.3 
Treatments ............................................................................................................. 62 
9.3.1 
Study treatment ..................................................................................... 62 
9.3.2 
Prior and concomitant medication ........................................................ 62 
9.4 
Analysis of the primary variable ............................................................................ 63 
9.4.1 
Variable(s) ............................................................................................. 63 


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9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 63 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 63 
9.4.4 
Supportive analyses ............................................................................... 64 
9.5 
Analysis of other variables .................................................................................... 64 
9.5.1 
Secondary efficacy variables ................................................................. 64 
 
 67 
9.5.3 
Safety variables ..................................................................................... 68 
9.5.4 
Health-related Quality of Life ............................................................... 69 
 
 71 
9.5.6 
Pharmacogenetics .................................................................................. 72 
9.5.7 
Biomarkers ............................................................................................ 72 
9.6 
Interim analyses ..................................................................................................... 72 
9.7 
Sample size calculation .......................................................................................... 72 
9.8 
Power for analysis of secondary variables ............................................................. 72 
10 Ethical considerations ........................................................................................................ 73 
10.1 
Regulatory and ethical compliance ........................................................................ 73 
10.2 
Informed consent procedures ................................................................................. 73 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 74 
10.4 
Publication of study protocol and results............................................................... 74 
11 Protocol adherence ............................................................................................................ 74 
11.1 
Protocol Amendments ........................................................................................... 74 
12 References ......................................................................................................................... 75 
13 Appendices ........................................................................................................................ 78 
13.1 
Appendix 1: Clinically notable laboratory values ................................................. 78 
 
 79 
13.3 
Appendix 3: Modified New York criteria ............................................................. 80 
13.4 
Appendix 4: Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................................. 81 
13.4.1 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 81 
 
 81 
13.4.3 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 82 
 
 84 
13.6 
Appendix 6: Guidelines for administering the PRO questionnaires ...................... 85 
 


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List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 35 
Table 6-1 
Assessment schedule ............................................................................. 40 
Table 7-1 
Summary of power for binary endpoints .............................................. 72 
Table 7-2 
Summary of power for continuous endpoints ....................................... 73 
Table 8-1 
Safety Analyses: Expanded Limits and Notable Criteria ...................... 78 
 
 79 
 
 79 
 
 
List of figures 
Figure 3-1 
 Study design ......................................................................................... 21 
Figure 9-1 
Testing Strategy .................................................................................... 66 
 
 


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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 
Assessment of SpondyloArthritis International Society criteria  
 
  
ASQoL 
Ankylosing Spondylitis Quality of Life Questionnaire  
AST/SGOT 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Classification 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
 
 
BSL 
Baseline 
CFR 
Code of Federal Regulation 
COX 
Cyclooxygenase 
(e)CRF 
electronic case report form 
CRP (hsCRP) 
(high sensitivity) C-Reactive Protein 
DMARD 
Disease Modifying Anti-rheumatic Drug 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram  
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
EMA/EMEA 
European Medicines (Evaluation) Agency 
 
 
  
  
 
 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice  
GGT  
Gamma Glutamyl Transferase 
FSH 
Follicle-stimulating Hormone 
hCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 


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HLA 
Human Leukocyte Antigen 
HRQoL 
Health-Related Quality of Life 
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 
IL 
Interleukin 
IN 
Investigator Notification 
IQS 
Integrated Quantitive Sciences 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology  
i.v. 
intravenous 
LLN 
lower limit of normal 
 
  
MCS 
Mental Component Summary  
MedDRA  
Medical Dictionary for Regulatory Affairs  
MMRM 
mixed-effects model repeated measures 
MRI 
Magnetic Resonance Imaging  
MTX 
Methotrexate 
NSAID 
Non-Steroidal Anti-Inflammatory Drug  
OC/RDC 
Oracle clinical/remote data capture 
PCS 
Physical Component Summary  
PFS 
Prefilled Syringe  
PK 
Pharmacokinetic 
PPD 
Purified Protein Derivative 
PRO 
Patient Reported Outcome 
QoL 
Quality of Life  
RANKL 
Receptor Activator of Nuclear Factor Kappa-B Ligand 
RDC 
Remote Data Capture  
SAE 
Serious Adverse Event 
SCR 
Screening 
s.c. 
Subcutaneous 
SF-36 
Medical Outcome Short Form (36) Health Survey  
SpA 
Spondyloarthritis 


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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
t.i.d. 
ter in die, three times a day 
TNF/TNFα 
Tumor Necrosis Factor  
TNF-IR 
TNFα Inhibitor Incomplete Responders  
ULN 
Upper Limit of Normal 
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; the point at which informed 
consent must be obtained (i.e., prior to starting any of the procedures 
described in the protocol) 
Epoch / Period 
A portion of the study which serves a specific purpose. Typical Epochs 
are: screening/recruitment, wash-out, treatment, and follow-up 
Escape medication 
Any new therapeutic intervention or a significant change to ongoing  
therapy made because a subject is experiencing either no benefit from 
participation in the trial or worsening/ exacerbation of their disease 
Inadequate response to 
TNFα 
Active disease despite stable treatment with anti-TNFα for at least 3 
months at a stable dose or for at least one dose in case of lack of 
tolerance 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CRF 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 definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new treatment.” 
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage 
Medication number 
A unique identifier on the label of each investigational / study drug 
package 
Premature subject 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed for 
progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment 
Study drug/ treatment 
Any treatment administered to the subject as part of the required study 
procedures; includes investigational treatment and any control drugs 
Study/investigational 
treatment discontinuation 
Point/time when subject permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature subject 
withdrawal 
Subject number 
A number assigned to each 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 reason: 
Due to changes in the regulatory environment in China, a primary endpoint analysis can be 
implemented and used for submission purpose. This will allow a much earlier (approximately 
9 months) submission than originally planned. To enable this, an additional analysis will be 
performed after all patients have completed the Week 16 for the primary endpoint assessments. 
Although unblinding will occur after the Week 16 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 study (Week 60 Follow up) and the final 
database lock has occurred. 
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 the following sections “Purpose and timing of interim analyses / design 
adaptations” (Section 3.5), “Treatment blinding” (Section 5.4), and “Interim Analysis” (Section 
9.6) have been amended to reflect the rationale given above for the primary endpoint analysis.  
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. 
The changes herein do NOT affect the trial specific model ICF. 


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Protocol summary 
Protocol number 
CAIN457F2308 
Title 
A randomized, double-blind, placebo-controlled, phase III multicenter 
study of subcutaneous secukinumab in prefilled syringes, to compare 
efficacy at 16 weeks with placebo and to assess safety and tolerability 
up to 52 weeks in subjects with active Ankylosing Spondylitis  
Brief title 
 
Study of efficacy and safety of secukinumab in patients with Ankylosing 
Spondylitis 
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 Ankylosing 
Spondylitis 
Primary Objective(s)  
To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 
16 is superior to placebo in subjects with active AS based on the 
proportion of subjects achieving an ASAS20 (Assessment of 
SpondyloArthritis International Society criteria) response. 
Secondary Objectives 
To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 
16 is superior to placebo based on the proportion of subjects achieving 
an ASAS40 response  
To demonstrate that the efficacy of secukinumab 150 mg s.c. 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 s.c. at Week 
16 is superior to placebo based on the proportion of subjects meeting 
the ASAS 5/6 response criteria  
To demonstrate that the efficacy of secukinumab 150 mg s.c. 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 s.c. at Week 
16 is superior to placebo based on the change from baseline in Short 
Form 36 physical component score  (SF-36 PCS) 
To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 
16 is superior to placebo based on the change from baseline in 
Ankylosing Spondylitis Quality of Life score (ASQoL) 
To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 
16 is superior to placebo based on the proportion of subjects achieving 
an ASAS partial remission 
Overall safety and tolerability of secukinumab compared to placebo as 
assessed by vital signs, clinical laboratory values and adverse event 
monitoring 
Study design 
This is a randomized, double-blind, placebo-controlled study 


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Population 
The study population will consist of 450 male and female patients (≥18 
years) with moderate to severe AS who fulfill the modified New York 
criteria for ankylosing spondylitis with prior documented radiological 
evidence (x-ray or radiologist’s report). 
Patients must have a history of active AS and report active disease, as 
measured by the following three assessments: 
- total BASDAI ≥ 4 on a scale of 0-10 
- spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10cm) 
- total back pain as measured by VAS ≥ 40 mm (0-100 mm) 
Approximately 80% of randomized patients will be from China (360 
Chinese patients) in order to evaluate the efficacy and safety in this 
patient population. 
Inclusion criteria 
Patient must be able to understand and communicate with the 
investigator and comply with the requirements of the study and must 
give written, signed and dated informed consent before  any study 
assessment is performed 
Male or non-pregnant, non-lactating female patients  at least 18 years of 
age  
Diagnosis of moderate to severe AS with prior documented radiologic 
evidence (x-ray or radiologist’s report) fulfilling the Modified New York 
criteria for AS 
Active AS assessed by BASDAI ≥4 (0-10) 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 had inadequate response or failure to respond to 
at least 2 NSAIDs at an approved dose for a minimum of 4 weeks in 
total and a minimum of  2 weeks for each NSAID prior to randomization, 
or less than 4 weeks if therapy had to be withdrawn due to intolerance, 
toxicity or contraindications 
Patients  who are regularly taking NSAIDs (including COX-1 or COX-2 
inhibitors) as part of their AS therapy are required to be on a stable dose 
for at least 2 weeks before randomisation 
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 to 
entry into study after an appropriate wash-out period prior to 
randomization: 
- 4 weeks for Enbrel® or “Yi Sai Pu”® (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 (s.c. route) 
- 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 


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- 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, 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 
Exclusion criteria 
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 with total ankylosis of the spine 
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 the 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 for 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, investigational agents (e.g., CAMPATH, anti-CD4, 
anti-CD5, anti-CD3, anti-CD19) 
Traditional Chinese medicine treatment for AS four weeks before 
randomization 
Pregnant or nursing (lactating) women, where pregnancy is defined as 
the state of a female after conception and until the termination of 
gestation, confirmed by a positive hCG laboratory test 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods 
of contraception during the entire study or longer if required by locally 
approved prescribing information (e.g., 20 weeks in EU).  
Active ongoing inflammatory diseases other than AS that might 
confound the evaluation of the benefits of secukinumab therapy, 
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Underlying metabolic, hematologic, renal, hepatic, pulmonary, 
neurologic, endocrine, cardiac, infectious or gastrointestinal conditions 
which in the opinion of the investigator immunocompromised the patient 
and/or places the patient at unacceptable risk in case of use of 
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 status of class III or IV), 
uncontrolled diabetes or very poor functional status precluding ability to 
perform self-care 
History of clinically significant liver disease or liver injury indicated by 
abnormal liver function tests, such as SGOT (AST), SGPT (ALT), 
alkaline phosphatase and 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 (exception: 
common cold) prior to randomization 
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 or a positive QuantiFERON TB-Gold test  
Known infection with 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, in situ 
carcinoma 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) 
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 
Blood donation or loss of 400 mL or more 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 
Efficacy assessments 
Assessment of SpondyloArthritis International Society (ASAS) response 
criteria 
Patient’s global assessment of disease activity (on VAS scale) 


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Patient’s assessment of back pain intensity (on VAS scale) 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
 
 
 
hsCRP 
 
 
 
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 ASAS20 being tested is that there is no 
difference in the proportion of subjects fulfilling the ASAS20 criteria at 
Week 16 in the secukinumab 150 mg regimen versus placebo regimen. 
Key words 
Ankylosing spondylitis, AS, chronic inflammatory disease, inflammatory 
back pain, secukinumab, AIN457 
 


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1 
Introduction 
1.1 
Background  
Ankylosing spondylitis (AS) is a chronic inflammatory disease which belongs to a group of 
conditions known as spondyloarthritides. It is mainly characterized by involvement of the axial 
skeleton and the sacroiliac joints, but also affects peripheral joints, entheses and extra-articular 
organs. A significant proportion of patients may present with associated extra-articular 
manifestations such as uveitis, psoriasis, inflammatory bowel disease, cardiovascular and 
pulmonary abnormalities. Generalized osteoporosis as well as regional osteopenia are common 
in AS patients and predispose them to non-traumatic fractures in spite of young age and gender 
(male).  The presence of the HLA-B27 antigen is strongly associated with AS: 90–95% of 
patients with AS who have European or Chinese ancestry carry this marker. Prevalence of HLA-
B27 varies with ethnicity and is approximately 8% among the general population in China 
(Huang 2012). 
AS affects up to 1.1% of the population, is associated with significant morbidity and disability, 
and thus constitutes a major socioeconomic burden. The prevalence of AS in China has been 
reported to range from 0.2% to 0.54% and is similar to that seen in other parts of the world (Bao 
2014). 
The first-line drug treatment of mild AS consists of non-steroidal anti-inflammatory drugs 
(NSAIDs). Treatment of NSAIDs-refractory AS is hampered by the lack of efficacy of virtually 
all standard disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX). 
As an exception, peripheral arthritis associated with AS may respond to sulfasalazine. Tumor 
necrosis factor (TNF) blocking agents were successfully added to the armamentarium to treat 
AS (Braun 2002) and subsequently demonstrated prolonged efficacy during up to eight years 
of follow-up (Baraliakos 2011). However, upon discontinuation of TNF blockers, the disease 
relapses quickly (Baraliakos 2005), indicating that the inflammatory process may only be 
suppressed but not completely abolished. Results reported in the ASSERT study, the largest 
study ever conducted on Magnetic Resonance Imaging (MRI) evaluation of spinal lesions in 
AS, demonstrated a near complete resolution of inflammatory lesions at the 24 week time point 
with anti-TNF therapy (Braun 2006). However, in other reports, AS inflammatory bone lesions 
depicted by MRI did not completely disappear under TNF antagonist therapy over a six-month 
study period. The bone lesions persisted despite full clinical remission, which suggests that the 
inflammatory process was still smoldering (Zochling 2007). Structural damage may be 
significant and is usually irreversible, with both osteoproliferative and osteodestructive changes 
observed on imaging studies. Multiple modalities are currently used to detect early and late 
structural changes, such as MRI, conventional x-ray, quantitative computed tomography and 
dual energy x-ray absorptiometry scan. Classic radiographic findings include syndesmophytes, 
with progression to total spinal fusion in some cases. Radiographs of the sacroiliac joint often 
show sclerosis, erosion, and eventually fusion. 
Together, these observations indicate that other treatments are needed to treat patients who do 
not respond to TNF blockers and/or who have incomplete resolution of inflammatory changes 
as evidenced on MRI studies. Current treatment options for patients with intolerance or an 
inadequate response to anti-TNFα agents are limited due to slow onset of activity, inconvenient 


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maintenance i.v. dosing for some regimens, and safety concerns. Interleukin (IL)-17A 
antagonism by secukinumab represents a novel approach to interfere with the chronic 
inflammatory process by selectively targeting the predominant cytokine of the unique subset of 
helper Th17 cells, as well as other cells that play a role in inflammation. Animal data suggest 
that IL-17 blockade reduces receptor activator of nuclear factor kappa-B ligand (RANKL) 
dependent osteoclastogenesis upstream of TNF alpha (Koenders 2005). Serum sRANKL levels 
and sRANKL/ osteoprotegerin ratios are up-regulated in patients with AS and have a 
relationship with bone mineral density and radiological changes (Kim 2006). Notably, 
secukinumab showed very good efficacy in subjects with AS based upon results of the Proof of 
Concept study (CAIN457A2209), in which the ASAS20 (Assessment of Spondyloarthritis 
International Society criteria) response rate at Week 6 was achieved by approximately 60% of 
the patients. 
Assuming a potential role of Th17 cells in the inflammatory infiltrate in AS, it can be speculated 
that locally disturbed homeostasis of osteoclastogenic and osteoblastogenic mechanisms 
characteristic of spondyloarthritis (SpA) might be amenable to correction via IL-17 antagonism. 
1.2 
Purpose  
The purpose of this global study is to provide up to 52 weeks of efficacy, safety and tolerability 
data to support registration of secukinumab for subcutaneous self-administration in subjects 
with active AS despite current or previous NSAID, DMARD and/or anti-TNFα therapy. 
Efficacy and safety data may be used to support the registration of secukinumab in China and 
other countries with a significant population of Asian ethnicity, for the treatment of active AS.  
2 
Study objectives 
2.1 
Primary objective 
To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to placebo 
in subjects with active AS based on the proportion of subjects achieving an ASAS20 
(Assessment of SpondyloArthritis International Society criteria) response. 
2.2 
Secondary objectives 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects achieving an ASAS40 response  
2. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline of high sensitivity C-Reactive Protein (hsCRP)  
3. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects meeting the ASAS 5/6 response criteria  
4. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline in total Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) 


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5. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline in Short Form 36 physical component score  
(SF-36 PCS) 
6. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline in Ankylosing Spondylitis Quality of Life 
score (ASQoL) 
7. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects achieving an ASAS partial remission 
8. Overall safety and tolerability of secukinumab compared to placebo as assessed by vital 
signs, clinical laboratory values and adverse event monitoring 


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3 
Investigational plan 
3.1 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-group 
design. A screening (SCR) period running up to 10 weeks before randomization will be used to 
assess eligibility, followed by 52 weeks of treatment.  
At baseline, patients will be randomized to one of the two treatment groups: 
• Group 1: 300 patients, 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 
• Group 2: 150 patients, placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, 4, 8, and 12, 
followed by secukinumab 150 mg (1 mL, 150 mg/mL) administration every four 
weeks starting at Week 16 
The patients will be stratified at randomization according to the region (China and non-China). 
Approximately 80% of randomized patients will be from China (360 Chinese patients) in order 
to evaluate the efficacy and safety in this patient population. No more than 30% TNFα Inhibitor 
Incomplete Responders (TNF-IR) patients will be enrolled in the study.   
Starting at Week 16, all patients will switch to open-label secukinumab 150 mg, including all 
placebo patients; however, all patients and investigators/site staff will remain blinded to the 
original randomized treatment group assignment (150 mg vs placebo). Study treatment will 
continue up to Week 48. 
An end of treatment visit is to be done 4 weeks after last study treatment administration and a 
post treatment follow-up visit is to be done 12 weeks after last study treatment administration 
for all subjects (regardless of whether they complete the entire study as planned or discontinue 
prematurely). 
 


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Figure 3-1 
 Study design 
 
Subjects will be instructed in detail how to self-administer the s.c. injection using PFS. Each 
injection will be administered into an appropriate injection site of the body (thighs, arms, or 
abdomen). All injections will be performed at the study site. Site personnel may administer the 
injections to subjects who are not able to, or feel insecure to self-administer (see Section 5.5.4 
for more details). 
Rescue medication is not allowed until Week 20 (see Section 5.5.6 for more details). However, 
subjects who are deemed by the investigator not to be benefiting from the study treatment based 
on safety and efficacy assessments or for any reason of their own accord will be free to 
discontinue participation in the study at any time. 
3.2 
Rationale of study design 
The double-blind, randomized, parallel-group, placebo-controlled design used in this global 
study is aligned with Phase III trials of other biologics and is in accordance with EMA/EMEA 
(European Medical Agency) guidelines (EMEA 2009) and available precedent. The treatment 
duration of the placebo group was kept relatively short and the group will be re-assigned to 
active treatment at the end of the primary endpoint analysis. The blinding to original treatment 
assignment is maintained beyond the primary endpoint so as to ensure reliable efficacy and 
safety measures over time, although study treatment from Week 16 on will be open-label 
secukinumab 150 mg s.c., as all patients will be on this same dose for the remainder of the study 
through Week 48. The regular assessments of disease activity ensure that subjects who 
experience worsening of the disease in any of the treatment groups can exit the study upon their 
own wish or based on the advice of the investigator at any time.  
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dosing regimens in this study rely on dose-efficacy relationships observed in the following 
AS studies: 
• A proof of concept trial (CAIN457A2209)  
• Phase III trial CAIN457F2310 in AS 
4
20
8
12
16*
24
28
32
36
40
44
48
52
F60
Week   -10 to BSL
Group 1
Secukinumab 150 mg s.c. 
N=300
Group 2
Placebo s.c.
N=150
Randomization
Secukinumab 150 mg administration s.c.
Placebo to secukinumab administration s.c.
Primary Endpoint at Week 16
*


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• Phase III trial CAIN457F2305 in AS 
Dose selection: 
The AS trials CAIN457F2305 and CAIN457F2310 assessed the efficacy of both 75 mg and 150 
mg s.c. maintenance doses with loading regimens consisting of either intravenous 
(CAIN457F2305: 3 doses of 10 mg/kg given every 2 weeks at Weeks 0, 2, and 4) or 
subcutaneous doses (CAIN457F2310: 4 weekly doses matching the maintenance dose of either 
75 mg or 150 mg given at Weeks 0, 1, 2, and 3). The relative exposure of the i.v. loading 
regimen (e.g., 700 mg x 3 doses = 2100 mg total through Week 4 for an average 70 kg adult 
patient) was higher than the s.c. loading regimens of 75 mg and 150 mg (75 or 150 mg x 5 doses 
= 375 or 750 mg total, respectively, through Week 4) and, theoretically, would exceed the drug 
exposure obtainable with a 300 mg s.c. loading regimen (300 mg x 5 doses = 1500 mg total 
through Week 4). Although neither CAIN457F2305 nor CAIN457F2310 assessed a 300 mg 
dose, the observation that the higher exposure from the i.v. loading regimen in CAIN457F2305 
did not provide greater efficacy than the 150 mg s.c. loading regimen in CAIN457F2310 
suggests that doses higher than 150 mg would not provide an additional efficacy benefit in AS. 
Specifically, the ASAS20, ASAS40, and BASDAI responses seen 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) or s.c. (CAIN457F2310; 60.8% for i.v.-150 mg vs 28.7% for placebo; 
61.1% for 150 mg s.c. vs 28.4% for placebo for ASAS20, respectively), demonstrate that 150 
mg is sufficient to provide clinically and statistically significant efficacy, whereas higher doses 
of secukinumab do not confer additional benefit. Of note, the 75 mg s.c. loading/s.c. 
maintenance regimen tested in CAIN457F2310 did not achieve statistically significant 
improvements in any of the efficacy endpoints in a predefined testing hierarchy, including 
ASAS20, ASAS40, hsCRP, ASAS5/6, BASDAI, SF-36-PCS, ASQoL and ASAS partial 
remission. Therefore, the 75 mg dose will not be pursued in further studies. 
Subcutaneous administration in PFS: 
Subcutaneous administration of secukinumab would extend the treatment options available to 
subjects with AS, particularly those wishing to self-administer their therapy. Subcutaneous 
administration of secukinumab has been studied in multiple phase II (psoriasis and RA) and 
phase III trials (uveitis, psoriasis, psoriatic arthritis, AS and RA) at doses ranging from 25, 75, 
150, to 300 mg every 4 weeks. In all these studies, subcutaneous administration of secukinumab 
was well tolerated and did not demonstrate clinically meaningful levels of immunogenicity.  
Subcutaneous injection from prefilled syringes (PFS) will provide a better treatment experience 
and added convenience compared with a lyophilisate requiring reconstitution or intravenous 
dosing. Patients with chronic diseases who are able to self-inject their medication demonstrate 
greater control of their treatment schedule and treatment setting, thus allowing greater 
independence, better adherence, improved therapeutic outcomes and freedom in their social, 
domestic, and professional lives, which results in economic benefits to both the patient and the 
healthcare system (Kivitz 2006; Chilton 2008). Self-injection may also offer psychological 
benefits over administration by healthcare professionals, including improved self-esteem 
(Hamm 2000). 


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Bioequivalence between the secukinumab lyophilisate and PFS formulations have been 
established in study CAIN457A2106 in 150 healthy volunteers in which the pharmacokinetics, 
safety and tolerability of the PFS and the lyophilisate formulation were compared. The ratio of 
PK exposure point estimates and confidence intervals for the two formulations were within the 
0.8-1.25 boundaries and therefore, the PFS met the standard criteria for assuming 
bioequivalence. The use of the PFS was safe and well tolerated. Therefore, it is considered 
appropriate to use secukinumab in PFS in multiple pivotal phase III studies, including this study, 
in the same dose and regimen as in the phase III studies that used the lyophilisate formulation. 
In summary, initial administration with four weekly doses of secukinumab 150 mg s.c. followed 
by maintenance dosing every 4 weeks at the same s.c. dose in PFS is expected to provide a rapid 
onset of action and statistically significant treatment effect. 
3.4 
Rationale for choice of comparator 
A placebo arm up to the primary endpoint at 16 weeks is included in this study. Due to the 
nature of the disease and the outcome measures used (ASAS criteria), a placebo arm is 
necessary to obtain reliable efficacy measurements. The continuation of the placebo group can 
be supported from an ethical standpoint, as subjects can continue on a range of concomitant 
treatments. Moreover, the inclusion of a placebo group is in accordance with health authority 
guidelines including EMA and available precedent. 
3.5 
Purpose and timing of interim analyses/design adaptations 
Analyses may be done after all patients complete the Week 16 visit of the study and before the 
final end-of-study analysis to support health authority review. The final analysis will be 
conducted after all patients complete the study at Week F60.  
Although unblinding will occur after the Week 16 database lock, the original randomization to 
active treatment vs. placebo will remain blinded to all investigators, site personnel and patients 
until all patients have completed the study and the Week F60 database lock has occurred.  
3.6 
Risks and benefits  
The risk to subjects 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 (IB). 
As of Jul-2015, over 12000 subjects have been enrolled in both completed and ongoing studies 
with secukinumab, with over 9600 patients across various indications (plaque psoriasis, 
rheumatoid arthritis, AS, psoriatic arthritis, multiple sclerosis, uveitis, Crohn’s disease, dry eye, 
polymyalgia rheumatica) and healthy subjects having received secukinumab at doses ranging 
from single and multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c.  
The risk profile of secukinumab in AS is informed by the safety experience from arthritides and 
psoriasis trials. In the dose-ranging rheumatoid arthritis trial CAIN457F2201 (237 patients), the 
most common side effects were infections in about 20-30% of patients (most mild to moderate). 
Gastrointestinal disorders were experienced by 8-12% of patients, skin rashes by 7-10%, joint 


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and muscle aches by 5-8%, and headaches by 1-3% of patients. However, these side effects 
were also seen in patients who received placebo.  
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.  
Taking into account the available safety data for the individual risks outlined in the IB, the 
expected risk profile of secukinumab from a mechanism of action perspective is anticipated to 
be similar compared with other approved cytokine-targeting therapies. In some trials, infections 
were numerically higher in the secukinumab treatment groups than in the placebo cohorts, 
although no dose-dependent increase in rates of serious infections was observed. This indicates 
that there may not be a direct exposure related effect on host defense. The safety data from the 
completed studies do not suggest any unexpected safety risk of concern or any particular pattern 
of event clustering other than those outlined in the IB. From the standpoint of the overall risk 
benefit assessment, the current trial with secukinumab is justified. 
4 
Population 
The study population will be comprised of patients (≥18 years old at the time of consent) with 
moderate to severe AS who fulfill the modified New York criteria for ankylosing spondylitis 
(described in Appendix 3) with prior documented radiological evidence (x-ray or radiologist’s 
report). 
Patients must have a history of active AS and report active disease as measured by the following 
three assessments: 
• total BASDAI ≥ 4 on a scale of 0-10 
• spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10cm) 
• total back pain as measured by visual analog scale (VAS) ≥ 40 mm (0-100 mm) 
This is a global study and it is expected that approximately 450 subjects will be randomized. 
Approximately 80% of randomized patients will be from China (360 Chinese patients) in order 
to evaluate the efficacy and safety in this patient population. A screening failure rate of 30% 
and post-randomization drop-out rate of 10% at primary endpoint are anticipated. Enrollment 
will stop as soon as the target number of randomized subjects is reached. No more than 30% 
TNF-IR patients will be enrolled in the study. 
Patients can be re-screened only once and no study-related re-screening procedure should be 
performed prior to written re-consent by the subject. Mis-randomization occurs when a subject 
who does not meet all eligibility criteria receives a randomization number in IRT in error; mis-
randomized patients will be treated as screen failures and will not be re-screened. 


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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 written, signed and dated informed 
consent before  any study assessment is performed 
2. Male or non-pregnant, non-lactating female patients  at least 18 years of age  
3. Diagnosis of moderate to severe AS with prior documented radiologic evidence (x-ray or 
radiologist’s report) fulfilling the Modified New York criteria for AS (Appendix 3),  
4. Active AS assessed by BASDAI ≥4 (0-10) at Baseline 
5. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline 
6. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline 
7. Patients should have had inadequate response or failure to respond to at least 2 NSAIDs at 
an approved dose for a minimum of 4 weeks in total and a minimum of  2 weeks for each 
NSAID prior to randomization, or less than 4 weeks if therapy had to be withdrawn due to 
intolerance, toxicity or contraindications 
8. Patients  who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their AS therapy are required to be on a stable dose for at least 2 weeks before 
randomisation 
9. Patients who have been on a TNFα inhibitor (not more than one) must have experienced 
an inadequate response to previous or current treatment given at an approved dose for at 
least 3 months prior to randomization or have been intolerant to at least one administration 
of an anti-TNFα agent 
10. Patients who have previously been on a TNFα inhibitor will be allowed to entry into study 
after an appropriate wash-out period prior to randomization: 
a. 4 weeks for Enbrel® or “Yi Sai Pu”® (etanercept) – with a terminal half-life of 102 ± 
30 hours (s.c. route) 
b. 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (s.c. 
route) 
c. 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) (s.c. route) 
d. 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
e. 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days 
11. Patients taking MTX (≤ 25 mg/week ) or sulfasalazine (≤ 3 g/day) are allowed to continue 
their medication, 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 
12. Patients on MTX must be on stable folic acid supplementation before randomization 
13. 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 


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discontinued for 8 weeks prior to randomization unless a cholestyramine washout has 
been performed 
14. Patients taking systemic corticosteroids have to be on a stable dose of ≤10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study.  
1. 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 
2. Patients with total ankylosis of the spine 
3. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, 
morphine) 
4. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or 
the IL-17 receptor 
5. 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 
6. History of hypersensitivity to the study drug or its excipients or to drugs of similar 
chemical classes 
7. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization 
8. Any intramuscular corticosteroid injection within 2 weeks before randomization 
9. Patients previously treated with any biological immunomodulating agents except for those 
targeting TNFα 
10. Patients who have taken more than one anti-TNFα agent 
11. Previous treatment with any cell-depleting therapies, including but not limited to anti-
CD20, investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19) 
12. Traditional Chinese medicine treatment for AS four weeks before randomization 
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 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 the 
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 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
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• 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 subjects on the 
study, the vasectomized male partner should be the sole partner for that subject  
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: 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. 
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 AS that might confound the evaluation 
of the benefits 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 
immunocompromised the patient and/or places the patient at unacceptable risk in case of 
use of 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 
precluding ability to perform self-care 
18. History of clinically significant liver disease or liver injury indicated by abnormal liver 
function tests, such as SGOT (AST), SGPT (ALT), alkaline phosphatase and serum 
bilirubin. The investigator should be guided by the following criteria: 
• Any single parameter may not exceed 2 x the 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 laboratory error. 
• If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into direct and indirect reacting bilirubin.  


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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 (exception: common cold) prior to 
randomization 
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 HIV, hepatitis B or hepatitis C at screening or randomization 
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, in 
situ carcinoma 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. 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 
28. Blood donation or loss of 400 mL or more blood within 8 weeks before dosing 
29. History or evidence of ongoing alcohol or drug abuse within the last six months before 
randomization 
30. Plans for administration of live vaccines during the study period or 6 weeks prior to 
randomization 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 


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5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Novartis 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 
Subjects will be provided with detailed instructions and guidance on how to self-administer the 
s.c injection using the PFS and following the Instructions for Use (IFU). The investigational 
drug will be administered by the subject into the appropriate injection site of the body under the 
supervision of the site staff. Site staff will administer the injection to subjects who are not able 
or feel insecure to self-administer the PFS injection. 
Note: The prefilled syringes are packed in double-blinded fashion for the blinded portion of the 
study and do not need to be prepared by the study site.  
The study medication will be labeled as follows: 
• Double-blind Secukinumab and Placebo PFS will be labeled as AIN457 150mg/ 
1mL/Placebo. 
• Secukinumab PFS will labeled as AIN457 150mg/1mL 
5.1.2 
Additional study treatment 
No additional treatment beyond investigational treatment is requested for this trial. 
5.2 
Treatment arms 
At Baseline eligible subjects will be randomized to one of the following two treatment arms in 
a 2:1 ratio: 
• Group 1: Secukinumab 150 mg  
• Group 2: Secukinumab Placebo  
All Subjects will receive blinded treatment weekly starting at baseline, Weeks 1, 2, 3 and 4, 
followed by dosing every four weeks starting at Week 4 until Week 16.  At Week 16, Group 1 
patients will continue using secukinumab 150 mg and Group 2 patients will start receiving 
secukinumab 150 mg dosing every four weeks.  Treatment will be provided open-label from 
Week 16 onward, as all patients will be taking 150 mg s.c. every 4 weeks; however, subjects, 
investigators, and site staff will remain blinded to initial randomized group assignment. 
5.3 
Treatment assignment, randomization 
At baseline, all eligible subjects will be randomized to one of the treatment arms via Interactive 
Response Technology (IRT). The investigator or his/her delegate will contact the IRT after 


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confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of investigational treatment 
to be dispensed to the subject. The randomization number will not be communicated to any of 
the site staff. 
Starting at Week 16, subjects who have been randomized to placebo at baseline will receive 
secukinumab 150 mg up to Week 52. Although site personnel and subjects are unblinded to 
current treatment assignment after Week 16 (as all patients will be on secukinumab 150 mg 
starting at Week 16), original treatment assignment, as per baseline randomization, will remain  
blinded to the patient, investigator, and site personnel until after final database lock and analyses. 
The randomization numbers will be generated using the following procedure to ensure that 
original treatment assignment is unbiased and concealed from subjects and investigator staff. A 
subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational drug(s). 
The randomization scheme for subjects 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. Unblinding will occur after Week 16 database 
lock to support regulatory submission. However, subjects, investigators, site personnel and 
persons performing the assessments will remain blinded to original treatment assignment from 
the time of randomization until the final database lock and analyses are completed, 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 with the following 
exception: bioanalyst; (2) The identity of the original randomized treatments administered 
through Week 16 will be concealed up to the final database lock and analyses are completed 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. 
Other unblinding of treatment dose or original randomized treatment assignment before the 
final database lock and analyses are completed will only occur in the case of patient 
emergencies (see Section 5.5.12). 
The randomization codes associated with patients from whom 
 samples are taken will be 
disclosed to the bioanalyst who will keep 
 results confidential until database lock. The 
bioanalyst will have access to the randomization list to facilitate analysis of the 
 
 samples (i.e., to avoid the unnecessary analysis of placebo samples). Whenever 
needed or requested by the clinical team, the bioanalyst will share information from 
 
measurements before clinical database lock in a blinded fashion 
. 


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The hsCRP results from samples collected during the treatment period will be revealed only 
after the database lock and analyses are completed. 
5.5 
Treating the patient  
5.5.1 
Patient numbering  
Each subject is uniquely identified by a Subject Number which is composed by the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
subject, the Subject Number will not be reused. 
Upon signing the informed consent form, the subject 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 subject to register them in the IRT. The site should select the 
electronic case report form (eCRF) book with a matching Subject Number from the electronic 
data capture (EDC) system to enter data. 
If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the Screening Phase 
Disposition eCRF page. 
Subjects may be re-screened once and will receive a new Subject Number after they have been 
re-consented. Subjects who are mis-randomized cannot be re-screened; mis-randomization 
occurs when a subject who does not meet all eligibility criteria receives a randomization number 
in error. 
5.5.2 
Dispensing the investigational treatment  
Each study site will be supplied by Novartis with investigational treatment (150 mg 
secukinumab vs placebo) in packaging of identical appearance. 
The investigational treatment packaging for secukinumab/placebo has a 2-part label. A unique 
medication number is printed on each part of this label, which corresponds to placebo or active 
treatment. Investigator staff will identify the investigational treatment packages to dispense to 
the subject by contacting the IRT and obtaining the medication numbers. Immediately before 
dispensing the package to the subject, investigator staff will detach the outer part of the label 
from the packaging and affix it to the respective source document (Drug Label Form) for the 
subject. 
5.5.3 
Handling of study 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. 


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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 subject except for the medication number. 
The PFS (150 mg active/placebo) sealed in an outer box must be stored in a access 
controlled/locked refrigerator between 2°C and 8°C (36°F and 46°F) and protected from light 
and should not be frozen. They must be carefully controlled in accordance with regulations 
governing investigational medicinal products and local regulations. 
The investigator must maintain an accurate record of the shipment and dispensing of 
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.  
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all partly used and unused investigational treatment (including placebo), packaging, 
drug labels, and a copy of the completed Drug Accountability log to Novartis as instructed. 
Destruction of the unused drug should be done according to local requirements and after 
approval by Novartis clinical team. 
5.5.4 
Instructions for prescribing and taking study treatment  
All study treatment (150 mg secukinumab/placebo) will be self-administered by the subject 
subcutaneously throughout the study, at the study site, after the study assessments for the visit 
have been completed. Site staff will administer the injection only to those subjects who feel 
insecure to self-administer the PFS injection. 
Detailed instructions for self-administration of the study treatment will be given in the 
instructions for use (IFU) provided to each subject. Self-injection will take place under the 
supervision of a site staff member. At the randomization visit, the subject will be instructed by 
the site staff, utilizing the IFU on how to self-inject via prefilled syringes. Subjects will be asked 
to raise questions, if they have any, and then to proceed with self-injection of the study drug.  
The first study treatment administration will occur at the randomization visit after the 
inclusion/exclusion criteria have been confirmed, all study scheduled assessments have been 
performed and the scheduled blood samples have been drawn. 
At study visits when pre-dose blood has to be drawn (Table 6-1), the subject will self-inject the 
study treatment only after blood samples have been taken. All dates and times of injections self-
administered by the subject during the study must be recorded in the Dosage Administration 
Record eCRF. Immediately before dispensing the package to the subject, investigator staff will 
detach the outer part of the label from the packaging and affix it to that subject’s source 
document (Drug Label Form).  
Once the s.c. injection has been completed and the condition of the subject is deemed stable by 
the investigator or designated healthcare professional, the subject can be discharged 
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 


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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. 
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: 
Study treatment interruption is only permitted if, in the opinion of the investigator, a subject is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In such 
cases study treatment should be interrupted only during the time that this risk is present and 
ongoing. Study treatment can be restarted at the next scheduled visit after resolution of the 
safety risk.  
The effect of secukinumab on live vaccines is unknown; therefore, live vaccines should not be 
administered during participation in the study.  In case a live vaccine has been administered due 
to a medical urgency, study treatment should be interrupted for 12 weeks. 
Any study treatment interruption must be recorded on the Dosage Administration Record eCRF. 
5.5.6 
Escape medication 
Escape medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the trial or worsening/exacerbation of their disease. Escape medication must not be used before 
completion of Week 20 assessments. Although no subject will be restricted from receiving 
necessary escape medications for lack of benefit or worsening of disease, if escape with 
prohibited biologics (as described in Section 5.5.8) occurs, subjects will be discontinued from 
the study and enter into the follow-up period after an end of study visit.  Efficacy will be 
assessed in detail at every study visit, and subjects who are deemed not to be benefiting from 
the study treatment based on safety and efficacy assessments by the investigator or for any 
reason on their own accord will be free to discontinue participation in the study at any time. 
Changes in NSAID concomitant therapy are permitted after Week 20 assessments as per 
investigator’s clinical judgment. Please see Section 5.5.7 and Section 5.5.8 for details. 
Any use of escape medication must be recorded in the Prior/Concomitant medications eCRF. 
5.5.7 
Concomitant treatment  
The investigator should instruct the subject to notify the study site about any new medications 
(including over-the-counter drugs, traditional Chinese medicine, calcium and vitamins) 
administered after the subject was enrolled into the study. All medications (other than study 
treatment), procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) must be recorded on the Prior and Concomitant medications or Procedures and 
Significant Non Drug Therapy eCRF. The reason, name of the drug, procedure or non-drug 
therapy should be listed. 
Guidelines for the use of specific medications are provided below: 
Methotrexate 


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Subjects taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 52, except if MTX-related adverse events 
develop. 
Folic acid 
Subjects on MTX must be taking folic acid supplementation before randomization and during 
the trial to minimize the likelihood of MTX-associated toxicity. 
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 can 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 subjects who 
require a drug elimination procedure. A subject who has received 8 g t.i.d. for 11 days can be 
safely randomized 4 weeks after the beginning of the 11-day treatment period. 
Systemic corticosteroids 
Treatment with systemic corticosteroids is permitted up to a maximum daily dose of 10 mg 
prednisone equivalent and if the dose was stable within the 2 weeks preceding randomization.  
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after Week 20, 
although the corticosteroid dose should not be reduced by more than 1 mg prednisone equivalent 
every 4 weeks. 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 20. After Week 20, no more than 1 joint per 24-week period may be injected. 
No single injection should exceed 40 mg of triamcinolone (or equivalent) and the total dose of 
intra-articular corticosteroid may not exceed 80 mg of triamcinolone (or equivalent) during any 
52-week period. Injection of intra-articular steroids is not permitted within 8 weeks prior to 
Week 52. 
Any change in the dose of systemic corticosteroids, or any corticosteroid injections, during the 
trial must be recorded on the corresponding eCRF page. 
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 inhibitors), 
low strength opioids and acetaminophen/paracetamol 
Subjects regularly using NSAIDs, low strength opioids, or paracetamol/acetaminophen should 
be on stable dose for at least 2 weeks before randomization to allow inclusion. They should 
remain on a stable dose in the study up to Week 20. 
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN within the 
2 weeks before randomization can continue to do so in the study; however, they have to refrain 
from any intake during at least 24 hours before a visit with disease activity assessment. 
After Week 20 assessments are completed, a change in the NSAIDs, low strength opioids, or 
paracetamol/acetaminophen treatment regimen is permitted 


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Any change of the NSAIDs, low strength opioids, or paracetamol/acetaminophen treatment 
during the trial should be recorded on the appropriate prior and concomitant medication eCRF 
page. 
5.5.8 
Prohibited Treatment 
Table 5-1 
Prohibited treatment 
Prohibited treatments 
Washout period  
(before randomization) 
Etanercept* 
4 weeks 
Infliximab* 
8 weeks 
Adalimumab, golimumab, certolizumab* 
10 weeks 
Unstable dose of MTX or sulfasalazine 
4 weeks 
Other DMARD (except MTX or sulfasalazine) 
4 weeks  
Leflunomide 
8 weeks  
Leflunomide with Cholestyramine washout 
4 weeks 
Unstable dose of NSAIDs (COX1 or COX2 inhibitors) 
(until Week 20) 
2 weeks 
Systemic corticosteroids > 10 mg prednisone equivalent** 
2 weeks  
Intra-articular steroids injections  
(until Week 20) 
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 discontinuation (see Section 5.5.8). 
** See details about corticosteroid management in Section 5.5.7. 
5.5.9 
Discontinuation of study treatment and premature withdrawal 
Subjects 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 subject’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 (Week 52) 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 F60 (12 weeks after last study treatment; see Table 6-1). The final 
follow-up visit should be performed before any new treatment is initiated. Study treatment 
discontinuation must also be recorded in IRT. 
Subjects who are prematurely withdrawn 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 subject. The following circumstances 
require study treatment discontinuation: 
• Withdrawal of informed consent 
• Emergence of the following adverse events: 
• Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with an 
unacceptable concomitant medication 
• 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 
• Life-threatening infection 
• Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the subject at a safety risk for continuation in the study 
(A general guidance on clinically notable laboratory values is provided in Appendix 1.) 
• Pregnancy 
• Use of  any biologic immunomodulating agent except secukinumab 
• Any protocol deviation that results in a significant risk to the subject’s safety 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given subject if there is a lack of improvement or worsening 
of their symptoms, or if on balance, he/she thinks that continuation would be detrimental to the 
subject’s well-being. 
The appropriate personnel from the site and Novartis will assess whether study treatment should 
be discontinued for any subject whose treatment code has been broken inadvertently for any 
reason. 
The investigator must also contact IRT to register the subject’s discontinuation from study 
treatment. 
5.5.10 
Withdrawal of consent  
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 


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Withdrawal of consent occurs when a subject does not want to continue participating in the 
study any more, that is, the subject does not want any further visits, assessments, or study related 
contact, and does not allow analysis of already obtained biologic material. 
If a subject withdraws consent, the investigator must make every effort to determine the primary 
reason for this decision and record this information in the Withdrawal of Consent eCRF. Study 
treatment must be discontinued and no further assessments conducted. All biological material 
that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient are not allowed unless safety findings require communication or follow-up. 
5.5.11 
Loss to follow-up  
For subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the subject, 
e.g., dates of telephone calls, registered letters, etc. A patient should not be 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 code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study patient who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. 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 dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• study drug name (if available) 
• patient number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.  
Study drug must be discontinued after emergency unblinding. 
5.5.13 
Study completion and post-study treatment  
A subject will be considered to have completed the study if he/she received a maximum of 52 
weeks of study treatment and upon completion of the scheduled study assessments and 
procedures up to and including Visit F60.  


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Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation will be recorded on the appropriate Study Phase Completion eCRF page. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing medical care. This 
medical 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 for 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 
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 list all of the assessments and indicate with an “X” when the visits are performed. 
Subjects should be seen for all visits on the designated day, or as closely as possible to the 
originally planned visit schedule. 
For visits scheduled through Week 4, the study treatment should not be administered within 
less than 7 days after the previous administration. 
For visits scheduled after Week 4, the study treatment should not be administered within less 
than 14 days after the previous administration. 
Subjects who prematurely discontinue study treatment should return for the end of treatment 
visit (4 weeks after the last study treatment administration), as well as return for the follow-up 
visit (F60), 12 weeks after 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 wash out prior anti-
rheumatic medications and will have a duration of up to 10 weeks, during which time the subject 
will sign the ICF, be evaluated for eligibility and allowed sufficient time 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 prior to randomization in the next 4 
weeks. 


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• If the washout period is more than 4 weeks, the subject 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 should not happen greater than 4 weeks prior 
to randomization. 
All subjects evaluated at Screening Visit 1 and 2 for Inclusion/Exclusion criteria should not be 
screen failed on the basis of medications requiring washout, unless the subject will be unable 
to complete the washout in the appropriate time frame before randomization. 
 


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Table 6-1 
Assessment schedule 
 
Screening1 
Treatment period 
PTFU 
Week 
SV1 
-10 to   
-4 
SV2 
≤ -4 
BSL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52* 
F60* 
Obtain Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria2,3 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history / 
current medical 
conditions2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medications 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AS assessment and 
history of extra-axial 
involvement4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular medical 
history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
S 
 
S 
 
 
S 
S 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
X 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
PPD skin test5 or 
QuantiFERON TB-Gold 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV screen6 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or MRI7 
 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening1 
Treatment period 
PTFU 
Week 
SV1 
-10 to   
-4 
SV2 
≤ -4 
BSL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52* 
F60* 
Hematology, blood 
chemistry, urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
Serum pregnancy test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
X  
X 
ECG 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Randomization via IRT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On-site administration of 
s.c. study treatment via 
PFS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications / 
non-drug therapy 
X 
Update as necessary 
Adverse events / SAE 
(including reactions at the 
injection site) 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 
Patient’s assessment of 
back pain intensity (VAS) 
 
 
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 
BASDAI 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
SF-36  
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 


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Screening1 
Treatment period 
PTFU 
Week 
SV1 
-10 to   
-4 
SV2 
≤ -4 
BSL 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52* 
F60* 
ASQoL 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
High sensitivity C-reactive 
protein (hsCRP) 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
X 
HLA-B27 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel9 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Cardiovascular panel 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
Treatment period  
completion form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-up completion form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
S: source documentation, 
PTFU: post-treatment follow-up 
1 If the subject’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 eCRFs available at SV1. 
3 A copy of the x-ray or radiologist’s report must be kept in the source documentation. 


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4 The following eCRFs are to be completed: AS Disease background eCRF, Modified New York criteria for AS eCRF and History of extra-axial 
involvement eCRF.     
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 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. 
7 A chest x-ray or MRI is required if it was not performed and evaluated within 3 months prior to screening. The x-ray should be performed after it is 
certain the subject meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The x-ray may be replaced by an MRI 
assessment. 
8 AEs / SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page. 
9 Sample must be obtained fasting. 
* For all subjects who discontinue or withdraw from the study, the investigator should ensure that the subject completes an end of treatment visit) 4 
weeks after last study treatment, and also returns after an additional 8 weeks for a post-treatment follow-up (PTFU) visit, F60 (12 weeks after last study 
treatment).  
 


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6.1 
Information to be collected on screening failures  
Subjects may discontinue from the study prior to randomization. These subjects are considered 
screening failures.  
If a subject 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, AS 
Disease background eCRF, Modified New York criteria for AS eCRF, History of extra-axial 
involvement 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 subjects who have signed informed consent and enter the Treatment period 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 informed consent. 
6.2 
Patient demographics/other baseline characteristics  
Subject demographic and baseline characteristics data to be collected on all subjects and to be 
recorded in the eCRF include: 
• Date of birth, age, sex, race, ethnicity and source of subject referral 
• Relevant AS 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), number and type of previous DMARDs 
used, date of diagnosis of AS, previous AS therapies, functional status class according to 
the New York criteria, cardiovascular medical history and smoking history 
Whenever possible, diagnoses and not symptoms will be recorded. 
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, as well as prior and concomitant procedures (significant non-drug 
therapies) will be entered in the Prior/Concomitant medications or Significant non-drug 
therapies eCRF page, respectively. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in (Section 5.5.5).  
6.4 
Efficacy 
• Assessment of SpondyloArthritis International Society (ASAS) response criteria 


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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 
 
 
 
 
 
6.4.1 
Assessment of SpondyloArthritis International Society criteria (ASAS) 
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 
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) 
The ASAS Response Criteria (ASAS 20) 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% (ASAS40) 
ASAS 40 response is defined as 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. 
6.4.1.4 
ASAS partial remission criteria 
The ASAS partial remission is defined as a value not above 2 units in each of the four main 
domains on a scale of 10. 


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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 VAS 
ranging from none to very severe in response to 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 in response to the question “Based on your assessment, please indicate 
what strength of back pain at any time did you experience during the last week?” and “Based 
on your assessment, please indicate what strength of back pain at night did you experience 
during the last week?”. For ASAS calculation the total back pain will be used. 
6.4.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
subjects with AS. The questions were chosen on the basis of predominant 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 0 through 10 scale 
(captured as 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) 
BASDAI consists of a 0 through 10 scale (0 indicating no problem and 10 indicating 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. Peripheral 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 weight, the mean (average) of the two scores relating to morning 
stiffness is taken into account (questions 5 and 6). The resulting 0 to 10 score is added to the 
scores for questions 1 through 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 the disease and subjects 
with scores of 4 or greater are usually good candidates for either a change in their medical 
therapy or 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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6.4.10 
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 the response to treatment. 
Since the results of this test may unblind the 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. 
6.4.13 
Appropriateness of efficacy assessments  
The efficacy outcome measures used in this study are standard measures used across all AS 
trials and are required for regulatory filing. 
6.5 
Safety  
• QuantiFERON TB-Gold test or PPD skin test 


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• Hepatitis and human immunodeficiency virus (HIV) screen 
• Physical examination 
• Vital signs 
• Height and weight 
• Electrocardiogram 
• Local tolerability (injection site reactions) 
• Laboratory evaluations 
• Pregnancy and assessment of fertility 
• 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 known prior to randomization to determine the subject’s eligibility for the trial. The test 
will be used to screen the subject population for latent tuberculosis infection.  
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
PPD skin test 
A PPD skin test is to be performed at screening and read before randomization to determine the 
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. 


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6.5.2 
Hepatitis and human immunodeficiency virus (HIV) screen 
Screening for hepatitis and HIV is optional, based on the judgment of the investigator or if 
required by local regulations. If hepatitis testing is performed, testing will include hepatitis B 
surface antigen (HBsAg) and anti-HCV antibodies. If HIV testing is performed, positive HIV 
screening will be confirmed by a second technique available at the respective local laboratory, 
e.g., Western blot. 
6.5.3 
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. 
6.5.4 
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. 
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.  
6.5.5 
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. 
6.5.6 
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. 
6.5.7 
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
Single 12 lead ECGs are collected. The original ECGs (on non-heat-sensitive paper or a 
certified copy on non-heat sensitive paper), appropriately signed, must be collected and 
archived at the study site.  
Clinically relevant abnormalities for the baseline ECG should be recorded on the relevant 
medical history/Current medical conditions eCRF page. 
Clinically relevant abnormalities noted after the baseline ECG should be reported as AEs 
(Section 7). 


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6.5.8 
Local tolerability (Injection site reactions) 
Local tolerability at the site of s.c. injection of the study treatment will be assessed in case of 
any local reaction, and followed up until this has disappeared.  
The assessment of pain, redness, swelling, induration, hemorrhage and itching, including 
severity (mild, moderate, severe) and duration, will be performed by a physician and will be 
recorded on the Adverse Events eCRF. 
6.5.9 
Laboratory evaluations 
A central laboratory will be used for analysis of the specimens collected listed below, with the 
exception of 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 subjects with laboratory tests with clinically 
significant abnormal results are to be followed until the values return to normal ranges or until 
a valid reason, other than treatment related AE, is defined. 
6.5.9.1 
Hematology 
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled visits.  
6.5.9.2 
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. 
6.5.9.3 
Lipid panel 
A lipid profile including High Density Lipoprotein (HDL), Low Density Lipoprotein (LDL), 
cholesterol and triglycerides will be done from a fasting blood sample. 
6.5.9.4 
Cardiovascular panel 
A cardiovascular profile including lipoprotein (a), apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be done from a blood sample. 
6.5.9.5 
Urinalysis 
Dipsticks will be provided to the sites by the central laboratory 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. 
6.5.10 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test 
performed at the second screening visit, and local urine pregnancy tests as indicated in Table 6-
1. 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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6.5.11 
Tolerability of secukinumab  
Tolerability will be assessed by adverse events, laboratory values, injection site reaction 
 
. 
 
6.5.13 
Appropriateness of safety measurements 
The safety measures used in this study are reliable and relevant standard measures for a biologic 
in AS. 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 of infectious process, in particular, 
pulmonary tuberculosis. The radiation exposure that results from the chest x-ray safety 
measurements are estimated to be far below 1 mS.  For effective radiation doses under 3 mS 
(300 mrem), the risk is considered to be minimal. Therefore, the radiation exposure in this study 
involves minimal risk and is necessary to ensure adequate safety measures before the treatment 
with a biologic. 
The safety assessments selected are standard and adequate for this indication/subject population. 
6.6 
Other assessments 
• Quality of Life questionnaires/ Patient reported outcomes (PROs) 
 
 
• HLA-B27 
 
 


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6.6.1 
Quality of Life questionnaires/ Patient reported outcomes (PROs) 
The impact of AS on various aspects of subject's health-related quality of life (HRQoL) will be 
assessed by the following instruments: 
• SF-36 v2 (Acute form) 
• 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 subject seeing the 
investigator for any clinical assessment or evaluation. The subject should be given sufficient 
instruction, space, time and privacy to complete the questionnaire. The study coordinator should 
check the questionnaire for completeness and encourage the subject to complete any missing 
responses. Guidelines for administering the PRO questionnaires can be found in Appendix 6. 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 any unsolicited comments written by the subject. If AEs or SAEs are 
confirmed, then the physician must record the events. Investigators should not encourage the 
subjects 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 HRQoL of patients. Given the acute 
nature of this disease, version 2, with a 1-week recall period, will be used in this study.  


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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 scores indicate better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment". 
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 
subjects at baseline. 
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 adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The occurrence of AEs should be sought by non-directive questioning of the subject at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
subject during or between visits or through physical examination, laboratory test, or other 
assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in a subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patients and identifying adverse events. Alert ranges for labs 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) 
An SAE is 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 


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• 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 any of the following: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 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 to prevent one of the outcomes listed above. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements; see. 
All AE’s should be treated appropriately. Treatment may include one or more of the following: 
no action taken (i.e., further observation only); study treatment dosage adjusted/temporarily 
interrupted; study drug(s) permanently discontinued; concomitant medication given; non-drug 
therapy given. The action taken to treat the AE should be recorded on the Adverse Event eCRF. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of Investigator 
Notifications (IN). This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. 
The investigator should also instruct each subject to report any new AE (beyond the protocol 
observation period) that the patient, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse event 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 12 weeks after last administered dose of study treatment 
or 30 days after the subject has stopped study participation (whichever is later) must be reported 
to Novartis within 24 hours of learning of its occurrence. 


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Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
Information about all SAEs (either initial or follow-up information) is collected and recorded 
in English on the paper or electronic (OC/RDC) Serious Adverse Event Report Form (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 Drug Safety and Epidemiology 
Department. The telephone and fax number of the contact persons in the local department of 
Drug Safety and Epidemiology (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 OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an existing 
SAE. These data will automatically be submitted to Novartis DS&E immediately after 
investigator signature or 24 hours after entry, whichever occurs first. 
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 may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same investigational treatment that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected 
and reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or as per national regulatory requirements in participating countries. 
7.3 
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 on the liver of blocking IL-17A. Standard liver function tests will be obtained at regular 
intervals, but special measures for liver safety monitoring are not planned. 


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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 on the kidney of blocking IL-17A. 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 
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 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 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  
8.1 
Site monitoring  
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Novartis 
representative will review the protocol and eCRFs with the investigators and their staff. During 
the study, the Field Monitor will visit the site regularly to check the completeness of subject 
records, the accuracy of entries on the eCRFs, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 


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the presence of informed consent, adherence to the inclusion/exclusion criteria, documentation 
of SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be 
disclosed. 
8.2 
Data collection  
Designated investigator site 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 subject data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis 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 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. 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using IRT. The system will be supplied by a vendor, who will also 
manage the database. The database will be sent electronically to Novartis. 
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. 
8.4 
Data Monitoring Committee  
A Data Monitoring Committee is neither required nor planned for this study. 
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 reviewed in a blinded fashion and adjudicated as they occur during 
the conduct of the trial. 


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Details regarding the adjudication process will be available in the relevant secukinumab 
Adjudication Committee charter. 
9 
Data analysis  
Summary statistics for continuous variables will generally include the number of subjects (N), 
minimum, lower quartile, mean, median, upper quartile, and maximum. For categorical or 
binary variables, the number and percent of subjects in each category will be presented. P-
values presented will be two-sided unless otherwise specified. 
Inferential efficacy comparisons with placebo will be performed on the first 16 weeks of 
treatment.   
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 2 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 to which subjects will be eligible to be randomized: 
Secukinumab 150 mg regimen 
Placebo regimen   
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 (see Section 9.1 for 
details).  
9.1 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, misrandomized subjects (misrandomized in IRT) will be excluded 
from the randomized set.  
Misrandomized subjects are defined as those subjects who were mistakenly randomized in IRT 
prior to the site confirming all eligibility criteria were met and to whom no study medication 
was given. Misrandomized 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.  
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.  
9.2 
Patient demographics and other baseline characteristics 
Demographics and baseline characteristics 
The following common background and demographic variables will be summarized:  
• Gender, age, China / non-China, race, ethnicity, weight, height, and BMI 


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Baseline disease characteristics will also be summarized for the following variables: 
• Patient’s global assessment of disease activity and other ASAS components, hsCRP, 
 
prior use 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 AS (years), modified New York criteria for AS, HLA-B27, 
 
total back pain (VAS),
 total BASDAI score, spinal pain 
(BASDAI question #2) 
. 
Medical history 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. 
To establish a baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether or not a subject currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not exist for that 
subject. 
9.3 
Treatments 
9.3.1 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of 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 subjects with cumulative exposure levels (e.g. any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented. 
9.3.2 
Prior and concomitant medication  
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term. 


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The number and percentage of subjects receiving prior and concomitant ankylosing spondylitis 
therapy will be presented by randomized treatment group as well as the reasons for stopping 
their therapies (primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other). 
Prior or concomitant medication will be identified by comparing recorded or imputed start and 
end dates of medication taken to the reference start date. 
9.4 
Analysis of the primary variable 
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 9.5.1 
9.4.1 
Variable(s) 
The primary efficacy variable is response to treatment according to the ASAS20 criteria at 
Week 16. The analysis of the primary variable will be based on the FAS. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The statistical hypothesis for ASAS20 being tested is that there is no difference in the proportion 
of subjects fulfilling the ASAS20 criteria at Week 16 in the secukinumab 150 mg regimen 
versus placebo regimen. 
Let p0 denote the proportion of ASAS20 responders at Week 16 for Placebo regimen and p1 
denote the proportion of ASAS20 responders at Week 16 for Secukinumab 150 mg regimen 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0, i.e. 
H1: Secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS20 
response at Week 16  
The primary analysis will be conducted via logistic regression with treatment, randomization 
stratum (region) as factors and weight as a covariate. Odds ratios and 95% CI will be 
presented comparing secukinumab 150 mg 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.) 
will be handled as follows: 
1. Subjects who drop out of the trial for any reason will be considered non-responders from 
the time they drop out through week 16 
2. Subjects who do not have the required data to compute response (e.g. ASAS components) 
at baseline and at the specific time will be classified as non-responders. 
Patients who were unblinded prior to the scheduled time point will be considered non-
responders from the time of unblinding up to Week 16. The primary analysis will use the non-
responder imputation.  
Continuous variables (e.g. ASAS components) will be analyzed using a mixed-effects model 
repeated measures (MMRM) which is valid under the missing at random assumption. For 
analyses of these parameters, if all post-baseline values are missing then these missing values 
will not be imputed and this subject will be removed from the analysis of the corresponding 


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variable, i.e. it might be that the number of subjects providing data to an analysis is smaller than 
the number of subjects in the FAS. 
Data collected after Week 16 will be analyzed as observed cases, in general. 
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. These analyses will center on the 
deviations in model assumptions, and the treatment of missing data. 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, ASAS20 response at Week 16 will also be evaluated using a non-parametric 
ANCOVA model (Koch 1998) with the same independent variables as the logistic regression 
model. In addition, further logistic regression models may be conducted which explore the 
impact of other baseline or disease characteristics on response.  
The impact of missing data on the analysis results 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 data analysis 
9.5 
Analysis of other variables 
9.5.1 
Secondary efficacy variables  
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below. Secondary efficacy variables will be analyzed using the FAS population.   
9.5.1.1 
ASAS40 response at Week 16 
ASAS40 response at Week 16 will be evaluated using logistic regression with treatment, 
randomization stratum (region) as factors and weight as a covariate. 
9.5.1.2 
Change from baseline of hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature suggests that the data are  not 
normally distributed (Huffman 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, analysis visit, randomization stratum (region) 
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 regimen at different analysis visits will be 
determined from the comparisons performed between secukinumab regimen 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. 


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9.5.1.3 
ASAS 5/6 response at Week 16 
ASAS 5/6 response at Week 16 will be evaluated using logistic regression with treatment, 
randomization stratum (region) as factors and weight as a covariate. 
9.5.1.4 
Change from baseline in BASDAI at Week 16 
The change from baseline to Week 16 in total BASDAI will be analyzed using MMRM with 
treatment regimen, randomization stratum (region) and analysis visit as factors and weight and 
baseline score as continuous covariates. Treatment by analysis visit and baseline by analysis 
visit will be included as interaction terms in the model. An unstructured covariance structure 
will be assumed for this model. The significance of the treatment effects for secukinumab 
regimens at different analysis visits will be determined from the comparisons performed 
between secukinumab regimens and placebo and/or secukinumab at the appropriate analysis 
visits. 
9.5.1.5 
ASAS partial remission 
Response at Week 16 to ASAS partial remission criteria will be evaluated using a logistic 
regression model with treatment, randomization stratum (region) as factors and weight as a 
covariate. 
9.5.1.6 
Change from baseline of SF-36 PCS and ASQoL at Week 16 
See Section 9.5.4 Health-related Quality of Life. 
9.5.1.7 
Testing strategy 
The following hypotheses will be tested each at 5% level of significance in pre-specified order 
as mentioned below using fixed-sequence test such that a family-wise type-I-error of 5% is kept: 
Primary objectives: 
H1: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to signs 
and symptoms (ASAS20 response) at Week 16  
Secondary objectives: 
H2: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to signs 
and symptoms (ASAS40 response) at Week 16  
H3: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in hsCRP at Week 16  
H4: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS 
5/6 response at Week 16 
H5: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to  change 
from baseline in total BASDAI at Week 16  
H6: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in SF-36 PCS at Week 16  


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H7: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in ASQoL  at Week 16  
H8: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS 
partial remission criteria at Week 16  
Figure 9-1 
Testing Strategy 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed closed 
testing procedure. 


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9.5.3 
Safety variables 
9.5.3.1 
Adverse events 
Treatment-emergent adverse events (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 on or before last dose + 84 days) will be summarized overall and in the Chinese 
population.  
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one adverse 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. Serious adverse events will also be summarized.  
These summaries may be presented separately by study periods.  
As appropriate, the incidence of AEs will be adjusted by treatment exposure and presented per 
100 subject-years of exposure.  
Separate summaries will be provided for death, serious adverse event, other significant adverse 
events leading to discontinuation and adverse events leading to dose adjustment (including 
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A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
If adjudication of major cardiovascular events is required, a summary of those events as 
reported by the investigator and confirmed by adjudication will be provided. 
9.5.3.2 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). Descriptive summary statistics for the change 
from baseline to each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post-baseline values.  
For each parameter, the maximum change from baseline within each study period will be 
evaluated analogously.  
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented by visit as well as for most extreme values post-baseline. 
 
 
 
9.5.3.4 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. 
9.5.3.5 
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 will be evaluated based on FAS. 
9.5.4.1 
SF-36 
The following variables will be evaluated:  
• SF-36 domain scores 
• SF-36 PCS and MCS scores 
• SF-36 PCS responder (improvement of ≥ 2.5 points; Lubeck 2004) 


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For the change in SF-36 summary scores (PCS and MCS), between-treatment differences will 
be evaluated using MMRM. Treatment group, analysis visit and randomization stratum (region) 
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. The significance of the treatment effect for 
secukinumab regimen at different analysis visits will be determined from the comparisons 
performed between secukinumab regimen and placebo at the 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 and randomization stratum (region) 
as factors, baseline SF-36 PCS score 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. 
9.5.4.2 
ASQoL 
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using MMRM.  Treatment group, analysis visit, randomization stratum 
(region) 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 effect for secukinumab regimen at 
different analysis visits will be determined from the comparison performed between 
secukinumab regimens and placebo and/or secukinumab at the appropriate analysis visits. 
 
 
 
 
 


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9.5.6 
Pharmacogenetics 
Not applicable 
9.5.7 
Biomarkers 
Not applicable 
9.6 
Interim analyses 
The primary endpoint analysis will be performed after all patients complete Week 16 in order 
to support regulatory submission. As the primary analysis is scheduled at Week 16, no 
adjustment will be made to the testing strategy to control family-wise type I error rate for this 
analysis. 
9.7 
Sample size calculation 
The sample size calculation is driven by the patient exposure requirements in the study 
population. An overall type I error (2-sided) 5% will be used to control type I error. 
Secukinumab 150 mg regimen will be tested versus placebo with respect to the primary 
endpoint (ASAS20 response at Week 16). A sample size of 300 patients in secukinumab 150 
mg group and 150 patients in placebo group (randomization ratio = 2:1) is chosen in order to 
expose 300 patients to secukinumab for safety evaluation and also to achieve adequate power 
for the primary and secondary endpoints for this study. 
Analysis of an unpublished phase III study showed a placebo response rate of about 28.4% and 
active drug response rate of 61.1% after 16 weeks for ASAS20. Using these assumptions, 
overall, the power for the ASAS20 endpoint should be about 99% with 300 patients in 
secukinumab 150 mg group and 150 patients in placebo group based on Fisher’s exact test 
(nQuery Advisor 7.0).  
9.8 
Power for analysis of secondary variables 
A summary of the assumptions and power for the primary and secondary efficacy parameters 
using the same unpublished study is shown in Table 7-1 for binary endpoints and Table 7-2 for 
continuous endpoints.   
Table 7-1 
Summary of power for binary endpoints 
Endpoint 
Response Rate 
Power 
 
Secukinumab 150 mg 
(N=300) 
Placebo (N=150) 
ASAS20 
61.1% 
28.4% 
99% 
ASAS40 
36.1% 
10.8% 
99% 
ASAS5/6 
43.1% 
8.1% 
99% 
ASAS partial remission 
13.9% 
4.1% 
92% 


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Table 7-2 
Summary of power for continuous endpoints 
Endpoint 
Mean change from baseline 
Common 
standard deviation 
Power 
 
Secukinumab 150 
mg (N=300) 
Placebo (N=150) 
hsCRP 
-0.60 
0.12 
0.84 
99% 
Total BASDAI 
-2.19 
-0.85 
2.10 
99% 
SF-36 PCS 
6.06 
1.92 
6.65 
99% 
ASQoL 
-4.00 
-1.37 
4.45 
99% 
 
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. 
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 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. 


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10.3 
Responsibilities of the investigator and IRB/IEC  
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
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. 


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12 
References 
References are available upon request. 
Anandarajah AP, Schwarz EM, Totterman S, et al. (2008) The effect of etanercept on 
osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic 
arthritis. Ann Rheum Dis; 67:296-301. 
Baraliakos X, Landewe R, Hermann K-G, et al. (2005) Inflammation in ankylosing 
spondylitis: a systematic description of the extent and frequency of acute spinal changes using 
magnetic resonance imaging. Ann Rheum Dis; 64:730-734. 
Baraliakos X, Listing J, Fritz C, Haibel H, et al. (2011) Persistent clinical efficacy and safety 
of infliximab in ankylosing spondylitis after 8 years--early clinical response predicts long-
term outcome. Rheumatology (Oxford); 50(9):1690-9. 
Biomarkers Definitions Working Group. (2001) Biomarkers and surrogate endpoints: 
Preferred definitions and conceptual framework. Clinical Pharmacology & Therapeutics; 
69:89-95. 
Braun J, Brandt J, Listing J, et al. (2002) Treatment of ankylosing spondylitis with infliximab. 
A randomized controlled multicenter trial. Lancet; 359:1187-93. 
Braun J, Landewé R, Hermann K-G, et al. (2006) Major reduction in spinal inflammation in 
patients with ankylosing spondylitis after treatment with infliximab. Arthritis Rheum; 
54:1646-52. 
Bretz F, Maurer W, Brannath W, et al. (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28(4):586-604. 
Brown AK, Quinn MA, Karim Z, et al. (2006) Presence of significant synovitis in rheumatoid 
arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: 
evidence from an imaging study may explain structural progression. Arthritis Rheum; 
54:3761-73. 
 
 
Chilton F, Collett RA. (2008) Treatment choices, preferences and decision-making by patients 
with rheumatoid arthritis. Musculoskeletal Care.; 6:1–14. 
Davis JC, Revicki D, van der Heijde D, et al (2007) Health-related quality of life outcomes in 
patients with active ankylosing spondylitis treated with adalimumab: results from a 
randomized controlled study. Arthritis & Rheumatism; 57(6):1050-1057. 
 
 
  
EMA guidance document: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2003/09/WC5
00003439.pdf 
 


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Hamm R, Patel B, Whittlestone T, Persad R(2000) Patient self-injection: a new approach to 
administering luteinizing hormone-releasing hormone analogues. BJU Int; 86:840-842.  
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al. (2003) Assessment of enthesitis 
in ankylosing spondylitis. Ann Rheum Dis; 62:127-32. 
Huffman K, Samsa G, Slentz C, et al. (2006) Response of high-sensitivity C-reactive protein 
to exercise training in an at-risk population. Am Heart J; 152(4):793-800. 
Inman RD, David JC Jr, et al. (2008) Efficacy and safety of golimumab in patients with 
ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III 
trial. Arthritis Rheum; 58(11):3402-12. 
Kim HR, Lee SH, Kim HY, et al. (2006) Elevated serum levels of soluble receptor activator 
of nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients 
with ankylosing spondylitis. Rheumatology; 45(10):1197-200. 
Kivitz A, Cohen S, Dowd JE, et al.(2006) Clinical assessment of pain, tolerability, and 
preference of an autoinjection pen versus a prefilled syringe for patient self-administration of 
the fully human, monoclonal antibody adalimumab: the TOUCH trial. Clin Ther; 28:1619–
1629. 
Koch GG, Tangen CM, Jung JW, et al. (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statistics in Medicine; 17:1863-92. 
Koenders MI, Lubberts E, Oppers Walgreen B, et al. (2005) Blocking of interleukin-17 during 
reactivation of experimental arthritis prevents joint inflammation and bone erosion by 
decreasing RANKL and interleukin-1. Am J Pathol; 167:141-9. 
Lubeck, DP. (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis.  Pharmacoeconomics 22(1): 27-38. 
 
 
 
McHorney CA, Ware JE and Raczek AE C (1992) The MOS 36-Item Short-Form Health 
Survey (SF-36). Medical Care; 31: 247-263. 
 
 
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. 
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 Vollenhoven RF, Klareskog L. (2003) Clinical responses to tumor necrosis factor a 
antagonists do not show a bimodal distribution: Data from the Stockholm Tumor Necrosis 
Factor a Followup Registry. Arthritis Rheum; 48(6):1500–1503. 
Ware JE and Donald Sherbourne C (1992) The MOS 36-Item Short-Form Health Survey (SF-
36). Medical Care; 30: 473-483. 
 
 
 
Zochling J, Baraliakos X, Hermann KG, et al. (2007) Magnetic resonance imaging in 
ankylosing spondylitis. Curr Opin Rheumatol; 19:346-50. 
 


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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 at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel. 
Table 8-1 
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 
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: Assessment of SpondyloArthritis International 
Society criteria (ASAS) 
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 
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) 
13.4.1 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those 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 10cm 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. 


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13.4.3 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The BASDAI consists of a zero 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? 


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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 resulting 0 to 10 number is added to the 
scores from questions 1-4.  The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical 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: Guidelines for administering the PRO 
questionnaires 
Before trial begins 
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial and 
identify any items where a subject’s response might highlight issues of potential concern. For 
example, one question in the SF-36 asks ‘How much of the time in the past 4 weeks- have you 
felt downhearted and blue?’ If a subject responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator. 
Before completion 
• Subjects should be provided with the correct questionnaire 
• at the appropriate visits, and 
• in the appropriate language 
• Subjects should have adequate space and time to complete the questionnaires 
• Questionnaire should be administered before the clinical examination 
During completion 
• Administrator may clarify the questions but should not influence the response 
• Only one response for each question 
• Also see ‘Addressing Problems and Concerns’ 
After completion 
• Check for completeness and not for content* 
• Check for multiple responses that were made in error 
*However, any response which may directly impact or reflect the subject’s medical 
condition (e.g. noting of depression) should be communicated by the study coordinator to 
the investigator). 
Addressing Problems and Concerns 
Occasionally a subject may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below. 
The patient does not want to complete the questionnaire(s) 
Tell the subject that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental, and social health problems of subjects. Emphasize that this 
information is as important as any of the other medical information, and that the questionnaire(s) 
is simple to complete. Suggest that the questionnaire(s) may be different from anything the 
respondent has filled in the past. If the subject still declines, retrieve the questionnaires. Record 
the reason for the decline, and thank the subject. 


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The patient is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain subject responses by reading out loud each 
question, followed by the corresponding response categories, and entering the subject’s 
response. No help should be provided to the subject by any person other than the designated 
study coordinator. The coordinator should not influence subject responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim. 
The patient wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the subject provide responses to the 
questions. Unless specified in the study protocol proxy data are not an acceptable substitute for 
subject self-report. Subjects should be discouraged from asking a family member or friend for 
help in completing a questionnaire. 
The patient does not want to finish completing the questionnaire(s) 
If non-completion is a result of the subject having trouble understanding particular items, ask 
the subject to explain the difficulty. Re-read the question for them verbatim, but do not rephrase 
the question. If the respondent is still unable to complete the questionnaire, accept it as 
incomplete. Thank the subject. 
The 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 subject that his/her answers will be pooled with other subjects’ answers and 
that they will be analyzed as a group rather than as individuals. Tell the subject that completed 
forms are not routinely shared with treating staff, and that their responses will only be seen by 
you (to check for completeness), and possibly the investigator. Any response which may 
directly impact on or reflect their medical condition (e.g. noting of severe depression) will be 
communicated by the coordinator to the physician. 
The patient asks the meaning of a question/item 
While completing the questionnaire, some subjects might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the subject by rereading the 
question for them verbatim. If the subject asks to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question. Subjects should 
answer the questions based on what they think the questions mean. 
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 


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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. 

SAP_001.pdf: 
Clinical Development 
Secukinumab (AIN457) 
CAIN457F2308 / NCT02896127
A randomized, double-blind, placebo-controlled, phase III multicenter 
study of subcutaneous secukinumab in prefilled syringes, to compare 
efficacy at 16 weeks with placebo and to assess safety and tolerability up 
to 52 weeks in subjects with active Ankylosing Spondylitis 
Statistical Analysis Plan (SAP) Amendment 3 
Author: 
, Trial Statistician; 
, Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
August 16, 2018 
Number of pages: 
49 
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. 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and 
title impacted 
(Current) 
19-Mar-
2018 
Prior 
to DBL 
 
 
 
 
 
 
To provide separate 
summaries for SAEs and 
significant AEs by site in 
China 
Amendment 1 
13.1 
 
 
To align with the changes in 
the protocol to include a 
primary analysis after all 
patients have completed the 
Week 16 visit.  
Amendment 1 
14.0 
22-Jul-
2018 
Prior 
to DBL 
To clarify significant AE 
Amendment 2 
13.1 
22-Jul-
2018 
Prior 
to DBL 
To follow convention in seed 
specification in MI 
Amendment 2 
16.2.3.1 
16-Aug-
2018 
Prior 
to DBL 
Added sensitivity analyses 
for hierarchy variables using 
patient’s global assessment 
for disease activity (VAS)  
Amendment 3 
11.5 
 


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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 ................................................................................................................. 7 
4 
Subjects and treatments ....................................................................................................... 8 
4.1 
Analysis sets ............................................................................................................ 8 
4.2 
Treatment groups ..................................................................................................... 9 
5 
Subgroup definitions ........................................................................................................... 9 
6 
Assessment windows, baseline and post baseline definitions, missing data handling ........ 9 
7 
Subject disposition, background and demographic characteristics ................................... 10 
7.1 
Subject disposition ................................................................................................. 10 
7.2 
Background and demographic characteristics ....................................................... 10 
8 
Medical history .................................................................................................................. 11 
9 
Study treatment .................................................................................................................. 11 
10 Concomitant medication .................................................................................................... 11 
11 Efficacy evaluation ............................................................................................................ 12 
11.1 
Description of efficacy variables ........................................................................... 12 
11.2 
Description of health-related quality of life variables ........................................... 18 
11.3 
Handling of missing data ....................................................................................... 20 
11.4 
Analysis of primary variable ................................................................................. 21 
11.5 
Analysis of secondary variables ............................................................................ 22 
 
 25 
11.7 
Analysis of health-related quality of life variables ................................................ 27 
12 
 evaluations (change / add PD, 
/PD, Biomarkers, as needed) ........... 28 
 
 28 
12.2 
Pharmacogenetics .................................................................................................. 29 
12.3 
Biomarkers ............................................................................................................. 29 
12.4 
/PD .................................................................................................................... 29 
13 Safety evaluation ............................................................................................................... 29 
13.1 
Adverse events ....................................................................................................... 29 
13.2 
Laboratory data ...................................................................................................... 31 
13.3 
Vital signs .............................................................................................................. 33 
13.4 
Electrocardiogram (ECG) ...................................................................................... 34 
 
 34 


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13.6 
Compound specific safety evaluation .................................................................... 34 
14 Interim analyses ................................................................................................................. 35 
15 Determination of sample size ............................................................................................ 35 
15.1 
Power for analysis of secondary variables ............................................................. 35 
16 Appendix ........................................................................................................................... 36 
16.1 
Visit Windows ....................................................................................................... 36 
16.2 
Statistical methodology and assumptions .............................................................. 40 
16.2.1 
Analysis of continuous data .................................................................. 40 
16.2.2 
Analysis of binary and categorical data ................................................ 42 
16.2.3 
Imputation methods ............................................................................... 43 
16.2.4 
Crude incidence and related risk estimates ........................................... 46 
16.2.5 
Exposure adjusted incidence rate and related risk estimates ................ 47 
16.3 
Additional sample size considerations ................................................................... 47 
17 References ......................................................................................................................... 48 


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 List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase/ Glutamic Pyruvic Transaminase/ GPT 
AS 
Ankylosing Spondylitis 
ASAS 
Assessment of Spondyloarthritis International Society criteria 
 
 
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 
 
 
BSL 
Baseline 
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 
 
 
 
  
FAS 
Full Analysis Set 
GGT 
Gamma Glutamyl Transferase 
HLA 
Human Leukocyte Antigen 
IRT  
Interactive Response Technology 
IVRS / IWRS 
Interactive Voice Response System / Interactive Web Response System 
MAR 
Missing At Random 
 
 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed Model Repeated Measures 
MTX 
Methotrexate 


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NRI 
Non-Responder Imputation 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCS 
Physical Component Summary 
PD 
Pharmacodynamic 
PG 
Pharmacogenetic 
PK 
Pharmacokinetic 
PRN 
According to need, as required 
PRO 
Patient Reported Outcome 
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 
TNF 
Tumor Necrosis Factor  
TNF-IR 
TNFα Inhibitor Incomplete Responders 
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale 
 
 


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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 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 
The primary objective is to demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 
16 is superior to placebo in subjects with active AS based on the proportion of subjects 
achieving an ASAS20 (Assessment of SpondyloArthritis International Society criteria) 
response. 
The following are the secondary objectives: 
1. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects achieving an ASAS40 response  
2. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline of high sensitivity C-Reactive Protein (hsCRP)  
3. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects meeting the ASAS 5/6 response criteria  
4. To demonstrate that the efficacy of secukinumab 150 mg s.c. 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. at Week 16 is superior to 
placebo based on the change from baseline in Short Form 36 physical component score  
(SF-36 PCS) 
6. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the change from baseline in Ankylosing Spondylitis Quality of Life 
score (ASQoL) 
7. To demonstrate that the efficacy of secukinumab 150 mg s.c. at Week 16 is superior to 
placebo based on the proportion of subjects achieving an ASAS partial remission 
8. Overall safety and tolerability of secukinumab compared to placebo as assessed by vital 
signs, clinical laboratory values and adverse event monitoring 
3 
Data presentation 
To support China AS submission, tables and figures will be generated for Chinese population 
and overall separately. Listings will be generated for overall and will be sorted by region (China 
and non-China), except for the listing of randomization allocation to treatment which will be 
sorted by the randomization number. 
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. 


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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 2 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). The 2 
treatment groups represent the regimens subjects will be eligible to be randomized to for the 
first 16 weeks of the study. 
• Secukinumab regimen: 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 
• Placebo regimen: placebo (1 mL) s.c. PFS at BSL, Weeks 1, 2, 3, 4, 8, and 12, followed 
by secukinumab 150 mg (1 mL, 150 mg/mL) administration every four weeks starting at 
Week 16 
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 AIN457F2308 this is the first 16-weeks of 
treatment. Comparative efficacy will be performed based on the FAS population using the 
randomized treatment. Data collected after Week 16 will generally be summarized descriptively 
on the FAS population using treatment sequence. 
Efficacy data following treatment switch 
Data will also be presented after Week 16, by a combination of the ‘original’ and ‘switch’ 
treatment groups and will be referred to as treatment sequence. These treatment sequences 
represent the treatment combinations the subjects experience over the course of the entire trial 
in case of switch (e.g., placebo patients who are reassigned to 150 mg secukinumab at Week 
16). 
4 
All listings will be presented by treatment 
sequence.Subjects and treatments  
4.1 
Analysis sets 
The following analysis sets will be used in this trial: 


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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 IVR 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.  
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. 
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 
• Placebo     
• Treatment sequence: 
• AIN457 150 mg 
• Placebo – AIN457 150 mg 
• Switch treatments (for patients who cross-over): 
• AIN457 150 mg 
5 
Subgroup definitions 
The primary and secondary endpoints will be analyzed by region (China and non-China). 
Analyses by previous use of TNF-α inhibitor will also be provided for total population and 
Chinese population.   
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.  


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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 16.1. 
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 16, Week 52, 
Week 60), 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. 
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), 
 prior use (yes/no) of TNF-alpha inhibitors, use (yes/no) and separate dose of 
methotrexate (mg/week), sulfasalazine (g/day) and systemic corticosteroids (mg/day) at 
randomization, time since first diagnosis of AS (years), modified New York criteria for AS, 


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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). 
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 ankylosing spondylitis medical history will also be provided. 
Smoking history will be summarized by treatment group. 
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). For subjects who discontinue, this will be the subject’s 
last visit in the corresponding treatment period. 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 


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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 prior and concomitant surgeries and procedures will be summarized by primary 
system organ class and MedDRA preferred term. 
Prior surgeries and procedures are defined as surgeries and procedures done prior to first dose 
of study treatment. Any surgeries and procedures done between the day of first dose of study 
treatment and within 84 days after last dose will be a concomitant surgeries and procedures, 
including those which were started pre-baseline and continued into the period where study 
treatment is administered. 
The number and percentage of subjects receiving prior ankylosing spondylitis therapy will be 
presented by randomized treatment group as well as the reasons for stopping their therapies 
(primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other) and the total 
duration of exposure to ankylosing spondylitis therapies previously. 
Prior or concomitant medication will be identified by comparing recorded or imputed start and 
end dates of medication taken to the reference start date. 
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 
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: 


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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) 


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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 back pain and nocturnal 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?”. 
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). 
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 


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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 


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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 16 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 16. 
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.  


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Patients who are unblinded prior to the scheduled timepoint will be considered non-responders 
from the time of unblinding up to Week 16. The primary analysis will use non-responder 
imputation.  
Continuous variables (e.g., ASAS components) 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. Model will be based on randomized treatment (Week 1 
to Week 16). 
Data collected after Week 16 will generally be presented as ‘observed case’; i.e. all available 
data for each time point will be included in the analyses. 
11.4 
Analysis of primary variable 
The primary efficacy variable is response to treatment according to the ASAS20 criteria at 
Week 16. The analysis of the primary variable will be based on the FAS patients. 
Description 
The ASAS Response Criteria (ASAS20) 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.  
Statistical analyses 
The statistical hypothesis for ASAS20 being tested is that there is no difference in the proportion 
of subjects fulfilling the ASAS20 criteria at Week 16 in secukinumab regimen versus placebo 
regimen.  
Let p0 denote the proportion of ASAS20 responders at Week 16 for Placebo regimen and p1 
denote the proportion of ASAS20 responders at Week 16 for Secukinumab 150 mg regimen, 
In statistical terms, H1: p1 = p0, HA1: p1 ≠ p0,  i.e. 
H1: Secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS20 
response at Week 16  
The primary analysis will be conducted via logistic regression with treatment, randomization 
stratum (region) as factors and baseline weight as a covariate. Odds ratios and 95% CI will be 
presented comparing secukinumab 150 mg regimen to placebo. 
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, ASAS20 response at Week 16 will also be evaluated using a non-parametric 


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ANCOVA model (Koch 1998) with the same independent variables as the logistic regression 
model. 
Interactions between treatment and selected baseline demographics and disease characteristics 
will be explored. 
The impact of missing data on the analysis results of ASAS20 response 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 data analysis 
11.5 
Analysis of secondary variables 
The secondary efficacy variables include, 
• response to treatment at Week 16 according to the ASAS40 criteria  
• change from baseline in hsCRP  at Week 16 
• response to treatment at Week 16 according to the ASAS5/6 criteria 
• change from baseline in total BASDAI score at Week 16 
• change in SF-36 PCS from baseline at Week 16 
• change in ASQoL from baseline 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 objectives: 
H1: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to signs 
and symptoms (ASAS20 response) at Week 16  
Secondary objectives: 
H2: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to signs 
and symptoms (ASAS40 response) at Week 16  
H3: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in hsCRP at Week 16  
H4: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS 
5/6 response at Week 16 
H5: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to  change 
from baseline in total BASDAI at Week 16  
H6: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in SF-36 PCS at Week 16  


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H7: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to change 
from baseline in ASQoL  at Week 16  
H8: 
secukinumab 150 mg regimen is not different to placebo regimen with respect to ASAS 
partial remission criteria at Week 16  
Figure 11-1 
Testing strategy 
                                                                   
 
The family-wise error will be set to α=5% and it will be controlled with the proposed closed 
testing procedure. 
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 16 
The ASAS 40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in 
at least three of the four main domains and no worsening at all in the remaining domain. 
Response at Week 16 to ASAS40 in the FAS will be evaluated using a logistic regression model 
with treatment, randomization stratum (region) as factors and baseline weight as a covariate. 
Odds ratios and 95% CI will be presented for comparison performed between secukinumab and 
placebo at Week 16. 
hsCRP at Week 16 
For the hsCRP, since evidence from the literature would suggest that the data is not normally 
distributed (Huffman 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 hsCRP relative to baseline will be evaluated using a 
mixed-effect model repeated measures (MMRM) with treatment group, analysis visit, and 
randomization stratum (region) as factors and loge baseline hsCRP and baseline 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 will be determined 
from comparison performed between secukinumab regimen 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. 
ASAS 5/6 at Week 16 
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five domains. 
The proportion of subjects meeting the response criteria at Week 16 will be evaluated using a 
logistic regression model with treatment group, randomization stratum (region) as factors and 
baseline weight as a covariate. Odds ratios and 95% CI will be presented for comparison 
performed between secukinumab regimen and placebo at Week 16. 
BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
a mixed-effect model repeated measures (MMRM) with treatment group, analysis visit, and 
randomization stratum (region) as factors, baseline BASDAI score and baseline 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 secukinumab treatment effect at Week 16 will 
be determined from comparison performed between secukinumab regimen and placebo at Week 
16. 
SF-36 PCS and ASQoL at Week 16 
See Section 11.7. 


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ASAS partial remission at Week 16 
Response at Week 16 to ASAS partial remission criteria will be evaluated using a logistic 
regression model with treatment, randomization stratum (region) as factors and baseline weight 
as a covariate. Odds ratios and 95% CI will be presented for comparison performed between 
secukinumab regimen and placebo at Week 16. 
Sensitivity analysis for hierarchy variables using patient’s global assessment 
of disease activity (VAS) 
During the data cleaning review process prior to database lock, a patient was found to have had 
a baseline value for “patient’s global assessment of disease activity (VAS)” completed out of 
sequence during a post-baseline visit, as documented in the vendor’s audit trail. Since this 
variable is a component of ASAS20, ASAS40 and ASAS 5/6 that require the calculation of 
change from baseline, a sensitivity analysis using the same logistic regression analysis for these 
hierarchy variables excluding this baseline value will be done. 


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11.7 
Analysis of health-related quality of life variables 
Ankylosing Spondylitis Quality of Life (ASQoL)  
For the change in ASQoL scores, between-treatment differences in the change in ASQoL scores 
will be evaluated using a mixed effect repeated measures model (MMRM). Treatment group, 
analysis visit, randomization stratum (region) will be used as categorical factors and baseline 
ASQoL score and baseline 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 
secukinumab treatment effect at different analysis visits will be determined from comparison 
performed between secukinumab regimen and placebo at the appropriate analysis visits. 
The proportion of subjects with improvements from baseline in ASQoL score meeting or 
exceeding minimal clinically important difference (MCID) will also be analyzed using a logistic 
regression model with treatment and randomization stratum (region) as factors, baseline 
ASQoL score and baseline weight as covariates up to Week 16. Odds ratios and 95% CI will 
be presented for treatment comparison. Post Week 16 the proportion of responders will be 
descriptively summarized along with its 95% confidence intervals for each treatment sequence. 
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 a mixed effect repeated measures model (MMRM). Treatment group, 
analysis visit and randomization stratum (region) will be included as categorical factors and 
baseline SF-36 score (PCS or MCS) and baseline 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. The significance of the secukinumab treatment effect at different analysis visits will be 
determined from comparison performed between secukinumab regimen and placebo at the 
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 and randomization stratum (region) 


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as factors, baseline SF-36 PCS score and baseline weight as covariates up to Week 16. Odds 
ratios and 95% CI will be presented for treatment comparison. Post Week 16, the proportion of 
responders will be descriptively summarized along with its 95% confidence intervals for each 
treatment sequence. 
The SF-36 domain scores will be summarized. 
12 
 evaluations (change / add PD, 
/PD, 
Biomarkers, as needed) 


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12.2 
Pharmacogenetics 
Not applicable. 
12.3 
Biomarkers 
Not applicable. 
12.4 
PK/PD 
Not applicable. 
13 
Safety evaluation 
Summaries may performed separately for initial (Week 1-16) and entire treatment periods.  The 
analyses of the follow-up period will be limited to summaries for treatment-emergent adverse 
events, serious adverse events and risks based on adverse events. 
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 


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by primary system organ class and preferred term. Confidence intervals for the crude rate will 
be derived as described in Section 16.2.4.1. In addition, exposure time-adjusted incidence rates 
including 95% confidence intervals will be provided for the entire treatment period (see Section 
16.2.5.1). 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 the secukinumab group starting from the most common event. Summaries (crude incidences 
only) will also be presented for AEs by severity and for study treatment related AEs. If a 
particular AE ‘severity’ is missing, this variable will be listed as missing and treated as missing 
in summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable.  
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
requiring concomitant medication. 
Separate summaries will be provided for SAEs and significant AEs that led to treatment 
discontinuation or dose adjustment or interruption by site in China. 
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. 
A listing of non-treatment emergent adverse events will be provided. These adverse events 
occurred before the first dose of the study treatment.  The crude incidence rate will be provided 
without treatment information. 
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, labs, 
ECG and vital signs for each analysis period is described in Table 13-1.  
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/ 
ECG), lab 
criteria 
Day 1 – 
Week 16 
• 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 


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Analysis 
period 
AEs & SAEs 
AEs by 
severity 
Study drug 
related AEs 
AEs-SMQ 
Risk 
Notables for 
(vitals/ 
ECG), lab 
criteria 
• at the PT level for common AEs, which is defined as at least 2% of the patients in the AIN457 group during 
the initial treatment period or events that had an incidence rate of at least 5.0 cases per 100 subject-years in 
the AIN457 group during the entire treatment period 
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. 
13.2 
Laboratory data 
The summary of lab data will only include treatment emergent 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, 
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). 


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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 
 
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. 
Note: Grade 4 Hemoglobin events were defined as fatal anemia. 
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 
• LDL, cholesterol, triglycerides: 
• >=ULN  
• >1.5 x ULN  
• >2.5 x ULN 
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 13-3: 


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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) 
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). 
13.3 
Vital signs 
The summary of vital signs will only include treatment emergent data, which are defined as 
those vital sign measurements after the first dose of study treatment and on or before last dose 
+ 84 days. 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as: 
change from baseline = post-baseline value – baseline value 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 13-4: 


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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) 
The summary of ECG will only include treatment emergent 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 be 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.   
 
  
 
 
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. 


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14 
Interim analyses 
The primary analysis will be performed after all subjects have completed the Week 16 visit in 
order to support regulatory filing.  As the primary analysis is scheduled at Week 16, no 
adjustments will be made to the testing strategy to control the family-wise type I error. The 
investigators, site personnel and monitors will continue to remain blinded to the treatment each 
subject received at randomization all patients have completed the study (Week 60 Follow up) 
and the final database lock has occurred. Additional analyses may be performed to support 
interactions with health authorities, as necessary. 
15 
Determination of sample size 
The sample size calculation is driven by the patient exposure requirements in the study 
population. An overall type I error (2-sided) 5% will be used to control type I error. 
Secukinumab 150 mg regimen will be tested versus placebo with respect to the primary 
endpoint (ASAS20 response at Week 16). A sample size of 300 patients in secukinumab 150 
mg group and 150 patients in placebo group (randomization ratio = 2:1) is chosen in order to 
expose 300 patients to secukinumab for safety evaluation and also to achieve adequate power 
for the primary and secondary endpoints for this study. 
Analysis of an unpublished phase III study showed a placebo response rate of about 28.4% and 
active drug response rate of 61.1% after 16 weeks for ASAS20. Using these assumptions, 
overall, the power for the ASAS20 endpoint should be about 99% with 300 patients in 
secukinumab 150 mg group and 150 patients in placebo group based on Fisher’s exact test 
(nQuery Advisor 7.0).  
15.1 
Power for analysis of secondary variables 
A summary of the assumptions and power for the primary and secondary efficacy parameters 
using the same unpublished study is shown in Table 15-1 for binary endpoints and Table 15-2 
for continuous endpoints.   
Table 15-1 
Summary of power for binary endpoints 
Endpoint 
Response Rate 
Power 
 
Secukinumab 150 mg 
(N=300) 
Placebo (N=150) 
ASAS20 
61.1% 
28.4% 
99% 
ASAS40 
36.1% 
10.8% 
99% 
ASAS5/6 
43.1% 
8.1% 
99% 
ASAS partial remission 
13.9% 
4.1% 
92% 
Table 15-2 
Summary of power for continuous endpoints 
Endpoint 
Mean change from baseline 
Common 
standard deviation 
Power 
 
Secukinumab 150 
mg (N=300) 
Placebo (N=150) 
hsCRP 
-0.60 
0.12 
0.84 
99% 
Total BASDAI 
-2.19 
-0.85 
2.10 
99% 


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Endpoint 
Mean change from baseline 
Common 
standard deviation 
Power 
 
Secukinumab 150 
mg (N=300) 
Placebo (N=150) 
SF-36 PCS 
6.06 
1.92 
6.65 
99% 
ASQoL 
-4.00 
-1.37 
4.45 
99% 
 
16 
Appendix 
16.1 
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 (W60) 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 16-1 
Analysis visit windows 
Analysis 
Visit 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 1 
8 
2-11 
2-11 
 
 
 
 
 
Week 2 
15 
12-18 
12-18 
2-22 
 
 
 
 
Week 3 
22 
19-25 
19-25 
 
 
 
 
 
Week 4 
29 
26-43 
26-43 
23-43 
2-71 
 
 
2-57 
Week 8 
57 
44-71 
44-71 
44-71 
 
 
 
 
Week 12 
85 
72-99 
72-99 
72-99 
 
 
 
58-99 
Week 16 
113 
100-127 
100-127 
100-127 
72-141 
2-141 
2-239 
100-141 
Week 20 
141 
128-155 
128-155 
128-155 
 
 
 
 
Week 24 
169 
156-183 
156-197 
156-197 
142-267 
142-267 
 
142-197 
Week 28 
197 
184-211 
 
 
 
 
 
 
Week 32 
225 
212-239 
198-253 
198-253 
 
 
 
198-253 
Week 36 
253 
240-267 
 
 
 
 
 
 
Week 40 
281 
268-295 
254-323 
254-323 
 
 
 
254-323 
Week 44 
309 
296-323 
 
 
 
 
 
 
Week 48 
337 
324-351 
 
 
 
 
 
 
Week 52 
365 
352-379 
324-379 
324-379 
268-379 
268-379 
240-379 
352-379 
Week 56 
393 
380-407 
 
 
 
 
 
 
Week 60 
421 
408-435 
380-435 
380-435 
380-435 
380-435 
380-435 
380-435 
Group1: Patient’s global assessment of disease activity (VAS), Patient’s assessment of back pain intensity 
(VAS), BASFI, BASDAI, Vital signs, hematology, blood chemistry, urinalysis 
Group2: 
 
 hsCRP 
Group3: SF-36,  
 
, 
, ASQoL, 
 
 Lipids 


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Analysis 
Visit 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group4: 
, Weight, 
 Cardiovascular panel  
Group5: ECG 
Group6: Urine pregnancy test 
* The first day of administration of randomized study treatment (first dose) is defined as Day 1. 


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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 16-2 
Rules for flagging variables 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
The last measurement made prior to administration of the first dose of study 
treatment – note this may include measurements taken on the day of 
randomization (e.g. lab). Baseline assessments scheduled for and captured on 
Day 1 will be considered baseline measurements regardless of the time of 
assessment. If a patient did not receive any dose of study treatment then the 
randomization date will be used. 
Only the date part will be considered if there is only one assessment on Day 1 
but if there are multiple assessments on Day 1, then the following rules will 
apply: 
1. If time of assessment exist, 
• 
select the last available measurement prior to the reference start 
date/time considering time 
• 
if no measurement prior to the reference start date/time then 
considering time select the earliest measurement post reference start 
date/time 
2. If time of assessment does not exist the measurement from the lowest 
CRF visit number will be used. 
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 from placebo to AIN 
within the window the following rules apply: 
1. 
If the analysis visit window is ≤ week 16, then 
• 
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 then the closest 
measurement after the switch to target will be used 
2. 
If the analysis visit window is > week 16, then 
• 
If available, the closest measurement to the target date which is 
after the switch date will be used 
• 
If there are no data after the switch then the closest to target before 
or on the switch date will be use 
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 use 
• 
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 from placebo to AIN 
within the window the following rules apply: 
1. 
If the analysis visit window is ≤ week 16, then 


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Timing of measurement 
Type of data 
Rule 
• 
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 then the closest 
measurement after the switch to target will be used 
2. 
If the analysis visit window is > week 16, then 
• 
If available, the closest measurement to the target date which is 
after the switch date will be used 
• 
If there are no data after the switch then the closest to target before 
or on the switch date will be use 
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 
• 
If CRF visit number is the same the average value 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 
16.2 
Statistical methodology and assumptions 
16.2.1 
Analysis of continuous data 
16.2.1.1 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.  
16.2.1.2 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; 
model outcome = treatment strata 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 secukinumab and placebo can be obtained. 


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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; 
model outcome = treatment strata visit baseline weight treatment*visit baseline*visit / 
ddfm=kr; 
repeated visit / type=un subject=; 
lsmeans treatment*visit / diff cl; 
run; 
Least-square-mean (LSM) estimates for each treatment group and LSM difference, confidence 
intervals and p-value for the difference between secukinumab and placebo 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 type=cs. If still no convergence, perform step 2. 
2. remove covariates in the following order until convergence: weight, baseline*visit, strata.  
16.2.1.3 Non-parametric analysis of covariance 
A non-parametric ANCOVA model (Koch 1998) will be used as sensitivity analysis for certain 
binary endpoints and also for continuous endpoints that risk having a large deviation from a 
normal distribution. 
The macro NParCov3 will be used (Zink 2012). Input dataset to the macro should only contain 
the two treatments to be compared and only data from one visit. 
The macro call will follow the below templates where covariates (in numeric format only) may 
be added or removed as required (max one strata variable can be specified). 
For continuous variables 
%nparcov3(outcomes=outcome, covars=cov1 cov2, c=1, hypoth=alt, strata=strata, 
trtgrps=treatment, transform=none, combine=first, dsnin=, dsnout=out); 
Data sets “_out_deptest” and “_out_ci” will be automatically created by the macro and contains 
the following: 
• “_out_deptest” provides estimate and p-value for the treatment difference, and 
• “_out_ci” provides a 95% confidence interval for the treatment difference. 


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For binary variables 
%nparcov3(outcomes=outcome, covars=cov1, c=1, hypoth=alt, strata=strata, 
trtgrps=treatment, transform=logistic, combine=first, dsnin=, dsnout=out); 
The odds ratio and confidence interval can be obtained from “_out_ratioci”. 
16.2.2 
Analysis of binary and categorical data 
16.2.2.1 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 
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*trt/ riskdiff; 
run; 
Note the response value should be sorted with ‘1’ ahead of ‘0’. 
16.2.2.2 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: 


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ods output diffs=lsm_diff convergencestatus=conv_status; 
proc logistic data=; 
by visit; 
class treatment strata / param=glm; 
model response = treatment strata weight; 
lsmeans treatment / diff cl exp; 
run; 
In cases where separation is a concern, 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: 
ods output exactoddsratio=exact_or; 
proc logistic data=data exactonly; 
by visit; 
class treatment strata / param=ref; 
model response = treatment strata; 
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. 
16.2.3 
Imputation methods 
16.2.3.1 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 


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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=4572308 nimpute=100 out=mi_out; 
by treatment; 
class strata; 
fcs reg (/details); 
var strata 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 
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 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=; 


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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:  
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 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. 


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16.2.4 
Crude incidence and related risk estimates  
16.2.4.1 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. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses. 
16.2.4.2 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. 


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16.2.4.3 Risk difference 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, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0.  
Exact unconditional confidence limits for the risk difference can be obtained with SAS 
procedure PROC FREQ and option RISKDIFF in the TABLES statement, specifying the 
RISKDIFF option also in the EXACT statement.   
16.2.5 
Exposure adjusted incidence rate and related risk estimates 
16.2.5.1 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.   
Table 16-3 
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 
16.3 
Additional sample size considerations 
There are no additional sample size considerations for this study. 


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17 
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