Conditions: Ankylosing Spondylitis
Keywords: Ankylosing Spondylitis NSAID ASAS ASAS-NSAID score Secukinumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 211
Healthy volunteers: no

Brief summary:
This study assessed the clinical Assessment of SpondyloArthritis international Society (ASAS) 20 response to secukinumab and evaluated to which extent concomitant nonsteroidal anti-inflammatory drug (NSAID) treatment can be reduced in patients treated with secukinumab or placebo following an initial run-in phase of stable NSAID therapy.

Detailed description:
This was a phase IV, 20-week, randomized, double-blind, 3-arm, placebo-controlled, parallel-group, multicenter study to examine the clinical response of secukinumab treatment in patients with ankylosing spondylitis as measured by the Assessment of SpondyloArthritis international Society (ASAS) 20 response and the nonsteroidal anti-inflammatory drug (NSAID)-sparing effect. This study evaluated to which extent nonsteroidal anti-inflammatory drug (NSAID) treatment can be reduced between Week 4 and Week 12 in patients randomized to secukinumab 150 mg or placebo following an initial run-in phase of 4 weeks on stable NSAID therapy. Two NSAID tapering approaches were evaluated in this study:

1. an early tapering approach in which NSAID were tapered at the start of secukinumab treatment,
2. a delayed tapering approach in which NSAID were tapered following 4 weeks of secukinumab treatment.

Patients were randomized 1:1:1 to one of the following treatment groups:

* Secukinumab - delayed NSAID tapering: Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).
* Secukinumab - early NSAID tapering: Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).
* Placebo: Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.

The primary objective of the study was to demonstrate that the efficacy of secukinumab 150 mg subcutaneous (s.c.) injection (with NSAID tapering) is superior to placebo based on the proportion of patients achieving an ASAS20 response at Week 12. To show superiority, both secukinumab treatment arms were pooled and compared against placebo.

Arms:
arm 1: Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind.

NSAID tapering allowed from Week 4 (delayed tapering). arm 2: Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind.

NSAID tapering allowed from Week 4 (early tapering). arm 3: Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20).

NSAID tapering allowed from Week 4.

Interventions: intervention 1: Secukinumab (AIN457) 150 mg s.c. intervention 2: Secukinumab (AIN457) 150 mg s.c. intervention 3: Placebo - Secukinumab (AIN457) 150 mg s.c.
Intervention descriptions: intervention 1: Induction: 5 x 150 mg secukinumab s.c. weekly Maintenance: 4 x 150 mg secukinumab s.c. every 4 weeks Delayed NSAID tapering (tapering following 4 weeks of secukinumab treatment). intervention 2: Induction: 5 x 150 mg secukinumab s.c. weekly Maintenance: 3 x 150 mg secukinumab s.c. every 4 weeks Early NSAID tapering (tapering at the start of secukinumab treatment). intervention 3: Placebo for 15 weeks. From Week 16 on, 5 x 150 mg secukinumab s.c. weekly.

Protocol document:
Prot_000.pdf: 
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Amended Protocol Version v01 Clean  
CAIN457FDE03 
Global Clinical Development - General Medicine 
CAIN457/ Secukinumab  
Clinical Trial Protocol CAIN457FDE03 / NCT02763046 
A randomized, double-blind, placebo-controlled multicenter 
study of Secukinumab (AIN457) to examine the clinical 
efficacy and the NSAID-sparing effect of Secukinumab over 
16 weeks in patients with ankylosing spondylitis (ASTRUM) 
Authors: 
 
Document type: 
Clinical Trial Protocol  
EUDRACT number: 
2015-004575-74 
Version number: 
v01 
Development phase: 
Phase IV 
Release date: 
10-Dec-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 ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
Glossary of terms ................................................................................................................. 8 
1 
Introduction ....................................................................................................................... 10 
1.1 
Background ............................................................................................................ 10 
1.2 
Purpose .................................................................................................................. 11 
2 
Study objectives ................................................................................................................. 12 
2.1 
Primary objective ................................................................................................... 12 
2.2 
Secondary objectives ............................................................................................. 12 
2.3 
Exploratory objectives ........................................................................................... 13 
3 
Investigational plan ........................................................................................................... 15 
3.1 
Study design .......................................................................................................... 15 
3.2 
Rationale of study design ...................................................................................... 17 
3.3 
Rationale of dose/regimen, route of administration and duration of treatment ..... 17 
3.4 
Rationale for choice of comparator ....................................................................... 18 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 18 
3.6 
Risks and benefits .................................................................................................. 18 
4 
Population .......................................................................................................................... 21 
4.1 
Inclusion criteria .................................................................................................... 21 
4.2 
Exclusion criteria ................................................................................................... 22 
5 
Treatment ........................................................................................................................... 25 
5.1 
Protocol requested treatment ................................................................................. 25 
5.1.1 
Investigational treatment ....................................................................... 25 
5.1.2 
Additional study treatment .................................................................... 26 
5.2 
Treatment arms ...................................................................................................... 26 
5.3 
Treatment assignment, randomization ................................................................... 26 
5.4 
Treatment blinding ................................................................................................ 27 
5.5 
Treating the patient ................................................................................................ 27 
5.5.1 
Patient numbering ................................................................................. 27 
5.5.2 
Dispensing the investigational treatment .............................................. 27 
5.5.3 
Handling of study treatment .................................................................. 28 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 28 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 29 
5.5.6 
Rescue medication ................................................................................ 30 
5.5.7 
Concomitant treatment .......................................................................... 30 


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5.5.8 
Prohibited treatment .............................................................................. 31 
5.5.9 
Discontinuation of study treatment ....................................................... 32 
5.5.10 
Withdrawal of consent .......................................................................... 33 
5.5.11 
Loss to follow-up .................................................................................. 34 
5.5.12 
Emergency breaking of assigned treatment code .................................. 34 
5.5.13 
Study completion and post-study treatment .......................................... 34 
5.5.14 
Early study termination ......................................................................... 35 
6 
Visit schedule and assessments ......................................................................................... 35 
6.1 
Information to be collected on Screening failures ................................................. 41 
6.2 
Patient demographics/other baseline characteristics ............................................. 41 
6.3 
Treatment exposure and compliance ..................................................................... 41 
6.4 
Efficacy .................................................................................................................. 41 
6.4.1 
Assessment of ASAS-NSAID score ..................................................... 42 
6.4.2 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................. 42 
6.4.3 
Patient’s global assessment of disease activity (VAS) ......................... 43 
6.4.4 
Patient’s assessment of back pain intensity (VAS) ............................... 43 
6.4.5 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 43 
6.4.6 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 43 
6.4.7 
Bath Ankylosing Spondylitis Metrology Index (BASMI linear) .......... 43 
6.4.8 
Medical Outcome Short Form Health Survey (SF-36) Version 2 
(Acute Form) ......................................................................................... 44 
6.4.9 
ASAS Health Index ............................................................................... 44 
6.4.10 
High sensitivity C-reactive protein (hsCRP) ......................................... 44 
6.4.11 
Erythrocyte sedimentation rate (ESR) .................................................. 45 
6.4.12 
Appropriateness of efficacy assessments .............................................. 45 
6.5 
Safety ..................................................................................................................... 45 
6.5.1 
QuantiFERON TB-Gold test or PPD skin test ...................................... 45 
6.5.2 
Chest X-ray or MRI .............................................................................. 46 
6.5.3 
Physical examination ............................................................................ 46 
6.5.4 
Vital signs.............................................................................................. 46 
6.5.5 
Height and weight ................................................................................. 46 
6.5.6 
Laboratory evaluations .......................................................................... 46 
6.5.7 
Electrocardiogram (ECG) ..................................................................... 47 
6.5.8 
Pregnancy and assessments of fertility ................................................. 47 
6.5.9 
Local tolerability (Injection site reactions) ........................................... 47 
6.5.10 
Tolerability of Secukinumab ................................................................. 48 
6.5.11 
Appropriateness of safety measurements .............................................. 48 


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6.6 
Other assessments .................................................................................................. 48 
6.6.1 
HLA-B27............................................................................................... 48 
6.6.2 
Resource utilization ............................................................................... 48 
6.6.3 
Pharmacokinetics .................................................................................. 48 
6.6.4 
Other biomarkers ................................................................................... 48 
7 
Safety monitoring .............................................................................................................. 49 
7.1 
Adverse events ....................................................................................................... 49 
7.2 
Serious adverse events ........................................................................................... 49 
7.2.1 
Definition of SAE ................................................................................. 49 
7.2.2 
SAE reporting........................................................................................ 50 
7.3 
Liver safety monitoring ......................................................................................... 52 
7.4 
Renal safety monitoring ......................................................................................... 52 
7.5 
Pregnancy reporting ............................................................................................... 54 
7.6 
Prospective suicidality assessment ........................................................................ 54 
8 
Data review and database management ............................................................................. 54 
8.1 
Site monitoring ...................................................................................................... 54 
8.2 
Data collection ....................................................................................................... 55 
8.3 
Database management and quality control ............................................................ 55 
8.4 
Data Monitoring Committee .................................................................................. 56 
8.5 
Adjudication Committee ........................................................................................ 56 
9 
Data analysis ...................................................................................................................... 56 
9.1 
Analysis sets .......................................................................................................... 56 
9.2 
Patient demographics and other baseline characteristics ....................................... 57 
9.3 
Treatments ............................................................................................................. 57 
9.4 
Analysis of the primary variable(s) ....................................................................... 58 
9.4.1 
Variable(s) ............................................................................................. 58 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 58 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 58 
9.4.4 
Supportive analyses ............................................................................... 59 
9.5 
Analysis of other variables .................................................................................... 59 
9.5.1 
Secondary efficacy variables ................................................................. 59 
9.5.2 
Exploratory efficacy variables .............................................................. 63 
9.5.3 
Safety variables ..................................................................................... 64 
9.5.4 
Resource utilization ............................................................................... 65 
9.5.5 
Pharmacokinetics .................................................................................. 65 
9.5.6 
Pharmacogenetics/pharmacogenomics ................................................. 65 
9.5.7 
Biomarkers ............................................................................................ 65 


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9.5.8 
PK/PD ................................................................................................... 65 
9.6 
Interim analyses ..................................................................................................... 65 
9.7 
Sample size calculation.......................................................................................... 65 
10  Ethical considerations ........................................................................................................ 66 
10.1 
Regulatory and ethical compliance ........................................................................ 67 
10.2 
Informed consent procedures ................................................................................. 67 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 67 
10.4 
Publication of study protocol and results............................................................... 68 
11  Protocol adherence ............................................................................................................ 68 
11.1 
Protocol Amendments ........................................................................................... 68 
12  References ......................................................................................................................... 68 
13  Appendices ........................................................................................................................ 69 
13.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 69 
13.2 
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements .......................................................................................................... 70 
13.3 
Appendix 3: Modified New York criteria ............................................................. 72 
13.4 
Appendix 4 ............................................................................................................ 72 
13.4.1 
Analysis and report of NSAID intake during clinical trials/studies ...... 72 
13.4.2 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................. 73 
13.4.3 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 74 
13.4.4 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 74 
13.4.5 
Bath Ankylosing Spondylitis Metrology Index (BASMI) .................... 74 
 
List of tables 
Table 5-1 
Prohibited treatment .............................................................................. 32 
Table 6-1 
Assessment schedule ............................................................................. 36 
Table 7-1 
Specific renal alert criteria and actions ................................................. 53 
Table 13-1 
Safety analyses: expanded limits and notable criteria ........................... 69 
Table 13-2 
Liver event and laboratory trigger definitions ...................................... 70 
Table 13-3 
Follow-up requirements for liver events and laboratory triggers .......... 70 
Table 13-4 
ASAS recommendations for the approach to collection of NSAID 
intake for use in clinical trials/epidemiological studies of 
spondyloarthritis .................................................................................... 73 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 16 


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List of abbreviations 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase 
AS 
 
Ankylosing spondylitis 
ASAS  
Assessment of SpondyloArthritis international Society 
AST 
 
aspartate aminotransferase 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI  
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
b.i.d.  
twice a day 
BSL 
 
Baseline 
CFR 
 
US Code of Federal Regulations  
CDS 
 
Core Data Sheet (for marketed drugs) 
COX-1 / 2 
Cyclooxygenase-1 / 2 
CPO 
 
Country Pharma Organization 
CRF 
 
Case Report/Record Form (paper or electronic) 
CRO  
Contract Research Organization 
CTC 
 
Common Toxicity Criteria 
CTRD  
Clinical Trial Results Database 
DMARD 
Disease-modifying antirheumatic drugs 
DS&E  
Drug Safety & Epidemiology 
ECG  
Electrocardiogram 
EDC  
Electronic Data Capture 
ESR 
 
Erythrocyte sedimentation rate 
GCP 
 
Good Clinical Practice 
hsCRP  
High sensitivity C-reactive protein 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
 
Independent Ethics Committee 
IFU 
 
Instructions for Use 
i.v. 
 
intravenous 
IRB 
 
Institutional Review Board 
IRT 
 
Interactive Response Technology 


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LFT 
 
Liver function test (raised serum transaminases and/or bilirubin levels) 
MedDRA 
Medical dictionary for regulatory activities 
MTX  
Methotrexate 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OC/RDC 
Oracle Clinical/Remote Data Capture 
o.d. 
 
once a day 
PFS 
 
Pre-filled syringe 
p.o. 
 
per orally 
SAE 
 
serious adverse event 
s.c. 
 
subcutaneous 
SpA 
 
Spondyloarthritides 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TNFα  
tumor necrosis factor alpha, 
VAS  
visual analog scale 
WHO  
World Health Organization  


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Investigational treatment 
All investigational drug(s) whose properties are being tested in 
the study as well as their associated treatment controls.  
This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage 
or tested in a fixed combination.  
Investigational treatment generally does not include protocol-
specified concomitant background therapies  when these are 
standard treatments in that indication 
Medication number 
A unique identifier on the label of each investigational/study drug 
package in studies  
Period 
A subdivision of a cross-over study 
Premature subject/patient 
withdrawal 
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless 
the patient will be followed for progression and/or survival 
Randomization number 
A unique identifier assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Study drug/ treatment 
Any single drug or combination of drugs administered to the 
patient as part of the required study procedures; includes 
investigational drug (s), active drug run-ins or background 
therapy  
Study/investigational 
treatment discontinuation 
Point/time when patient permanently stops taking 
study/investigational treatment  for any reason; may or may not 
also be the point/time of premature patient withdrawal 
Subject Number  
A number assigned to each patient who enrolls into the study  
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study 
 
 
 
 
 
 
 
 
 


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Amendment 1 
Amendment rationale  
This protocol amendment is issued for the following reasons: 
 Based on results from MEASURE III (CAIN457F2314), MEASURE IV (CAIN457F2320) 
and COAST V (Ixekizumab - NCT02696785) studies, the assumptions for the power 
calculation of the primary and a selection of secondary and exploratory objectives were re-
evaluated, leading to changes in the statistical analysis plan. The three studies mentioned 
above suggest that the placebo response might be somewhat higher, leading to a potentially 
smaller difference between active treatment and placebo than assumed during the planning of 
this trial. Therefore, in order to keep sufficient power, it was decided to pool the two 
Secukinumab arms for the primary analysis. This new evaluation triggered an adaption of a 
set of objectives. The primary objective was adapted so that data of Group 1 (Secukinumab 
150 mg s.c. “delayed tapering”) and of Group 2 (Secukinumab 150 mg s.c. “early tapering”) 
are pooled and ASAS20 response at week 12 are compared against placebo. For the other re-
evaluated secondary and exploratoy objectives, data is pooled and is compared against placebo 
according to the same schema. In the course of this amendment the amount of randomized 
patients can be reduced to a smaller size (approx. 190) than originally expected (approx. 204), 
while maintaining adequate power for primary and secondary analyses.  
 The amendment is used to describe the ASAS Health Index (chapter 6.4.9) in a more detailed 
way. Besides the 17 aspects of health, the 9 questions regarding environmental factors in 
patients with AS are mentioned.   
None of the changes described in this amended protocol are made due to newly emerged safety 
considerations. 
 
 
 
 


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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 (SpA). It is mainly characterized by involvement of 
the axial skeleton and 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. IL-17A has been shown to play an important role 
in driving the body’s immune response in psoriasis and SpA conditions, including PsA and AS 
(Van Baarsen et al 2011).  
Cosentyx® (Secukinumab) is a recombinant monoclonal antibody that neutralizes the activity 
of IL-17A. Secukinumab is the first IL-17A inhibitor with positive Phase 3 results for the 
treatment of PsA and AS. In January 2015, Secukinumab (at a dose of 300 mg) became the first 
IL-17A inhibitor approved in Europe as a first-line systemic treatment for moderate-to-severe 
plaque psoriasis in adult patients, and in the United States (US) as a treatment for moderate-to-
severe plaque psoriasis in adult patients who are candidates for systemic therapy or 
phototherapy (light therapy). Secukinumab 
Clinical trials of Secukinumab in ankylosing spondylitis 
The safety and efficacy of Secukinumab has been assessed in 590 patients in 2 randomized, 
double-blind, placebo-controlled, Phase 3 studies (MEASURE 1: CAIN457F2305; and 
MEASURE 2: CAIN457F2310, Sieper et al 2015) in patients with active AS with a Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 despite non-steroidal 
anti-inflammatory drugs (NSAIDs), corticosteroid or disease-modifying anti-rheumatic drug 
(DMARD) therapy. The efficacy and safety of Secukinumab 75 mg and 150 mg were evaluated 
vs. placebo with either an i.v. or s.c. loading regimen. In the MEASURE 1 and MEASURE 2 
study, 27.0% and 38.8% of patients, respectively, were previously treated with an anti-TNFα 
agent and discontinued the anti-TNFα agent due to either lack of efficacy or intolerance (anti-
TNFα-IR patients). The primary endpoint was at least a 20% improvement in Assessment of 
Spondyloarthritis International Society (ASAS20) criteria at Week 16.  
In both AS studies, Secukinumab-treated patients (150 mg in MEASURE 2 and both regimens 
in MEASURE 1) demonstrated significantly improved signs and symptoms at Week 16; a 
comparable magnitude of response and efficacy was maintained up to Week 52. The magnitude 
of response (treatment difference versus placebo) with regards to signs and symptoms at Week 
16 was similar in anti-TNFα-naïve and anti-TNFα-inadequate responder patients in both 
studies, with higher absolute response rates in anti-TNFα-naïve patients. Efficacy was 
maintained in anti-TNFα-naïve and anti-TNFα-IR patients up to Week 52 in both studies.  
In MEASURE 2, treatment with Secukinumab 150 mg resulted in greater improvement in 
ASAS20, ASAS40, high-sensitivity C-reactive protein (hsCRP), ASAS 5/6 and BASDAI score 
compared with placebo at Week 16. The onset of action of Secukinumab 150 mg occurred as 
early as Week 1 for ASAS20 (superior to placebo). ASAS20 responses were improved at Week 
16 in both anti-TNFα-naïve patients (68.2% vs. 31.1%; p<0.05) and anti-TNFα-IR patients 
(50.0% vs. 24.1%; p<0.05) for Secukinumab 150 mg compared with placebo, respectively. 


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Non-steroidal anti-inflammatory drugs in ankylosing spondylitis 
NSAIDs (including COX-1 or COX-2 inhibitors) are the standard therapy for patients with AS 
(van der Hejde et al 2011). While effective in relieving pain and improving disease activity in 
many patients, NSAIDs are associated with side effects that may cause concerns particularly in 
the context of a life-long treatment at high daily intake doses for diseases such as AS. For 
example, it has recently been shown that the NSAID diclofenac increases the risk of myocardial 
infarction in patients with SpA (Dubreuil et al 2014). NSAIDs have also been associated with 
gastrointestinal side effects (Lanas et al 2006) and a potential acceleration of chronic kidney 
disease progression (Nderitu et al 2013). 
According to the ASAS / European League Against Rheumatism (EULAR) recommendations 
(van der Hejde et al 2011), patients who show an inadequate response to at least 2 NSAIDs 
administered at the maximum recommended dose over a total period of 4 weeks should be 
treated with a biologic. When switching to a biologic in clinical practice, the refractory NSAID 
treatment is often kept as a concomitant treatment to the biologic. There is currently no clinical 
or scientific guidance on how, when and how fast NSAIDs should be discontinued or tapered 
after initiation of the biologic treatment.  
Clinical trials have already shown that NSAID intake could be considerably reduced in AS 
patients treated with anti- TNF compounds (e.g. Poddubnyy et al 2013, Konttinen et al 2007, 
Braun et al 2002). In these studies, NSAID usage could be reduced in over 50% of patients by 
more than 50% of the baseline value and could even be completely stopped in up to 20% of the 
analyzed patients (Braun et al 2002). However, in these trials, patients were not explicitly 
advised how to reduce NSAIDs. Furthermore, the nonsteroidal anti-inflammatory drug 
assessment of the spondyloarthritis international society score (ASAS-NSAID score), which 
has been developed as a standardized method of evaluating NSAID intake in clinical trials has 
not been used as an endpoint in many of the trials (Dougados et al 2011). 
In a recently published prospective, randomized, placebo-controlled trial on the NSAID sparing 
effect of etanercept (Dougados et al 2014), a dramatic reduction of NSAID intake (up to two 
thirds) was observed. However, the reduction in NSAID intake was associated with 
considerably lower clinical ASAS20 response rates compared to the Phase 3 clinical trial of 
etanercept in AS (i.e. 44% vs. 57% at Week 8). This finding raises questions as to whether or 
not reducing NSAIDs may potentially counteract the achievement of treatment goals (i.e. 
reduction of disease activity) and whether or not there is an optimal time point for starting 
NSAID tapering. 
1.2 
Purpose 
The current study will assess the clinical ASAS20 response to Secukinumab and evaluate to 
which extent concomitant NSAID treatment can be reduced between Week 4 and Week 12 in 
patients treated with Secukinumab 150 mg or placebo. Furthermore, the clinical trial will assess 
the clinical ASAS20 response to Secukinumab and evaluate to which extent concomitant 
NSAID treatment can be reduced between Week 4 and Week 12 in patients treated with 
Secukinumab 150 mg or placebo following an initial run-in phase of 4 weeks on stable NSAID 
therapy. Two different time points of NSAID tapering initiation will be evaluated in this study: 
1. a delayed tapering approach in which NSAID will be tapered following 4 weeks  of 
Secukinumab treatment at stable NSAID therapy.  


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2. an early tapering approach in which NSAID will be tapered immediately after initiation 
of Secukinumab treatment 
These 2 approaches will be evaluated compared to placebo in order to assess whether the early 
or delayed NSAID tapering is superior to placebo in terms of clinical ASAS20 response and 
extent of reduction in NSAID intake. 
As a patient-reported outcome, pain is a major patient-relevant efficacy parameter in clinical 
practice in AS. This study will therefore monitor overall neck, back and hip pain on a continuous 
basis. It will be recommended that NSAID should be tapered if the patient reports an 
improvement in back pain or a level below a certain threshold. It is anticipated that the results 
of this study may provide guidance for the systematic adjustment of concomitant NSAID 
treatment in AS patients based on their initial response to Secukinumab, thereby leading to 
optimization of the therapeutic strategy with Secukinumab. In case of a positive outcome 
concerning the NSAID reduction, e.g. no drop in clinical efficacy for Secukinumab between 
Week 4 and Week 12 at significantly reduced NSAID intake, this study could trigger the 
development of a guidance concerning NSAID reduction applicable for all AS patients starting 
a biologic treatment. 
2 
Study objectives 
2.1 
Primary objective  
 
To demonstrate that the efficacy of Secukinumab 150 mg s.c. (with NSAID tapering) is superior 
to placebo based on the proportion of patients achieving an ASAS20 response at week 12. To 
show superiority, both Secukinumab treatment arms will be pooled and compared against 
placebo. 
2.2 
Secondary objectives 
1. To demonstrate that the change from baseline in ASAS-NSAID score at week 12 is 
superior for Secukinumab 150 mg s.c. as compared to placebo. To show superiority, both 
Secukinumab treatment arms will be pooled and compared against placebo. 
2. To demonstrate that the efficacy of Secukinumab 150 mg s.c at week 12 is superior to 
placebo based on the change from baseline in the total BASDAI. To show superiority, 
both Secukinumab treatment arms will be pooled and compared against placebo. 
3. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 
with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to 
placebo based on the proportion of patients achieving an ASAS20 response. 
4. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 
with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to 
placebo based on the proportion of patients achieving an ASAS20 response. 
5. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 
with NSAID tapering allowed from week 4; “early tapering”) at Week 16 is superior to 
placebo based on the proportion of patients achieving an ASAS20 response. 


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6. To demonstrate that the change from baseline in ASAS-NSAID score at Week 12 is 
superior for Secukinumab 150 mg s.c. (Secukinumab from week 0 with NSAID tapering 
allowed from week 4; “delayed tapering”) as compared to placebo. 
7. To demonstrate that the change from baseline in ASAS-NSAID score at Week 12 is 
superior for Secukinumab 150 mg s.c . (Secukinumab from week 4 with NSAID tapering 
allowed from week 4; “early tapering”) as compared to placebo.  
8. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 
with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to 
placebo based on the change from baseline in the total BASDAI. 
9. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 
with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to 
placebo based on the change from baseline in the total BASDAI. 
10. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 
with NSAID tapering allowed from week 4; “early tapering”) at Week 16 is superior to 
placebo based on the change from baseline in the total BASDAI. 
11. To demonstrate that the efficacy of Secukinumab 150 mg s.c. at week 12 is superior to 
placebo based on the change from baseline in health-related Quality of Life as measured 
by the SF-36 PCS. 
12. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 0 
with NSAID tapering allowed from week 4; “delayed tapering”) at Week 12 is superior to 
placebo based on the change from baseline in health-related Quality of Life as measured 
by the SF-36 PCS. 
13. To demonstrate that the efficacy of Secukinumab 150 mg s.c. (Secukinumab from week 4 
with NSAID tapering allowed from week 4; “early tapering”) at Week 12 is superior to 
placebo based on the change from baseline in health-related Quality of Life as measured 
by the SF-36 PCS. 
14. To compare between both Secukinumab regimens concerning the change from baseline in 
ASAS-NSAID score after 12 weeks of Secukinumab exposure (ASAS-NSAID index at 
Week 12 for “delayed tapering” vs. Week 16 for “early tapering”). 
 
2.3 
Exploratory objectives 
1. To compare between both Secukinumab regimens concerning the change from baseline in 
the BASDAI after 12 weeks of Secukinumab exposure (BASDAI at Week 12 for “delayed 
tapering” vs. Week 16 for “early tapering”). 
2. To evaluate change in patient reported neck, back and hip pain (BASDAI question 2; 
Appendix 4) beginning from Secukinumab treatment on a continuous basis in patients 
exposed to Secukinumab 150 mg s.c. for 12 weeks vs. placebo. 
3. To evaluate change in patient reported neck, back and hip pain (BASDAI question 2; 
Appendix 4) from baseline on a continuous basis in patients randomized Secukinumab 
150 mg s.c. (Secukinumab from week 0 with NSAID tapering allowed from week 4; 
“delayed tapering”) vs. placebo from week 0 to week 12. 
4. To evaluate change in patient reported neck, back and hip pain (BASDAI question 2; 
Appendix 4) from baseline on a continuous basis in patients randomized Secukinumab 
150 mg s.c. (early tapering) vs. placebo from week 0 to week 16. 


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5. To compare ASAS20 response rates at week 4 in Secukinumab 150 mg. s.c. 
(Secukinumab from week 0 with NSAID tapering allowed from week 4; “delayed 
tapering”) vs. week 20 in the patients switching from Placebo after 4 weeks of 
Secukinumab exposure each. 
6. Total ASAS-NSAID [Area Under Curve (AUC)] Score from treatment start with 
Secukinumab to a Secukinumab exposure of 12 weeks. 
7. Total ASAS-NSAID [Area Under Curve (AUC)] Score from Week 4 to Week 16 for each 
treatment arm 
8. Proportion of patients with no NSAID intake after Secukinumab exposure of 12 weeks 
9. Proportion of patients with no NSAID intake at week 12 
10. Change from Baseline in the ASAS Health Index after Secukinumab exposure of 12 
weeks 
11. Change from Baseline in the ASAS Health Index at week 12 
12. Spinal mobility assessed by Bath Ankylosing Spondylitis Metrology Index (BASMI) 
linear scores  
13. ASAS40 response rate over time 
14. ASAS20 response rate over time 
15. ASAS5/6 response rate over time 
16. Change from baseline in hsCRP  
17. Change from baseline in total BASDAI over time 
18. BASDAI 50 response over time  
19. ASAS partial remission over time 
20. Change from baseline in ASAS components, including: 
a. Patient’s global assessment of disease activity 
b. Total spinal pain 
c. Inflammation as measured by the mean of BASDAI questions 5 and 6 
d. Bath Ankylosing Spondylitis Functional Index (BASFI)  
21. Change from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-
Reactive Protein (CRP) and ASDAS-Erythrocyte Sedimentation Rate (ESR) 
22. ASDAS inactive disease as defined by ASDAS < 1.3 
23. ASDAS clinically important improvement (change in ASDAS ≥ 1.1) and major 
improvement (change in ASDAS ≥ 2.0) 
24. To assess overall tolerability and safety of Secukinumab at reduced NSAID intake.  
25. To evaluate the reasons given by the patient in the patient diary on why he was not able to 
taper NSAIDs despite reduced spinal pain 
26. To compare both Secukinumab regimens between week 12 (delayed tapering) and week 
16 (early tapering) concerning all primary, secondary and exploratory objectives [at these 
timepoints, patients will have had the same exposure time to Secukinumab of 12 weeks] 
 


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3 
Investigational plan 
3.1 
Study design 
This is a 20-week, randomized, double-blind, 3-arm, placebo-controlled, parallel-group, 
multicenter study of Secukinumab (AIN457) to examine the clinical response as measured by 
the ASAS20 and the NSAID-sparing effect of Secukinumab treatment. The clinical efficacy 
(ASAS20 response) and the cumulative NSAID sparing effect of two strategies of NSAID 
tapering after initiation of Secukinumab will be evaluated as compared to placebo:  
Patients will be randomized 1:1:1 to one of the following treatment groups: 
 Secukinumab - delayed NSAID tapering: Secukinumab 150 mg s.c. at weeks 0, 1, 2, 3, 
4, 8, 12, 16 and 20 with placebo injections at Week 5, 6, 7 and 17, 18, 19 to maintain the 
blind. 
 Secukinumab – early NSAID tapering: Placebo at weeks 0, 1, 2, 3 to maintain the blind; 
followed by Secukinumab 150 mg s.c. at Week 4, 5, 6, 7, 8, 12, 16 and 20 with 
intermittent Placebo injections at week 17, 18, 19 to maintain the blind. 
 Placebo: Placebo at weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments 
of the secondary endpoint have been performed, these patients will receive Secukinumab 
150 mg s.c. at weeks 16, 17, 18, 19 and 20. 
The patients will be stratified at randomization according to their status of prior TNFα inhibitor 
exposure, i.e. TNFα inhibitor naive patients or TNFα inhibitor inadequate responders (TNFα-
IR). The only condition that will be placed on enrollment targets for each stratum is that no less 
than 60% of patients (122 patients) are TNFα inhibitor naïve, i.e., no more than 40% of patients 
(82 patients) are TNFα-IR. In theory the percentage of TNFα inhibitor naïve patients could 
reach 100%, although that is not anticipated. 


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Figure 3-1 
Study design 
 
All patients will be advised to continue on the maximum recommended/tolerated dose of 
NSAIDs for the first 4 weeks of the trial.  
A follow-up visit is to be done 4 weeks after last study treatment administration for all subjects, 
regardless of whether they complete the entire study as planned or discontinue prematurely. 
NSAID tapering strategy 
All patients will be advised to taper/discontinue their NSAID intake starting at Week 4 to Week 
20. Patients may use NSAIDs on an on-demand basis to avoid an unacceptable worsening of 
disease activity. 
From Week 16 on, those patients originally randomized to placebo will self-inject Secukinumab 
150 mg at weeks 17, 18, 19 and 20, while patients originally randomized to either of the 
Secukinumab groups will receive their next Secukinumab injection after Week 16 at Week 20 
with Placebo injections at weeks 17, 18, 19 to maintain the blinding of the treatment assignment 
for the secondary / exploratory endpoint analyses. 
Patients will be asked to capture NSAID intake and level of AS neck, back and hip pain 
(BASDAI question 2; see Appendix 4) on a daily basis in a patient diary. Guidance will be 


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provided to patients that NSAID intake should be reduced upon an improvement in back pain 
and that the reduction should preferably happen step-wise and instead of an abrupt stop of any 
NSAID intake. However, deviance from this guidance will be acceptable and may be discussed 
between investigator and patient. Patients may deviate from this guidance if required, e.g. 
NSAID use necessary for non-spinal pain (e.g. entheses, peripheral joints, and headache). Also, 
if pain levels increase, patients may increase NSAID usage on an on-demand basis. The 
reduction in NSAID intake will be assessed using the ASAS-NSAID score (Dougados et al 
2012). 
3.2 
Rationale of study design 
This phase IV trial utilizes a double-blind, randomized, parallel-group, placebo-controlled 
design. According to the ASAS/EULAR recommendations (van der Hejde et al. 2011); patients 
who show an inadequate response to at least 2 NSAIDs over a 4-week period in total at the 
maximum recommended dose patients should be treated with a biologic unless contraindicated. 
When switching to a biologic, in clinical practice the refractory NSAID treatment is kept as 
concomitant treatment in addition to the biologic treatment. There is currently no clinical or 
scientific guidance on how, when and how fast NSAIDs should be discontinued. 
In the current study it will be evaluated to which extent NSAID treatment can be reduced 
between Week 4 and Week 12 in patients randomized to Secukinumab 150 mg or placebo 
following an initial run-in phase of 4 weeks on stable NSAID therapy. Two NSAID tapering 
approaches will be evaluated in this study: 
1) an early tapering approach in which NSAID will be tapered at the start of Secukinumab 
treatment,  
2) a delayed tapering approach in which NSAID will be tapered following 4 weeks of 
Secukinumab treatment.  
These 2 strategies will be evaluated compared to placebo in order to assess whether the early or 
delayed NSAID tapering is superior in terms of clinical ASAS20 response and NSAID sparing 
strategy. 
The ASAS-NSAID score was developed as a standard method of evaluating NSAID intake in 
clinical studies (Dougados et al 2011; Dougados et al 2012). There, the current study will use 
the ASAS-NSAID score to assess the potential NSAID sparing effect of Secukinumab. 
3.3 
Rationale of dose/regimen, route of administration and duration 
of treatment 
The dosing of Secukinumab in this study with 4-weekly 150 mg s.c injections after weekly 
Secukinumab 150 mg s.c. loading doses for the first 4 weeks of therapy relies upon dose-
efficacy relationships observed in a proof of concept (PoC) trial (CAIN457A2209) and 2 phase 
III trials (CAIN457F2305, CAIN457F2310) in AS, as described below. 
The PoC trial in AS (CAIN457A2209) suggested that after 2 i.v. Secukinumab doses of 10 
mg/kg given 3 weeks apart, Secukinumab demonstrated high efficacy, achieving an ASAS20 
response at Week 6 in 59% of the patients on Secukinumab versus 24% on placebo, and was 
well-tolerated (Baeten 2013). The ongoing trials in AS, CAIN457F2305 and CAIN457F2310, 
assessed the efficacy of both 75 mg and 150 mg s.c. maintenance doses with loading regimens 


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consisting of either intravenous doses (CAIN457F2305: 3 doses of 10 mg/kg given every 2 
weeks at BSL, Weeks 2 and 4) or subcutaneous doses (CAIN457F2310: 4 weekly doses 
matching the maintenance dose of either 75 mg or 150 mg given at BSL, Weeks 1, 2, and 3). 
Given the similarity of the ASAS20 response 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: 60.8% for IV-150 mg vs 28.7% for placebo) or s.c. (CAIN457F2310: 61.1% 
for IV-150 mg vs 27.0% for placebo), 150 mg is a sufficient dose to provide clinically and 
statistically significant efficacy, whereas higher i.v. loading doses of Secukinumab do not 
appear to confer a greater response on the primary endpoint of ASAS20 at Week 16. 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 tested in a pre-defined 
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. 
3.4 
Rationale for choice of comparator 
The use of early and delayed tapering arms is to evaluate when and how fast NSAIDs can be 
discontinued after initiating Secukinumab therapy. 
A placebo arm up to week 16 is included in this study. Due to the nature of the disease and the 
outcome measures used (e.g., ASAS20), a placebo arm is necessary to obtain reliable efficacy 
measurements. This is particularly important as all primary and key secondary endpoints of this 
trial are based on patient reported outcomes which may be more susceptible to bias in an open 
label setting.  The continuation of the placebo group up to including the week 12 injection can 
be supported from an ethical standpoint, as patients can continue on a range of concomitant 
treatments. To obtain unbiased results for the primary endpoint analysis and the blinded 
evaluation of different time points of initiation of NSAID tapering, it is necessary to switch 
placebo patients not before all week 16 assessments have been performed and to maintain 
blinding for the initial treatment group assignment. 
Moreover, the inclusion of a placebo group is in accordance with previously implemented 
methodology and in compliance with the EMA/EMEA (European Medicines Agency) 
guidelines for clinical trials in AS (EMA 2009). 
3.5 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
3.6 
Risks and benefits 
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure (IB). 
Data from two pivotal trials in ankylosing spondylitis (AS) CAIN457F2305 and 
CAIN457F2310 demonstrate safety and efficacy of Secukinumab in the treatment of AS.  
Based on these data secukinumab was approved on 19 November 2015 by the European 
Commission for the treatment of active ankylosing spondylitis in adults who have responded 
inadequately to conventional therapy. 


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3.6.1.1 
Study CAIN457F2305 in ankylosing spondylitis (AS) 
This 104-week, double-blind, placebo-controlled study randomized 371 patients with moderate 
to severe ankylosing spondylitis (AS) despite current or previous NSAIDs, DMARDs and/or 
TNF-α inhibitor therapy to 10mg/kg IV load (baseline, Week 2, and Week 4)-75 mg sc every 4 
wks maintenance (n=124); IV load regimen-150 mg sc maintenance (n=125), or to placebo IV 
load and sc maintenance (n=122).  At Week 16, non-responder placebo pts would be 
randomized to 75mg or 150mg maintenance dose without a loading regimen and all remaining 
(responder) placebo pts would be randomized to 75mg or 150 mg maintenance regimen at Week 
24.  The primary objective was superiority to placebo based on Assessment of Spondyloarthritis 
International Society criteria (ASAS) 20 response rate at week 16. 
An interim analysis with a cut-off date of 10-Dec-2013 was performed and included efficacy 
data up to Week 52 and all safety data up to that cut-off date of the study for all patients 
(regardless of study visit at that time).  Over the entire treatment period at time of the data cut-
off, the median duration of exposure was 475 days for any 75 mg group and 463 days for any 
150 mg group.  
Both secukinumab arms were superior to placebo for the primary endpoint of ASAS 20 response 
at Week16: 59.7% for IV-75 mg and 60.8% for IV-150 mg ( p<0.0001) vs. 28.7% for placebo. 
Additionally, both secukinumab IV-75 mg and IV-150 mg groups were superior to placebo at 
Week 16 for all endpoints tested in the hierarchical testing strategy. Among those, ASAS 40 
response was 33.1% (p=0.0003) for IV-75 mg and 41.6% (p<0.0001) for IV-150 mg compared 
with 13.1% for placebo and significantly lower ratios of post-baseline to baseline hsCRP values 
for IV-75 (0.45) and IV-150 mg (0.40) vs. placebo (0.97) were reported (both comparisons, 
p<0.0001). 
 
Secukinumab was efficacious through 16 weeks of treatment in both anti-TNF-α naive patients 
and patients with an inadequate response or intolerance to prior anti-TNF-α therapy. ASAS 20 
and ASAS 40 response rates for secukinumab vs. placebo observed  for TNF-α inhibitor naive 
pts were numerically higher (ASAS 20 (60.0% and 66.3%) and ASAS 40 (34.4% and 48.9%)) 
than for TNF-α inhibitor inadequate responders (ASAS 20: 58.8% and 45.5%; ASAS 40: 29.4% 
and 21.2%) for the IV-75 mg and IV-150 mg regimens, respectively. 
All treatment responses on primary and secondary variables at Week 16 were sustained through 
Week 52, with dose-separation observed between the IV-150 mg and IV-75 mg regimens as 
patients approached Week 52, which favored the higher maintenance dose of 150 mg sc on 
higher hurdle clinical efficacy endpoints such as ASAS 40, ASAS partial remission, and 
BASDAI 50.    
The safety profile of secukinumab for both IV loading regimens showed no new or unexpected 
safety signals. Infections were more frequent with secukinumab compared to placebo and 
showed dose dependence in non-serious infections, with the majority consisting of upper 
respiratory tract infections. Serious infections were rare in both secukinumab treatment arms.  
Two deaths were reported: a suicide secondary to depression in a placebo patient, and 
respiratory failure secondary to cardiac failure and pulmonary fibrosis in a patient on IV-75 
mg.  Neither death was suspected to be related to study treatment. 
The incidence of AEs up to Week 16 was higher in both IV-75 mg (66.9%) and IV-150 mg 
(69.6%) groups vs. placebo (55.7%). This was driven primarily by non-serious infections and 


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infestations (mainly nasopharyngitis), which was the most frequently affected primary SOC.  
Comparable crude incidence rates of serious AEs and discontinuations due to AEs were 
reported in the placebo group compared with either secukinumab dose group up to Week 16.  
Over the entire treatment period, treatment-emergent AEs were reported with a higher 
incidence in the Any 150 mg group (85.1%) than in the Any 75 mg group (76.5%), which 
included patient originally randomized to placebo who were later re-randomized to either dose 
of secukinumab from Week 16 onward. This difference was driven primarily by non-serious 
infections and infestations (mainly nasopharyngitis, pharyngitis, influenza, rhinitis). The rate 
of SAEs was similar between the two secukinumab regimens (10.1% in the Any 75 mg group 
and 9.4% in the Any 150 mg group).  
3.6.1.2 
Study CAIN457F2310 in ankylosing spondylitis (AS) 
This 5-year double-blind, placebo-controlled study randomized 219 patients with moderate to 
severe ankylosing spondylitis (AS) despite current or previous NSAIDs, DMARDs and/or 
TNF-α inhibitor therapy to Secukinumab 75 mg s.c. load (baseline, Weeks 1, 2, and 3) and 75 
mg sc maintenance (every 4 weeks starting at Week 4) (n=73); secukinumab 150 mg s.c load 
and maintenance (n=72); or placebo load and maintenance (n=74).  At Week 16 all placebo 
patients were re-randomized 1:1 to 75mg or 150mg s.c. maintenance dose regimen.   
An interim analysis with a cut-off date of 04-Aug-2014 was performed when the last patient 
completed Week 52 of the study.  Efficacy results at Week 52 and safety data up to the cut-off 
date for all patients (regardless of study visit at the time) are described below. 
Secukinumab 150 mg s.c. demonstrated a rapid onset of response and superior efficacy over 
placebo in measures of disease signs and symptoms, physical function, quality of life and 
objective markers of inflammation. The secukinumab 150 mg sc load and maintenance dose 
group, but not the 75 mg sc load and maintenance dose group, had significantly greater 
responses than placebo at Wk 16, with respect to the primary endpoint (ASAS 20; 61.1% for 
SC-150 mg vs 27.0% for placebo) and all secondary endpoints (ASAS 40, hsCRP, ASAS 5/6, 
BASDAI, SF-36 PCS and ASQoL) except for ASAS partial remission. Secukinumab was 
efficacious through 16 weeks of treatment in both anti-TNF-α naive patients and patients with 
an inadequate response or intolerance to prior anti-TNF-α therapy.  Concerning ASAS40, 
Secukinumab 150 mg s.c. was superior to placebo at Week 16, with a rate of 36.1% (adjusted 
p=0.0008) vs. 10.8% for placebo, while 75 mg s.c. (26.0%) was not significant. All treatment 
responses on primary and secondary variables at Week 16 were sustained through Week 52, 
with higher response rates observed for 150 mg s.c compared with 75 mg s.c. for nearly all 
efficacy endpoints.  
Higher ASAS 20 and ASAS 40 response rates for secukinumab vs. placebo were observed 
regardless of previous TNF-α use. TNF-α inhibitor naive patients had numerically higher rates 
of ASAS 20 response (150 mg: 68.2%; 75 mg: 51.1%, placebo: 31.1%) and ASAS 40 
response (150 mg: 43.2%; 75 mg: 31.1%, placebo: 17.8%) than TNF-α inhibitor inadequate 
responder patients (ASAS 20: 50.0% for 150 mg, 25.0% for 75 mg and 24.1% for placebo; 
ASAS 40: 25.0% for 150 mg, 17.9% for 75 mg and 0.0% for placebo), with consistently 
higher response rates for 150 mg compared with 75 mg. 
The safety profile of secukinumab in this study showed no new or unexpected safety signals. 


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One patient in the secukinumab 75 mg group who had a history of CAD, a significant 
smoking history, and elevated LDL and lipoprotein A levels at baseline died from an acute 
myocardial infarction on Day 22, which was not suspected to be related to study treatment. 
AE incidence up to Week 16 was higher in the secukinumab 150 mg group (65.3%) compared 
with the secukinumab 75 mg s.c. group (57.5%) and comparable to the placebo group 
(63.5%). The AE rate in the secukinumab 150 mg s.c. group was driven primarily by non-
serious infections (mainly nasopharyngitis). Rates of SAEs and discontinuations due to AEs 
up to Week 16 were low and comparable in the secukinumab groups compared with the 
placebo group.  
Over the entire treatment period, treatment-emergent AE rates were comparable between the 2 
secukinumab dose groups (83.8% patients in the Any secukinumab 75 mg s.c. group and 
82.1% in the Any secukinumab 150 mg s.c. group). SAE rates over the entire treatment period 
were similar between the two secukinumab dose groups (8.6% with the Any 75 mg group and 
7.5% with the Any 150 mg group). 
Over the entire treatment period, a slightly higher proportion of patients in the Any-
secukinumab-150 mg s.c. arm (5.7%) discontinued due to an AE compared to the Any-
secukinumab-75 mg s.c. arm (3.8%). All AEs that led to discontinuation were single events 
with no trends across treatment arms. No patient discontinued due to an infection event. 
Based on the benefit-risk profile of secukinumab in AS and other approved indications, it is 
considered appropriate to initiate this study. 
The benefit-risk profile of Secukinumab in AS and other approved indications remains 
favorable and unchanged. It is therefore considered appropriate to initiate this study. 
4 
Population 
Men and women ≥ 18 years of age who fulfill the modified New York criteria for AS (described 
in Appendix 3) and have active disease as defined by a BASDAI ≥4 on a scale of 0-10 and 
spinal pain (BASDAI Question 2) of ≥4 cm on a 0–10 numeric rating scale will be included. 
The study will be a multi-centric study planned to be conducted across 30-45 sites in Germany. 
The study is aimed to randomize a total of approximately 204 patients. Due to statistical 
adaptions, the required amount of randomized patients can be reduced to a total of 
approximately 190.  
Subjects may be re-screened but no study-related re-screening procedure should be performed 
prior to written re-consent by the subject. 
4.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study assessment is performed 
2. Male or non-pregnant, non-lactating female patients at least 18 years of age 
3. Diagnosis of active AS with prior documented radiologic evidence (X-ray or radiologist’s 
report) fulfilling the Modified New York criteria for AS (Appendix 3)  


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4. Active AS assessed by total BASDAI ≥ 4 (0-10) at baseline 
5. Spinal pain as measured by BASDAI Question 2 ≥ 4 cm on a 0-10 cm numeric rating 
scale at baseline 
6. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at baseline 
7. Patients should have been on at least 2 different NSAIDs at the highest recommended 
dose for at least 4 weeks in total in the past, prior to randomization, with an inadequate 
response or failure to respond, or less if therapy had to be reduced due to intolerance, 
toxicity or contraindications 
8. Patients must report regular intake of NSAIDs of at least 50% of the highest 
recommended dose at Screening. Patients with prior TNFα inhibitor therapy must report 
regular intake of NSAIDs of at least 50% of the highest recommended dose at baseline 
after the appropriate washout 
9. Patients are required to be on a stable dose of NSAIDs  for at least 2 weeks before 
randomization 
10. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after an appropriate wash-out period prior to randomization: 
 4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 hours 
(s.c. route) 
 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. 
infusion) 
 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) (s.c. route) 
 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days 
11. Patients who have been on a TNFα inhibitor (not more than two) 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. No more than 40% of patients may have previously received anti-
TNFα agents 
12. Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 g/day) are allowed to continue 
their medication and must have taken it for at least 3 months and be on a stable dose for 
at least 4 weeks prior to randomization 
13. Patients on MTX must be on stable folic acid supplementation before randomization 
14. Patients who are on a DMARD other than MTX or sulfasalazine must discontinue the 
DMARD 4 weeks prior to randomization, except for leflunomide, which has to be 
discontinued for 8 weeks prior to randomization unless a cholestyramine washout has 
been performed 
15. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization 
4.2 
Exclusion criteria 
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 


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3. 
Chest X-ray or MRI with evidence of ongoing infectious or malignant process, obtained 
within 3 months of screening and evaluated by a qualified physician 
4. 
Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone, 
morphine) 
5. 
Previous exposure to Secukinumab or any other biologic drug directly targeting IL-17 or 
IL-17 receptor 
6. 
Use of any investigational drug and/or devices within 4 weeks of randomization, or a 
period of 5 half-lives of the investigational drug, whichever is longer or participation in 
another clinical study (interventional or non-interventional) in the same indication during 
enrollment in this study 
7. 
History of hypersensitivity to the study drug or its excipients or to drugs of similar 
chemical classes 
8. 
Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
randomization 
9. 
Any intramuscular corticosteroid injection within 2 weeks before randomization 
10. Patients previously treated with any biological immunomodulating agents, except those 
targeting TNFα 
11. Patients who have taken more than two anti-TNFα agents 
12. Previous treatment with any cell-depleting therapies including but not limited to anti-
CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19) 
13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) laboratory test  
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
entire study or longer if required by locally approved prescribing information (e.g. 20 
weeks in EU). Effective contraception methods include: 
 Total abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception  
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment  
 Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient  
 Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository  
 Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
 Placement of an intrauterine device or intrauterine system 


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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 benefit of Secukinumab therapy, including inflammatory bowel disease or uveitis 
16. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions, which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at unacceptable risk for 
participation in an immunomodulatory therapy 
17. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or very poor functional 
status unable to perform self-care 
18. History of clinically significant liver disease or liver injury as indicated by abnormal 
liver function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum 
bilirubin. The Investigator should be guided by the following criteria: 
 Any single parameter may not exceed 2 x upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to enrollment/randomization, to rule 
out lab error. 
 If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. 
19. History of renal trauma, glomerulonephritis, or patients with one kidney only, or a serum 
creatinine level exceeding 1.5 mg/dL (132.6 µmol/L) 
20. Screening total WBC count <3,000/µL, or platelets <100,000/µL or neutrophils 
1,500/µL or hemoglobin <8.5 g/dL (85 g/L) 
21. Active systemic infections during the last two weeks prior to randomization (exception: 
common cold) 
22. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by either a positive purified protein derivative (PPD) skin test (the 
size of induration will be measured after 48-72 hours, and a positive result is defined as 
an induration of ≥ 5 mm or according to local practice/guidelines) or a positive 
QuantiFERON TB-Gold test as indicated in the assessment schedule in Table 6-1. 
Patients with a positive test may participate in the study if further work up (according to 
local practice/guidelines) establishes conclusively that the patient has no evidence of 
active tuberculosis. If presence of latent tuberculosis is established, then treatment 
according to local country guidelines must have been initiated 
23. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C 
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24. History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system within the past 5 years (except for basal cell carcinoma 
or actinic keratoses that have been treated with no evidence of recurrence in the past 3 
months, carcinoma in situ of the cervix or non-invasive malignant colon polyps that have 
been removed) 
25. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial 
26. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
27. Inability or unwillingness to receive injections with PFS 
28. Any medical or psychiatric condition which, in the Investigator’s opinion, would 
preclude the participant from adhering to the protocol or completing the study per 
protocol 
29. Donation or loss of 400 mL or more of blood within 8 weeks before dosing 
30. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization 
31. Plans for administration of live vaccines during the study period or 6 weeks prior to 
randomization  
32. Patients who are intolerant to NSAIDs 
5 
Treatment 
5.1 
Protocol requested treatment 
5.1.1 
Investigational treatment 
Novartis/CRO will supply the following study treatments: 
 Investigational treatment: 
 Secukinumab 150 mg provided in a 1 mL PFS  (1 PFS for 150 mg dose) 
 Reference therapy:  
 Secukinumab placebo (Placebo) provided in a 1 mL PFS 
At the BSL visit, patients will be instructed by the site staff, utilizing the IFU, on how to self-
inject using a PFS. Patients will be asked to raise any questions and then to proceed with self-
injection. At the Week 1 visit, patients will be asked to refer to the IFU and to proceed directly 
with self-injection of the study drug (i.e., no prior retraining) for the remainder of the trial. 
However, if the patient is not comfortable self-injecting the study treatment, then the site staff 
may administer it for the patient. From Week 3, patients will be allowed to self-administer the 
study treatment at home during the optional visits in which there are no scheduled assessments 
at the site (see Table 6-1 below). If the patient is not comfortable self-injecting the study 
treatment, then a caregiver may administer it for the patient or the patient can come to the site 
at an optional visit to have the study drug administered by the study staff. 
Note: The Secukinumab PFSs are packed in double-blinded fashion until the end of the trial 
and therefore, do not need to be prepared by the study site. The study medication will be labeled 
as follows: 


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 Double-blind Secukinumab and Placebo PFS will be labeled AIN457 
150mg/1mL/Placebo. 
For detailed instructions on storage of the investigational treatments, please refer to 
Section 5.5.3. 
5.1.2 
Additional study treatment 
Continuation of the concomitant administration of NSAIDs as prescribed before inclusion into 
the trial is planned beyond the investigational treatment to evaluate the extent of NSAID sparing 
effect of Secukinumab in this trial. 
5.2 
Treatment arms 
Patients will be assigned to one of the following three treatment arms in a ratio of 1:1:1. 
 Group 1: Secukinumab 150 mg s.c. at Week 0, 1, 2, 3, 4, 8, 12, 16 and 20; Placebo 
injections at Week 5, 6, 7 and 17, 18, 19 to maintain the blind for the initial treatment 
assignment 
 Group 2: Placebo at Weeks 0, 1, 2, 3 followed by Secukinumab 150 mg s.c. at 
Week 4, 5, 6, 7, 8, 12, 16 and 20 with Placebo at Week 17, 18, 19 to maintain the blind 
for the initial treatment assignment 
 Group 3: Placebo at Weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. From Week 16, patients 
will be switched to receive Secukinumab 150 mg s.c. at Week 16, 17, 18, 19, and 20 
 
5.3 
Treatment assignment, randomization 
At baseline visit, all eligible patients will be randomized via Interactive Response Technology 
(IRT) to 1 of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of investigational treatment 
to be dispensed to the patient. The randomization number will not be communicated to the 
caller. 
From Week 16 onwards, all patients will receive Secukinumab 150 mg. Those patients 
originally randomized to placebo will self-inject Secukinumab 150 mg after Week 16 at Week 
17, 18, 19 and 20, while patients originally randomized to either of the Secukinumab groups 
will receive their next Secukinumab injection at Week 20 with Placebo injections at weeks 17, 
18, 19 to maintain the blinding of initial treatment assignment. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced using a validated system that automates the random 
assignment of patient 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 Biometry 
using a validated system that automates the random assignment of medication numbers to packs 
containing the investigational drug(s).  


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Original treatment assignment, as per baseline randomization, will remain double-blinded to 
the patient, investigator, and site personnel until after the Week 24 database lock and analyses. 
 
5.4 
Treatment blinding 
This is a double-blind randomized treatment trial. However, after completion of Week 16 
assessments of the primary endpoint, patients initially randomized to placebo will be switched 
to receive Secukinumab 150 mg s.c. every week with intermittent placebo injections in both 
active arms at weeks 17, 18, 19 to maintain the blind for the initial treatment assignment. 
Until the end of the trial, all original randomized treatment assignments will be double-blinded 
to patients, investigators, and site personnel.  
Unblinding of treatment dose or original randomized treatment assignment will only occur in 
the case of patient emergencies (see Section 5.5.12). 
The hsCRP results from samples collected during the treatment period will not be revealed to 
the site.  
5.5 
Treating the patient 
5.5.1 
Patient numbering 
Each patient is uniquely identified in the study by a combination of his/her center number and 
patient number. The center number is assigned by Novartis to the investigative site. Upon 
signing the informed consent form, the patient is assigned a patient number by the IRT.  Upon 
signing of the ICF by the patient, the investigator or his/her staff will contact the IRT and 
provide the requested identifying information for the patient to register them into the IRT. Only 
the assigned patient number should be entered in the field labeled “Patient ID” on the EDC data 
entry screen. Once assigned to a patient, the Patient ID will not be reused.  If the patient fails to 
be randomized for any reason, the IRT must be notified within 2 days that the patient was not 
randomized. The reason for not being randomized will be entered on the Screening Log, and 
the Demography eCRF should also be completed. 
 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied by Novartis with study treatment in packaging of identical 
appearance. 
The study treatment packaging for Secukinumab/placebo has a 2-part label. A unique 
medication number is printed on each part of this label. Investigator staff will identify the 
investigational treatment package(s) to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). 
 


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5.5.3 
Handling of study treatment 
5.5.3.1 
Handling of investigational treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all 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. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance. 
Medication labels will be in German and comply with the legal requirements of Germany. They 
will include storage conditions for the study treatment but no information about the patient 
except for the medication number. The PFS (150 mg active/placebo) sealed in an outer box 
must be stored in a access controlled/locked refrigerator between 2°C and 8°C and protected 
from light. They must be carefully controlled in accordance with regulations governing 
investigational medicinal products and local regulations. The investigator must maintain an 
accurate record of the shipment and dispensing of study treatment in a drug accountability log. 
Monitoring of drug accountability will be performed by monitors during site visits or remotely 
and at the completion of the trial. Patients will be asked to return all unused study treatment and 
packaging at the end of the study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed Drug 
Accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site. 
Destruction of the unused drug should be done according to local requirements and after 
approval by Novartis/CRO clinical team. 
5.5.3.2 
Handling of other study treatment 
Not applicable. 
5.5.4 
Instructions for prescribing and taking study treatment 
Study treatment (150 mg Secukinumab and placebo) will be administered s.c. by 1 mL PFS 
throughout the study as 1 mL/150 mg Secukinumab or 1 mL placebo, respectively. 
Administration of study treatment will occur via self-injection by the patient from Baseline 
through to Week 20. Administration of study treatment must occur after the study assessments 
for the visit have been completed. The PFS with the ready-to-use study treatment solution will 
be provided by the site staff to the patient. Detailed instructions on the self-administration of 
the study treatment will be described in the IFU for Secukinumab and provided to each patient. 
At the Baseline visit, patients will be instructed by the site staff, utilizing the IFU, on how to 
self-inject using a PFS. Patients will be asked to raise questions, if they have any, and then to 
proceed with self-injection. At the Week 1 visit, patients will be asked to refer to the IFU and 
to proceed directly with self-injection of the study drug (i.e. no prior retraining) for the 
remainder of the trial. However, if the patient is not comfortable self-injecting the study 
treatment, then the site staff may administer it for the patient. 
All kits of study treatment assigned by the IRT will be recorded in the IRT. 


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The investigator should promote compliance by instructing the patient to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the patient’s 
safety and the validity of the study. The patient should be instructed to contact the investigator 
if he/she is unable for any reason to take the study treatment as directed. 
Subcutaneous administration with pre-filled syringe (PFS) 
Secukinumab solution for s.c. injection (150 mg in 1 mL active/placebo) will be provided in a 
PFS.  
The study treatment solution must be injected into normal areas of the skin. 
Patients will be instructed by the site staff on how to self-inject study treatment using a PFS, 
following the IFU. After training at the Baseline visit, the injections will be self-administered 
into an appropriate site of the body (thighs, arms, abdomen), and each injection should be given 
at a different injection site to reduce the risk of injection reaction. Each new injection should be 
given at least 2.5 cm from the previously used site. If the patient chooses the abdomen, the area 
5 cm around the navel should be avoided. Investigational drug should not be injected into areas 
where the skin is tender, bruised, red, or hard, or where patient has scars or stretch marks. 
Injection sites should be rotated among appropriate sites to reduce the risk of injection reactions. 
The PFSs with study treatment solution should be kept at 2 to 8°C, protected from light and 
should not be stored frozen. Prior to administration the boxes containing the PFSs with study 
treatment solution should be allowed to come to room temperature unopened for about 20 
minutes before administration. Used PFSs should be disposed immediately after use in a sharps 
container or according to the regulatory needs of the respective countries.  
Any PFS for which a defect or malfunction is noticed prior to or during the injection at any of 
the study visits must be kept at the site until guidance is received from Novartis/CRO on 
whether it should be returned to Novartis/CRO for investigation or discarded. Devices identified 
as defective should be stored according to local guidelines, until specific instruction is discussed 
with Novartis/CRO personnel. Additionally, from baseline onwards, any noticed defect, 
malfunction, problem during the injections or product complaints with the PFS should be 
recorded in the source document. Sites should detail the issue, the date, the kit number and the 
visit number. The site will be asked to record, based on their judgment, whether the observed 
issue was primarily related to the device or to the user. Device malfunctions should also be 
immediately reported to Novartis/CRO personnel as a necessary replacement kit may need to 
be provided. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Investigational treatment dose adjustments are not permitted. 
Investigational treatment interruption is only permitted if, in the opinion of the investigator, a 
patient is deemed to be placed at a significant safety risk unless administration of investigational 
treatment is temporarily interrupted. In such cases study treatment should be interrupted only 
during the time that this risk is present and ongoing. Investigational 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. 


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Any study treatment interruption must be recorded on the Dosage Administration Record eCRF. 
5.5.6 
Rescue medication 
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a patient is experiencing either no benefit from participation in 
the trial or worsening/exacerbation of their disease. Rescue medication must not be used before 
completion of Week 12 assessments. Although no patient will be restricted from receiving 
necessary rescue medications for lack of benefit or worsening of disease, if rescue with 
prohibited biologics (as described in Section 5.5.8) occurs, patients 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 patients who are deemed not to be benefiting from the study 
treatment based upon safety and efficacy assessments by the investigator or for any reason on 
their own accord will be free to discontinue the study at any time. Changes in NSAID 
concomitant therapy are permitted after Week 4 assessments and should ideally be performed 
according to the non-binding NSAID tapering guidelines provided to the patient at the week 4 
visit. Please see Section 5.5.7 and Section 5.5.8 for details. 
Use of rescue medication must be recorded on the Prior and Concomitant medications in the 
eCRF page. 
5.5.7 
Concomitant treatment 
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the patient was enrolled into the study must be recorded 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 
Patients 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 12, except if MTX-related adverse events 
develop. 
Folic acid 
Patients on MTX must be taking folic acid supplementation before randomization and during 
the trial to minimize the likelihood of MTX associated toxicity. 
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 may be considered. Cholestyramine could be given orally to wash-
out the drug at a dose of 8 g t.i.d. Cholestyramine reduced plasma levels of the active 
leflunomide metabolite by approximately 40% in 24 hours and by 49% to 65% in 48 hours in 3 
healthy volunteers. The administration of cholestyramine is recommended in patients who 


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require a drug elimination procedure. If a patient receives 8 g t.i.d. for 11 days he/she could 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 12, 
although the corticosteroid dose should not be reduced by more than 1 mg prednisone equivalent 
every 4 weeks. 
After Week 12, the dose and regimen of systemic corticosteroids may be modified as per 
investigator’s judgment and patient need. 
Any change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page. 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 12. After Week 12, 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 
20-week period. Injection of intra-articular steroids is not permitted within 8 weeks prior to 
Week 20. 
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors), low strength opioids and acetaminophen/paracetamol 
Patients 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 4. 
Changes in the NSAID intake will be captured by the patient in the patient diary and checked 
and be transferred into the eCRF at all scheduled study visits after week 4. 
Patients taking 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 12 assessments are completed, a change in the low strength opioids, or 
paracetamol/acetaminophen treatment regimen is permitted. 
Any change of the 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 
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of the washout 
period unless otherwise specified below. 
Live vaccines should not be given until 12 weeks after last study treatment administration. 


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Table 5-1 
Prohibited treatment 
Prohibited treatments 
Washout period  
(before randomization) 
Etanercept* 
4 weeks 
Infliximab* 
8 weeks 
Adalimumab, golimumab, certolizumab* 
10 weeks 
Unstable dose of MTX or sulfasalazine 
(until Week 12) 
4 weeks 
Other DMARD (except MTX or sulfasalazine) 
4 weeks  
Leflunomide 
8 weeks  
Leflunomide with cholestyramine washout 
4 weeks 
Systemic corticosteroids > 10 mg prednisone equivalent** 
(until Week 12) 
2 weeks  
Intra-articular steroids injections  
(until Week 12) 
4 weeks 
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 
Patients may voluntarily discontinue investigational treatment for any reason at any time. 
Patients who prematurely discontinue the study should undergo an end of treatment visit 
(corresponds to the Week 20 visit and also return for the end of study visit at Week 24 (4 weeks 
after last study treatment (see Table 6-1). The final follow-up visit (Week 24) should be 
performed before any new treatment is initiated. Study treatment discontinuation must also be 
recorded in the eCRF and in the IRT. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw from the study), the 
investigator should show "due diligence" by documenting in the source documents steps taken 
to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
Patients who are prematurely withdrawn from the study will not be replaced. 


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Discontinuation of study treatment 
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment would result in a significant safety risk for a patient. The following circumstances 
require study treatment discontinuation: 
 Withdrawal of informed consent 
 Emergence of the following AEs: 
 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 patient 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 patient’s safety 
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given patient 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 
patient’s well-being. 
For patients who discontinue study treatment, a Dosage Administration Record eCRF should 
be completed, giving the date and primary reason for stopping study treatment. 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
5.5.10 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material. 
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. 
Investigational 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 
communicating or follow-up. 


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5.5.11 
Loss to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the patient, 
family or family physician as agreed in the informed consent and by documenting in the source 
documents steps taken to contact the patient, e.g. dates of telephone calls, registered letters, etc. 
A patient should not be formally considered lost to follow-up until his/her scheduled end of 
treatment visit would have occurred. 
5.5.12 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to treat the 
patient safely and efficaciously. Most often, investigational treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
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 be able to unblind details of 
the investigational drug treatment for the specified patient in the IRT system.  
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact his/her 
backup in cases of emergency when he/she is unavailable. The investigator will provide 
protocol number, investigational treatment name if available, patient number, and instructions 
for contacting the sponsor (or any entity to which it has delegated responsibility for emergency 
code breaks) to the patient in case an emergency treatment code break is required at a time when 
the investigator and backup are unavailable. 
Study patient must be discontinued after emergency unblinding. 
As per Novartis standard operating procedures (SOPs) it is one of the primary responsibilities 
of each investigator to be available in case of an urgent emergency unblinding for one of his/her 
patients. 
5.5.13 
Study completion and post-study treatment 
A patient will be considered to have completed the study if he/she received a maximum of 20 
weeks of study treatment and upon completion of the scheduled study assessments and 
procedures up to and including the follow up visit (Week 24). 
Information on the patient’s completion or discontinuation from the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion eCRF 
page. 
In any case, the investigator or site staff must contact the IRT as soon as possible to record the 
patient’s study completion (Week 24) and/or discontinuation. 
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic DMARD. In case of a biologic treatment, 
a waiting period of 3 months before initiating the treatment is recommended. 


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5.5.14 
Early study termination 
The study can be terminated at any time for any reason by Novartis for any reason specified in 
the clinical trial study contract. Should this be necessary, the patient should be seen as soon as 
possible and treated 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 sponsor 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 lists all of the assessments and indicates with an “x” when the Visits are performed. 
For visits scheduled through Week 4, the study treatment should not be administered less than 
7 days after the previous administration. For visits scheduled after Week 4, the study treatment 
should not be administered less than 14 days after the previous administration. At a minimum, 
patients will be contacted for safety evaluations during the 30 days following the end of 
treatment visit at Week 20, including a final contact at the 30-day point. Documentation of 
attempts to contact the patient should be recorded in the source documentation.  
Subjects who prematurely discontinue should return for the End-of-treatment visit (corresponds 
to the week 20 visit) 4 weeks after the last study treatment administration, as well as return for 
the follow-up (week 24). 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 (up to 10 weeks) in duration based on the time required to washout 
prior anti-rheumatic and other medications and will have a duration, during which time the 
patient will sign the informed consent form (ICF), be evaluated for eligibility and sufficient 
time is allowed for potential medication washout, in addition to all other assessments indicated 
in Table 6-1. 
Screening will consist of 2 consecutive visits. During Screening Visit 1, initial assessments will 
be performed as outlined in Table 6-1. At that visit, the duration of the washout period will be 
determined and Screening Visit 2 will be performed as follows: 
 If the washout period is ≤ 4 weeks the investigator should proceed directly to Screening 
Visit 2 on the same day and complete all assessments in the next 4 weeks prior to 
randomization. 
 If the washout period is more than 4 weeks, the patient will be instructed to initiate the 
necessary washout regimen and return for Screening Visit 2 at 4 weeks prior to 
randomization. 
The rationale is that in all cases Screening Visit 2 must occur within the 4 weeks prior to 
randomization and should ideally be performed no less than 2 weeks prior to randomization to 
allocate time for laboratory analyses and shipment of medication. 
All patients evaluated at Screening Visit 1 and 2 for eligibility should not be screen failed on 
the basis of a medication requiring washout, unless the patient will be unable to complete the 
washout in the appropriate time frame before randomization. 


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Table 6-1 
Assessment schedule 
 
Screening1 
Treatment 1 
Treatment 2 
Follow Up 
Screening 
Visit 1 
Screening 
Visit 2 
Week 
-10 
to -4 
 -4 to 
-2 
BSL 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
17 
18 
19 
20 
F24 
Obtain informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Site visit 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
Inclusion/Exclusion 
criteria2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/ current 
medical condition 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AS assessment3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular 
medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG4 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Physical exam4 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
X 
Height, weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
X 


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Screening1 
Treatment 1 
Treatment 2 
Follow Up 
Screening 
Visit 1 
Screening 
Visit 2 
Week 
-10 
to -4 
 -4 to 
-2 
BSL 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
17 
18 
19 
20 
F24 
PPD skin test5 or 
QuantiFERON TB-
Gold test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray or 
MRI6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, blood 
chemistry, 
urinalysis 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
Serum pregnancy 
test 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of 
s.c. study treatment 
via  PFS 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication/ non-
drug therapy 
X 
Update as necessary 


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Screening1 
Treatment 1 
Treatment 2 
Follow Up 
Screening 
Visit 1 
Screening 
Visit 2 
Week 
-10 
to -4 
 -4 to 
-2 
BSL 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
17 
18 
19 
20 
F24 
Adverse 
events/SAEs (if 
applicable, 
including injection 
site reactions)7 
X 
NSAID intake 
reported in eCRF 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Provide NSAID 
Diary to patient and 
instruct patient 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
 
 
 
 
NSAID intake 
captured in patient 
diary 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Check NSAID diary 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
X 
 
Patient’s global 
assessment of 
disease activity 
(VAS) 
 
 
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 
BASFI 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
X 


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Screening1 
Treatment 1 
Treatment 2 
Follow Up 
Screening 
Visit 1 
Screening 
Visit 2 
Week 
-10 
to -4 
 -4 to 
-2 
BSL 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
17 
18 
19 
20 
F24 
BASDAI 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
X 
Spinal mobility 
(BASMI Linear + 
chest expansion) 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
 
SF-36 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
ASAS Health Index 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Erythrocyte 
Sedimentation Rate 
(ESR) 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
High sensitivity  
C-reactive protein 
(hsCRP) 
 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
HLA-B27 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 If the patient’s washout period ≤ 4 weeks, Screening visit 1 (SV1) and Screening visit 2 (SV2) can be performed on the same day. 
2 Eligibility and relevant medical history assessments are conducted at SV1, SV2 and Baseline (BSL) / Day 1’. The data for all three visits should be 
recorded on the corresponding eCRFs available at SV1. 
3 The following eCRFs are to be completed: AS Disease background eCRF, Modified New York criteria for AS eCRF 
4 These assessments are source documentation only and will not be entered into the 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. 


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Screening1 
Treatment 1 
Treatment 2 
Follow Up 
Screening 
Visit 1 
Screening 
Visit 2 
Week 
-10 
to -4 
 -4 to 
-2 
BSL 
1 
2 
3 
4 
5 
6 
7 
8 
12 
16 
17 
18 
19 
20 
F24 
6 A chest X-ray or MRI is required if it was not performed and evaluated within 3 months prior to Screening. The X-ray should be performed after it is 
certain the patient meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The X-ray may be replaced by an MRI 
assessment. 
7 AEs/SAEs occurring after the patient has signed the informed consent must be captured on the appropriate eCRF page. SAEs must be recorded from 
signing of informed consent, AEs must be captured from the BSL visit on. 
* For all patients who discontinue or withdraw from the study, the investigator should ensure that the patient completes an end of treatment visit. 


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6.1 
Information to be collected on Screening failures 
Patients may discontinue from the study prior to randomization. These patients are considered 
Screening failures. 
If a patient discontinues before entering the double-blind treatment period at baseline, the 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 demography data, the reason for failing (screening failure log) and informed 
consent will be collected for those patients who fail to enter the treatment phase.  
Reporting of potential SAE which may have occurred from time of signing informed consent 
until screening failure time should be followed as described in Section 7.2 
6.2 
Patient demographics/other baseline characteristics 
Patient demographic and baseline characteristics data to be collected on all patients and to be 
recorded in the eCRF include: 
 Year of birth, age, sex, race and source of patient referral 
 Relevant AS and general medical history/current medical condition data until the start of 
study treatment, number 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 will be entered in the Prior/Concomitant medications or Significant non-
drug therapies eCRF page.  
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in (Section 5.5.5). Compliance will also be assessed by a Novartis/CRO monitor 
using information provided by the authorized site personnel. 
6.4 
Efficacy 
 Assessment of SpondylArthritis International Society criteria (ASAS)20 
 ASAS-NSAID score  
 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) 
 Spinal mobility assessed by Bath Ankylosing Spondylitis Metrology Index (BASMI) 


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 hsCRP and ESR 
6.4.1 
Assessment of ASAS-NSAID score 
The ASAS-NSAID score will be calculated in accordance with the ASAS recommendations 
(Dougados et al 2011). NSAID intake will be collected in accordance with the ASAS 
recommendations (i.e., name, mean dose, number of days of intake during a period of time). 
Thereafter, the ASAS-NSAID score will be calculated considering both the daily dose of the 
specific NSAID(s) and the percentage of days of intake of the NSAID(s) during a given period 
of time. 
Detailed information for calculating the ASAS-NSAID score is given in Appendix 4. 
6.4.2 
Assessment of SpondyloArthritis International Society criteria (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper 2009). 
The main ASAS domains are as follows: 
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 
The additional assessment domains are as follows: 
5. Spinal mobility represented by the BASMI lateral spinal flexion assessment 
6. C-reactive protein (acute phase reactant) 
Investigator must review the results timely and document adverse events, if applicable.  
ASAS Response Criteria-20% (ASAS20) 
ASAS20 response is defined as an improvement of ≥ 20% and ≥ 1 unit on a scale of 10 in 
at least 3 of the 4 main domains and no worsening of ≥ 20% and ≥ 1 unit on a scale of 10 in the 
remaining domain. 
6.4.2.1 
ASAS Response Criteria-40% (ASAS40) 
ASAS40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 in at 
least three of the four main domains and no worsening at all in the remaining domain. 
6.4.2.2 
ASAS 5/6 improvement criteria 
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six 
domains. 
6.4.2.3 
ASAS partial remission criteria 
The ASAS partial remission criteria are defined as a value not above 2 units in each of the four 
main domains on a scale of 10. 


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6.4.3 
Patient’s global assessment of disease activity (VAS) 
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question, "How active was 
your disease on average during the last week?”. 
6.4.4 
Patient’s assessment of back pain intensity (VAS) 
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from no 
pain to unbearable pain, after the question “Based on your assessment, please indicate what is 
the amount of back pain at any time that you experienced during the last week?” and “Based 
on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?” 
6.4.5 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. The ten questions were chosen with major input from patients with AS. 
The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the patients’ ability to cope with everyday life. A 0 through 10 scale (captured by a 
continuous VAS) is used to answer the questions. The mean of the ten scales gives the BASFI 
score – a value between 0 and 10. 
6.4.6 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS: 
1. Fatigue
2. Spinal pain
3. Joint pain / swelling
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)
5. Morning stiffness duration
6. Morning stiffness severity
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the scores 
from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0–10 BASDAI 
score. Scores of 4 or greater suggest suboptimal control of disease, and patients with scores of 
4 or greater are usually good candidates for either a change in their medical therapy or for 
enrollment in clinical trials evaluating new drug therapies directed at AS. BASDAI is a quick 
and simple index taking between 30 seconds and 2 minutes to complete. 
6.4.7 
Bath Ankylosing Spondylitis Metrology Index (BASMI linear) 
The BASMI is a validated instrument that uses the minimum number of clinically appropriate 
measurements that assess accurately axial status, with the goal to define clinically significant 
changes in spinal movement. Parameters include: 


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1. Lateral spinal flexion 
2. Tragus-to-wall distance 
3. Lumbar flexion (modified Schober)  
4. Maximal intermalleolar distance  
5. Cervical rotation angle 
Additionally, the following assessments should be taken: 
6. Chest expansion 
7. Occiput-to-wall distance 
Detailed information on the assessments is described in Appendix 4. 
6.4.8 
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 1993). 
Two overall summary scores, the Physical Component Summary (PCS) and the Mental 
Component Summary (MCS) also can be computed (Ware 1994). The SF-36 has proven useful 
in monitoring general and specific populations, comparing the relative burden of different 
disease, differentiating the health benefits produced by different treatments, and in screening 
individual patients. 
The purpose of the SF-36 in this study is to assess the health-related QoL of patients. Given the 
acute nature of this disease, version 2, with a 1-week recall period, will be used in this study. 
Investigator must review the results timely and document adverse events, if applicable. 
6.4.9 
ASAS Health Index 
The ASAS Health Index (ASAS HI) is an index that measures an individual’s status of 
functioning, disability and health in individuals and is designed specifically for 
spondyloarthritis patients. (ASAS HI) (12). 
The ASAS HI is a linear composite measure that contains 17 items of functioning and health 
and 9 environmental factors addressing categories of support/relationships, attitudes and health 
services with dichotomous response options: “I agree” and “I do not agree”. The result forms a 
unidimensional scale providing a sum score representing a wide spectrum of different levels of 
functioning (Kiltz et al. 2014). 
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 response to treatment. 
Since the results of this test may unblind study personnel, results from the central laboratory 
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. 


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6.4.11 
Erythrocyte sedimentation rate (ESR) 
ESR is helpful in diagnosing inflammatory diseases and is used to monitor disease activity and 
response to therapy. ESR will be performed locally at the investigative site using a centrally 
provided assessment kit. 
6.4.12 
Appropriateness of efficacy assessments  
The ASAS-NSAID score is used to determine the NSAID sparing effect of biologic i.e. the 
timing of discontinuation/tapering of NSAID(s) after initiating treatment with Secukinumab. 
The other efficacy outcome measures used in this study are the standard measures used across 
all AS trials. 
6.5 
Safety 
 QuantiFERON TB-Gold test or PPD skin test 
 Chest X-ray or MRI 
 Physical examination 
 Vital signs 
 Height and weight 
 Laboratory evaluations 
 Pregnancy and assessment of fertility 
 Local tolerability (injection site reactions) 
 Tolerability of Secukinumab 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (e.g. evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered. 
6.5.1 
QuantiFERON TB-Gold test or PPD skin test 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at Screening. 
Patients with a positive test may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis, or if presence of latent tuberculosis is established then treatment according to local 
country 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 patient’s eligibility for the trial. 
The test will be used to screen the patient population for latent tuberculosis infection.  
 The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 
PPD skin test 
 A PPD skin test is to be performed at Screening and read before randomization to determine 
the patient’s eligibility for the trial. The test dose is bioequivalent to 5 tuberculin units of 


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standard PPD injected intradermally, usually into the volar surface of the forearm. The site 
is cleaned and the PPD extract is then injected into the most superficial layer under the skin. 
If given correctly, the injection should raise a small wheal of about 5 mm, which resolves 
within 10-15 minutes. 
Because the reaction (induration) will take 48-72 hours to develop, the patients must return to 
the study center within that time for a proper evaluation of the injection site. This will determine 
whether the patient has had a significant reaction to the PPD test. A reaction is measured in 
millimeters of induration (hard swelling) at the site. A PPD skin induration ≥5 mm (or according 
to local practice/guidelines) is interpreted as a positive result. 
6.5.2 
Chest X-ray or MRI 
A chest X-ray or MRI at Screening (or within 3 months prior to Screening) will be performed 
to rule out the presence of a pulmonary malignancy of infectious process, in particular 
tuberculosis. 
6.5.3 
Physical examination  
The physical examination will include the examination of general appearance, skin, neck, eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological system. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF which meet the 
definition of an SAE must be recorded in the Adverse Event eCRF. All findings meeting the 
definition of an AE must be recorded from the first administration of study drug on.  
6.5.4 
Vital signs  
This will include blood pressure and pulse rate measurements after 5 minutes rest in sitting 
position. 
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study. 
6.5.5 
Height and weight  
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured. 
If possible, body weight assessments should be performed by the same study site staff member 
using the same scale throughout the study. 
6.5.6 
Laboratory evaluations  
A central laboratory will be used for analysis of all specimens collected as listed in the 
sub-sections below (except for urinalysis and ESR). Details on the collections, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the 
laboratory manual. Clinically significant abnormalities must be recorded on the relevant section 
of the medical history/Current medical conditions/AE CRF page as appropriate. All patients 
with laboratory tests containing clinically significant abnormal values are to be followed until 


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the values return to normal ranges or until a valid reason, other than treatment related AE, is 
defined. 
Clinically notable laboratory results are defined in Appendix 1. 
6.5.6.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential counts, 
and platelet count will be measured at scheduled visits. 
6.5.6.2 
Clinical chemistry 
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid. 
6.5.6.3 
Urinalysis 
Dipsticks will be provided by the central laboratory to the sites for local urinalysis assessments. 
The urinalysis results for standard parameters such as protein, glucose, blood and WBCs will 
be recorded in the appropriate eCRF page. 
 
6.5.7 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as indicated in Table 6-1. 
ECGs can be performed externally at a qualified physician but the investigator/qualified site 
staff must review the tracing. The tracing must then be stored with the subject's source 
documents. If the ECG findings at screening are clinically relevant and would prevent the 
subject from participating in the study (taking into account the subject's overall status as well 
as the medication profile), the subject should be recorded a screen failure and should not receive 
treatment. Findings at the later ECG readings will be reported as adverse or serious adverse 
events. If these findings constitute a reason for premature patient withdrawal or would render 
the overall risk-benefit evaluation of continued participation and treatment in the study 
unfavorable for the patient, the patient must discontinue study medication. 
6.5.8 
Pregnancy and assessments of fertility  
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test (serum 
pregnancy test) performed at the second Screening visit and local urine pregnancy tests as 
indicated in Table 6-1. 
A positive urine pregnancy test requires immediate interruption of study drug until serum β-
hCG is performed and found to be negative. 
6.5.9 
Local tolerability (Injection site reactions) 
The local tolerability at the site of s.c. injection of the study treatment will be assessed in case 
of any local reaction, until this has disappeared.  


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The assessment of pain, redness, swelling, induration, hemorrhage and itching will be 
performed by a physician and will be recorded on the Adverse Events eCRF, including the 
severity (mild, moderate, severe) and the duration. 
6.5.10 
Tolerability of Secukinumab  
Tolerability will be assessed by adverse events, laboratory values and injection site reaction. 
6.5.11 
Appropriateness of safety measurements  
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in AS. According to local recommendations, a chest X-ray should be performed in 
clinical practice before initiation of an immunomodulating biologic therapy for AS (DGRh 
2009). The radiation exposure that results from the chest X-ray safety measurements at 
Screening 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 reliable safety measures before the 
treatment with a biologic. 
While hsCRP results are not automatically communicated to the site by the central lab, it will 
be acceptable to perform a CRP measurement at a local lab in case this is warranted for safety 
reasons. 
 The safety assessments selected are standard and adequate for this indication/patient 
population.  
6.6 
Other assessments 
 HLA-B27 
6.6.1 
HLA-B27 
A blood sample to analyze Human Leukocyte Antigen-B27 (HLA-B27) will be obtained from 
all patients 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. 
6.6.2 
Resource utilization 
No measures of Healthcare Resource Utilization (RU) will be collected in the study. 
6.6.3 
Pharmacokinetics 
Not applicable. 
6.6.4 
Other biomarkers 
Not applicable. 


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7 
Safety monitoring 
7.1 
Adverse events 
An AE is the appearance or worsening of any undesirable sign, symptom, or medical condition 
occurring after first intake of study drug even if the event is not considered to be related to study 
drug. Study drug includes the investigational drugs under evaluation that are given during any 
period of the study. 
Medical conditions/diseases present before first intake of study drug are only considered 
adverse events if they worsen after study start. Abnormal laboratory values or test results 
constitute AEs only if they induce clinical signs or symptoms, require dose reduction or 
temporary or permanent study drug discontinuation or require therapy. 
All AEs with a date of onset up to 30 days following after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit whichever is later) 
must be reported. 
The occurrence of AEs should be sought by non-directive questioning of the patient at each 
visit during the study. AEs may also be detected when they are volunteered by the patient during 
or between visits or through physical examination, laboratory test, or other assessments. All 
adverse events must be recorded on the Adverse Events CRF with the following information: 
1. the severity grade (mild, moderate, severe) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. whether it constitutes a serious adverse event (SAE) 
All AEs should be treated appropriately. Treatment may include 1 or more of the following: no 
action taken (i.e. further observation only); study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant medication given; 
non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged. The action 
taken to treat the AE should be recorded on the Adverse Event CRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, seriousness, the suspected relationship to the study drug, the 
interventions required to treat  it, and the outcome. 
The investigator should also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any 1 of the following 
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 is fatal or life-threatening  
 results in persistent or significant disability/incapacity 
 constitutes a congenital anomaly/birth defect 
 requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
 elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
 social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent 1 of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 7.2.2. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until 30 days after the patient has stopped study 
participation (defined as time of last dose of study drug taken or last visit 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 30 day period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study drug. For patients who discontinue study 
medication, SAEs still need to be reported until the end of study, regardless of their suspected 
relationship to study medication.  
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 is collected and recorded on the Serious Adverse Event Report 
Form.  The investigator must assess the relationship to study drug, complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the German 
Novartis Clinical Safety & Epidemiology Department. The SAE form should also include 
information about the concomitant NSAID medication. The telephone and telefax number of 
the contact persons in the German department of Clinical Safety and Epidemiology, 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. 
All SAEs occurring during the follow-up period will be entered in the Adverse Events CRF 
pages. In addition, an SAE Report Form should be completed. Follow-up information will be 
sent to the same person to whom the original SAE Report Form was sent, using a new SAE 
Report Form stating that this is a follow-up to the previously reported SAE and giving the date 
of the original report.  The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the patient continued or withdrew from study participation. 
Adverse reactions under a Novartis drug of which investigator became aware prior to or during 
Screening and which were not yet reported should be forwarded to the local Novartis Clinical 
Safety & Epidemiology Department. This adverse reaction report including the administered 
Novartis drug and causality assessment should be forwarded independently from the described 
procedure. Serious adverse reactions occurring under non-Novartis drugs which are not 
investigational medicinal product (IMP) should be forwarded either to the national competent 
authority (BfArM or PEI), the Drug Commission of the German Medical Association or the 
respective marketing authorization holder. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study drug, a Clinical Safety & 
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 drug 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 
Directive2001/20/EC or as per national regulatory requirements in participating countries. 


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7.3 
Liver safety monitoring 
Secukinumab has not been studied specifically in patient with hepatic impairments. No 
pharmacokinetic data are available in these patients. However IgGs are mainly eliminated via 
catabolism and hepatic impairment is not expected to influence clearance of Secukinumab. 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study: 
 Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
 Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Please refer to Table 13-1 in Appendix 2 for complete definitions of liver laboratory triggers 
and liver events.  
Every liver laboratory trigger or liver event as defined in Table 13-1 of Appendix 2 should be 
followed up by the investigator or designated personal at the trial site as summarized below. 
Detailed information is outlined in Table 13-2 in Appendix 2. 
For the liver laboratory trigger: 
 Repeating the LFT (Liver Function Test) within the next week to confirm elevation. 
Repeat laboratory tests should be entered on the appropriate unscheduled local laboratory CRF 
page. 
 If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
 Repeating the LFT to confirm elevation as appropriate 
 Discontinuation of the investigational drug if appropriate 
 Hospitalization of the patient if appropriate 
 A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
 An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages, including the liver 
event overview eCRF pages. 
7.4 
Renal safety monitoring 
Secukinumab has not been studied specifically in patient with renal impairments. No 
pharmacokinetic data are available in patients with renal impairment. The renal elimination of 


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intact Secukinumab, an IgG monoclonal antibody, is expected to be low and of minor 
importance. 
To ensure patient safety and enhance reliability in determining the nephrotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events has to be followed.  
The following two categories of renal adverse events have to be considered during the course 
of the study: 
1. Serum event: 
 confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status 
2. Urine event:  New onset (≥1+) proteinuria, hematuria or glucosuria; or 
 Doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine 
ratio (PCR) (if applicable). 
Every renal laboratory trigger or renal event as defined in Table 7-1 should be followed up by 
the investigator or designated personnel at the trial site as summarized below. 
Table 7-1 
Specific renal alert criteria and actions 
Serum Event 
Serum creatinine increase 
25 – 49% compared to baseline 
Confirm 25% increase after 24-48h  
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine 
increase   50 % compared to baseline 
Follow up within 24-48h if possible 
Consider drug interruption  
Consider patient hospitalization /specialized treatment 
Urine Event 
New dipstick proteinuria ≥ 1+ 
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold 
Albumin-creatinine ratio (ACR) ≥ 30 
mg/g or ≥ 3 mg/mmol; 
Protein-creatinine ratio (PCR )≥ 150 
mg/g or >15 mg/mmol 
Confirm value after 24-48h 
Perform urine microscopy 
Consider drug interruption / discontinuation  
New dipstick glucosuria ≥ 1+ not due to 
diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR  
New dipstick hematuria ≥ 1+ not due to 
trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR  
 
For all renal events: 


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Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed  
Monitor patient regularly (frequency at investigator’s discretion) until either:  
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 
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 occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the investigational treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.  
7.6 
Prospective suicidality assessment 
Not applicable 
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/CRO will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis/CRO employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of patient records, the accuracy of entries on the eCRFs, the adherence 
to the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis/CRO monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the 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 staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they have 
been trained.  
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff / CRO staff review the data entered into the CRFs 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 (or a designated CRO). 
ECG records will be kept at the site as source data. 
Diary data will be entered into a paper diary by the patient. The study staff will check the diary 
and enter the data into the eCRF. The database will be sent electronically to Novartis (or a 
designated CRO). 
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of 
Novartis.  
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 


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locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Trial 
Statistician and Statistical Reporting and the Clinical Trial Leader. 
8.4 
Data Monitoring Committee 
Not required. 
8.5 
Adjudication Committee 
Not required. 
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 generally focus on the first 12-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 3 treatment groups. These treatment groups represent the regimens subjects will be 
eligible to be randomized to.  
Secukinumab (“delayed tapering”) regimen: Secukinumab 150 mg s.c. at Week 0, 1, 2, 3, 4, 
8, 12, 16 and 20; Placebo injections at Week 5, 6 and 7 and 17, 18. 19. 
Secukinumab  (“early tapering”) regimen: Placebo at Weeks 0, 1, 2, 3 followed by 
Secukinumab 150 mg s.c. at Week 4, 5, 6, 7, 8, 12, 16 and 20 with additional Placebo injections 
at week 17, 18. 19. 
Placebo regimen: Placebo at Weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. From Week 16, patients will 
be switched to receive Secukinumab 150 mg s.c. at Week 16, 17, 18, 19, and 20. 
9.1 
Analysis sets  
Randomized set: The randomized set will be defined as all subjects who were randomized.  
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, and in the 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. 


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9.2 
Patient demographics and other baseline characteristics  
Demographics and baseline characteristics 
The following common background and demographic variables will be summarized: 
 Gender, age, race, weight, height, and BMI 
Baseline disease characteristics will also be summarized for the following variables: 
 Duration of disease, TNF- alpha inhibitor status (naïve or inadequate responder), Patient’s 
global assessment of disease activity and other ASAS components, hsCRP, ESR, number 
of prior biologic AS therapies, dose of methotrexate or other DMARD at randomization 
Medical history 
Any significant prior or active medical condition at the time of signing informed consent will 
be coded using the MedDRA dictionary. These medical conditions will be summarized by 
primary system organ class and preferred term. 
9.3 
Treatments  
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. 
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. 
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) 
and the total duration of exposure to ankylosing spondylitis therapies previously. 


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9.4 
Analysis of the primary variable(s) 
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 9.4.1 and Section 9.5.1. 
9.4.1 
Variable(s) 
The primary efficacy variable is response to treatment according to the ASAS20 criteria at 
Week 12. The analysis of the primary variable will be based on the FAS subjects. The analysis 
of the primary variable will be based on the following estimand: 
o Analysis set: FAS 
o Variable of interest: proportion of patients achieving treatment response as defined by the 
ASAS20 criteria at Week 12. 
o Intervention effect: effect between a secukinumab pooled groups vs. placebo regardless of 
adherence to randomized treatment. 
Summary measure: Odds ratio (OR) 
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 in the pooled Secukinumab groups at week 12 versus 
placebo regimen. 
In statistical terms, H1: p1 = p0, HA: p1 ≠ p0, where p0 and p1 denotes the proportion of ASAS20 
responders at Week 12 in the placebo and pooled Secukinumab groups. .Secukinumab groups 
will be pooled using their measurements at week 12. 
H1: Secukinumab ( pooled) is not different to placebo with respect to ASAS20 response at week 
12. 
The primary analysis will be conducted via logistic regression with treatment, TNF-α status 
(previously exposed / never exposed), and CRP status (above central lab ULN / equal or below 
central lab ULN) as factors. The two Secukinumab groups will be pooled using a linear contrast. 
Odds ratios and 95% CI will be presented comparing Secukinumab (pooled) to placebo. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Missing data for ASAS20 response and other binary efficacy variables (e.g. ASAS5/6, etc.) for 
data up to Week 20 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 20 
2. Subjects who do not have the required data to compute response (e.g. ASAS components) 
at baseline and at the specific time point will be classified as non-responders. 
Patients who were 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 the non-responder 
imputation. 
Continuous variables (e.g. ASAS components) up to Week 20 will be analyzed using a mixed-
effects model repeated measures (MMRM) which is valid under the missing at random (MAR) 
assumption. For analyses of these parameters, if all post-baseline values are missing then these 


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missing values will not be imputed and this subject will be removed from the analysis of the 
corresponding variable, i.e. it might be that the number of subjects providing data to an analysis 
is smaller than the number of subjects in the FAS. 
Additionally, under the assumption of missing at random, multiple imputation by treatment may 
be performed for baseline weight as well as for all baseline and post-baseline efficacy variables 
of interest during the trial. 
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 addition, further logistic regression models may be conducted which explore the impact of 
other baseline or disease characteristics on response. 
In case of a substantial number of missing values, their impact on the analysis results may be 
assessed as well by repeating the logistic regression model using ways to handle missing data. 
These may include, but are not limited to: 
a) Tipping point analysis 
b) Observed data analysis 
9.5 
Analysis of other variables 
9.5.1 
Secondary efficacy variables  
The secondary efficacy variables are listed below. Secondary efficacy variables will be 
analyzed using the FAS population. 
 ASAS20 response at Week 12/16. 
 ASAS-NSAID response at Week 12. 
 Change from baseline in BASDAI at Week 12/16. 
 Change from baseline in SF36 physical component score at Week 12/16. 
 Change from baseline in ASAS-NSAID score at Week 12 for Secukinumab (delayed 
tapering) vs. change from baseline in ASAS-NSAID score at Week 16 for Secukinumab 
(early tapering) 
 Change from baseline in BASDAI at Week 12 for Secukinumab (delayed tapering) vs 
change from baseline in BASDAI at Week 16 for Secukinumab (early tapering). 
 Change from baseline in BASDAI question 2 
 ASAS20 response at Week 4 for Secukinumab (delayed tapering) vs. ASAS20 response at 
Week 20 for placebo group 
Testing strategy 
The following hypotheses will be included in the testing strategy, and type-I-errors will be set 
such that a family-wise type-I-error of 5% is kept: 
Primary objective: 


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H1: Secukinumab 150 mg s.c. (pooled Secukinumab groups) is not different to placebo regimen 
with respect to signs and symptoms (ASAS20 response) at Week 12 
Secondary objectives: 
H2: Secukinumab 150 mg s.c. (pooled Secukinumab groups) is not different to placebo regimen 
with respect to change from baseline in ASAS-NSAID score at Week 12 
H3: Secukinumab 150 mg s.c. (pooled Secukinumab groups) is not different to placebo regimen 
with respect to change from baseline in total BASDAI score at Week 12 
H4: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with respect 
to signs and symptoms (ASAS20 response) at Week 12 
H5: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to signs and symptoms (ASAS20 response) at Week 12 
H6: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to signs and symptoms (ASAS20 response) at Week 16 
H7: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with respect 
to change from baseline in ASAS-NSAID score at Week 12 
H8: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to change from baseline in ASAS-NSAID score at Week 12 
H9: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with respect 
to change from baseline in total BASDAI score at Week 12 
H10: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to change from baseline in total BASDAI score at Week 12 
H11: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to change from baseline in total BASDAI score at Week 16 
 
These hypotheses will in principal be tested hierarchically in ascending order. However, since 
some hypotheses for individual group comparisons are already contained in the higher-ranked, 
pooled comparisons for the same endpoint (i.e. H4 and H5 are contained in H1, H7 and H8 are 
contained in H2 and H9 and H10 are contained in H3) these individual hypothesis can be tested 
simultaneously. The justification is that as soon as the pooled hypothesis has been rejected 
(e.g. H1 ), at least one of the two contained individual hypotheses (e.g. H4 and H5) must be 
false and there is only a potential for at most one type-I-error. Therefore H4 and H5 can be 
tested simultaneously once all higher-ranked hypotheses have been rejected. The same 
argument applies to H7 and H8 and to H9 and H10. The following chart displays the testing 
strategy graphically: 
 


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First the hypotheses (H1) for the primary objective (ASAS20 for Secukinumab pooled at week 
12) versus placebo will be tested. If this hypothesis can be rejected at level α, H2 will be tested 
and so on  until H4. H4. and H5 will be tested simultaneously. If both can be rejected, H6 will 
be tested and so on. As soon as a hypothesis fails to be rejected at level α, all tests of the 
following hypotheses (except the paired hypothesis in the same knot) will be regarded as 
exploratory only and will not provide any confirmatory evidence, irrespective of their nominal 
p-values. Of note, in the description above, rejection of a hypothesis refers to rejection of the 
two-sided hypothesis; however the level of a rejected hypothesis is only passed on according 


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to the procedure for the test of another hypothesis if the treatment effect is in favor of the 
Secukinumab regimen. The family-wise error will be set to α=5% and it will be controlled 
with the proposed semi-hierarchical testing strategy. 
ASAS20 at week 12  
Response at Week 12 to ASAS20 for Secukinumab (delayed-tapering) versus placebo will be 
evaluated using a logistic regression model with treatment as a factor and baseline weight as a 
covariate. 
ASAS20 at week 16  
Response at Week 16 to ASAS20 for Secukinumab (early-tapering) versus placebo will be 
evaluated using a logistic regression model with treatment as a factor and baseline weight as a 
covariate. 
ASAS-NSAID at Week 12 
Between-treatment differences in the change in ASAS-NSAID relative to baseline will be 
evaluated using a mixed-effect model repeated measures (MMRM). Treatment group and 
analysis visit as factors, baseline ASAS-NSAID and weight as continuous covariates. Treatment 
by analysis visit and baseline ASAS-NSAID 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 pooled treatment effect will be determined from a linear 
contrast comparing the (mean of the) two Secukinumab regimens to placebo. The significance 
of the two individual Secukinumab treatment group effects will be determined from the pairwise 
comparisons performed between Secukinumab regimens and placebo. 
BASDAI at Week 12/16 
The change from baseline to Week 12/16 in total BASDAI will be analyzed using a MMRM 
with treatment regimen 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 Secukinumab treatment effect will be determined from the 
pairwise comparisons performed between Secukinumab regimens and placebo. 
Other secondary variables 
SF-36 PCS  
For the change in SF-36 PCS, between-treatment differences will be evaluated using a mixed 
effect repeated measures model (MMRM). Treatment group and analysis visit will be included 
as categorical factors and baseline SF-36 PCS score and weight as continuous covariates. 
Treatment by analysis visit and baseline SF-36 PCS 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 will be determined from the 
pairwise comparisons performed between Secukinumab regimens and placebo. 


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Between-treatment comparisons for binary variables in the FAS population (e.g. ASAS20) at 
individual analysis visits will be evaluated using a logistic regression model with treatment as 
a factor and weight as a covariate for any analysis up to end of study. 
Continuous variables (e.g. change from baseline in BASDAI question 2) will be evaluated using 
a MMRM with treatment regimen 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 pairwise comparisons performed between Secukinumab 
regimens and placebo and/or Secukinumab at the appropriate analysis visits.  
9.5.2 
Exploratory efficacy variables 
The exploratory efficacy variables are listed below. Exploratory efficacy variables will be 
analyzed using the FAS population. 
 Total ASAS-NSAID [Area Under Curve (AUC)] Score from treatment start with 
Secukinumab to a Secukinumab exposure of 12 weeks. 
 Total ASAS-NSAID [Area Under Curve (AUC)] Score From Week 4 to Week 16  
 Proportion of patients with no NSAID intake after Secukinumab exposure of 12 weeks 
 Proportion of patients with no NSAID intake at week 12. 
 Change from Baseline in the ASAS Health Index after Secukinumab exposure of 12 
weeks 
 Change from Baseline in the ASAS Health Index at week 12 
 Change from baseline in BASMI 
 ASAS40 response  
 ASAS20 response  
 ASAS5/6 response  
 Change from baseline in hsCRP  
 Change from baseline in total BASDAI  
 BASDAI 50 response  
 ASAS partial remission  
 Change from baseline in ASAS components including: 
a. Patient global disease activity 
b. Total spinal pain 
c. Inflammation (average of BASDAI questions 5 and 6) 
d. BASFI 
 Change from baseline in ASDAS-CRP and ASDAS-ESR 
 ASDAS inactive disease as defined by ASDAS < 1.3 
 ASDAS clinically important improvement (change in ASDAS ≥ 1.1) and major 
improvement (change in ASDAS ≥ 2.0)  
 Reasons given in the patient diary on why he was not able to taper NSAIDs despite 
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Secukinumab groups at week 12 (delayed tapering) and week 16 (early tapering) will be 
compared for all primary, secondary and exploratory variables that have not been outlined. 
Variables such as hsCRP whose distribution is not anticipated to be normal will be transformed 
and analyzed on the loge scale. All other details and analyses regarding the exploratory efficacy 
variables will be outlined in the statistical analysis plan. 
9.5.3 
Safety variables  
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) will be summarized.  
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 will be presented separately by study periods, i.e. Weeks 1-16 and after Week 
16. 
As appropriate, the incidence of AEs will be 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 
study treatment discontinuation). 
A graphical display of relative frequencies within system organ classes and relative risks, as 
appropriate, will be presented. 
When adjudication is required of major cardiovascular events, a summary of those types of 
events as reported by the investigator and confirmed by adjudication will be provided. 
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. 
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 


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normal, low, or high. These summaries will be presented by laboratory test and treatment 
group. Shifts will be presented by visit as well as for most extreme values post-baseline.  
Vital signs 
Analysis of the vital sign measurements using 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. 
HLA-B27 
Human Leukocyte Antigen-B27 (HLA-B27) will be summarized at baseline and listed. 
9.5.4 
Resource utilization 
Not applicable. 
9.5.5 
Pharmacokinetics  
Not applicable. 
9.5.6 
Pharmacogenetics/pharmacogenomics  
Not applicable. 
9.5.7 
Biomarkers  
Not applicable. 
9.5.8 
PK/PD  
Not applicable. 
9.6 
Interim analyses  
Not applicable. 
9.7 
Sample size calculation 
All sample size and power considerations are performed using EAST 6. 
The sample size was calculated based on the phase III results of the MEASURE2 study, which 
used the same dose and loading regimen as will be applied in this trial. Under the assumption 
of 56.9% ASAS20 responders in the Secukinumab (delayed tapering) group and 27.0% in the 
placebo group, a sample size of 62 patients per group is required to have 90% power to show 
superiority of Secukinumab over placebo at a two sided α=5%. 
For the comparison of the the early tapering group at week 16 vs. placebo, the same treatment 
effect is expected, leading to the same sample size. To compensate for some dropout and other 
protocol deviations, the sample size will be increased to 68 per arm. The total sample size of 
this trial will thus be 204. At the time of writing this amendment, about 190 patients have been 
recruited into this trial and it seems unlikely that a sample > 200 can be recruited within 
reasonable time. With this sample size, the (newly introduced) comparison of pooled 


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Secukinumab groups vs. placebo, the trial would still have almost 80 % (78%) power if the 
placebo response was somewhat higher (35%) than originally assumed..  
Other secondary endpoints 
It will be assumed that the amount of NSAID reduction observed in the etanercept SPARSE 
trial (Dougados et al. 2014), of 63.9 vs. baseline (etanercept) and 36.6 for placebo, with an 
estimated standard deviation of 40 will be seen in this trial for both Secukinumab groups versus 
placebo. Based on this assumption both secukinmab groups will have >90% power to show 
superiority over placebo for NSAID reduction. 
For the total BASDAI parameter, 62 patients per treatment group should yield a power of 
approximately 91%, assuming a a treatment difference of 1.8 with a standard deviation of 2.8 
(van der Heijde 2006). For SF-36 PCS, 62 patients per treatment group yield a power of 
approximately 87.5%, assuming mean change of 6.9 on both Secukinumab regimen and mean 
change of 1.6 on placebo with common standard deviation of 8.7 (Davis 2007).    
10 
Ethical considerations 
Study documentation, record keeping and retention of documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 


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regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
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. 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 an informed consent form that 
complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study.  
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study 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. 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, patient recruitment procedures 
(e.g., advertisements) and any other written information to be provided to patients. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 


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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 for patients safety may be implemented 
immediately provided the Health Authorities are subsequently notified by protocol amendment 
and the reviewing IRB/IEC is notified. Notwithstanding the need for approval of formal 
protocol amendments, the investigator is expected to take any immediate action required for the 
safety of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, the reporting requirements identified in section 7 Safety Monitoring 
should be followed. 
12 
References 
References are available upon request 
Blauvelt A, Prinz J, Gottlieb AB, et al (2014) Secukinumab administration by pre-filled 
syringe: efficacy, safety, and usability results from a randomized controlled trial in psoriasis 
(FEATURE). Br J Dermatol.(published online ahead of print August 16, 2014). 
Braun et al. Treatment of active ankylosing spondylitis with infliximab: a randomised 
controlled multicentre trial; Lancet 2002; 359: 1187–93. 
Dougados M, Simon P, Braun J et al (2011) ASAS recommendations for collecting, analysing 
and reporting NSAID intake in clinical trials/epidemiological studies in axial 
spondyloarthritis. Ann Rheum Dis;70(2):249-51. 


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Dougados M, Wood E, Combe B et al (2014) evaluation of the nonsteroidal anti-inflammatory 
drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, 
randomized, double-blind, placebo-controlled SPARSE study. Arthritis Res Ther;16(6):481. 
Dubreuil M (2014) myocardial infarction risk with diclofenac use in spondyloarthropathy 
versus non-inflammatory low back pain. ACR/ARHP Annual Meeting 2014; Boston, MA.  
Arthritis Rheumatol. Supplement 66(10):Abstract no. 554;S243. 
Kiltz U, van der Heijde D, Boonen A, Braun J (2014) The ASAS Health Index (ASAS HI) – a 
new tool to assess the health status of patients with spondyloarthritis; Clin Exp Rheumatol 
2014; 32 (Suppl. 85):S105-S108 
Konttinen L, Tuompo R, Uusitalo T et al (2007) anti-TNF therapy in the treatment of 
ankylosing spondylitis: the Finnish experience; Clin Rheumatol (2007)26(10):1693–1700. 
Nderitu P, Doos L, Jones PW et al (2013) non-steroidal anti-inflammatory drugs and chronic 
kidney disease progression: a systematic review. Fam Practice;30(3):247–55. 
Poddubnyy D, Hermann KG, Callhoff J et al (2014) ustekinumab for the treatment of patients 
with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-
concept study (TOPAS); Ann Rheum Dis;73(5):817-23. 
Sieper et al. 2015. Secukinumab significantly improves signs and symptoms of active 
ankylosing spondylitis: 52-Week Data from MEASURE 2, A Randomized, Double-Blind, 
Placebo-Controlled Phase 3 Trial with Subcutaneous Loading and Maintenance Dosing. 
EULAR Annual Meeting, Rome Italy, 2015. Oral presentation (presentation number 168) 
Van der Hejde D, Sieper J, Maksymowych WP et al (2011) update of the international ASAS 
recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann 
Rheum Dis;70(6):905-8. 
Van Baarsen LGM, Lebre MC, van der Coelen D, et al (2011) IL-17 levels in synovium of 
patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis: Target validation in 
various forms of arthritis. Ann Rheum Dis;70:A79.  
13 
Appendices 
13.1 
Appendix 1: Clinically notable laboratory values and vital signs 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Clinically notable values will be forwarded to Novartis/CRO at the same time that they are sent 
to investigators. Any action based on these laboratory values should be discussed with 
Novartis/CRO personnel. 
 
 
 
Table 13-1 
Safety analyses: expanded limits and notable criteria 
 
Final Harmonization 


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Notable Criteria 
Laboratory Variable 
 
Standard Units 
SI Units 
LIVER FUNCTION AND RELATED VARIABLES 
SGOT (AST) 
 
>3 x ULN 
>3 x ULN 
SGPT (ALT) 
 
>3 x ULN 
>3 x ULN 
Bilirubin 
 
>2 x ULN 
>2 x ULN 
Alkaline phosphatase 
 
>2.5 x ULN 
>2.5 x ULN 
 
 
 
 
RENAL FUNCTION, METABOLIC AND ELECTROLYTE VARIABLES 
Creatinine (serum) 
 
>2 x ULN 
>2 x ULN 
HEMATOLOGY VARIABLES 
Hemoglobin:  
20 g/L decrease from baseline 
Platelet count:  
<100x10E9/L 
White blood cell count: 
<0.8 x LLN 
Neutrophils:  
<0.9 x LLN 
13.2 
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements 
Table 13-2 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
LIVER LABORATORY 
TRIGGERS 
3 x ULN < ALT / AST  5 x ULN 
 1.5 x ULN < TBL  2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
ALT or AST > 3 × ULN and INR > 1.5  
 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any adverse event potentially indicative of a liver toxicity *  
 
Table 13-3 
Follow-up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s 
Law casea 
Discontinue the study drug 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
 


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Criteria 
Actions required 
Follow-up monitoring 
ALT or AST 
> 8 × ULN 
Discontinue the study drug 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and 
INR > 1.5 
Discontinue the study drug 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 5 to ≤ 8 × ULN 
Repeat LFT within 48 hours 
If elevation persists, continue follow-up 
monitoring 
If elevation persists for more than 2 
weeks, discontinue the study drug 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
Discontinue the study drug 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN  
(patient is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of 
known bone 
pathology) 
Repeat LFT within 48 hours 
If elevation persists, establish 
causality 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of 
known Gilbert 
syndrome) 
Repeat LFT within 48 hours 
If elevation persists, discontinue the 
study drug immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 1.5 to ≤ 2 × 
ULN 
(patient is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the patient  
Investigator discretion 
Monitor LFT within 1 to 4 weeks 
or at next visit 
Jaundice 
Discontinue the study drug 
immediately 
Hospitalize the patient 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
Any AE 
potentially 
indicative of a 
liver toxicity* 
Consider study drug interruption or 
discontinuation  
Hospitalization if clinically appropriate 
Establish causality 
Complete liver CRF 
Investigator discretion 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver 
damage-related conditions; the non-infectious hepatitis; the benign, malignant and unspecified 
liver neoplasms 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × 
ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) 
stable values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at 
elevated level after a maximum of 6 months, (4) liver transplantation, and (5) death. 
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. 
13.4 
Appendix 4 
13.4.1 
Analysis and report of NSAID intake during clinical trials/studies 
1. As soon as the information contained in Table 13-4 is available (eg, name, mean dose, 
number of days of intake during a period of time), the recommendation is to analyse/report 
the data in terms of NSAID equivalent dose in mg/day on a 0–100 scale. The 150 mg 
equivalent diclofenac is set to 100. When the exact number of days with NSAID intake is 
not known (usually when the interval of time between 2 visits exceeds 2 weeks), it is 
recommended to refer to the semi-quantitative estimation summarised in Table 13-4. In 
this case, a score of 7/7 is proposed for the answer ‘every day’, 6/7 for >5 days/week, 4/7 
for >3 to ≤5 days/week, 2 for >1 to ≤3 days/ week, 0.5 for ≤1 day/week and 0 if the patient 
did not take any NSAID during the study period (Dougados et al 2011). 
The general formula for the calculation is: 
(equivalent NSAID score) × (days of intake during period of interest) × (days per week)/(period 
of interest in days) 


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For example, if during a period of interest (between 2 visits) of 6 months, the patient has taken 
piroxicam 20 mg during 4 months and if during this 4-month period he has taken piroxicam 3–
5 days per week the calculation is as follows: 
100 (20 mg piroxicam score) × 120 (4 months) × 4/7 (3–5 days/week)/180 (6 months) = 38.1 
If the patient has used 10 mg piroxicam during the remaining 2 months on 2 days a week, the 
NSAID score for this period is: 
50 (10 mg piroxicam score) ×60 (2 months) × 2/7 (1–3 days/week)/180 (6 months) = 4.8 
In this example the total score for the 6 month period is 42.9 (38.1 plus 4.8). 
Table 13-4 
ASAS recommendations for the approach to collection of NSAID 
intake for use in clinical trials/epidemiological studies of 
spondyloarthritis 
NSAID intake since the last visit  
Yes □   
 
No □ 
NSAID name 
Average daily 
intake 
Days with intake 
Starting date 
Ending date 
 
------------------- 
 
 
 
I___I___I___I 
mg 
□ <1 day/week 
□ 1–3 days/week 
□ 3–5 days/week 
□ ≥5 days/week 
□ Everyday 
 
I__I__II__I__II__I__I 
 
 
I__I__II__I__II__I__I 
 
Ongoing 
 
27. When the name and the dose of the NSAID intake are not available but the number of 
days with NSAID intake is available, the recommendation is to present the results as the 
percentage days with at least NSAID intake during a period of time. 
28. When the only available data are the NSAID intake at a specific visit, the recommendation 
is to present the results as the percentage patients taking an NSAID at a specifi c visit. 
13.4.2 
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) 


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13.4.3 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. The 10 questions were chosen with a major input from patients with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the patient’s ability to cope with everyday life. A 10 cm visual analog scale (VAS) is 
used to answer the questions. The mean of the 10 scales gives the BASFI score – a value 
between 0 and 10. 
13.4.4 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS: 
 How would you describe the overall level of fatigue/tiredness you have experienced? 
 How would you describe the overall level of AS neck, back or hip pain you have had? 
 
 How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had? 
 How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure? 
 How would you describe the overall level of morning stiffness you have had from the 
time you wake up? 
 How long does your morning stiffness last from the time you wake up? 
To give each symptom equal weighting, the mean (average) of the 2 scores relating to morning 
stiffness (questions 5 and 6) is taken. The mean of questions 5 and 6 is added to the scores from 
questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 BASDAI score. 
Scores of 4 or greater suggest suboptimal control of disease, and patients with scores of 4 or 
greater are usually good candidates for either a change in their medical therapy or for enrollment 
in clinical trials evaluating new drug therapies directed at Ankylosing Spondylitis. BASDAI is 
a quick and simple index (taking between 30 seconds and 2 minutes to complete). 
13.4.5 
Bath Ankylosing Spondylitis Metrology Index (BASMI) 
Cervical rotation 
Cervical rotation is measured twice with the patient supine on plinth, head in neutral position, 
forehead horizontal (if necessary, with the head on a pillow or foam block, which must be 
documented for future reassessments). A goniometer (preferably a gravity goniometer) is placed 
centrally on the forehead. Patient rotates head as far as possible to the right, keeping shoulders 
still; ensure no neck flexion or side flexion occurs. The angle between the sagittal plane and the 
new plane after rotation is recorded. The higher reading of 2 assessments is recorded in degrees. 
The same procedure is repeated twice for the left side. Record the mean of the higher reading 
from the right side and the higher reading from the left side. 


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Tragus to wall distance 
Tragus to wall distance is measured twice with the patient’s heels and back rested against the 
wall. The chin should be at usual carrying level and the patient takes maximal effort to touch 
the head against the wall. The distance between the tragus and the wall is assessed on each side, 
and an average of the 2 distances from each side is calculated. The procedure is repeated, and 
the shorter of the 2 average assessments is reported. 
Spinal lateral flexion (lumbar lateral flexion) 
Patient stands with heels and buttocks touching the wall, knees straight, shoulders back, and 
hands by the side. The patient bends to the right side as far as possible, without lifting the left 
foot/heel or flexing the right knee and maintaining a straight posture with heels, buttocks, and 
shoulders against the wall. The distance from the third fingertip to the floor when patient bends 
to the side is subtracted from the distance when patient stands upright. The higher of 2 tries is 
recorded. The maneuver is repeated on the left side. Record the mean of the larger difference 
from the right side and the larger difference from the left side.  
Lumbar flexion (modified Schober index) 
Patient is standing erect. Set marks in upright position 5 cm below and 10 cm above lumbosacral 
junction (spinal section of a line joining the dimples of Venus). Measure the difference between 
the distance between marks in a standing position (15 cm) versus a forward flexed position 
when the patient bends forward as far as possible, keeping the knees straight. The procedure is 
repeated, and the higher difference of the 2 tries is reported. 
Maximal intermalleolar distance 
Patient is lying down with the legs separated as far as possible with knees straight and toes 
pointing upwards. Alternatively, the patient stands and separates the legs as far as possible. 
Distance between medial malleoli is measured, and the higher of the 2 readings is recorded. 
Chest expansion 
Chest expansion is measured with the patient’s hands resting on or behind the head. The 
measurement is taken at the fourth intercostal level anteriorly. The difference between maximal 
inspiration and expiration in cm (to the nearest 0.1 cm) is recorded twice, and the higher 
difference of the 2 tries is reported. 
Occiput-to-wall distance 
Occiput to wall distance is measured twice with the patient’s heels and back rested against the 
wall. The chin should be at usual carrying level, and the patient takes maximal effort to touch 
the head against the wall. The distance between the occiput and the wall is assessed, and the 
shorter of the 2 readings is reported. 

SAP_001.pdf: 
Clinical Development 
 AIN457F 
CAIN457FDE03 / NCT02763046
A randomized, double-blind, placebo-controlled 
multicenter study of Secukinumab (AIN457) to examine the 
clinical efficacy and the NSAID-sparing effect of 
Secukinumab over 16 weeks in patients with ankylosing 
spondylitis (ASTRUM)
Statistical Analysis Plan (SAP) 
Author: 
, Trial Statistician 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
15-Oct-19
Number of pages: 
59 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason 
for update 
Outcome for update 
Section and title 
impacted 
(Current) 
15-Oct-19 
Before 
DBL 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ..........................................................................................................3 
List of abbreviations .....................................................................................................5 
1 
Introduction ..................................................................................................................7 
1.1 
Study design ......................................................................................................7 
1.2 
Study objectives and endpoints...........................................................................9 
2 
Statistical methods ......................................................................................................15 
2.1 
Data analysis general information.....................................................................15 
2.1.1 
General definitions ...........................................................................16 
2.1.2 
Visit windows ..................................................................................17 
2.2 
Analysis sets....................................................................................................20 
2.2.1 
Subgroup of interest .........................................................................20 
2.3 
Patient disposition, demographics and other baseline characteristics ..................20 
2.3.1 
Patient disposition ............................................................................21 
2.3.2 
Patient demographic and other baseline characteristics ......................21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) .....................................................................................................24 
2.4.1 
Study treatment / compliance ............................................................24 
2.4.2 
Prior, concomitant and post therapies ................................................25 
2.5 
Analysis of the primary objective .....................................................................25 
2.5.1 
Estimand of primary variable ............................................................26 
2.5.2 
Statistical hypothesis, model, and method of analysis of primary 
estimand ..........................................................................................26 
2.5.3 
Handling of missing values/censoring/discontinuations .....................26 
2.5.4 
Supportive analyses ..........................................................................27 
2.6 
Analysis of the key secondary objective ...........................................................27 
2.7 
Analysis of secondary efficacy objective(s) ......................................................27 
2.7.1 
Secondary endpoints.........................................................................27 
2.7.2 
Statistical hypothesis, model, and method of analysis ........................28 
2.7.3 
Handling of missing values/censoring/discontinuations .....................31 
2.8 
Safety analyses ................................................................................................31 
2.8.1 
Adverse events (AEs) .......................................................................31 
2.8.2 
Deaths .............................................................................................33 
2.8.3 
Laboratory data ................................................................................33 
2.8.4 
Other safety data ..............................................................................37 
2.9 
Pharmacokinetic endpoints...............................................................................37 
2.10 
PD and PK/PD analyses ...................................................................................37 


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2.11 
Patient-reported outcomes ................................................................................37 
2.12 
Biomarkers ......................................................................................................39 
2.13 
Other Exploratory analyses ..............................................................................39 
2.14 
Interim analysis ...............................................................................................41 
3 
Sample size calculation ...............................................................................................41 
4 
Change to protocol specified analyses..........................................................................41 
5 
Appendix....................................................................................................................42 
5.1 
Imputation rules...............................................................................................42 
5.1.1 
Study drug .......................................................................................42 
5.1.2 
AE date imputation...........................................................................42 
5.1.3 
Concomitant medication date imputation...........................................44 
5.1.4 
Medical History date of diagnosis imputation ....................................45 
5.2 
AEs coding/grading .........................................................................................45 
5.3 
Laboratory parameters derivations....................................................................45 
5.4 
Statistical models .............................................................................................45 
5.5 
Score derivations and response criteria .............................................................47 
5.5.1 
Assessment of Spondyloarthritis International Society (ASAS) ..........47 
5.5.2 
Ankylosing spondylitis disease activity score (ASDAS) ....................48 
5.5.3 
Bath ankylosing spondylitis disease activity index (BASDAI) ...........49 
5.5.4 
Bath ankylosing spondylitis functional index (BASFI).......................49 
5.5.5 
ASAS Health Index ..........................................................................49 
5.5.6 
Bath Ankylosing Spondylitis Metrology Index (BASMI linear) .........50 
5.5.7 
ASAS-NSAID Score ........................................................................51 
5.6 
Rule of exclusion criteria of analysis sets..........................................................53 
6 
Reference ...................................................................................................................59 


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List of abbreviations 
AE 
Adverse event 
ALT  
Alanine aminotransferase 
AS  
Ankylosing spondylitis 
ASAS  
Assessment of SpondyloArthritis international Society 
AST  
Aspartate aminotransferase  
BASDAI  
Bath Ankylosing Spondylitis Disease Activity Index  
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BASFI 
Bath Ankylosing Spondylitis Functional Index 
BASMI 
Bath Ankylosing Spondylitis Metrology Index 
b.i.d. 
twice a day 
BSL 
Baseline 
CFR 
US Code of Federal Regulations 
CDS 
Core Data Sheet (for marketed drugs) 
COX-1 / 2 
Cyclooxygenase-1 / 2 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRD 
Clinical Trial Results Database 
DMARD 
Disease-modifying antirheumatic drugs 
DMC 
Data Monitoring Committee  
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ESR 
Erythrocyte sedimentation rate 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
hsCRP 
High sensitivity C-reactive protein 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 


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IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
LFT 
Liver function test (raised serum transaminases and/or bilirubin levels) 
MedDRA 
Medical dictionary for regulatory activities 
MTX 
Methotrexate 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
OC/RDC 
Oracle Clinical/Remote Data Capture 
o.d. 
once a day 
PK 
Pharmacokinetics 
PFS 
Pre-filled syringe 
p.o. 
per orally 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
s.c. 
subcutaneous 
SpA 
Spondyloarthritides 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TNFα 
tumor necrosis factor alpha 
TFLs 
Tables, Figures, Listings 
VAS 
visual analog scale 
WHO 
World Health Organization 
 


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1 
Introduction 
This document contains details of the statistical methods which will be used in the phase IV 
clinical trial CAIN457FDE03. This document gives detailed statistical methodology used in the 
analysis of this study. This is a 20-week, randomized, double-blind, 3-arm, placebo-controlled, 
parallel-group, multicenter study of Secukinumab (AIN457) to examine the clinical response 
as measured by the ASAS20 and the NSAID-sparing effect of Secukinumab treatment. 
Data will be analyzed by statistical software SAS version 9.4 according to the data analysis 
Section 9 of the study protocol which is available in Appendix 16.1.1 of the CSR. Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the CSR. 
 
1.1 
Study design 
This is a 20-week, randomized, double-blind, 3-arm, placebo-controlled, parallel-group, 
multicenter study of Secukinumab (AIN457) to examine the clinical response as measured by 
the ASAS20 and the NSAID-sparing effect of Secukinumab treatment. The clinical efficacy 
(ASAS20 response) and the cumulative NSAID sparing effect of two strategies of NSAID 
tapering after initiation of Secukinumab will be evaluated as compared to placebo: 
Treatment arms 
Patients will be randomized 1:1:1 to one of the following treatment groups:  
• Secukinumab - delayed NSAID tapering: Secukinumab 150 mg s.c. at weeks 0, 1, 2, 
3, 4, 8, 12, 16 and 20 with placebo injections at Week 5, 6, 7 and 17, 18, 19 to maintain 
the blind.  
• Secukinumab – early NSAID tapering: Placebo at weeks 0, 1, 2, 3 to maintain the 
blind; followed by Secukinumab 150 mg s.c. at Week 4, 5, 6, 7, 8, 12, 16 and 20 with 
intermittent Placebo injections at week 17, 18, 19 to maintain the blind.  
• Placebo: Placebo at weeks 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments 
of the secondary endpoint have been performed, these patients will receive 
Secukinumab 150 mg s.c. at weeks 16, 17, 18, 19 and 20.  
The patients will be stratified at randomization according to their status of prior TNFα inhibitor 
exposure, i.e. TNFα inhibitor naive patients or TNFα inhibitor inadequate responders (TNFα-
IR). The only condition that will be placed on enrollment targets for each stratum is that no less 
than 60% (i.e. 114)of patients are TNFα inhibitor naïve, i.e., no more than 40% (i.e. 76) of 
patients are TNFα-IR. In theory the percentage of TNFα inhibitor naïve patients could reach 
100%, although that is not anticipated. 
For primary analysis both the secukinumab treatment arms will be pooled and compared against 
placebo. 
Primary analysis time point  
The primary analysis will be performed at 12 weeks. 


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Planned number of patients 
The study is aimed to randomize a total of approximately 190 patients, men or women ≥ 18 
years of age who fulfill the modified New York criteria (Explained in the protocol Appendix 3) 
for AS and have active disease as defined by a BASDAI ≥4 on a scale of 0-10 and spinal pain 
(BASDAI Question 2) of ≥4 cm on a 0–10 numeric rating scale. 
This will be a multi-centric study planned to be conducted across 30-45 sites in Germany.  
Subjects may be re-screened but no study-related re-screening procedure should be performed 
prior to written re-consent by the subject. 
Interim analyses 
No interim analysis will be performed for this study. 
Figure 1.1-1: Study Design  
 


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1.2 
Study objectives and endpoints 
Table 1.2-1 
Objectives and related endpoints 
Objective 
Endpoint 
Primary objective 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (with NSAID 
tapering) is superior to placebo based on the 
proportion of patients achieving an ASAS20 
response at week 12. To show superiority, 
both Secukinumab treatment arms will be 
pooled and compared against placebo. 
Proportion of patients fulfilling ASAS20 criteria 
in 
the 
pooled Secukinumab groups 
(i.e. 
Secukinumab delayed tapering and Secukinumab 
early tapering) and placebo regimen at Week 12. 
Secondary objective 
To demonstrate that the change from 
baseline in ASAS-NSAID score at week 12 
is superior for Secukinumab 150 mg s.c. as 
compared to placebo. 
To show superiority, both Secukinumab 
treatment arms will be pooled and compared 
against placebo. 
Mean change from baseline  in ASAS-NSAID 
score for pooled Secukinumab groups and placebo 
regimen at Week 12.  
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c at week 12 is 
superior to placebo based on the change 
from baseline in the total BASDAI.  
To show superiority, both Secukinumab 
treatment arms will be pooled and compared 
against placebo. 
 
Mean change from baseline  in total BASDAI 
score for pooled Secukinumab groups and placebo 
regimen at Week 12 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 0 with NSAID tapering allowed 
from week 4; “delayed tapering”) at Week 
12 is superior to placebo based on the 
proportion of patients achieving an ASAS20 
response.  
 
Proportion of patients fulfilling ASAS20 criteria 
for Secukinumab (delayed tapering) versus 
placebo regimen at week 12 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 4 with NSAID tapering allowed 
from week 4; “early tapering”) at Week 12 
Proportion of patients fulfilling ASAS20 criteria 
for Secukinumab (early tapering) versus placebo 
regimen at week 12 


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is superior to placebo based on the 
proportion of patients achieving an ASAS20 
response. 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 4 with NSAID tapering allowed 
from week 4; “early tapering”) at Week 16 
is superior to placebo based on the 
proportion of patients achieving an ASAS20 
response. 
 
Proportion of patients fulfilling ASAS20 criteria 
for Secukinumab (early tapering) versus placebo 
regimen at week 16  
 
To demonstrate that the change from 
baseline in ASAS-NSAID score at Week 12 
is superior for Secukinumab 150 mg s.c. 
(Secukinumab from week 0 with NSAID 
tapering allowed from week 4; “delayed 
tapering”) as compared to placebo.  
Mean change from baseline in ASAS-NSAID for 
Secukinumab (delayed tapering) and Placebo at 
Week 12  
 
To demonstrate that the change from 
baseline in ASAS-NSAID score at Week 12 
is superior for Secukinumab 150 mg s.c . 
(Secukinumab from week 4 with NSAID 
tapering allowed from week 4; “early 
tapering”) as compared to placebo.  
Mean change from baseline in ASAS-NSAID for 
Secukinumab (early tapering) and Placebo at Week 
12  
 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 0 with NSAID tapering allowed 
from week 4; “delayed tapering”) at Week 
12 is superior to placebo based on the 
change from baseline in the total BASDAI. 
Mean change from baseline in total BASDAI 
score for Secukinumab (delayed tapering) and 
placebo regimen at Week 12 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 4 with NSAID tapering allowed 
from week 4; “early tapering”) at Week 12 
is superior to placebo based on the change 
from baseline in the total BASDAI.  
Mean change from baseline in total BASDAI 
score for Secukinumab (early tapering) and 
placebo regimen at Week 12 
 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 4 with NSAID tapering allowed 
from week 4; “early tapering”) at Week 16 
is superior to placebo based on the change 
from baseline in the total BASDAI.  
Mean change from baseline in total BASDAI 
score for Secukinumab (early tapering) and 
placebo regimen at Week 16 
 


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 To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. at week 12 is 
superior to placebo based on the change 
from baseline in health-related Quality of 
Life as measured by the SF-36 PCS. 
 
Mean change from baseline in SF-36 PCS in the 
pooled Secukinumab groups (i.e. Secukinumab 
delayed tapering and Secukinumab early tapering) 
and placebo regimen at Week 12. 
 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 0 with NSAID tapering allowed 
from week 4; “delayed tapering”) at Week 
12 is superior to placebo based on the 
change from baseline in health-related 
Quality of Life as measured by the SF-36 
PCS.  
Mean change from baseline in SF-36 PCS for 
Secukinumab (delayed tapering) and placebo 
regimen at Week 12. 
 
To demonstrate that the efficacy of 
Secukinumab 150 mg s.c. (Secukinumab 
from week 4 with NSAID tapering allowed 
from week 4; “early tapering”) at Week 12 
is superior to placebo based on the change 
from baseline in health-related Quality of 
Life as measured by the SF-36 PCS.   
Mean change from baseline in SF-36 PCS for 
Secukinumab (early tapering) and placebo 
regimen at Week 12. 
 
To compare between both Secukinumab 
regimens concerning the change from 
baseline in ASAS-NSAID score after 12 
weeks of Secukinumab exposure (ASAS-
NSAID index at Week 12 for “delayed 
tapering” vs. Week 16 for “early tapering”).  
Mean change from baseline in total ASAS-NSAID 
score after 12 weeks of Secukinumab exposure 
(ASAS-NSAID index at Week 12 for “delayed 
tapering” vs. Week 16 for “early tapering”). 
Exploratory objective 
To compare between both Secukinumab 
regimens concerning the change from 
baseline in the BASDAI after 12 weeks of 
Secukinumab exposure (BASDAI at Week 
12 for “delayed tapering” vs. Week 16 for 
“early tapering”).  
 
Mean change from baseline in the BASDAI after 
12 weeks of Secukinumab exposure (BASDAI at 
Week 12 for “delayed tapering” vs. Week 16 for 
“early tapering”). 
To evaluate change in patient reported neck, 
back and hip pain (BASDAI question 2) 
beginning from Secukinumab treatment on a 
continuous basis in patients exposed to 
Secukinumab 150 mg s.c. for 12 weeks vs. 
placebo.  
Mean change in patient reported neck, back and 
hip pain score (BASDAI question 2) from baseline 
at Week 12 for secukinumab 150 mg s.c. (delayed 
tapering) vs. placebo. 
Mean change in patient reported neck, back and 
hip pain score from baseline at week 16 for 


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secukinumab 150 mg s.c. (early tapering) vs. 
placebo. 
To evaluate change in patient reported neck, 
back and hip pain (BASDAI question 2; 
Appendix 4) from baseline on a continuous 
basis in patients randomized Secukinumab 
150 mg s.c. (Secukinumab from week 0 with 
NSAID tapering allowed from week 4; 
“delayed tapering”) vs. placebo from week 0 
to week 12.  
 
Mean change in patient reported neck, back and 
hip pain score (BASDAI question 2) from baseline 
for secukinumab 150 mg s.c. (delayed tapering) 
vs. placebo from baseline (week 0) to week 12. 
 
To evaluate change in patient reported neck, 
back and hip pain (BASDAI question 2; 
Appendix 4) from baseline on a continuous 
basis in patients randomized Secukinumab 
150 mg s.c. (early tapering) vs. placebo from 
week 0 to week 16.  
 
Mean change in patient reported neck, back and 
hip pain score from baseline for secukinumab 150 
mg s.c. (early tapering) vs. placebo from week 0 to 
week 16. 
To compare ASAS20 response rates at week 
4 
in 
Secukinumab 
150 
mg. 
s.c. 
(Secukinumab from week 0 with NSAID 
tapering allowed from week 4; “delayed 
tapering”) vs. week 20 in the patients 
switching from Placebo after 4 weeks of 
Secukinumab exposure each.  
Proportion of patients fullfilling ASAS20 criteria 
at week 4 for secukinumab 150 mg s.c. (delayed 
tapering) vs. week 20 in patients switching from 
placebo after weeks of secukinumab exposure. 
To explore the total ASAS-NSAID [Area 
Under Curve (AUC)] Score from treatment 
start with Secukinumab to a Secukinumab 
exposure of 12 weeks.  
 
Total ASAS-NSAID [Area Under Curve (AUC)] 
Score for both secukinumab arms from week 0 to 
week 12 for secukinumab 150 mg s.c. (delayed 
tapering) and from week 0 to week 16 for  
secukinumab 150 mg s.c. (early tapering). 
To explore the total ASAS-NSAID [Area 
Under Curve (AUC)] Score from Week 4 to 
Week 16 for each treatment arm. 
Total ASAS-NSAID [Area Under Curve (AUC)] 
Score for each treatment arm from Week 4 to Week 
16.  
To explore the efficacy of secukinumab 
based on the proportion of patients with no 
NSAID intake after Secukinumab exposure 
of 12 weeks. 
Proportion of patients with no NSAID intake at 
week 12 for secukinumab 150 mg s.c. (delayed 
tapering) and at week 16 for secukinumab 150 mg 
s.c. (early tapering). 
 
To explore the efficacy of Secukinumab 150 
mg s.c. in patients with no NSAID intake at 
week 12.   
Proportion of patients with no NSAID intake at 
week 12 for each treatment arm. 


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To explore the efficacy of Secukinumab 150 
mg s.c. based on ASAS Health Index after 
Secukinumab exposure of 12 weeks.  
Mean change from Baseline in the ASAS Health 
Index at week 12 for secukinumab 150 mg s.c. 
(delayed tapering) and at 
week 16 
for 
secukinumab 150 mg s.c. (early tapering).  
 
To explore the efficacy of Secukinumab 150 
mg s.c. assesed by ASAS Health Index at 
week 12.  
Mean change from Baseline in the ASAS Health 
Index at week 12.  
To explore the Spinal mobility assessed by 
Bath Ankylosing Spondylitis Metrology 
Index (BASMI) linear scores.  
Mean change from baseline in BASMI linear 
scores. 
To explore the efficacy of Secukinumab 150 
mg s.c. in achieving the ASAS40 response 
over time.  
Proportion of patients fulfilling the ASAS40 
criteria in each treatment group over time.  
To explore the efficacy of Secukinumab 150 
mg s.c. in achieving the ASAS20 response 
over time. 
Proportion of patients fulfilling the ASAS20 
criteria in each treatment group over time 
To explore the efficacy of Secukinumab 150 
mg s.c. in achieving the ASAS5/6 response 
over time. 
Proportion of patients fulfilling the ASAS5/6 
criteria in each treatment group over time. 
To explore the efficacy of Secukinumab 150 
mg s.c. assesed by hsCRP. 
Mean change from baseline in hsCRP.  
To explore the efficacy of Secukinumab 150 
mg s.c.assesed by total BASDAI over time.  
Mean change from baseline in total BASDAI 
score in each treatment group over time. 
To explore the efficacy of Secukinumab 150 
mg s.c.in achieving BASDAI 50 response 
over time. 
Proportion of patients fulfilling  BASDAI 50 
response criteria in each treatment group over 
time. 
To explore the efficacy of Secukinumab 150 
mg s.c.in achieving ASAS partial remission 
response over time.  
Proportion of patients fulfilling  ASAS partial 
remission criteria in each treatment group over 
time  
To explore the efficacy of Secukinumab 150 
mg s.c. assesed by ASAS components, 
including:  
a. Patient’s global assessment of disease 
activity  
b. Total spinal pain  
c. Inflammation as measured by the mean of 
BASDAI questions 5 and 6  
Mean change from baseline for each treatment 
group in ASAS components including:  
a. Patient global disease activity  
b. Total spinal pain  
c. Inflammation (average of BASDAI  questions 5 
and 6)  
d. BASFI  
 


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d. Bath Ankylosing Spondylitis Functional 
Index (BASFI  
To evaluate secukinumab 150 mg s.c. versus 
placebo in achieving an improvement in 
Ankylosing Spondylitis Disease Activity 
Score (ASDAS)-C-Reactive Protein (CRP) 
and ASDAS-Erythrocyte Sedimentation 
Rate (ESR)  
Mean change from baseline in ASDAS-CRP and 
ASDAS-ESR for each treatment group. 
To evaluate secukinumab 150 mg s.c  versus 
placebo with ASDAS inactive disease as 
defined by ASDAS < 1.3  
Proportion of patients with ASDAS inactive 
disease (i.e ASDAS < 1.3).  
To evaluate secukinumab 150 mg s.c  versus 
placebo in ASDAS clinically important 
improvement (change in ASDAS ≥ 1.1) and 
major improvement (change in ASDAS ≥ 
2.0)  
Proportion of patients with ASDAS clinically 
important improvement (change in ASDAS ≥ 1.1) 
and major improvement (change in ASDAS ≥ 2.0)  
To assess overall tolerability and safety of 
Secukinumab at reduced NSAID intake.  
Overall safety, as measured by frequency and 
severity of adverse events and changes in 
laboratory, vital signs and ECG values from 
baseline. 
To evaluate the reasons given by the patient 
in the patient diary on why he was not able 
to taper NSAIDs despite reduced spinal 
pain.  
Proportion of patients for each reason given in the 
patient diary on why he was not able to taper 
NSAIDs despite reduced spinal pain. 
To compare the secukinumab arms (pooled 
Group1 and Group2) concerning ASAS20 
response criteria after exposition of 12 
weeks against placebo at week 12. 
Proportion of patients fulfilling ASAS20 criteria 
in the pooled Secukinumab groups after exposure 
of 12 weeks (i.e. Secukinumab delayed tapering at 
week 12 and Secukinumab early tapering at week 
16) and placebo regimen at Week 12. 
To compare the secukinumab arms (pooled 
Group1 and Group2) concerning ASAS20 
response criteria after exposition of 12 
weeks against placebo at week 16. 
Proportion of patients fulfilling ASAS20 criteria 
in the pooled Secukinumab groups after exposure 
of 12 weeks (i.e. Secukinumab delayed tapering at 
week 12 and Secukinumab early tapering at week 
16) and placebo regimen at Week 16. 
To compare the secukinumab arms (pooled 
Group1 and Group2) concerning ASAS-
NSAID score after exposition of 12 weeks 
against placebo at week 12. 
Total ASAS-NSAID 
score in the pooled 
Secukinumab groups after exposure of 12 weeks 
(i.e. Secukinumab delayed tapering at week 12 and 
Secukinumab early tapering at week 16) and 
placebo regimen at Week 12. 
To compare the secukinumab arms (pooled 
Group1 and Group2) concerning ASAS-
Total ASAS-NSAID 
score in the pooled 
Secukinumab groups after exposure of 12 weeks 


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NSAID score after exposition of 12 weeks 
against placebo at week 16. 
(i.e. Secukinumab delayed tapering at week 12 and 
Secukinumab early tapering at week 16) and 
placebo regimen at Week 16. 
To compare both Secukinumab regimens 
between week 12 (delayed tapering) and 
week 16 (early tapering) concerning all 
primary, 
secondary 
and 
exploratory 
objectives (at these timepoints, patients will 
have had the same exposure time to 
Secukinumab of 12 weeks) 
 
 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The data will be analyzed by Novartis on all patient data after database lock for the respective 
trial period. It is planned that the data from all centers that participate in this protocol will be 
used for analysis. Analysis datasets and statistical outputs will be produced using the most 
recent SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global 
programming & statistical environment (GPS). 
Continuous data will be summarized by n, mean, standard deviation (SD), median, first and 
third quartiles, minimum and maximum. Categorical data will be presented by absolute and 
relative frequencies (n and %). Summary statistics will also be presented graphically wherever 
applicable. 
If not otherwise specified, p-values and confidence intervals will be two-sided. Unless 
otherwise stated, the level of significance will be set to 5% (two-sided, family-wise type-I-
error). 
Decimal places 
Decimal places will be as follows: 
• p-value: 4 decimal places; if p-value is less than 0.0001, display <0.0001. 
• Standard error and standard deviation: data precision + 2 decimal places 
• Mean, quartile, percentile and median: data precision + 1 decimal place 
• Minimum and maximum: same as data precision 
• Percentages: 1 decimal place, 0% will be displayed as 0.0 and 100% will be displayed 
as 100.0. 
• Odds ratios and risk ratios will be displayed with two decimal places. 
• Confidence interval (CI): data precision + 2 decimal place. 


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P-values will not be concatenated with “*” stars in case of significance. 
2.1.1 
General definitions  
Study treatment: Study treatment refers to:   
• Investigational treatment: Secukinumab 150 mg s.c. injection provided in a 1 mL PFS 
(1 PFS for 150 mg dose). 
• Reference treatment: Secukinumab placebo (Placebo) s.c. injection provided in a 1 mL 
PFS. 
Two secukinumab arms will be pooled for the primary analysis and for specified secondary 
analysis. 
Study treatment start and end date: Study treatment start date is defined as the first date 
when study drug is administered and recorded on the Dose Administration Record (DAR) CRF 
page. Similarly, study drug end date is defined as the last date when a non-zero dose of study 
drug is administered and recorded on the DAR CRF page. 
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for the 
safety analysis  and  (event date – randomization date + 1 day)  for the efficacy analysis. For 
events prior to study drug start date or randomization date (e.g., an adverse event occurred 
before the start of first dose), study day will be negative and calculated as (event date – study 
drug start date) and (event date – randomization date) for safety and efficacy analysis 
respectively.  
Screening, baseline and post-baseline definitions  
Screening will consist of 2 consecutive visits. During Screening Visit 1, initial assessments will 
be performed, the duration of the washout period will be determined and Screening Visit 2 will 
be performed as follows:  
• If the washout period is ≤ 4 weeks the investigator should proceed directly to Screening 
Visit 2 on the same day and complete all assessments in the next 4 weeks prior to 
randomization.  
• If the washout period is more than 4 weeks, the patient will be instructed to initiate the 
necessary washout regimen and return for Screening Visit 2 at 4 weeks prior to 
randomization. 
However in general, screening refers to any procedures (e.g., checking inclusion and exclusion 
criteria) performed prior to the date of first dose of study treatment (for safety analysis) or prior 
to the randomization date (for efficacy analysis).  
For efficacy analyses, baseline is the last assessment, i.e. the last non-missing 
observation,   (including unscheduled visits) obtained before the randomization. All 
assessments obtained after randomization are considered as post-baseline unless otherwise 
specified. 


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For safety analyses, baseline is the last assessment (including unscheduled visits) obtained on 
or before the first dose of study treatment (i.e. treatment start date). All assessments obtained 
after the first dose of study treatment are considered as post-baseline unless otherwise specified. 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, LAB assessments if no pre-treatment value exists, 
values obtained after first dose of treatment can be used as baseline only if it was collected on 
the same day as first dose.  
Study completion: A patient will be considered to have “completed the study” if he/she 
received a maximum of 20 weeks of study treatment and upon completion of the scheduled 
study assessments and procedures up to and including the follow up visit (Week 24). 
Study periods: The study has 3 periods: a screening period consisting of two visits (screening 
visit 1 and screening visit 2), a treatment period consisting of treatment period 1,  treatment 
period 2, and  follow up period of 4 weeks. 
Treatment Period: There are 2 treatment periods for this study defined as: 
Treatment Period 1 is defined as a placebo-controlled, double-blind treatment period starting 
from baseline till Week 16 pre-dose. 
Treatment Period 2 is a double-blinded treatment period starting from Week 16 post-dose till 
Week 20. 
Lost to follow up: The patients whose study completion status is unclear because they fail to 
appear for study visits without stating an intention to withdraw. A patient should not be formally 
considered lost to follow-up until his/her scheduled end of treatment visit would have occurred. 
2.1.2 
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. When visit windows are 
used, all visits will be re-aligned, i.e., they will be mapped into one of the visit windows. E.g., 
if the Week 4 visit of a subject is delayed and occurs on Day 46 instead of on Day 29, say, it 
will be re-aligned to visit window Week 8. In the case of major deviations from the visit 
schedule, or due to unscheduled visits, several assessments of a subject may fall in a particular 
visit window (either scheduled or unscheduled). Statistical approaches to handle multiple 
assessments in a given visit window are specified below.  
Of note, subjects are allowed to have gaps in visits. All data collected will be displayed in 
listings. 


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Table 2-1 
Analysis visit windows 
Analysis Visit 
Week 
Scheduled Day 
Visit Window 
Baseline 
BSL 
1 
Up to Day 1* 
Week 1 
1 
8 
Day 2-11 
Week 2 
2 
15 
Day 12-18 
Week 3 
3 
22 
Day 19-25 
Week 4 
4 
29 
Day 26-32 
Week 5 
5 
36 
Day 33-39 
Week 6 
6 
43 
Day 40-46 
Week 7 
7 
50 
Day 47-53 
Week 8 
8 
57 
Day 54-71 
Week 12 
12 
85 
Day 72-99 
Week 16 
16 
113 
Day 100-116 
Week 17 
17 
120 
Day 117-123 
Week 18 
18 
127 
Day 124-130 
Week 19 
19 
134 
Day 131-137 
Week 20 
20 
141 
Day 138-165 
* Baseline measurement before the first drug administration for safety assessments and before the 
randomization for efficacy assessments. For efficacy visit windows, refer to date of randomization. 
 
For parameters, which are not collected at every visit, visit windows defined in Table 2-1 will 
be combined. For example, if a parameter is measured at Week 12 and Week 20 only, Week 12 
visit window will extend from Day 2 to Day 99 (combining Week 1 to Week 12 visit windows), 
Week 24 will extend from Day 100 to Day 165 (combining Week 16 to Week 20).  
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 2-2 
Rules for flagging values 
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). If a patient did not receive any dose of study treatment 
then the randomization date will be used. 


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Timing of 
measurement 
Type of data 
Rule 
Post-baseline 
efficacy 
All data 
• 
For visits without switch of treatment in the window, the 
measurement closest to the target will be used. In the 
event two measurements are taken equally apart (e.g. 
1 before target date and 1 after) the first one will be 
used.  
• 
For visits during which the patient switches from 
placebo to AIN the following will be done: 
o 
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 (i.e. the closest 
measurement to target which is on 
placebo). 
 
If there are no data on or before the switch 
then the closest measurement to the target 
date after the switch will be used. 
o 
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 (i.e. the closest 
measurement to target which is on AIN). 
 
If there are no data AFTER the switch then 
the closest measurement to the target date 
before the switch will be used. 
Post-baseline safety 
Summary visit 
information (e.g. 
lab, ECG, etc.) 
• 
For visits without switch of treatment in the window, the 
measurement closest to the target will be used. In the 
event two measurements are taken equally apart (e.g. 
1 before target date and 1 after) the first one will be 
used.  
• 
For visits during which the patient switches from 
placebo to AIN the following will be done: 
o 
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 (i.e. the closest 
measurement to target which is on 
placebo). 
 
If there are no data on or before the switch 
then the closest measurement to the target 
date after the switch will be used. 
o 
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 (i.e. the closest 
measurement to target which is on AIN). 
 
If there are no data AFTER the switch then 
the closest measurement to the target date 
before the switch will be used. 


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Timing of 
measurement 
Type of data 
Rule 
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.  
 
 
2.2 
Analysis sets 
Randomized set: The randomized set will be defined as all subjects who were randomized.  
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, and in the 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. 
2.2.1 
Subgroup of interest 
Summary of the primary variable will also be presented by the below subgroups: 
• ASAS-NSAID  
o Lower user groups (baseline score <75) 
o Higher user group (baseline score >=75) 
• Gender 
o Male 
o Female 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
All data about disposition, patient demographics and baseline characteristics, including derived 
variables, will be summarized by treatment groups (secukinumab delayed tapering, 
secukinumab early tapering and placebo) and overall with summary descriptive statistics for all 
the patients in Randomized set. Continuous data will be summarized by n, mean, standard 
deviation, median, first and third quartiles, minimum and maximum. Categorical data will be 
presented by absolute frequency and percentages. 
The number of the analysis populations will be described and the reasons for excluding a patient 
from any particular population will be provided with the number of protocol violators for each 
criterion. The difference between treatment groups with respect to protocol deviations and 
reasons for dropout will be examined by summarizing the protocol deviations by treatment 
groups and overall on the all patients. 


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2.3.1 
Patient disposition 
Summary of disposition for screening phase and study completion phase will be presented 
separately. 
For screening phase disposition, the number and percentage of patients screened, completed 
screening phase, screen failures  along with the reasons for screen failures as captured in CRF 
and randomized for all screened patients. 
For study completion phase disposition, the number and percentage of patients  completed the 
study and discontinued from the study will be summarized by treatment groups and overall with 
reasons for discontinuation for all patients in Randomized set. 
Listing for patients whether they completed or discontinued from the study at screening phase 
and study completion phase disposition will be provided separately with the date of 
discontinuation and primary reason for discontinuation.Listing for protocol deviations will be 
presented seperately for all the patients in Full Analysis Set. 
2.3.2 
Patient demographic and other baseline characteristics 
The following demographic and baseline variables, if collected, will be summarized based on 
randomized set: 
Demographic variables: 
Continuous variables: 
• Age (years) 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) will be calculate as (body weight in kilograms) / (height in meters)2 
• Smoking usage (Pack years) 
Categorical variables: 
• Age categories (<65 years, >=65 and <75 years, 75 years and older) 
• Gender (Male, Female) 
• Race (Caucasian, Black, Asian, Other) 
• Smoking status (Never, current, former) 
• Source of patient referral 
o Physician's own practice 
o Physician referral 
o Print advertisement 
o Newsletter/educational material 
o Novartis internet site 


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o Non-Novartis internet site 
o Clinical trial registry 
o Other 
Baseline disease characteristics variables: 
Continuous variables: 
• Duration of disease (months) 
• Dose of  methotrexate or other DMARD at randomization  
• Patient’s global assessment of disease activity 
• Patient’s assessment of back pain intensity 
• BASMI 
• BASDAI 
• BASFI 
• hsCRP 
• ASDAS-CRP 
• ESR (Erythrocyte Sedimentation Rate) 
• ASDAS-ESR 
• Number of prior biologic AS therapies  
• ASAS Health Index  
• SF-36 Physical Component Score 
• SF-36 Mental Component Score 
 
Categorical variables: 
• TNF- alpha inhibitor status  
o Naïve  
o Inadequate responder 
• History of Extra-Axial Involvement 
o Uveitis 
o Psoariasis 
o Inflammatory bowel disease 
o Dactylitis 
o Enthesitis 
o Peripheral arthritis 


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• HLA-B27 status 
o Positive 
o Negative 
• hsCRP category 
o hsCRP-level ≤ 5 mg/L 
o hsCRP-level > 5 mg/L 
• ASDAS-CRP disease state 
o Inactive disease (ASDAS < 1.3) 
o Low disease activity (ASDAS>= 1.3 and ASDAS< 2.1) 
o High disease activity (ASDAS >= 2.1 and ASDAS<=3.5) 
o Very high disease activi ty (ASDAS > 3.5) 
• NSAIDs or selective COX-2-inhibitors usage 
• Corticoisteroids (prednisone or equivalent) usage 
o  ≤7.5 mg/day  
o >7.5 mg/day 
• PPD test 
o Negative 
o Positive 
• SF-36  
o Physical Component Score 
o Mental Component Score 
• Enviromental factors related to ASAS HI 
Medical history 
Any significant prior or active medical condition as captured in CRF 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. 
Summaries for cardiovascular medical history and ankylosing spondylitis medical history will 
be provided as well, if collected. 
Smoking history will be summarized by treatment group. 
Unless otherwise specified, analyses will be based on the randomized set. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The summaries by treatment will be performed by the randomized treatment or treatment 
sequence. 
• Randomized treatment: 
o AIN457 150mg (delayed tapering) 
o AIN457 150mg (early tapering) 
o Placebo 
• Treatment sequence: 
o AIN457 150mg (delayed tapering) 
o AIN457 150mg (early tapering) 
o Placebo-AIN457 150mg 
 
The analysis of study treatment data will be based on the safety set.  
Duration of exposure 
Duration of exposure will be defined as the time from first dose of study treatment to the time 
of end of treatment period. For patients who discontinue, this will be the patient’s last visit in 
the treatment period. 
The exposure to investigational drug (number of doses) and duration of exposure to study 
treatment will be summarized by treatment group and overall. 
In addition, the number and percentage of patients with cumulative exposure levels (e.g. any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 5 weeks, ≥ 6 weeks, ≥ 7 weeks, ≥ 8 
weeks, ≥  12 weeks, ≥ 16 weeks, ≥  17 weeks, ≥  18 weeks, ≥  19 weeks, ≥  20 weeks) will be 
presented. 
Compliance  
Compliance will be calculated based on documented study treatment administration details and 
displayed by treatment group and overall. Total actual dose will be compared with the total dose 
patients should take as per protocol and derived compliance will be summarized. 
Total actual dose will be derived as  
Total actual dose = Actual amount of dose of Secukinumab 150 mg upto week 20 × Frequency 
of dose upto week 20. 
The treatment compliance will be calculated by Statistical Programming team as  
Treatment compliance (%) =  
the actual number of injections received by a patient
the scheduled number of injections
× 100. 


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Compliance  is  expected  to  be  100%,  unless  temporary interruption  is  needed  for  safety 
reasons. Compliance will  also be assessed by a Novartis monitor using information provided 
by the authorized site personnel. 
Drug interruptions  
The number and percentage of patients with permanent study drug interruptions and the reasons 
that led to the interruption will be summarized by treatment group and overall on the Safety set. 
2.4.2 
Prior, concomitant and post therapies 
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.  
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) 
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.  
Safety set will be used for the above analysis. 
2.5 
Analysis of the primary objective 
The primary objective is to demonstrate that the efficacy of Secukinumab 150 mg s.c. (with 
NSAID tapering) is superior to placebo based on the proportion of patients achieving an 
ASAS20 response at week 12.  
To show superiority, both Secukinumab treatment arms will be pooled and compared against 
placebo. 
Primary variable 
ASAS20 response is defined as an improvement of ≥ 20% and ≥ 1 unit on a scale of 10 from baseline 
in at least 3 of the 4 main domains and no worsening of ≥ 20% and ≥ 1 unit on a scale of 10 in the 
remaining domain. 


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2.5.1 
Estimand of primary variable 
Proportion of patients fulfilling ASAS20 criteria in the pooled Secukinumab groups and 
Placebo regimen at Week 12. The analysis of the primary endpoint will be based on the FAS 
population. The analysis of the primary variable will be based on the following estimand:  
• Population: patients in full analysis set  
• Variable of interest: proportion of patients achieving treatment response as defined by the 
ASAS20 criteria at Week 12.  
• Intervention effect: effect between a secukinumab pooled groups vs. placebo regardless of 
adherence to randomized treatment.  
• Summary measure: Odds ratio (OR) of ASAS20 response for secukinumab pooled groups 
and placebo 
2.5.2 
Statistical hypothesis, model, and method of analysis of primary 
estimand 
The statistical hypothesis for ASAS20 being tested is  
                                                     Ho : p1 = p0 
 
                      v/s 
                                              H1 : p1≠  p0 
where p0 denotes the proportion of ASAS20 responders in the placebo and p1 denotes the 
proportion of ASAS20 responders in the pooled Secukinumab groups at week 12. 
Secukinumab groups will be pooled using their measurements at week 12. 
The primary analysis will be performed using logistic regression with treatment, TNF-α status 
(previously exposed / never exposed), and CRP status (above central lab ULN / equal or below 
central lab ULN) as factors. The two Secukinumab groups will be pooled using a linear contrast. 
Odds ratios and 95% CI will be presented comparing the Secukinumab (pooled) groups to 
placebo. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data for ASAS20 response for data up to Week 20 will be handled as follows:  
Non-responder imputation: 
1. Patients who drop out of the trial for any reason will be considered non-responders from the 
time they drop out through Week 20.  
2. Patients who do not have the required data to compute ASAS20 response  at baseline and at 
the specific time point will be classified as non-responders.  
Patients who were 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 the non-
responder imputation. 


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Additionally, under the assumption of missing at random, multiple imputation by treatment may be 
performed for baseline weight as well as for all baseline and post-baseline efficacy variables of 
interest during the trial. 
 
2.5.4 
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 addition, further logistic regression models may be conducted which explore the impact of 
other baseline or disease characteristics on response.  
In case of a substantial number of missing values, their impact on the analysis results may be 
assessed as well by repeating the logistic regression model using ways to handle missing data. 
These may include, but are not limited to:  
a) Tipping point analysis  
b) Observed data analysis  
These analyes will not be included in the CSR. 
2.6 
Analysis of the key secondary objective 
Not applicable. 
2.7 
Analysis of secondary efficacy objective(s) 
Refer to Table 1.2-1 of Section 1 for the list of secondary objectives. 
2.7.1 
Secondary endpoints 
The secondary efficacy variables are listed below. Secondary efficacy variables will be 
analyzed using the FAS population.  
• ASAS20 response at Week 12/16.  
• ASAS-NSAID response at Week 12.  
• Change from baseline in BASDAI at Week 12/16.  
• Change from baseline in SF36 physical component score at Week 12/16.  
• Change from baseline in ASAS-NSAID score at Week 12 for Secukinumab (delayed 
tapering) vs. change from baseline in ASAS-NSAID score at Week 16 for 
Secukinumab (early tapering)  
• Change from baseline in BASDAI at Week 12 for Secukinumab (delayed tapering) vs 
change from baseline in BASDAI at Week 16 for Secukinumab (early tapering).  
• Change from baseline in BASDAI question 2  
• ASAS20 response at Week 4 for Secukinumab (delayed tapering) vs. ASAS20 
response at Week 20 for placebo group  


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Please refer to the main definition section. 
2.7.2 
 Statistical hypothesis, model, and method of analysis 
Testing strategy  
The following hypotheses will be included in the testing strategy, and type-I-errors will be set 
such that a family-wise type-I-error of 5% is kept:  
Primary objectives: 
• H1: Secukinumab 150 mg s.c. (pooled secukinumab groups) is not different to placebo 
regimen with respect to signs and symptoms (ASAS20 response) at Week 12. 
Secondary objectives: 
• H2: Secukinumab 150 mg s.c. (pooled Secukinumab groups) is not different to placebo 
regimen with respect to change from baseline in ASAS-NSAID score at Week 12  
• H3: Secukinumab 150 mg s.c. (pooled Secukinumab groups) is not different to placebo 
regimen with respect to change from baseline in total BASDAI score at Week 12  
• H4: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with 
respect to signs and symptoms (ASAS20 response) at Week 12  
• 
H5: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to signs and symptoms (ASAS20 response) at Week 12 
• H6: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with 
respect to signs and symptoms (ASAS20 response) at Week 16. 
• H7: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with 
respect to change from baseline in ASAS-NSAID score at Week 12.  
• H8: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with 
respect to change from baseline in ASAS-NSAID score at Week 12.  
• H9: Secukinumab 150 mg s.c. (delayed tapering) is not different to placebo regimen with 
respect to change from baseline in total BASDAI score at Week 12.  
• 
H10: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with respect 
to change from baseline in total BASDAI score at Week 12 
• H11: Secukinumab 150 mg s.c. (early tapering) is not different to placebo regimen with 
respect to change from baseline in total BASDAI score at Week 16. 
These hypotheses will in principal be tested hierarchically in ascending order. However, since 
some hypotheses for individual group comparisons are already contained in the higher-ranked, 
pooled comparisons for the same endpoint (i.e. H4 and H5 are contained in H1, H7 and H8 are 
contained in H2 and H9 and H10 are contained in H3) these individual hypothesis can be tested 
simultaneously. The justification is that as soon as the pooled hypothesis has been rejected (e.g. 
H1 ), at least one of the two contained individual hypotheses (e.g. H4 and H5) must be false and 
there is only a potential for at most one type-I-error. Therefore H4 and H5 can be tested 
simultaneously once all higher-ranked hypotheses have been rejected. The same argument 
applies to H7 and H8 and to H9 and H10. 


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The following chart displays the testing strategy graphically: 
 
First the hypotheses (H1) for the primary objective (ASAS20 for Secukinumab pooled at week 
12) versus placebo will be tested. If this hypothesis can be rejected at level α, H2 will be tested 
and so on until H4. H4 and H5 will be tested simultaneously. If both can be rejected, H6 will be 
tested and so on. As soon as a hypothesis fails to be rejected at level α, all tests of the following 
hypotheses (except the paired hypothesis in the same knot) will be regarded as exploratory only 
and will not provide any confirmatory evidence, irrespective of their nominal p-values. Of note, 
in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
procedure for the test of another hypothesis if the treatment effect is in favor of the Secukinumab 


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regimen. The family-wise error will be set to α=5% and it will be controlled with the proposed 
semi-hierarchical testing strategy. 
 
Analysis of secondary efficacy variables 
 
ASAS20 at week 12  
Response at Week 12 to ASAS20 for Secukinumab (delayed-tapering) versus placebo will be 
evaluated using a logistic regression model with treatment as a factor and baseline weight as a 
covariate.  
ASAS20 at week 16  
Response at Week 16 to ASAS20 for Secukinumab (early-tapering) versus placebo will be 
evaluated using a logistic regression model with treatment as a factor and baseline weight as a 
covariate. 
Refer to Appendix section 5.1 for calculation of ASAS20. 
 
ASAS-NSAID at Week 12  
Between-treatment differences in the change in ASAS-NSAID relative to baseline will be 
evaluated using a mixed-effect model repeated measures (MMRM). Treatment group and 
analysis visit as factors, baseline ASAS-NSAID and weight as continuous covariates. Treatment 
by analysis visit and baseline ASAS-NSAID by analysis visit will be included as interaction 
terms in the model. Initially an unstructured covariance structure will be assumed for the model. 
The significance of the Secukinumab pooled treatment effect will be determined from a linear 
contrast comparing the (mean of the) two Secukinumab regimens to placebo. The significance 
of the two individual Secukinumab treatment group effects will be determined from the pairwise 
comparisons performed between Secukinumab regimens and placebo.  
Refer to Appendix section 5.1 for calculation of ASAS-NSAID  scores. 
 
BASDAI at Week 12/16  
The change from baseline to Week 12/16 in total BASDAI will be analyzed using a MMRM 
with treatment regimen 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 Secukinumab treatment effect will be determined from the 
pairwise comparisons performed between Secukinumab regimens and placebo. The adjusted 
(LS) mean difference will be calculated as a point estimate together with the corresponding 
95% confidence interval and p-value. 
Refer to Appendix section 5.1 for calculation of BASDAI scores. 
Other secondary variables  


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SF-36 PCS  
For the change in SF-36 PCS, between-treatment differences will be evaluated using a mixed 
effect repeated measures model (MMRM). Treatment group and analysis visit will be included 
as categorical factors and baseline SF-36 PCS score and weight as continuous covariates. 
Treatment by analysis visit and baseline SF-36 PCS 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 will be determined from the 
pairwise comparisons performed between Secukinumab regimens and placebo.  
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing data for ASAS20 response and other binary efficacy variables (e.g. ASAS5/6, etc.) for 
data up to Week 20 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 20.  
2. Subjects who do not have the required data to compute response (e.g. ASAS components) at 
baseline and at the specific time point will be classified as non-responders.  
Patients who were unblinded prior to the scheduled timepoint will be considered non-
responders from the time of unblinding up to Week 16. The secondary analysis will use the 
non-responder imputation only.  
2.8 
Safety analyses 
For all safety analyses, the Safety set will be used. 
Summaries may be performed separately for different treatment periods.  
The analyses of the follow-up period will be limited to summaries for treatment-emergent 
adverse events, and serious 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 patients who received not the treatment randomized, i.e. who received erroneously 
the wrong treatment at least once, an additional AE listing will be prepared displaying which 
events occurred after the treatment errors and also the relationship with study drug. 
2.8.1 
Adverse events (AEs) 
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 events until 30 days for AE and  SAE after 
last dose of study treatment) will be summarized by primary system organ class and preferred 
term.  


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The summaries will be presented separtely by study periods i.e. week 1-16 and after week 16. 
In addition, exposure time-adjusted incidence rates including 95% confidence intervals will be 
provided for the entire treatment period to adjust for differences in exposure. A graphical 
display of the crude rates and exposure-adjusted incidence rates will be presented for all AEs 
and serious AEs by system organ classA graphical display of relative frequencies within system 
organ classes and relative risks, as appropriate, will be presented.  
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term).  
The most common adverse events reported (>1 % in any group for each preferred term in the 
SOC-PT table or > 1 % in any group) will be presented in descending frequency according to 
its incidence in total secukinumab group (combining all secukinumab treatment groups) starting 
from the most common event. 
Summaries (crude incidences only) will also be presented for AEs by severity and for study 
treatment related AEs.If a particular AE ‘severity’ is missing, this variable will be listed as 
missing and treated as missing in summaries. If a subject reported more than one adverse event 
with the same preferred term, the adverse event with the greatest severity will be presented. If 
a subject reported more than one adverse event within the same primary system organ class, the 
subject will be counted only once with the greatest severity at the system organ class level, 
where applicable. 
Separate summaries will be provided for  
• adverse events suspected to be related to study drug by the investigator 
• deaths 
• adverse events leading to discontinuation 
• adverse events leading to temporary dose interruption. 
The MedDRA version used for reporting the study will be described in a footnote. 
Follow-up period summaries will be done for all patients in follow-up. 
A listing of non-treatment emergent adverse events will be done. These adverse events  
occurred before the first dose of the study treatment.  
Algorithms for date imputations will be provided in Programming Specifications. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• 
a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• 
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 


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For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE 
 
2.8.1.1 
 Serious adverse event 
Serious adverse events will be summarized by presenting, for each treatment group, the number 
and percentage of patients having at least one SAE, having an SAE in each primary system 
organ class and having each individual AE (preferred term). For SAEs occurred during 
screening a listing will be prepared for all patients screened including screening failures. 
2.8.1.2 
Adverse events of special interest (AESIs) 
• The following events will be considered as adverse events of special interest: 
• Infection and infestations 
• Mood disorder/ depression 
• Inflammatory bowel disease 
The crude rates and exposure-adjusted incidence rates for AESIs will be summarized.  
Important note: For the evaluation of AESIs risks primary and secondary system organ classes 
of the MedDRA dictionary will be considered. 
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Such groups consist of adverse events for which there 
is a specific clinical interest in connection with secukinumab or adverse events, which are 
similar in nature (although not identical). Note that certain adverse events may be reported 
within multiple groupings. 
All AESI groupings are defined through the use of PT, high level terms (HLT), SOC, SMQ , 
NMQ or through a combination of these components.  
The AESI search table will be used to map reported adverse events to the notable adverse events 
groupings. The list of adverse events of special interest may be updated during the course of the 
trial based on accumulating safety data. Therefore, the clinical study report will list the AE 
groupings used and provide a listing of the corresponding AESI search table. 
2.8.2 
Deaths 
Deaths will be separately summarized by treatment group and overall on the safety set. Also, 
listing of deaths will be provided on safety set. 
2.8.3 
Laboratory data 
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. 


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Hematology 
The following hematology variables will be analyzed : 
• Hemoglobin,  
• hematocrit,  
• red blood cell count, 
•  white blood cell count with differential counts, and 
•  platelet count. 
Chemistry 
Serum chemistries will include  
• glucose,  
• urea,  
• creatinine,  
• total bilirubin,  
• AST (SGOT),  
• ALT (SGPT),  
• GGT,  
• alkaline phosphatase,  
• sodium,  
• potassium,  
• bicarbonate,  
• calcium,  
• phosphorous,  
• total protein,  
• albumin, and  
• uric acid. 
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 patients with both baseline and post 
baseline values and will be calculated as: 
                                 change from baseline = post baseline value – baseline value 


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For each parameter, the maximum change from baseline within each study period will be 
analyzed analogously. 
In addition, shift tables will be provided for all parameters to compare a patient’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high The shifts to the most extreme laboratory test value within a treatment period will 
be presented(including category “high and low”). These summaries will be presented by 
laboratory test and treatment group. 
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2.8-1: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG). 
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety. 
Table 2.8-1  
CTCAE grades for laboratory parameters to be analyzed 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
Platelet count 
decreased 
<LLN – 75.0 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 xULN 
>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 


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Cholesterol high >ULN - 7.75 mmol/L 
>7.75 - 10.34 
mmol/L 
>10.34 - 12.92 mmol/L >12.92 mmol/L 
Hypertriglycerid
emia 
1.71 - 3.42 mmol/L 
>3.42 - 5.7mmol/L 
>5.7 - 11.4 mmol/L 
>11.4 mmol/L 
*Note: for “creatinine increased” the baseline criteria do not apply 
 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire) 
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial 
treatment phase. Patients 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 2.8-3 below: 
Table 2.8-2  
Liver-related events 
Parameter 
Criterion 
ALT 
AST 
ALT or AST 
TBL 
ALP 
ALT or AST &  
TBL 
 
 
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
>3xULN; >5xULN; >8xULN >10xULN; >20xULN 
>1.5xULN, >2xULN, >3xULN, 
>2xULN, >3xULN. >5xULN 
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 patients 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 


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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 patients with abnormal laboratory data. 
Data of patients with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing. 
HLA-B27  
Human Leukocyte Antigen-B27 (HLA-B27) will be summarized at baseline and also listing 
will be provided. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable. 
2.8.4.2 
Vital signs 
Analysis in vital signs 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 (sitting SBP, DBP (mmHg) and pulse(beats/min)) ) and treatment group. 
Change from baseline will only be summarized for patients with both baseline and post-baseline 
values and will be calculated as: 
change from baseline = post-baseline value – baseline value. 
2.8.4.3 
Urine pregnancy test 
Descriptive summaries using number and percentages and listings will be provided for urine 
pregnancy results (positive, negative) by visit for each treatment period. 
2.9 
Pharmacokinetic endpoints   
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable. 
2.11 
Patient-reported outcomes 
Variables related to health-related quality of life (HR-QoL) are described below. All HR-QoL 
variables will be evaluated based on FAS patients.  
ASAS Health Index and enviromental factors related to ASAS HI 


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The ASAS Health Index (ASAS HI) is an index that measures an individual’s status of 
functioning, disability and health in individuals and is designed specifically for 
spondyloarthritis patients. (ASAS HI) (12).  
 
The ASAS health index is a linear composite measure and contains 17 items (dichotomous 
response option: “I agree” and “I do not agree”).  
Each statement on the ASAS Health Index is given a score of 1 = I agree OR 0 = I do not agree. 
All item scores are summed up to give a total score that ranges from 0 (good functioning) to 17 
(poor functioning). 
Summary of  ASAS Health Index and environmental factors related to ASAS HI  scores will 
be presented. 
Bath Ankylosing Spondylitis Functional Index (BASFI)  
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those patients with AS. The ten questions were chosen with major input from patients with AS. 
The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the patients’ ability to cope with everyday life. A 0 through 10 scale (captured by a 
continuous VAS) is used to answer the questions. The mean of the ten scales gives the BASFI 
score – a value between 0 and 10. 
Frequency of BASFI response along with the summary of BASFI score will be presented. 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS:  
1. Fatigue  
2. Spinal pain  
3. Joint pain / swelling  
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)  
5. Morning stiffness duration  
6. Morning stiffness severity  
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the scores 
from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0–10 BASDAI 
score. Scores of 4 or greater suggest suboptimal control of disease, and patients with scores of 
4 or greater are usually good candidates for either a change in their medical therapy or for 
enrollment in clinical trials evaluating new drug therapies directed at AS. 
For analysis of BASDAI refer to section 2.7.2  
SF-36 Health Survey 


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The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy subjects and patients with acute and 
chronic conditions. It consists of eight subscales that can be scored individually: Physical 
Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role- 
Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 
burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients. 
For analysis of SF-36 refer to section 2.7.2 
 
 
2.12 
Biomarkers 
Not applicable. 
2.13 
Other Exploratory analyses 
 
All the exploratory efficacy evaluation will be performed on FAS population. Refer to Table 
1.2-1 of Section 1 for the list of exploratory endpoints. 
The following exploratory efficacy variables will be summarized on the FAS for all applicable 
analysis visits unless otherwise specified.  
1. Total ASAS-NSAID [Area Under Curve (AUC)] Score from treatment start with 
Secukinumab to a Secukinumab exposure of 12 weeks.  
2. Total ASAS-NSAID [Area Under Curve (AUC)] Score From Week 4 to Week 16  
3. Proportion of patients with no NSAID intake after Secukinumab exposure of 12 weeks  
4. Proportion of patients with no NSAID intake at week 12.  
5. Change from Baseline in the ASAS Health Index after Secukinumab exposure of 12 
weeks  
6. Change from Baseline in the ASAS Health Index at week 12  
7. Change from baseline in BASMI  
8. ASAS40 response  
9. ASAS20 response  
10. ASAS5/6 response  
11. Change from baseline in hsCRP  
12. Change from baseline in total BASDAI  
13. BASDAI 50 response  


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14. ASAS partial remission  
15. Change from baseline in ASAS components including:  
Patient global disease activity  
Total spinal pain  
Inflammation (average of BASDAI questions 5 and 6)  
BASFI  
16. Change from baseline in ASDAS-CRP and ASDAS-ESR  
17. ASDAS inactive disease as defined by ASDAS < 1.3  
18. ASDAS clinically important improvement (change in ASDAS ≥ 1.1) and major 
improvement (change in ASDAS ≥ 2.0)  
19. Reasons given in the patient diary on why he was not able to taper NSAIDs despite 
reduced spinal pain  
All endpoints relating to exploratory objectives will be summarized descriptively. Summary 
statistics will include absolute frequencies and percentages for the categorical variables and the 
number of patients (n), minimum, mean, median and maximum for continuous variables. 
Change from baseline will also be presented for some exploratory variables based on the the 
endpoints mentioned in section 1 Table 1.2-1. Graphical representation will also be performed 
if required. 
The following exploratory endpoints will also be summarized categorically as absolute and 
relative frequencies (proportions, %). 
• Proportion of patients fullfilling ASAS20 criteria at week 4 for secukinumab 150 mg 
s.c. (delayed tapering) vs. week 20 in patients switching from placebo after weeks of 
secukinumab exposure. 
• Proportion of patients with no NSAID intake at week 12 for secukinumab 150 mg s.c. 
(delayed tapering) and at week 16 for secukinumab 150 mg s.c. (early tapering). 
• Proportion of patients with no NSAID intake at week 12 for each treatment arm. 
• Proportion of patients fulfilling the ASAS40 criteria in each treatment group over time. 
• Proportion of patients fulfilling the ASAS20 criteria in each treatment group over time. 
• Proportion of patients fulfilling the ASAS5/6 criteria in each treatment group over time. 
• Proportion of patients fulfilling  BASDAI 50 response criteria in each treatment group 
over time. 
• Proportion of patients fulfilling  ASAS partial remission criteria in each treatment group 
over time. 
• Proportion of patients with ASDAS inactive disease (i.e ASDAS < 1.3). 
• Proportion of patients with ASDAS clinically important improvement (change in 
ASDAS ≥ 1.1) and major improvement (change in ASDAS ≥ 2.0). 


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• Proportion of patients for each reason given in the patient diary on why he was not able 
to taper NSAIDs despite reduced spinal pain. 
• Proportion of patients fulfilling ASAS20 criteria in the pooled Secukinumab groups 
after exposure of 12 weeks (i.e. Secukinumab delayed tapering at week 12 and 
Secukinumab early tapering at week 16) and placebo regimen at Week 12. 
• Proportion of patients fulfilling ASAS20 criteria in the pooled Secukinumab groups 
after exposure of 12 weeks (i.e. Secukinumab delayed tapering at week 12 and 
Secukinumab early tapering at week 16) and placebo regimen at Week 16. 
• Total ASAS-NSAID score in the pooled Secukinumab groups after exposure of 12 
weeks (i.e. Secukinumab delayed tapering at week 12 and Secukinumab early tapering 
at week 16) and placebo regimen at Week 12. 
• Total ASAS-NSAID score in the pooled Secukinumab groups after exposure of 12 
weeks (i.e. Secukinumab delayed tapering at week 12 and Secukinumab early tapering 
at week 16) and placebo regimen at Week 16. 
Total BASDAI, BASDAI question 1 and question 2 and ASAS-NSAID score (each in Y-axis) 
compared to time (X-axis) will be presented graphically. 
2.14 
Interim analysis 
No interim analysis is planned for this study.  
3 
Sample size calculation 
All sample size and power considerations are performed using EAST 6.  
The sample size was calculated based on the phase III results of the MEASURE2 study, which 
used the same dose and loading regimen as will be applied in this trial. Under the assumption 
of 56.9% ASAS20 responders in the Secukinumab (delayed tapering) group and 27.0% in the 
placebo group, a sample size of 62 patients per group is required to have 90% power to show 
superiority of Secukinumab over placebo at a two sided α=5%.  
For the comparison of the the early tapering group at week 16 vs. placebo, the same treatment 
effect is expected, leading to the same sample size. To compensate for some dropout and other 
protocol deviations, the sample size will be increased to 68 per arm. The total sample size of 
this trial will thus be 204. At the time of writing the amendment, about 190 patients have been 
recruited into this trial and it seems unlikely that a sample > 200 can be recruited within 
reasonable time. With this sample size, the (newly introduced 190) comparison of pooled 
Secukinumab groups vs. placebo, the trial would still have almost 80 % (78%) power if the 
placebo response was somewhat higher (35%) than originally assumed.  
4 
Change to protocol specified analyses 
Not applicable. 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
• Investigational treatment: 
• Secukinumab 150 mg s.c. injection provided in a 1 mL PFS (1 PFS for 150 mg 
dose). 
• Reference treatment: 
• Secukinumab placebo (Placebo) s.c. injection provided in a 1 mL PFS. 
 
5.1.2 
AE date imputation 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date (TRTSTD) 
Not used 
TRT M 
TRT Y 
 
The following matrix explains the logic behind the imputation. 
 
MON 
MISSING
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
NC 
Uncerta in 
NC 
Uncerta in 
NC 
Uncerta in 
NC 
Uncerta in 
YYYY < TRTY 
( D ) 
Before Treatment Start 
( C ) 
Before Treatment Start 
( C ) 
Before Treatment Start 
( C ) 
Before Treatment Start 
YYYY = TRTY 
(B) 
Uncerta in 
( C ) 
Before Treatment Start 
(A) 
Uncerta in 
(A) 
After Treatment Start 
YYYY > TRTY 
(E) 
After Treatment Start 
(A) 
After Treatment Start 
(A) 
After Treatment Start 
(A) 
After Treatment Start 
 
The following table is the legend to the logic matrix. 
If AE end date is complete and AE end date < Treatment start date or AE end date is partial 
and AE imputed end date < Treatment start date, then AE start reference = min (informed 
consent date, earliest visit date from SV) Else if AE end date is partial,AE end date > = 
Treatment start date or AE is ongoing , then AE start reference = treatment start date. 
 
Relationship 
Time imputation 
Before AE start reference 
Partial date indicates AE start date 
prior to AE start reference 
 
After AE start reference 
Partial date indicates AE start date 
after AE start reference 
 


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


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


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(E) 
01JANYYYY 
Concomitant Medication End Date Imputation 
If not ongoing then - 
Imputed date = date part of CMENDTC,  if complete date 
Imputed date = min(completion/discontinuation visit date,  DEC 31) , if month is missing, (C2, 
D, E) 
Imputed date = min(completion/discontinuation visit date, last day of the Month) , if day is 
missing. (A, B, C1) 
Concomitant Medication Date Flag 
If not a complete date then 
Y - If year of the imputed date is not equal to YYYY  else M – If month of the imputed date is 
not equal to MON else D. 
5.1.3.1 
Prior therapies date imputation 
Not applicable. 
5.1.3.2 
Post therapies date imputation 
Not applicable. 
5.1.4 
Medical History date of diagnosis imputation 
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared to 
the treatment start date. 
• If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY) 
• Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY) 
If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG month 
is equal to study treatment start month), the imputed DIAG date is set to one day before study 
treatment start date. 
5.2 
AEs coding/grading 
Not applicable. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
Covariance (ANCOVA) model: 


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Endpoints with continuous data type expected to be normally distributed will be analyzed using 
an analysis of covariance (ANCOVA) model with treatment and baseline stratification factors, 
baseline weight and baseline value and as covariates. Confidence intervals for the difference 
between each dose of secukinumab and placebo will be calculated. 
SAS code for ANCOVA: 
proc mixed data=aaa; 
class TRT STRATA; 
model response = TRT STRATA WEIGHT BASE / s; 
lsmeans TRT / diff; 
run; 
 
In addition, key secondary variables measured at all post baseline visits up to Week 20 will be 
analyzed using longitudinal mixed effects ANCOVA model with treatment, baseline 
stratification factor and analysis visit as factors; and weight, baseline value, treatment by visit 
and baseline by visit interactions as covariates. 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 pairwise comparisons performed between 
secukinumab regimens and placebo at the appropriate analysis visits. 
SAS code for mixed model: 
proc mixed data=aaa; 
class TRT USUBJID AVISITN STRATA; 
model CHG=TRT STRATA AVISITN WEIGHT BASE TRT*AVISITN BASE*AVISITN 
/ s ddfm=kr; 
lsmeans TRT*AVISITN / diff cl; 
repeated AVISITN / type=un subject=USUBJID; 
Run; 
In case the MMRM model does not converge the following sequential steps will be used: 
1. change ddfm=kr to ddfm=bw. If still no convergence, perform step 2. 
2. change type=un to type=cs. If still no convergence, perform step 3. 
3. remove covariates of the model based on the scenario.  
Logistic regression model: 
Certain binary outcome variables, e.g. response outcomes, will be evaluated using a logistic 
regression model with treatment regimen, weight, stratum if applicable. Odds ratios will be 
computed for comparisons of AIN457 regimens versus control(s) utilizing the logistic 
regression model fitted. 
SAS code for logistic regression: 
 
Proc logistic data=aaa; 
Class TRT STRATA / param=glm; 
Model AVAL = TRT WEIGHT STRATA; 
Lsmeans TRT / diff cl exp; 
Ods output diffs=lsm_diff; 
Run; 


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In cases where separation is a concern for the primary endpoint at Week 12, e.g. 0% or 100% 
response in one treatment (sub)group, an exact logistic regression model will be applied to all 
visits. To ensure convergence, this model will not include any continuous covariates. 
 
Proc logistic data=aaa exactonly; 
Class TRT STRATA / param=glm; 
Model AVAL = TRT STRATA; 
Exact TRT / estimate=both; 
Ods output exactoddsratio=exactoddsratio; 
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 
for each AIN457 group versus placebo comparison. In this case, no odds ratios or confidence 
intervals can be estimated due to 0% response in one of thegroups, but p-values may be 
calculated. 
 
Proc freq data=aaa; 
Table TRT * AVAL / fisher; 
Where TRT in (“AIN457 xx mg” “Placebo”); 
Run; 
5.5 
Score derivations and response criteria 
5.5.1 
Assessment of Spondyloarthritis International Society (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper et al 2009): 
1. Patient’s global assessment of disease activity measured on a VAS scale. 
2. Patient’s assessment of IBP, represented by either total or nocturnal pain scores, both 
measured on a VAS scale. For ASAS response analysis, the total back pain score will be used. 
3. Function represented by BASFI average of 10 questions regarding ability to perform specific 
tasks as measured by VAS scale. 
4. Morning stiffness, represented by the average of the last 2 questions on the 6-question 
BASDAI regarding morning stiffness 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)  
 
ASAS response criteria (ASAS 20) 
The ASAS Response Criteria (ASAS 20) was defined as an improvement of ≥ 20% and ≥ 1 unit 
on a scale of 10 in at least 3 of the 4 main domains and no worsening of ≥ 20% and ≥ 1 unit on 
a scale of 10 in the remaining domain. Or 


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The ASAS Response Criteria (ASAS 20) was defined as an improvement of ≥ 20% and ≥ 10 
unit on a scale of 100 in at least 3 of the 4 main domains and no worsening of ≥ 20% and ≥ 10 
unit on a scale of 100 in the remaining domain. 
 
ASAS response criteria (ASAS 40) 
The ASAS 40 response was defined as an improvement of ≥ 40% and ≥ 2 units on a scale of 10 
in at least 3 of the 4 main domains and no worsening at all in the remaining domain. 
 
ASAS 5/6 improvement criteria  
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six 
domains. 
 
ASAS partial remission criteria  
The ASAS partial remission criteria are defined as a value not above 2 units in each of the four 
main domains on a scale of 10. 
5.5.2 
Ankylosing spondylitis disease activity score (ASDAS) 
The ASDAS (Sieper et al 2009, Lukas et al 2009) is a composite index to assess disease 
activity in AS.The ASDAS-C-reactive protein (CRP) will be utilized to assess the disease 
activity status. 
 
Parameters used for the ASDAS include: 
• Total back pain (BASDAI question 2) 
• Patient global assessment of disease activity 
• Peripheral pain/swelling (BASDAI question 3) 
• Duration of morning stiffness (BASDAI question 6) 
• CRP in mg/liter 
 
Disease activity states: inactive disease, low disease activity, high disease activity, and 
very high disease activity. The 3 values selected to separate these states were < 1.3 between 
inactive disease and low disease activity, < 2.1 between moderate disease activity and 
high disease activity, and > 3.5 between high disease activity and very high disease activity. 
Selected cutoffs for improvement scores were a change ≥ 1.1 unit for “minimal clinically 
important improvement” and a change ≥ 2.0 units for “major improvement” (Machado et al 
2011). 
The following formula will be used to derive ASDAS-CRP: 
ASDAS-CRP = 0.121 x total back pain + 0.110 x patient global + 0.073 x peripheral 
pain/swelling + 0.058 x duration of morning stiffness + 0.579 x Ln(CRP+1). 
ASDAS-ESR = 0.08 x Back Pain + 0.07 x Duration of Morning Stiffness + 0.11 x Patient Global 
+ 0.09 x Peripheral Pain/Swelling + 0.29 x √(ESR) 


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All assessments will be performed in 0-10 scale. 
 
5.5.3 
Bath ankylosing spondylitis disease activity index (BASDAI) 
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of axSpA: 
1. Fatigue 
2. Spinal pain 
3. Joint pain/swelling 
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments) 
5. Morning stiffness duration 
6. Morning stiffness severity 
To give each symptom equal weighting, the mean (average) of the 2 scores relating to morning 
stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the scores from 
questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0-10 BASDAI score. 
Scores of 4 or greater suggest suboptimal control of disease, and patients with scores of 4 or 
greater are usually good candidates for either a change in their medical therapy or for enrollment 
in clinical trials evaluating new drug therapies directed at AS. BASDAI is a quick and simple 
index taking between 30 seconds and 2 minutes to complete.  
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 the total sum should be divided by 4 instead of 5. If two of Q1 to Q4 is missing the sum 
should be divided by 3. BASDAI 50 response is defined as at least a 50% improvement 
(decrease) in total BASDAI score, as compared to the Baseline total BASDAI score. 
5.5.4 
Bath ankylosing spondylitis functional index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those 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. If 
there are missing questions the average of the non-missing items is used (Braun 2009, van 
Tubergen 2001). 
5.5.5 
ASAS Health Index 
The ASAS health index is a linear composite measure and contains 17 items (dichotomous 
response option: “I agree” and “I do not agree”).  


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Each statement on the ASAS Health Index is given a score of 1 = I agree OR 0 = I do not agree. 
All item scores are summed up to give a total score that ranges from 0 (good functioning) to 17 
(poor functioning). Items No 7 and 8 are not applicable for all patients. For those patients who 
ticked the response “not applicable”, the sum score is analysed based on n=16 or n=15, 
respectively. 
A total score can be analysed if no more than 20% of the data are missing. The total score is 
calculated as follows for respondents with one to a maximum of three missing responses: 
 
 
Cases with more than three missing responses cannot be allocated a total score. 
5.5.6 
Bath Ankylosing Spondylitis Metrology Index (BASMI linear) 
The BASMI is a validated instrument that uses the minimum number of clinically appropriate 
measurements that assess accurately axial status, with the goal to define clinically significant 
changes in spinal movement. Parameters include: 
1. lateral lumbar flexion (cm) 
2. tragus-to-wall distance (cm) 
3. lumbar flexion (modified Schober) (cm) 
4. intermalleolar distance (cm) 
5. cervical rotation angle (cm) 
Additionally, the following assessments should be taken: 
6. chest expansion 
7. occiput-to-wall distance 
The assessments A of the first five components into the scores S using the equations are given 
in Table 5-1(van der Heijde et al, 2013).  
Table 5-1 
Equations for the conversion of the assessments A into scores S for 
the five components of the BASMI linear 
 
S = 0 if 
Between 0 and 10 
S = 10 if 
Lateral lumbar flexion* (cm) 
A ≥ 21.1 
S = (21.1 – A)/2.1 
A ≤ 0.1 
Tragus-to-wall distance* (cm) 
A ≤ 8 
S = (A – 8)/3 
A ≥ 38 
Lumbar flexion (modified Schober) (cm) 
A ≥ 7.4 
S = (7.4 – A)/0.7 
A ≤ 0.4 


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S = 0 if 
Between 0 and 10 
S = 10 if 
Intermalleolar distance (cm) 
A ≥ 124.5 
S = (124.5 – A)/10 
A ≤ 24.5 
Cervical rotation angle*(°) 
A ≥ 89.3 
S = (89.3 – A)/8.5 
A ≤ 4.3 
* For lateral lumbar flexion, tragus-to-wall distance, and cervical rotation the average of right and left should be taken. 
If a score lies beyond the range 0-10, the values 0 or 10 have to be used, respectively. 
For facilitating computer calculations with “if … then … else” fields in a table calculation program such as Microsoft Excel, 
the limits of the linear ranges are also given. The BASMIlinear is the mean of the five scores. 
5.5.7 
ASAS-NSAID Score 
The recommendations by ASAS (Dougados 2010) will be used to score each patient’s NSAID 
use during specific time periods. The components that go into the calculation of the score is the 
type of NSAID, average daily dose, length in days of the time period of interest and the number 
of days with NSAID intake within the time period of interest. The final score should  be between 
0 and 100 but can in rare cases be larger than 100.  
The scoring of NSAIDs is described below. 
Score 
Intake 
0 
No intake 
100 
150 mg diclofenac, 600 mg etodolac, 150 mg 
indometacin, 20 mg piroxicam, 1000 mg 
naproxen, 90 mg etoricoxib, 200 mg ketoprofen, 
20 mg tenoxicam,200 mg aceclofenac, 200 mg 
flurbiprofen, 15 mg meloxicam, 400 mg 
celecoxib, 2400 mg 
ibuprofen, 400 mg 
phenylbutazone. 
The CRF provided dose information will be handled as follows: 
• Doses > maximum dose will be scored as > 100 
• Missing doses will be scored with maximum daily dose for the current NSAID (i.e. 
score of 100) 
Drug start and end dates are needed in order to know the number of days an NSAID was 
prescribed. In case they are missing, the following rules will be used: 
• Missing start dates will assume the start date of medication is Day -28 (i.e. prior to start 
of study drug) 
• Missing end dates will assume the end date of medication is the patient’s last day in the 
Study 


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• If the study drug is ongoing when the patient discontinues then the drug end date will 
be equal to the day of discontinuation. The period end date will also end on the day of 
discontinuation 
The table below presents the score associated with the dosing frequency as specified by the 
ASAS definition and how the different database entries will be categorized. The frequency was 
not consistently specified in the ASAS publication, the below categorization was selected. 
Table 5-2 
Mapping of dosing frequency to NSAID score 
Frequency 
Scores 
Database entry 
Patient did not take any NSAID 
during the period of interest 
0/7 
 
<1 day/week 
0.5/7 
Q2W, MISSING, PRN, UNK, 
ASNEEDED, QM, Q4W, Q3W 
≥1 − <3 days/week 
2/7 
Q1W, WEEKLY, BIW 
≥3 − <5 days/week 
4/7 
TIW, QIW 
≥5 − <7 days/week 
6/7 
 
Everyday 
7/7  
TID, BID, DAILY, Q24H, QID, 
QD 
Note: Q2W=every 2 weeks, PRN=as needed, UNK=unknown, Q1W=one a week, BIW=twice a week, 
TIW=three times a week, TID=three times a day, BID=twice a day, QIW= four times a week, 
Q24H=QID=QD=one a day, QM=one a month; Q4W=one every 4 weeks; Q3W=one every 3 weeks. 
To calculate the NSAID cumulative score the following formula will be used for each NSAID 
being taken: 
100*(Daily dose / pre-specified max dose) * frequency score * (min(medication end date, 
period end date) – max(medication start date, period start date) + 1 = range of days patient used 
the medication) / number of days the patient was in the period. 
In case a patient takes more than one type of NSAID, changes the dose or the frequency of 
NSAID during the period of interest, additional scores will be calculated for each new 
combination and the final score for that patient is the sum of all scores. 


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5.6 
Rule of exclusion criteria of analysis sets 


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Deviation ID Description of Deviation 
Exclusion in 
Analyses 
Severity 
code 
INCL01 
Patients have not signed Informed Consent 
Form prior to initiation of any studyrelated 
procedure 
INCLUDE IN 
EVERYTHING 
0 
INCL02a 
Age criteria not met 
INCLUDE IN 
EVERYTHING 
0 
INCL02b 
Pregnant or Lactating female patients 
INCLUDE IN 
EVERYTHING 
0 
INCL03 
Are modified New York Criteria for Ankylosing 
Spondylitis fulfilled or  met Is No in Modified 
New York criteria form 
INCLUDE IN 
EVERYTHING 
0 
INCL04 
BASDAI Average Score less than 4 at baseline   INCLUDE IN 
EVERYTHING 
0 
INCL05 
BASDAI Question 2  is less than  4 cm at 
baseline                       
INCLUDE IN 
EVERYTHING 
0 
INCL06 
Total back pain  is less than  40 mm at baseline   INCLUDE IN 
EVERYTHING 
0 
INCL07 
Patient is not on at least 2 different NSAIDs at 
the highest recommended dose for at least 4 
weeks in total in the past, prior to 
randomization 
INCLUDE IN 
EVERYTHING 
0 
INCL08a 
Patient has not reported regular intake of 
NSAIDs of at least 50 percent of the highest 
recommended dose at Screening 
INCLUDE IN 
EVERYTHING 
0 
INCL08b 
Patient with prior TNFα alpha inhibitor therapy 
has not reported regular intake of NSAIDs of at 
least 50 percent of the highest recommended 
dose at baseline after the appropriate washout. 
INCLUDE IN 
EVERYTHING 
0 
INCL09 
Patient is not on a stable dose of NSAIDs for at 
least 2 weeks before randomization. 
INCLUDE IN 
EVERYTHING 
0 
INCL10 
Patient  has previously been on a TNF alpha 
inhibitor however, an appropriate washout 
period was not maintained prior to 
randomization 
INCLUDE IN 
EVERYTHING 
0 
INCL11 
Pt on TNF alpha I and not exprncd inadequate 
response to previous or current trtmnt at  
approved dose for at least 3M prior to Rndz or 
not intolerant to at least 1 administration of  anti 
TNF alpha 
INCLUDE IN 
EVERYTHING 
0 
INCL11a 
 patients that did not tolerate TNF alpha 
inhibitor or that were inadequate responder are 
eligible for study however the reason for 
discontinuation is equal other in Concomitant 
medication CRF 
INCLUDE IN 
EVERYTHING 
0 
INCL12 
If a patient taking MTX or sulfasalazine 
continues taking, but either took MTX 
prevoiusly for shorter than 3 Months or the 
INCLUDE IN 
EVERYTHING 
0 


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dose was not stable in the last 4 week prior to 
randomization 
INCL13 
Patient on MTX is not on stable folic acid 
supplementation before randomization 
INCLUDE IN 
EVERYTHING 
0 
INCL14 
Patient has not discontinued DMARD  4 weeks 
prior to randomization 
INCLUDE IN 
EVERYTHING 
0 
INCL15 
Patients taking systemic corticosteroids have to 
be on a stable dose 
INCLUDE IN 
EVERYTHING 
0 
EXCL01 
Chest Xray or MRI with evidence of ongoing 
infectious or malignant process, obtained within 
3 months of screening and evaluated by a 
qualified physician 
INCLUDE IN 
EVERYTHING 
0 
EXCL02 
Patients taking high potency opioid analgesics  
eg methadone hydromorphone and morphine 
INCLUDE IN 
EVERYTHING 
0 
EXCL03 
Previous exposure to Secukinumab or any 
other biologic drug directly targeting IL17 or 
IL17 receptor 
INCLUDE IN 
EVERYTHING 
0 
EXCL04 
Use of any IND and or devices within 4W of 
RNDMZ or period of 5 halflives of 
investigational drug or participation in another 
study in the same indication during enrollment 
in this study 
INCLUDE IN 
EVERYTHING 
0 
EXCL05 
History of hypersensitivity to the study drug or 
its excipients or to drugs of similar chemical 
classes 
INCLUDE IN 
EVERYTHING 
0 
EXCL06 
Any therapy by intraarticular injections 
example corticosteroid within 4 weeks before 
randomization 
INCLUDE IN 
EVERYTHING 
0 
EXCL07 
Any intramuscular corticosteroid injection within 
2 weeks before randomization 
INCLUDE IN 
EVERYTHING 
0 
EXCL08 
Patients previously treated with any biological 
immunomodulating agents except those 
targeting TNF alpha 
INCLUDE IN 
EVERYTHING 
0 
EXCL09 
Patients who have taken more than two anti 
TNF alpha agents 
INCLUDE IN 
EVERYTHING 
0 
EXCL10 
Previous treatment with any cell depleting 
therapies including but not limited to anti CD20 
or investigational agents example CAMPATH 
anti-D4 antiCD5 antiCD3 antiCD19 
INCLUDE IN 
EVERYTHING 
0 
EXCL11 
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 
INCLUDE IN 
EVERYTHING 
0 
EXCL12 
Women of childbearing potential not using 
effective contraception methods during entire 
study or longer if required by locally approved 
prescribing info                                       
INCLUDE IN 
EVERYTHING 
0 
EXCL13 
Active ongoing inflammatory diseases other 
than AS that might confound the evaluation of 
INCLUDE IN 
EVERYTHING 
0 


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the benefit of Secukinumab therapy, including 
inflammatory bowel disease or uveitis 
EXCL14 
Underlying conditions which in the opinion of 
the investigator immunocompromises the 
patient and or places the patient at 
unacceptable risk for participation in an 
immunomodulatory therapy 
INCLUDE IN 
EVERYTHING 
0 
EXCL15 
Significant medical problems or diseases or 
very poor functional status unable to perform 
self care 
INCLUDE IN 
EVERYTHING 
0 
EXCL16 
History of clinically significant liver disease or 
liver injury as indicated by abnormal liver 
function tests such as SGOT AST and SGPT 
ALT alkaline phosphatase or serum bilirubin 
INCLUDE IN 
EVERYTHING 
0 
EXCL17 
History of renal trauma glomerulonephritis or 
patients with one kidney only or a serum 
creatinine level exceeding 1.5 milligram per 
decilitre 132.6 micromol per litre 
INCLUDE IN 
EVERYTHING 
0 
EXCL18 
Screening total WBC count less than 3000 per 
micro litre or platelets less than 100000 per 
microlitre or neutrophils less than 1500 per 
micro litre or hemoglobin less than 85 gram per 
litre 
INCLUDE IN 
EVERYTHING 
0 
EXCL19 
Active systemic infections during the last two 
weeks prior to randomization exception: 
common cold 
INCLUDE IN 
EVERYTHING 
0 
EXCL20a 
History of ongoing, chronic or recurrent 
infectious disease or evidence of tuberculosis 
infection. 
INCLUDE IN 
EVERYTHING 
0 
EXCL20b 
History of ongoing, chronic or recurrent 
infectious disease or evidence of tuberculosis 
infection 
INCLUDE IN 
EVERYTHING 
0 
EXCL21 
Known infection with human immunodeficiency 
virus HIV  hepatitis B or hepatitis C at 
screening or randomization 
INCLUDE IN 
EVERYTHING 
0 
EXCL22 
History of lymphoproliferative disease or any 
known malignancy or history of malignancy of 
any organ system within the past 5 years 
INCLUDE IN 
EVERYTHING 
0 
EXCL23 
Current severe progressive or uncontrolled 
disease which in the judgment of the clinical 
investigator renders the patient unsuitable for 
the trial 
INCLUDE IN 
EVERYTHING 
0 
EXCL24 
Inability or unwillingness to undergo repeated 
venipuncture 
Example  because of poor tolerability or lack of 
access to veins 
INCLUDE IN 
EVERYTHING 
0 
EXCL25 
Inability or unwillingness to receive injections 
with PFS 
INCLUDE IN 
EVERYTHING 
0 
EXCL26 
Any medical or psychiatric condition which  in 
the Investigators opinion, would preclude the 
INCLUDE IN 
EVERYTHING 
0 


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participant from adhering to the protocol or 
completing the study per protocol 
EXCL27 
Donation or loss of 400 mL or more of blood 
within 8 weeks before dosing 
INCLUDE IN 
EVERYTHING 
0 
EXCL28 
History or evidence of ongoing alcohol or drug 
abuse, within the last six months before 
randomization 
INCLUDE IN 
EVERYTHING 
0 
EXCL29 
Plans for administration of live vaccines during 
the study period or 6 weeks prior to 
randomization 
INCLUDE IN 
EVERYTHING 
0 
EXCL30 
Patients who are intolerant to NSAIDs 
INCLUDE IN 
EVERYTHING 
0 
COMD01 
Concomitant use of  Etanercept during the 
study 
INCLUDE IN 
EVERYTHING 
0 
COMD02 
Concomitant use of Infliximab during the study 
INCLUDE IN 
EVERYTHING 
0 
COMD03 
Concomitant use of following medications 
during the study 
 
Adalimumab 
 golimumab certolizumab 
INCLUDE IN 
EVERYTHING 
0 
COMD04 
Concomitant use of Leflunomide during the 
study 
INCLUDE IN 
EVERYTHING 
0 
COMD05 
Systemic corticosteroids use within 2 weeks 
prior to Baseline                                                    
INCLUDE IN 
EVERYTHING 
0 
COMD06 
Intra articular steroids injections use during the 
study 
INCLUDE IN 
EVERYTHING 
0 
COMD07 
MTX dose is changed between BL and W12 for 
reason other than an AE 
INCLUDE IN 
EVERYTHING 
0 
COMD08 
Patient taking MTX do not take folic acid 
supplementation during the study 
INCLUDE IN 
EVERYTHING 
0 
COMD09 
The corticosteroid dose reduced by more than 
1 mg prednisone equivalent every 4 weeks 
INCLUDE IN 
EVERYTHING 
0 
COMD10 
Pts regularly using NSAIDs low strength 
opioids paracetamol acetaminophen not on 
stable dose for at least 2W before 
randomization to allow inclusion  Or not on a 
stable dose in the study up to W4 
INCLUDE IN 
EVERYTHING 
0 
COMD11 
Live vaccines less than 6 weeks before 
randomization or 
 
Live vaccines given before 12 weeks after last 
study treatment administration. 
INCLUDE IN 
EVERYTHING 
0 
COMD12 
Incorrect study medication given OR additional 
study medication given 
INCLUDE IN 
EVERYTHING 
0 
COMD13 
Patient not discontinued study drug despite 
severe or serious AE that is not compatible with 
administration of study medication 
INCLUDE IN 
EVERYTHING 
0 


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Analysis set exclusions based on population codes 
Analysis set  
Population codes that cause a subject to be 
excluded 
RAN  
NA 
SAF  
2, 3, 6 
FAS  
1, 3 
Population code text 
Population Code 
Population code text 
 
0 
INCLUDE IN EVERYTHING 
1 
EXCLUDE FROM FULL ANALYSIS SET (FAS) 
2 
EXCLUDE FROM SAFETY SET (SAF) 
3 
EXCLUDE FROM FAS AND SAF 
COMD14 
Concomitant use of Systemic corticosteriods  
greater than 10mg prednisone equivalent 
INCLUDE IN 
EVERYTHING 
0 
COMD15 
No Unstable dose of MTX other DMARD Any 
investigational treatment or participation in any 
interventional trial & Analgesics other than 
paracetamol/acetaminophen or low strength 
opinions PRN 
INCLUDE IN 
EVERYTHING 
0 
TRT01 
Incorrect, missed or partial doses of study 
medication administered 
INCLUDE IN 
EVERYTHING 
0 
OTHR01 
Urinalysis not performed. 
INCLUDE IN 
EVERYTHING 
0 
OTHR02 
Physical examination not performed.  
INCLUDE IN 
EVERYTHING 
0 
TRT02 
Intake of low strength opioids is reported 24 
hours before a visit with disease activity. 
INCLUDE IN 
EVERYTHING 
0 
TRT03 
Mishandling of investigational product. 
INCLUDE IN 
EVERYTHING 
0 
TRT04 
During intermediate storage of IMP no 
Tmin/Tmax data available. According to 
decision of Novartis QP medication should not 
be used, but was already dispensed to patient.  
INCLUDE IN 
EVERYTHING 
0 
TRT05 
Time frame between 2 IMP injections not 
respected.  
INCLUDE IN 
EVERYTHING 
0 
OTHR03 
Patient is outside the recommended visit 
window, not followed as per protocol. 
INCLUDE IN 
EVERYTHING 
0 
OTHR04 
ECG was not performed as per assessment 
schedule. 
INCLUDE IN 
EVERYTHING 
0 


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6 
Reference 
Braun et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled 
multicentre trial; Lancet 2002; 359: 1187–93. 
Dougados M, Simon P, Braun J et al (2011) ASAS recommendations for collecting, analysing and 
reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. Ann 
Rheum Dis;70(2):249-51. 
Dougados M, Wood E, Combe B et al (2014) evaluation of the nonsteroidal anti-inflammatory drug-
sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, randomized, 
double-blind, placebo-controlled SPARSE study. Arthritis Res Ther;16(6):481.