Conditions: Ankylosing Spondylitis
Keywords: Active axSpA Axial spondyloarthritis non-radiographic-axSpA nr-axSpA ankylosing spondylitis AS inflammatory back pain sacroiliitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 527
Healthy volunteers: no

Brief summary:
The purpose of this global study was to demonstrate the efficacy, safety, and tolerability of an intravenous (i.v.) regimen of secukinumab compared to placebo in participants with active ankylosing spondylitis (AS) or non-radiographic axial spondyloarthritis (nr-axSpA ) at Week 16 despite current or previous non-steroidal anti inflammatory drugs (NSAID), disease-modifying antirheumatic drugs (DMARD) and/or anti Tumor Necrosis Factor (TNF) therapy. In addition, to further support efficacy and safety of an i.v. regimen, data was collected for up to 52 weeks of treatment.

Detailed description:
This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design to study the efficacy, safety, and tolerability of treatment with intravenous secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg administered every four weeks starting at Week 4) in subjects with active axial spondyloarthritis (axSpA). The study population consisted of active of 413 participants with AS and 113 participants with active nr-axSpA.

This study consisted of 4 periods totaling up to 70 weeks: the screening period (up to 10 weeks), the treatment period 1 (total duration of 16 weeks), treatment period 2 (total duration of 36 weeks) followed by the safety follow up period of 8 weeks after the end of treatment visit (at Week 60) regardless of whether participant completed the study as planned or discontinued prematurely.

At baseline, participants were randomized to one of the two treatment groups and stratified to disease condition (AS or nr-axSPa):

* Group 1: secukinumab 6 mg/kg i.v.) at baseline and which was followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52) at clinic visits
* Group 2: i.v. placebo at baseline, Weeks 4, 8, and 12 and switched to secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52) at clinic visits

Although study treatment was open label secukinumab i.v. starting at Week 16, all subjects and investigators/site staff remained blinded to original treatment assignment to ensure unbiased efficacy and safety assessments for the remainder of the study. This study enrolled participants with active disease despite current or previous NSAIDs, conventional DMARDs and/or TNF inhibitor therapy or intolerance to these therapies. The regular assessment of disease activity ensured that subjects who experienced worsening of disease in any of the treatment groups could exit the study at any time upon their own accord or based on the advice of the investigator.

A temporary pause of study recruitment only was implemented from 09-Apr-2020 to 11-May-2020, due to the COVID-19 pandemic, but not for study visits, assessments or other conduct of the study.

Arms:
arm 1: Secukinumab intravenous (i.v.) regimen arm 2: Placebo intravenous (i.v.) regimen

Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: The subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 (exposure through Week 52) intervention 2: The subjects will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through Week 48 (exposure through Week 52)

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
AIN457 
Clinical Trial Protocol CAIN457P12301 / NCT04156620 
A randomized, double-blind, placebo-controlled, parallel 
group, phase III multicenter study of intravenous 
secukinumab to compare efficacy at 16 weeks with placebo 
and to assess safety and tolerability up to 52 weeks in 
subjects with active Ankylosing Spondylitis or non-
radiographic axial SpondyloArthritis 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
2019-001177-90 
Version number: 
00 (Original Protocol) 
Clinical Trial Phase: 
III 
Release date: 
16-Aug-2019
Property of Novartis/sponsor 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 13 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.2 
Purpose .................................................................................................................. 21 
2 
Objectives and endpoints ................................................................................................... 21 
3 
Study design ...................................................................................................................... 26 
4 
Rationale ............................................................................................................................ 28 
4.1 
Rationale for study design ..................................................................................... 28 
4.1.1 
Rationale for choice of background therapy ......................................... 28 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 29 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 29 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 30 
4.5 
Risks and benefits .................................................................................................. 30 
5 
Population .......................................................................................................................... 31 
5.1 
Inclusion criteria .................................................................................................... 32 
5.2 
Exclusion criteria ................................................................................................... 33 
6 
Treatment ........................................................................................................................... 35 
6.1 
Study treatment ...................................................................................................... 35 
6.1.1 
Investigational and control drugs .......................................................... 35 
6.1.2 
Additional study treatments .................................................................. 36 
6.1.3 
Treatment arms/group ........................................................................... 36 
6.1.4 
Treatment duration ................................................................................ 36 
6.2 
Other treatment(s) .................................................................................................. 36 
6.2.1 
Concomitant therapy ............................................................................. 37 
6.2.2 
Prohibited medication ........................................................................... 38 
6.2.3 
Rescue medication ................................................................................ 39 
6.3 
Subject numbering, treatment assignment, randomization .................................... 40 
6.3.1 
Subject numbering ................................................................................ 40 
6.3.2 
Treatment assignment, randomization .................................................. 40 
6.4 
Treatment blinding ................................................................................................ 41 


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6.5 
Dose escalation and dose modification.................................................................. 41 
6.5.1 
Dose escalation guidelines .................................................................... 42 
6.5.2 
Dose modifications ................................................................................ 42 
6.5.3 
Follow-up for toxicities ......................................................................... 42 
6.6 
Additional treatment guidance ............................................................................... 43 
6.6.1 
Treatment compliance ........................................................................... 43 
6.6.2 
Recommended treatment of adverse events .......................................... 44 
6.6.3 
Emergency breaking of assigned treatment code .................................. 44 
6.7 
Preparation and dispensation ................................................................................. 44 
6.7.1 
Handling of study treatment and additional treatment .......................... 45 
7 
Informed consent procedures ............................................................................................ 45 
8 
Visit schedule and assessments ......................................................................................... 46 
8.1 
Screening ............................................................................................................... 52 
8.1.1 
Information to be collected on screening failures ................................. 52 
8.1.2 
Re-screening .......................................................................................... 53 
8.2 
Subject demographics/other baseline characteristics............................................. 53 
8.3 
Efficacy .................................................................................................................. 53 
8.3.1 
Assessment of SpondyloArthritis International Society criteria 
(ASAS) .................................................................................................. 54 
8.3.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........ 55 
 
 55 
8.3.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) ..................... 55 
8.3.5 
Patient’s global assessment of disease activity (VAS) ......................... 55 
8.3.6 
Patient’s assessment of back pain intensity (VAS) ............................... 55 
 
 56 
8.3.8 
Medical Outcome Short Form Health Survey (SF-36) Version 2 
(Acute Form) ......................................................................................... 56 
8.3.9 
Ankylosing Spondylitis Quality of Life (ASQoL) ................................ 56 
8.3.10 
High Sensitivity C-reactive protein (hsCRP) ........................................ 57 
 
 57 
 
 57 
8.3.13 
ASDAS-CRP and ASDAS response categories .................................... 57 
 
 57 
 
 58 
8.3.16 
Sleep improvement................................................................................ 59 


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8.3.17 
Appropriateness of efficacy assessments .............................................. 60 
8.4 
Safety ..................................................................................................................... 60 
8.4.1 
QuantiFERON TB-Gold test or PPD skin test ...................................... 61 
8.4.2 
Hepatitis and human immunodeficiency virus (HIV) screen ................ 62 
8.4.3 
Laboratory evaluations .......................................................................... 62 
8.4.4 
Electrocardiogram (ECG) ..................................................................... 63 
8.4.5 
Local tolerability (Injection site reactions) ........................................... 63 
8.4.6 
Pregnancy and assessments of fertility ................................................. 63 
8.4.7 
Tolerability of secukinumab ................................................................. 63 
 
 64 
8.4.9 
Other safety evaluations ........................................................................ 64 
8.4.10 
Appropriateness of safety measurements .............................................. 64 
8.5 
Additional assessments .......................................................................................... 65 
 
 65 
8.5.2 
Trial Feedback Questionnaires .............................................................. 66 
 
 66 
8.5.4 
HLA-B27............................................................................................... 66 
8.5.5 
Pharmacokinetics .................................................................................. 67 
 
 68 
8.5.7 
Activity/Mobility improvement ............................................................ 69 
8.5.8 
Sacroiliac Joint X-ray ............................................................................ 70 
8.5.9 
Sacroiliac Joint MRI ............................................................................. 70 
9 
Study discontinuation and completion .............................................................................. 70 
9.1 
Discontinuation ...................................................................................................... 70 
9.1.1 
Discontinuation of study treatment ....................................................... 70 
9.1.2 
Withdrawal of informed consent ........................................................... 71 
9.1.3 
Lost to follow-up ................................................................................... 72 
9.1.4 
Early study termination by the sponsor ................................................. 72 
9.2 
Study completion and post-study treatment .......................................................... 72 
10 Safety monitoring and reporting ........................................................................................ 73 
10.1 
Definition of adverse events and reporting requirements ...................................... 73 
10.1.1 
Adverse events ...................................................................................... 73 
10.1.2 
Serious adverse events (SAEs) .............................................................. 75 
10.1.3 
SAE reporting........................................................................................ 76 
10.1.4 
Pregnancy reporting .............................................................................. 76 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 77 
10.2 
Additional Safety Monitoring ................................................................................ 77 


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10.2.1 
Liver safety monitoring ......................................................................... 77 
10.2.2 
Renal safety monitoring ........................................................................ 78 
11 Data Collection and Database management ...................................................................... 78 
11.1 
Data collection ....................................................................................................... 78 
11.2 
Database management and quality control ............................................................ 79 
11.3 
Site monitoring ...................................................................................................... 79 
12 Data analysis and statistical methods ................................................................................ 80 
12.1 
Analysis sets .......................................................................................................... 80 
12.2 
Subject demographics and other baseline characteristics ...................................... 81 
12.3 
Treatments ............................................................................................................. 82 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 82 
12.4.1 
Definition of primary endpoint(s) ......................................................... 82 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 83 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 83 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 84 
12.5 
Analysis of secondary endpoints ........................................................................... 84 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 84 
12.5.2 
Safety endpoints .................................................................................... 88 
12.5.3 
Pharmacokinetics .................................................................................. 89 
 
 90 
 
 90 
 
 90 
12.5.7 
Patient Reported Outcomes (PROs) ...................................................... 90 
 
 92 
12.7 
Interim analyses ..................................................................................................... 94 
12.8 
Sample size calculation.......................................................................................... 95 
12.8.1 
Primary endpoint(s) ............................................................................... 95 
12.8.2 
Secondary endpoint(s) ........................................................................... 95 
13 Ethical considerations and administrative procedures ...................................................... 96 
13.1 
Regulatory and ethical compliance ........................................................................ 96 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 96 
13.3 
Publication of study protocol and results............................................................... 96 
13.4 
Quality Control and Quality Assurance ................................................................. 97 
14 Protocol adherence ............................................................................................................ 97 
14.1 
Protocol amendments............................................................................................. 97 
15 References ......................................................................................................................... 98 
16 Appendices ...................................................................................................................... 101 


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16.1 
Appendix 1: Clinically notable laboratory values and vital signs ....................... 101 
16.2 
Appendix 2: Modified New York criteria ........................................................... 102 
16.3 
Appendix 3: ASAS, BASFI 
 ............................................................ 102 
 
 104 
16.5 
Appendix 5: Guidelines for administering the PRO questionnaires .................... 105 
16.6 
Appendix 6: Liver event and laboratory trigger definitions and follow-up 
requirements ........................................................................................................ 107 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 21 
Table 6-1 
Prohibited medication ........................................................................... 38 
Table 8-1 
Assessment Schedule ............................................................................ 47 
 
 58 
Table 8-3 
Assessments & Specifications............................................................... 60 
Table 8-4 
Specifications of Laboratory evaluations .............................................. 62 
 
 64 
Table 8-6 
PK sample log ....................................................................................... 67 
 
 69 
 
 69 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 77 
Table 12-1 
Summary of power for binary secondary endpoints ............................. 95 
Table 12-2 
Summary of power for continuous endpoints ....................................... 95 
Table 16-1 
Safety Analyses: Expanded Limits and Notable Criteria .................... 101 
 
 104 
Table 16-3 
Liver Events and Laboratory Trigger Definitions ............................... 107 
Table 16-4 
Follow up Requirements for Liver Events and Laboratory Triggers .. 108 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 28 
Figure 4-1 
Median concentration profiles ............................................................... 29 
Figure 12-1 
Testing strategy ..................................................................................... 88 
 


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List of abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AS 
Ankylosing spondylitis 
ASAS 
Assessment of SpondyloArthritis International Society 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
ASQoL 
Ankylosing Spondylitis Quality of Life 
AST 
aspartate aminotransferase 
axSpA 
Axial spondyloarthritis 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index  
BASFI 
Bath Ankylosing Spondylitis Functional Index 
 
 
BDR 
Bioanalytical Data Report 
BMI 
Body Mass Index 
BSL 
Baseline 
BUN 
blood urea nitrogen 
Cavg 
Average concentration 
CFR 
Code of Federal Regulation 
CK 
creatine kinase 
Cmax 
Maximum concentration  
Cmin 
Minimum concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CMV 
Cytomegalovirus  
CO 
Country Organization 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
cs-DMARD  
conventional synthetic Disease Modifying Anti-rheumatic Drug 
CSR 
Clinical Study Report 
CTC 
Common Toxicity Criteria 
Ctrough 
trough concentration 
CTT 
Clinical Trial Team 
DILI 
Drug-Induced Liver Injury  
DMARD 
Disease Modifying Anti-rheumatic Drug 
 
 
EBV 
Epstein-Barr Virus  
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 


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eGFR 
estimated glomerular filtration rate  
ELISA 
Enzyme-linked immunosorbent assay 
EMA  
European Medical Agency 
 
 
 
  
 
 
EU  
European Union 
 
 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
gamma glutamyl transferase 
h 
hour 
HDL 
High Density Lipoprotein 
HIV 
human immunodeficiency virus 
HLA 
Human Leukocyte Antigen  
HRQoL 
Health-related quality of life 
hsCRP 
high sensitivity C-Reactive Protein 
HSV 
Herpes Simplex Virus  
i.v. 
intravenous 
IB 
Investigator's Brochure 
IBD 
inflammatory bowel disease  
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
 
 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test 
LiV 
Liquid in Vial 
LLN 
lower limit of normal 
LLOQ 
Lower limit of quantification 
LOCF 
Last Observation Carried Forward 
MAR 
Missing at random 
 
 
 
 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
ml 
milliliter(s) 
mL 
milliliter(s) 


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MMRM 
Mixed effect Model for Repeated Measurements 
MRI 
Magnetic Resonance Imaging  
MTX 
Methotrexate 
nr-axSpA 
non-radiographic axial spondyloArthritis 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NY 
New York 
PCS 
Physical Component Summary 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPD 
Purified Protein Derivative  
PRN 
as needed 
PRO 
Patient Reported Outcomes 
PsA 
Psoriatic Arthritis 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
prothrombin time 
q4w 
Every 4 weeks 
QMS 
Quality Management System 
QoL 
Quality of Life  
RBC 
Red blood cell(s) 
rem 
roentgen equivalent man 
s.c. 
subcutaneous 
SAE 
serious adverse event 
SCR 
Screening 
SD 
standard deviation 
SF-36 
Medical Outcome Short Form (36) Health Survey  
SF-36 PCS 
Short Form-36 Physical Component Summary 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SI 
Sacroiliac 
SIJ  
Sacroiliac Joint 
SOP 
Standard operating procedure 
SpA 
Spondyloarthritis 
 
 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
Sv 
sievert (1 milliSv (mSv) = 100 millirem (mrem)) 
t.i.d 
three times a day 
TBIL/TBL 
total bilirubin 
TNF-IR  
TNFα Inhibitor Incomplete Responder 
TNF/TNFα 
Tumor Necrosis Factor  
ts-DMARD 
targeted synthetic Disease Modifying Anti-rheumatic Drug 
ULN 
upper limit of normal 
US 
United States 


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VAS 
Visual Analog Scale  
vs. 
versus 
WBC 
white blood cell(s) 
WHO 
World Health Organization 
 
 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study drug used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug. 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance” 
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 other treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used within approved indication/dosage. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system 
Patient 
An individual with the condition of interest 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature 
subject 
withdrawal 
Point/time when the subject exits from the study prior to the planned completion 
of all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned. 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A subject who is screened but is not treated or randomized 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when subject permanently stops taking study drug for any reason; 
may or may not also be the point/time of premature subject withdrawal. 
Study 
drug/treatment 
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy. 
Study treatment 
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s) 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date 
Subject 
An individual who has consented to participate in this study. The term Subject 
may be used to describe either a healthy volunteer or a patient. 


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Subject number 
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc. 
Variable 
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints. 
Withdrawal of 
consent (WoC) 
Withdrawal of consent from the study is defined as when a subject does not 
want to participate in the study any longer and does not want any further visits 
or assessments and does not want any further study related contact and does 
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Protocol summary 
Protocol 
number 
CAIN457P12301 
Full Title 
A randomized, double-blind, placebo-controlled, parallel group, phase III 
multicenter study of intravenous secukinumab to compare efficacy at 16 weeks with 
placebo and to assess safety and tolerability up to 52 weeks in subjects with active 
Ankylosing Spondylitis or non-radiographic axial SpondyloArthritis 
Brief title 
Study to demonstrate the efficacy, safety and tolerability of an intravenous (i.v.) 
regimen of secukinumab compared to placebo in subjects with active axSpA 
Sponsor 
and 
Clinical Phase 
Novartis 
Phase III 
Investigation 
type 
Biological 
Study type 
Interventional 
Purpose 
and 
rationale 
The purpose of this global study is to demonstrate the efficacy, safety, and 
tolerability of an intravenous (i.v.) regimen of secukinumab compared to placebo in 
subjects with active axSpA at Week 16 despite current or previous NSAID, DMARD 
and/or anti Tumor Necrosis Factor (TNF) therapy. In addition, to further support 
efficacy and safety of an i.v. regimen, data will be collected for up to 52 weeks of 
treatment. Efficacy and safety data may be used to support the registration of i.v. 
secukinumab in the US and other countries for treatment of subjects with active 
axSpA. 
Primary 
Objective(s)  
To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to 
placebo in subjects with active axspA (AS and nr-axSpA) based on the proportion 
of subjects achieving an ASAS40 (Assessment of SpondyloArthritis International 
Society criteria) response. 
Secondary 
Objectives 
1. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to 
placebo based on the proportion of subjects achieving Ankylosing Spondylitis 
Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) major 
improvement  
2. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the change from baseline in total Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI)  
3. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the proportion of subjects meeting the ASAS 5/6 
response criteria  
4. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on Bath Ankylosing Spondylitis Functional Index (BASFI) 
5. To evaluate the efficacy of i.v. secukinumab compared to placebo after 16 
weeks of treatment by assessing Short Form-36 Physical Component 
Summary (SF-36 PCS) 
6. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the change from baseline in Ankylosing Spondylitis 
Quality of Life (ASQoL) scores 
7. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the change from baseline in high sensitivity C-Reactive 
Protein (hsCRP)  


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8. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the proportion of subjects achieving an ASAS20 response 
9. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the proportion of subjects achieving Ankylosing 
Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) inactive 
disease  
10. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the proportion of subjects achieving ASAS partial 
remission 
11. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior 
to placebo based on the change from baseline in Pittsburgh Sleep Quality 
Index (PSQI) 
12. Overall safety and tolerability of i.v. secukinumab compared to placebo as 
assessed by physical exams, vital signs, laboratory assessments and adverse 
event monitoring 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, 
parallel-group design to study the efficacy, safety, and tolerability of treatment with 
intravenous secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg 
administered every four weeks starting at Week 4) in subjects with active axSpA. 
Population 
The study population will consist of male and female subjects (≥18 years old at the 
time of consent) with active axSpA (radiographic AS or non-radiographic axSpA). 
The diagnosis of axSpA must fulfill the ASAS criteria of inflammatory back pain for 
at least 6 months AND onset before 45 years of age. The diagnosis of radiographic 
AS must fulfill the Modified New York criteria for ankylosing spondylitis with prior 
documented radiological evidence (x-ray or a radiologists report). 
Subjects with nr-axSpA (no definitive radiographic evidence of changes in the 
sacroiliac joints that would meet the modified New York criteria for AS) must fulfill 
the following ASAS classification criteria for axSpA: 
a. Sacroiliitis on MRI with ≥ 1 SpA feature OR HLA-B-27 is positive with ≥2 SpA 
features AND 
b. Objective signs of inflammation at screening, evident by either MRI with SI joint 
inflammation AND / OR hsCRP > ULN (as defined by the central lab) 
In addition, all subjects must have evidence of active axSpA as measured by the 
following three assessments: 
• total BASDAI ≥4 cm on a scale of 0-10 cm 
• spinal pain as measured by BASDAI question #2 ≥4 cm (0-10 cm) 
• total back pain as measured by visual analog scale (VAS) ≥40 mm (0-100 mm) 
Included subjects must have evidence of active disease despite current or previous 
NSAID, conventional DMARD and/or anti-TNF therapy. 
This is a global interventional study and it expected that approximately 500 subjects 
are randomized (400 with active AS and 100 with nr-axSpA) to evaluate the efficacy 
and safety of intravenous secukinumab in this subject population. 
Key 
Inclusion 
criteria 
1. Subject must be able to understand and communicate with the investigator, 
comply with the requirements of the study. and must give written, signed and dated 
informed consent before any study assessment is performed 
2. Male and non-pregnant, non-lactating female patients ≥ 18 years of age 
3. Diagnosis of axSpA according to ASAS criteria 


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a. Inflammatory back pain for at least 6 months 
b. Onset before 45 years of age 
4. For subjects with AS: Diagnosis of moderate to severe AS with prior documented 
radiologic evidence (x-ray or radiologist’s report) fulfilling the Modified New York 
criteria for AS 
5. For subjects with nr-axSpA:  
X-ray of SIJ negative (centrally read) for AS by Modified NY criteria AND 
a. Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B-27 positive 
with ≥2 SpA features AND 
b. Objective signs of inflammation at screening, evident by either MRI with SIJ 
inflammation (centrally read) AND / OR hsCRP > ULN (as defined by the central 
lab) 
6. Active axial SpA assessed by BASDAI ≥4 cm (0-10 cm) at Baseline 
7. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline 
8. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline 
9. Subjects should have had inadequate response or failure to respond to at least 
2 NSAIDs at an approved dose for a minimum of 4 weeks in total and a minimum 
of 2 weeks for each NSAID prior to randomization, or less than 4 weeks if therapy 
had to be withdrawn due to intolerance, toxicity or contraindications 
10. Subjects who are regularly taking NSAIDs (including COX-1 or COX-2 
inhibitors) as part of their AS or nr-axSpA therapy are required to be on a stable 
dose for at least 2 weeks before randomization 
11. Subjects who are intolerant or have been inadequate responders to a TNF 
inhibitor (not more than one) will be allowed to enter into the study (not more than 
20% per group). They must have experienced an inadequate response to previous 
or current treatment at an approved dose for at least 3 months prior to 
randomization, or have been intolerant to at least one administration of an anti-TNF 
agent. These subjects will undergo an appropriate wash-out period prior to 
randomization, if required 
a. 4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 
30 hours 
b. 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days 
c. 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) 
d. 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
e. 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days 
12.Subjects taking methotrexate (MTX) (≤ 25 mg/week ) or sulfasalazine (≤ 3 g/day) 
are allowed to continue their medication and must have taken it for at least 3 
months and have to be on a stable dose for at least 4 weeks prior to randomization. 
Subjects on MTX must be on folic acid supplementation before randomization 
13. Subjects who are on a conventional DMARD other than MTX or sulfasalazine 
must discontinue the DMARD 4 weeks prior to randomization, except for 
leflunomide, which must be be discontinued 8 weeks prior to randomization, unless 
a cholestyramine washout has been performed 


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14.Subjects taking systemic corticosteroids must be on a stable dose of ≤10 
mg/day prednisone or equivalent for at least 2 weeks before randomization 
Key Exclusion 
criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this 
study 
1. Subjects with total ankylosis of the spine 
2. 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 
3. Subjects taking moderate and high potency opioid analgesics (e.g. methadone, 
hydromorphone, morphine) 
4. Presence of significant medical problems which at investigator’s discretion, will 
prevent the subject from participating in the study, including but not limited to the 
following: Subjects with severely reduced kidney function (estimated glomerular 
filtration 
rate 
(eGFR) 
<29 
ml/min/1.73m2), 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) 
5. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks 
before randomization 
6. Underlying conditions (including, but not limited to metabolic, hematologic, renal, 
hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) 
which in the opinion of the investigator significantly immunocompromises the 
subject and/or places the subject at unacceptable risk for receiving an 
immunomodulatory therapy 
7. 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 
8. Active systemic infections during the last two weeks (exception: common cold) 
prior to randomization or any infection that reoccurs on a regular basis 
9. 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 8-1. Subjects with a positive test may participate in 
the study if further work up (according to local practice/guidelines) establishes 
conclusively that the subject has no evidence of active tuberculosis. If presence of 
latent tuberculosis is established, then treatment according to local country 
guidelines must have been initiated 
10. Past medical history of infection with HIV or hepatitis B prior to randomization 
or active infection or on treatment for Hepatitis C at randomization 
11. History of lymphoproliferative disease or any known malignancy, or history of 
malignancy of any organ system treated or untreated within the past 5 years, 
regardless of whether there is evidence of local recurrence or metastases (except 
for skin Bowen’s disease, or basal cell carcinoma or actinic keratoses that have 
been treated with no evidence of recurrence in the past 12 weeks; carcinoma in 
situ of the cervix or non-invasive malignant colon polyps that have been removed) 
12. Inability or unwillingness to undergo repeated venipuncture (e.g., because of 
poor tolerability or lack of access to veins) 


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13. Pregnant or nursing (lactating) women, where pregnancy is defined as the state 
of a female after conception and until the termination of gestation, confirmed by a 
positive hCG laboratory test 
14. 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) 
15. History of clinically significant liver disease or liver injury indicated by abnormal 
liver function tests, such as SGOT (AST), SGPT (ALT), alkaline phosphatase and 
serum bilirubin. The investigator should be guided by the following criteria: 
· Any single parameter may not exceed 2 x the upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more 
as soon as possible, and in all cases, at least prior to randomization, to rule-out 
laboratory error. 
· If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. In any case, serum 
bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L) 
16. Significant medical problems or diseases, including but not limited to the 
following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York 
Heart Association status of class III or IV), uncontrolled diabetes, or very poor 
functional status precluding ability to perform self-care 
17. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, unless they are using effective methods of contraception 
during the entire study or longer if required by locally approved prescribing 
information (e.g., 20 weeks in EU) 
18. Active ongoing inflammatory diseases other than axSpA that might confound 
the evaluation of the benefits of secukinumab therapy, including inflammatory 
bowel disease or uveitis 
19. Current severe progressive or uncontrolled disease which in the judgment of 
the clinical investigator renders the subject unsuitable for the trial 
20. Use of other investigational drugs at the time of enrollment, or within 5 half- 
lives of enrollment, or within 4 weeks until the expected pharmacodynamic effect 
has returned to baseline, whichever is longer; or longer if required by local 
regulations 
21. Previous exposure to secukinumab (AIN457) or any other biologic drug directly 
targeting IL-17 or the IL-17 receptor 
22. 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) 
Study 
treatment 
At baseline, subjects with active AS and nr-axSpA will be randomized to one of the 
two treatment groups: 
Group 1: approximately 200 AS subjects and 50 nr-axSpA subjects; These subjects 
will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), 
followed by the administration of secukinumab 3 mg/kg i.v. every four weeks 
starting at Week 4 through Week 48 (exposure through week 52). 
Group 2: approximately 200 AS subjects and 50 nr-axSpA subjects; These subjects 
will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , followed 


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by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four weeks 
through Week 48 (exposure through week 52). 
Efficacy 
assessments 
• Assessment of SpondyloArthritis International Society (ASAS) response 
criteria; ASAS40, ASAS20, ASAS 5/6 and ASAS partial remission 
• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
• Bath Ankylosing Spondylitis Disease Activity Index 50 (BASDAI50) 
• Bath Ankylosing Spondylitis Functional Index (BASFI) 
• Patient’s global assessment of disease activity (VAS) 
• Patient’s assessment of back pain intensity (VAS) 
 
 
• Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute Form) 
• Ankylosing Spondylitis Quality of Life (ASQoL) 
• High sensitivity C-Reactive Protein (hsCRP) 
 
 
 
 
 
• Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein 
(CRP) and ASDAS response categories 
 
 
 
 
• Sleep improvement (
 sleep PROs) 
Key 
safety 
assessments 
• Physical examination 
• Vital signs 
• Height and weight 
• QuantiFERON TB-Gold test or PPD skin test 
• Hepatitis and human immunodeficiency virus (HIV) screen 
• Laboratory evaluations (Hematology, clinical chemistry, lipid panel, 
cardiovascular Panel, urinalysis and pregnancy test) 
• Evaluation of AE/ SAE’s 
• Local tolerability (Injection site reactions) 
• Pregnancy and assessment of fertility 
• Tolerability of secukinumab 
 
 
Other 
assessments 
• Quality of Life questionnaires/ Patient reported outcomes (PROs) 
• Trial Feedback Questionnaires 
 
 
• HLA-B27 
• Pharmacokinetics 
 
 
• Activity/Mobility improvement 
• Sacroiliac Joint X-ray 
• Sacroiliac Joint MRI 
Data analysis 
The primary endpoint in the study is the proportion of subjects who achieve an 
ASAS40 response at Week 16. The statistical hypothesis for ASAS40 being tested 


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is that there is no difference in the proportion of subjects fulfilling the ASAS40 
criteria at Week 16 in the secukinumab i.v. regimen versus placebo. 
Let p0 denote the proportion of ASAS40 responders at Week 16 for placebo 
regimen and p1 denote the proportion of ASAS40 responders at Week 16 for 
secukinumab i.v. regimen. 
In statistical terms, H1: p1= p0, HA1: p1≠ p0, i.e., 
H1: secukinumab i.v. regimen is not different to placebo regimen with respect to 
ASAS40 response at Week 16 
The primary endpoint of ASAS40 at Week 16 in the FAS will be evaluated using a 
logistic regression with treatment and randomization stratum (disease condition) as 
factors and weight as a covariate. Difference in marginal response proportions with 
p-value and respective 95% confidence interval will be estimated from the logistic 
regression model for the comparison of secukinumab i.v. regimen versus placebo. 
The secondary endpoints include ASDAS-CRP major improvement, BASDAI, 
ASAS 5/6, BASFI, SF-36 PCS, ASQoL, hsCRP, ASAS20, ASDAS-CRP inactive 
disease, ASAS partial remission and PSQI at Week 16. 
The binary secondary endpoints (e.g., ASAS 5/6, etc.) will be evaluated via a 
logistic regression with treatment and randomization stratum (disease condition) as 
factors and weight as a covariate. 
The change from baseline in continuous secondary endpoints (e.g., BASDAI, etc.) 
will be evaluated using MMRM with treatment group, stratification factor (disease 
condition) and analysis visit as categorical factors, baseline measure and weight 
as continuous covariates, and treatment by analysis visit and baseline measure by 
analysis visit as interaction terms. An unstructured covariance structure will be 
assumed for the model. 
Safety analyses will include summaries of AEs, laboratory measurements, and vital 
signs. 
Key words 
Active axSpA, Axial spondyloarthritis, non-radiographic-axSpA, nr-axSpA, 
ankylosing spondylitis, AS, inflammatory back pain, sacroiliitis, intravenous 
secukinumab 


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1 
Introduction 
1.1 
Background 
Axial spondyloarthritis (axSpA) is a type of spondyloarthritis mainly affecting the axial 
skeleton, characterized by spinal inflammation and inflammatory back pain. AxSpA is among 
the most common chronic inflammatory joint disorders, with recent estimates of prevalence in 
Caucasian populations in the range of 1–2% (Baraliakos and Braun 2011). Patients with chronic 
back pain (onset before 45 years of age) are classified as having axSpA if they fulfill either the 
clinical arm or the imaging arm of the Assessment of SpondyloArthritis International Society 
(ASAS) classification criteria (Rudwaleit et al 2009). 
Based on the presence or absence of sacroiliitis on conventional X-ray radiographs, axSpA 
patients are further classified into two conditions: non-radiographic-axSpA (nr-axSpA) and 
ankylosing spondylitis (AS). Patients with evidence of sacroiliitis on X-ray fulfilling the 1984 
modified New York diagnostic criteria (van der Linden et al 1984) are classified as having AS, 
whereas patients who do not show sacroiliitis on X-ray, but may show evidence of sacroiliitis 
on MRI, are classified as having nr-axSpA. 
AS is characterized mainly by involvement of the axial skeleton and sacroiliac (SI) joints, but 
peripheral joints, entheses and extra-articular organs may also be affected. A significant 
proportion of AS patients may present with associated extra-articular manifestations such as 
uveitis, psoriasis, inflammatory bowel disease (IBD), or cardiovascular and pulmonary 
abnormalities. Generalized osteoporosis, as well as regional osteopenia are common in AS 
patients and predispose them to non-traumatic fractures, despite a predominantly younger age 
and male gender distribution. The presence of the Human Leukocyte Antigen (HLA)-B27 is 
strongly associated with AS; 90–95% of patients with AS who have European ancestry carry 
this marker. AS affects up to 1.1% of the population, is associated with significant morbidity 
and disability, and thus constitutes a major socioeconomic burden. 
Studies and registry data have shown that nr-axSpA patients have similar levels of disease 
activity, pain, and health-related quality of life impairment as observed in AS patients 
(Wallis et al 2013). Disease parameters and response rates to treatment with tumor necrosis 
factor (TNF) antagonists are similar in patients with AS and nr-axSpA, supporting the concept 
that axSpA is a disease with distinct stages (Song et al 2013). Furthermore, with a longer 
duration of symptoms, most patients who start with nr-axSpA ultimately develop radiographic 
evidence consistent with AS. In an investigation of 329 patients with axSpA, evidence of 
radiographic sacroiliitis was present in 40-86% of patients, in accordance with the duration of 
symptoms (<10 to  > 20 years) (Said-Nahal et al 2000), with many nr-axSpA patients 
progressing to AS over time. Nonetheless, it is estimated that 10-15% of nr-axSpA patients do 
not develop radiographic sacroiliitis (Sieper and van der Heijde 2013). Thus, nr-axSpA may 
represent an early stage of AS, but may also be a form of the disease which causes much pain 
without leading to structural changes of the axial skeleton (Baraliakos and Braun 2015). In 
short, patients recognized as having axSpA, either with AS or nr-axSpA, present with similar 
clinical characteristics, the same burden of disease, and the same response to anti-inflammatory 
medication. A study evaluating the efficacy and safety of secukinumab 150 mg s.c. q4w vs. 
placebo (CAIN475H2315) in patients with nr-axSpA is currently ongoing. 


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First-line medication of mild AS consists of non-steroidal anti-inflammatory drugs (NSAIDs). 
Treatment of NSAID-refractory AS is hampered by the lack of efficacy of virtually all 
conventional disease modifying anti-rheumatic drugs (DMARDs), including methotrexate 
(MTX). As an exception, peripheral arthritis associated with AS may respond to sulfasalazine 
and methotrexate. TNF blocking agents were successfully added to the armamentarium to treat 
AS (Braun et al 2002) and subsequently demonstrated prolonged efficacy up to eight years of 
follow-up (Baraliakos et al 2011). However, upon discontinuation of TNF blockers the disease 
relapses quickly (Baraliakos et al 2005), indicating that the inflammatory process may have 
only been inhibited but not completely abolished. 
Secukinumab is a fully human IgG1 antibody that selectively binds to and neutralizes the 
proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab targets IL-17A, inhibiting 
its interaction with the IL-17 receptor expressed on various cell types including keratinocytes 
and synoviocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, 
chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to 
autoimmune and inflammatory diseases, including psoriasis, psoriatic arthritis (PsA) and AS. 
To date, s.c. secukinumab is approved in over 90 countries for the clinical management of PsA 
and AS. 
1.2 
Purpose 
The purpose of this global study is to demonstrate the  efficacy, safety, and tolerability of an 
intravenous (i.v.) regimen of secukinumab compared to placebo in subjects with active axSpA, 
including AS and nr-axSpA at Week 16 despite current or previous NSAID, conventional 
DMARD and/or anti TNF therapy. In addition, to further support efficacy and safety of an i.v. 
regimen, data will be collected for up to 52 weeks of treatment. Efficacy and safety data may 
be used to support the registration of i.v. secukinumab in the US and other countries for 
treatment of subjects with active axSpA. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo in 
subjects with active axSpA (AS and nr-axSpA) 
based on the proportion of subjects achieving an 
ASAS40 (Assessment of SpondyloArthritis 
International Society criteria) response. 
• ASAS40 response at Week 16, 
defined as improvement of ≥ 
40% and an absolute 
improvement from baseline of 
≥20 units (range 0–100) in ≥ 3 
of the following 4 domains: 
back pain [10 cm visual 
analogue scale (VAS)], patient 
global assessment of disease 
activity (10 cm VAS), physical 
function (BASFI; range 0–100) 
and inflammation (mean score 


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Objective(s) 
Endpoint(s) 
of items 5 and 6 of the 
BASDAI; both 10 cm VAS) 
without any worsening in the 
remaining domain. 
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the proportion of subjects achieving 
Ankylosing Spondylitis Disease Activity Score 
(ASDAS)-C-Reactive Protein (CRP) major 
improvement  
• ASDAS-CRP major 
improvement defined as a 
change (decrease) in the score 
of at least 2.0 units  
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the change from baseline in total Bath 
Ankylosing Spondylitis Disease Activity Index 
(BASDAI)  
• Change from baseline in total 
BASDAI 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the proportion of subjects meeting the 
ASAS 5/6 response criteria  
• Subjects achieving ASAS 5/6 
response defined as: 
improvement of ≥20% in at 
least five of six domains 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on Bath Ankylosing Spondylitis Functional 
Index (BASFI) 
• Change from baseline of 
BASFI 
• To evaluate the efficacy of i.v. secukinumab 
compared to placebo after 16 weeks of treatment 
by assessing Short Form-36 Physical Component 
Summary (SF-36 PCS) 
• Absolute & percent change 
from baseline in SF-36 PCS 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the change from baseline in Ankylosing 
Spondylitis Quality of Life (ASQoL) scores 
• Absolute & percent change 
from baseline in ASQoL 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the change from baseline in high 
sensitivity C-Reactive Protein (hsCRP)  
• Change from baseline in 
hsCRP 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the proportion of subjects achieving an 
ASAS20 response 
• The ASAS Response Criteria 
(ASAS20) is defined as an 
improvement of ≥20% and ≥1 
unit on a scale of 10 in at least 
three of the four main domains 
and no worsening of ≥20% and 


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Objective(s) 
Endpoint(s) 
≥1 unit on a scale of 10 in the 
remaining domain. 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the proportion of subjects achieving 
Ankylosing Spondylitis Disease Activity Score 
(ASDAS)-C-Reactive Protein (CRP) inactive 
disease  
• ASDAS-CRP inactive disease 
as defined by an ASDAS-CRP 
score below 1.3 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the proportion of subjects achieving 
ASAS partial remission 
• ASAS partial remission criteria 
are defined as a value not 
above 2 units in each of the 
four main ASAS domains on a 
scale of 0-10 
• To demonstrate that the efficacy of i.v. 
secukinumab at Week 16 is superior to placebo 
based on the change from baseline in Pittsburgh 
Sleep Quality Index (PSQI)  
• Change from baseline in PSQI 
• Overall safety and tolerability of i.v. secukinumab 
compared to placebo as assessed by physical 
exams, vital signs, laboratory assessments and 
adverse event monitoring 
• Physical exams, vital signs, 
laboratory assessments, and 
adverse event monitoring 


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Objective(s) 
Endpoint(s) 


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Objective(s) 
Endpoint(s) 
3 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-
group design to study the efficacy, safety, and tolerability of treatment with intravenous 
secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg administered every four 
weeks starting at Week 4) in subjects with active axSpA. The study population consists 
of approximately 400 subjects with active AS and approximately 100 subjects with active nr-
axSpA, despite current or previous NSAID, conventional DMARD and / or TNF inhibitor 
therapy, or intolerance to these therapies. A screening (SCR) period of up to 10 weeks will be 
used to assess eligibility, followed by randomization to 52 weeks of study treatment.  
At baseline, subjects with active AS and nr-axSpA will be randomized to one of the two 
treatment groups: 
• Group 1: approximately 200 AS subjects and approximately 50 nr-axSpA subjects; These 
subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), 
followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at 
Week 4 through Week 48 (exposure through Week 52). 
• Group 2: approximately 200 AS subjects and approximately 50 nr-axSpA subjects; These 
subjects will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , 


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followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four 
weeks through Week 48 (exposure through Week 52). 
This study will consist of 4 periods totaling 70 weeks: the screening period (up to 10 weeks), 
the treatment period 1 (total duration of 16 weeks) and the treatment period 2 (total duration of 
36 weeks) followed by the safety follow up period of 8 weeks after the end of treatment visit 
(i.e., Week 52). 
The subjects will be stratified at randomization according to disease condition (i.e., AS or nr-
axSpA). No more than 20% TNF Inhibitor Incomplete Responders (TNF-IR) subjects will be 
enrolled in the study. Starting at Week 16, all subjects will switch to open-label intravenous 
secukinumab, including all placebo subjects. 
No subject will be on placebo treatment after Week 16, because axSpA is considered a chronic 
disease with no ‘true’ and lasting placebo response. However, all subjects and investigators/site 
staff will remain blinded to the original randomized treatment group assignment (secukinumab 
treatment vs placebo). Study treatment will continue up to Week 52. An end of treatment visit 
(i.e., Week 52) is to be done 4 weeks after last study treatment administration and a post 
treatment follow-up visit (i.e., Week 60) is to be done 8 weeks after the end of treatment visit 
for all subjects (regardless of whether they complete the entire study as planned or discontinue 
prematurely). All i.v. infusions will be performed at the study site and site personnel will 
administer the infusions to subjects. 
Rescue medication is not allowed until Week 16. However, subjects who are deemed by the 
investigator not to be benefiting from the study treatment based on safety and efficacy 
assessments or for any reason of their own accord will be free to discontinue participation in 
the study at any time. The study will have a primary endpoint analysis at Week 16. Therefore, 
the primary analysis will be performed with Week-16 data once the last subject has completed 
the Treatment Period 1. 


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Figure 3-1 
Study Design 
 
4 
Rationale 
4.1 
Rationale for study design 
The double-blind, randomized, parallel-group, placebo-controlled design used in this study is 
aligned with Phase III trials of other biologics and is in accordance with EMA (European 
Medical Agency) guidelines (EMA 2017) and available precedent. The treatment duration of 
the placebo group has been kept short and the group will be re-assigned to active treatment once 
the Week 16 visit for primary endpoint assessments has been reached. Although study treatment 
is open label secukinumab i.v. starting at Week 16, blinding to original treatment assignment 
will be maintained, so as to ensure unbiased efficacy and safety assessments for the remainder 
of the study.  
A non-dosing visit has been included at Week 25. Efficacy measures and a PK sample collected 
at that visit will be used to assess the dynamic of the efficacy response in steady or quasi-steady 
state condition between the administration of two doses as well as its relationship with 
secukinumab concentration. This will allow exploration of the possible effect of the route of 
administration on the efficacy response. 
4.1.1 
Rationale for choice of background therapy 
Clinical management of axSpA by pharmacotherapy includes the use of NSAIDs and 
conventional DMARDs, and if insufficient response, biologic agents (i.e., TNF-inhibitor 
therapy or anti-IL17 agents). 


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This study intends to enroll patients with active disease despite current or previous NSAIDs, 
conventional DMARDs and/or TNF inhibitor therapy or intolerance to these therapies. A 
background of NSAID therapy and/or concomitant therapy with methotrexate (≤25 mg/week) 
or sulfasalazine (≤ 3 g/day) will be acceptable, if dose and route of administration have been 
stable for at least two weeks with NSAIDs and/or four weeks with MTX or sulfasalazine, prior 
to the randomization visit. Inclusion of patients with active axSpA who are TNF-IR (up to 20% 
in each group) in the study also makes the background patient population more representative 
of the real world clinical scenario. 
4.2 
Rationale for dose/regimen and duration of treatment 
 
 
 Hence, the proposed i.v. 
regimen is expected to deliver an exposure within the approved s.c. doses of secukinumab. 
Considering the large amount of clinical data collected so far and understanding of the PK 
profile for secukinumab in AS, it is expected that the clinical response with the proposed i.v. 
regimen will be similar to that observed with current approved s.c. regimens. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
A placebo arm up to the primary endpoint at Week 16 is included in this study. Due to the nature 
of the disease and the outcome measures used (ASAS criteria), a placebo arm is necessary to 
reliably evaluate the efficacy and safety of the active drug. The continuation of the placebo 


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group up to the primary endpoint assessment at Week 16 can be supported from an ethical 
standpoint, as subjects can continue on a range of concomitant treatments. 
The parallel-group placebo controlled design used in this study is aligned with Phase III trials 
of other biologics in this disease area including registration studies of s.c. secukinumab in 
axSpA and is also in accordance with EMA guidelines (EMA 2017). The treatment duration of 
the placebo group is relatively short and the placebo group will be re-assigned to active 
treatment at Week 16. The regular assessment of disease activity ensures that subjects who are 
experiencing worsening of disease in any of the treatment groups can exit the study at any time 
upon their own accord or based on the advice of the investigator. 
4.4 
Purpose and timing of interim analyses/design adaptations 
The primary endpoint analysis (Week-16 analysis) will be performed after all subjects complete 
the Week-16 visit in order to support regulatory filings. 
Additional analyses may be performed to support health authority interactions, as necessary. 
The investigators, site personnel, subjects and monitors will remain blinded to the original 
treatment assignment groups until Week-60 analysis has been completed. 
4.5 
Risks and benefits 
Secukinumab has demonstrated either preliminary or confirmed efficacy in several 
inflammatory diseases including psoriasis, psoriatic arthritis and ankylosing spondylitis. The 
safety profile of secukinumab is primarily based on the aggregate safety data from 10 large 
completed phase II/III psoriasis trials. The evaluation of safety data from completed phase II/III 
AS trials did not show additional safety concerns. 
Secukinumab was generally safe and well-tolerated. The most frequently reported adverse 
events are infections, especially upper respiratory tract with secukinumab relative to placebo. 
There was an increase in mucosal or cutaneous candidiasis with secukinumab compared to 
placebo, but the cases were mostly mild or moderate in severity, non-serious, and responsive to 
standard treatment. 
There was a small increase in mild neutropenia cases with secukinumab compared to placebo. 
Common Toxicity Criteria (CTC) AE grade 3 neutropenia (<1.0-0.5x109/L) was uncommonly 
observed with secukinumab, most were transient and reversible without a temporal relationship 
to serious infections. 
Hypersensitivity reactions including urticarial and a rare event of anaphylactic reaction to 
secukinumab were also observed in clinical studies. 
Taking into account the individual risks as outlined above, the expected risk profile of the i.v. 
regimen of secukinumab from a mechanism of action perspective is anticipated to be similar to 
that seen with the approved s.c. secukinumab regimens. The risk to subjects in this trial will be 
minimized by compliance with the eligibility criteria, close clinical monitoring and extensive 
guidance to the investigators, provided in the current version of the Investigator’s Brochure 
(IB). 


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Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study. 
From the standpoint of the overall risk-benefit assessment, the current trial with secukinumab 
is justified. 
5 
Population 
The study population will consist of male and female subjects (≥18 years old at the time of 
consent) with active axSpA (AS or nr-axSpA). The diagnosis of axSpA must fulfill the ASAS 
criteria of inflammatory back pain for at least 6 months AND onset before 45 years of age. For 
a diagnosis of AS, subjects must fulfill the Modified New York criteria for AS (see 
Section 16.2) with prior documented radiological evidence (x-ray or a radiologists report). 
Subjects with nr-axSpA (no definitive radiographic evidence of changes in the sacroiliac joints 
that would meet the modified New York criteria for AS) must fulfill the following ASAS 
classification criteria for axSpA: 
a. Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B27 is positive with 
≥2 SpA features AND 
b. Objective signs of inflammation at screening, evident by either MRI with SI joint 
inflammation (centrally read) AND / OR hsCRP > ULN (as defined by the central 
lab) 
In addition, all subjects must have evidence of active axSpA as measured by the following three 
assessments: 
• total BASDAI ≥4 cm on a scale of 0-10 cm 
• spinal pain as measured by BASDAI question #2 ≥4 cm (0-10 cm) 
• total back pain as measured by visual analog scale (VAS) ≥40 mm (0-100 mm) 
Included subjects must have evidence of active disease despite current or previous NSAID, 
conventional DMARD and/or anti-TNF therapy. 
This is a global interventional study and it is expected that approximately 500 subjects are 
randomized  (approximately 400 subjects with active AS and approximately 100 subjects with 
nr-axSpA) to evaluate the efficacy and safety of i.v. secukinumab in this subject population. 
A screening failure rate of 25% and post-randomization drop-out rate of 10% prior to the time 
of the primary endpoint assessments (Week 16) are anticipated. Enrollment will stop as soon as 
the target number of randomized subjects is reached.   
No more than 20% TNF-IR subjects will be enrolled in the study.   
Subjects can be re-screened only once and no study-related re-screening procedure should be 
performed prior to written re-consent by the subject. Mis-randomization occurs when a subject 
who does not meet all eligibility criteria receives a randomization number in IRT in error; mis-
randomized subjects will be treated as screen failures and will not be re-screened. However, if 
the subject randomized in error was dosed then he/she will be discontinued. 


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5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1. Subject must be able to understand and communicate with the investigator, comply with 
the requirements of the study. and must give written, signed and dated informed consent 
before any study assessment is performed 
2. Male and non-pregnant, non-lactating female patients ≥ 18 years of age 
3. Diagnosis of axSpA according to ASAS criteria 
a. Inflammatory back pain for at least 6 months 
b. Onset before 45 years of age 
4. For subjects with AS: Diagnosis of AS with prior documented radiologic evidence (x-ray 
or radiologist’s report) fulfilling the Modified New York criteria for AS 
5. For subjects with nr-axSpA:  
X-ray of SIJ negative (centrally read) for AS by Modified NY criteria AND 
a. Sacroiliitis on MRI (centrally read) with ≥ 1 SpA feature OR HLA-B-27 positive with 
≥2 SpA features AND 
b. Objective signs of inflammation at screening, evident by either MRI with SIJ 
inflammation (centrally read) AND / OR hsCRP > ULN (as defined by the central 
lab) 
6. Active axial SpA assessed by BASDAI ≥4 cm (0-10 cm) at Baseline 
7. Spinal pain as measured by BASDAI question #2 ≥ 4 cm (0-10 cm) at Baseline 
8. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline 
9. Subjects should have had inadequate response or failure to respond to at least 2 NSAIDs at 
an approved dose for a minimum of 4 weeks in total and a minimum of 2 weeks for each 
NSAID prior to randomization, or less than 4 weeks if therapy had to be withdrawn due to 
intolerance, toxicity or contraindications 
10. Subjects who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their AS or nr-axSpA therapy are required to be on a stable dose for at least 2 weeks 
before randomization 
11. Subjects who are intolerant or have been inadequate responders to a TNF inhibitor (not 
more than one) will be allowed to enter into the study (not more than 20% per group). 
They must have experienced an inadequate response to previous or current treatment at an 
approved dose for at least 3 months prior to randomization, or have been intolerant to at 
least one administration of an anti-TNF agent. These subjects will undergo an appropriate 
wash-out period prior to randomization, if required 
a. 4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 
30 hours 
b. 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days 
c. 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) 
d. 10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days 
e. 10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days 


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12. Subjects taking methotrexate (MTX) (≤ 25 mg/week ) or sulfasalazine (≤ 3 g/day) are 
allowed to continue their medication and must have taken it for at least 3 months and have 
to be on a stable dose for at least 4 weeks prior to randomization. Subjects on MTX must 
be on folic acid supplementation before randomization 
13. Subjects who are on a conventional DMARD other than MTX or sulfasalazine must 
discontinue the DMARD 4 weeks prior to randomization, except for leflunomide, which 
must be be discontinued 8 weeks prior to randomization, unless a cholestyramine washout 
has been performed 
14. Subjects taking systemic corticosteroids must be on a stable dose of ≤10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study 
1. Subjects with total ankylosis of the spine 
2. 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 
3. Subjects taking moderate and high potency opioid analgesics (e.g. methadone, 
hydromorphone, morphine) 
4. Presence of significant medical problems which at investigator’s discretion, will prevent 
the subject from participating in the study, including but not limited to the following: 
Subjects with severely reduced kidney function (estimated glomerular filtration rate 
(eGFR) <29 ml/min/1.73m2), 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) 
5. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
Randomization 
6. Underlying conditions (including, but not limited to metabolic, hematologic, renal, 
hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in 
the opinion of the investigator significantly immunocompromises the subject and/or places 
the subject at unacceptable risk for receiving an immunomodulatory therapy 
7. 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 
8. Active systemic infections during the last two weeks (exception: common cold) prior to 
randomization or any infection that reoccurs on a regular basis 
9. 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 8-1. 
Subjects with a positive test may participate in the study if further work up (according to 
local practice/guidelines) establishes conclusively that the subject has no evidence of 
active tuberculosis. If presence of latent tuberculosis is established, then treatment 
according to local country guidelines must have been initiated 
10. Past medical history of infection with HIV or hepatitis B prior to randomization or active 
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11. History of lymphoproliferative disease or any known malignancy, or history of 
malignancy of any organ system treated or untreated within the past 5 years, regardless of 
whether there is evidence of local recurrence or metastases (except for skin Bowen’s 
disease, or basal cell carcinoma or actinic keratoses that have been treated with no 
evidence of recurrence in the past 12 weeks; carcinoma in situ of the cervix or non-
invasive malignant colon polyps that have been removed) 
12. Use or planned use of prohibited concomitant medication (see Section 6.2.2) 
13. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
14. 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 
15. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization 
16. 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) 
17. History of clinically significant liver disease or liver injury indicated by abnormal liver 
function tests, such as SGOT (AST), SGPT (ALT), alkaline phosphatase and serum 
bilirubin. The investigator should be guided by the following criteria: 
• Any single parameter may not exceed 2 x the upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to randomization, to rule-out 
laboratory error. 
• If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. In any case, serum 
bilirubin should not exceed the value of 1.6 mg/dL (27 µmol/L) 
18. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or very poor functional status 
precluding ability to perform self-care 
19. Plans for administration of live vaccines during the study period or within 6 weeks prior to 
randomization 
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during the 
entire study or longer if required by locally approved prescribing information (e.g., 20 
weeks in EU). Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
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 
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• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception 
• Placement of an intrauterine device or intrauterine system 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six 
weeks prior to randomization. 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 childbearing potential. 
21. Active ongoing inflammatory diseases other than axSpA that might confound the 
evaluation of the benefits of secukinumab therapy, including inflammatory bowel disease 
or uveitis 
22. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the subject unsuitable for the trial 
23. Use of other investigational drugs at the time of enrollment, or within 5 half- lives of 
enrollment, or within 4 weeks until the expected pharmacodynamic effect has returned to 
baseline, whichever is longer; or longer if required by local regulations 
24. History of hypersensitivity to any of the study drug constituents 
25. Previous exposure to secukinumab (AIN457) or any other biologic drug directly targeting 
IL-17 or the IL-17 receptor 
26. 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) 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Novartis will supply the following study treatments:  
Investigational Treatment: 
• Secukinumab liquid in vial (LiV) for i.v. infusion provided in glass vials, 
 
 


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Reference Therapy: 
• Secukinumab placebo 
 for i.v. infusion provided in 5 mL LiV. 
The LiV glass vials are packed in double-blind (treatment period 1, up to and including Week 
12) and open label fashion (treatment period 2, from Week 16 onwards). For detailed 
instructions for storage, handling and administration of study treatment, please refer to 
the Pharmacist Manual. 
The study medication will be labeled as follows: 
• Double blind Secukinumab Liquid in Vial will be labeled as AIN457 
 
Placebo. 
• Open label Secukinumab Liquid in Vial will be labeled as AIN457 
 
6.1.2 
Additional study treatments 
No other treatment/s beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
At baseline, all eligible subjects will be randomized to one of the two treatment arms in a 1:1 
ratio via Interactive Response Technology (IRT): 
• Group 1: 200 AS subjects and 50 nr-axSpA subjects ; These subjects will receive 
secukinumab  6 mg/kg i.v. at randomization (i.e. BSL), followed by the administration of 
secukinumab 3 mg/kg i.v. every four weeks starting at Week 4 through Week 48 
(exposure through Week 52). 
• Group 2: 200 AS subjects and 50 nr-axSpA subjects ; These subjects will receive i.v. 
placebo at randomization (i.e. BSL) and at Weeks 4, 8, and 12, followed by the 
administration of secukinumab 3 mg/kg i.v. at Week 16 and every four weeks through 
Week 48 (exposure through Week 52). 
All subjects will receive blinded treatment every four weeks starting at baseline and until Week 
16. At Week 16, subjects from Group 1 will continue using secukinumab 3 mg/kg i.v. and 
subjects from Group 2 will start receiving secukinumab 3 mg/kg i.v. every four weeks (see 
Figure 3-1). 
Treatment will be provided open-label from Week 16 onwards, as all subjects will be receiving 
3 mg/kg i.v. every 4 weeks; however, the investigators, site personnel, subjects and 
monitors will remain blinded to initial randomized group assignment. 
6.1.4 
Treatment duration 
The planned duration of treatment is 52 weeks. Subjects may be discontinued from treatment 
earlier (see Section 9.1.1) due to unacceptable toxicity, disease progression and/or at the 
discretion of the investigator or the subject. 
6.2 
Other treatment(s) 
No additional treatment beyond investigational drug is provided in this trial. 


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6.2.1 
Concomitant therapy 
The investigator should instruct the subject to notify the study site about any new medications 
(including over-the-counter drugs, calcium and vitamins) administered after the subject was 
enrolled into the study. All medications (other than study treatment), procedures and significant 
non-drug therapies (including physical therapy and blood transfusions) must be recorded on the 
Prior and Concomitant medications or Procedures and Significant Non Drug Therapy eCRF. 
The reason, name of the drug, procedure or non-drug therapy should be listed. 
Guidelines for the use of specific medications are provided below: 
Methotrexate (MTX) 
Subjects taking MTX (up to 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization and maintained stable until Week 16. 
Folic acid 
Subjects on MTX must be taking folic acid supplementation before randomization and during 
the trial to minimize the likelihood of MTX associated toxicity. 
Systemic corticosteroids 
Treatment with systemic corticosteroids is permitted up to a maximum daily dosage of 10 mg 
prednisone equivalent and if the dose was stable within the 2 weeks preceding randomization. 
The subject should remain on a stable dose until Week 16. 
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after Week 
16, although the corticosteroid dose should not be reduced more than 1 mg prednisone 
equivalent every 4 weeks. 
Any change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page. 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization 
and up to Week 16. After Week 16, no more than 1 joint per 24-week period may be injected . 
No single injection should exceed 40 mg of triamcinolone (or equivalent) and the total dose of 
intra-articular corticosteroid may not exceed 80 mg of triamcinolone (or equivalent) during any 
52-week period. Injection of intra-articular steroids is not permitted within 8 weeks prior to 
Week 52. 
Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors), low strength opioids and acetaminophen/paracetamol 
Subjects on regular use of NSAIDs or paracetamol/acetaminophen should be on stable dose for 
at least 2 weeks before randomization to allow inclusion in the study. 
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN within the 
2 weeks before randomization can continue to do so in the study; however, they have to refrain 
from any intake during at least the 24 hours before a visit with disease activity assessment. 
Regular dosing with low strength opioids is not permitted. 
After the Week 16 assessments are completed, a change in the NSAID intake regimen is 
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Any change of the NSAID/paracetamol/acetaminophen treatment during the trial should be 
recorded on the corresponding eCRF page. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in Table 6-1 is NOT allowed after the start of the washout 
period unless specified otherwise below. Live vaccines should not be given until 12 weeks after 
last study treatment administration. 
Table 6-1 
Prohibited medication 
Medication 
Washout period 
(before randomization) 
Action 
(after randomization) 
Any biologic drugs, including 
but not limited to TNFα 
inhibitors, secukinumab, or 
other biologic drugs targeting 
IL-17 or IL-17 receptor 
Etanercept 
Infliximab 
Adalimumab, golimumab, 
certolizumab 
Biological immunomodulating 
agents > 3 different TNFα 
Inhibitors: never 
 
 
4 weeks 
8 weeks 
10 weeks 
Discontinue investigational 
treatment 
Any cell-depleting therapies 
including but not limited to anti-
CD20 or investigational agents 
[e.g., alemtuzumab (Campath), 
anti-CD4, anti-CD5, anti-CD3, 
and anti-CD19] 
Never 
Discontinue investigational 
treatment 
Conventional 
synthetic DMARDs (with the 
exception of MTX and 
sulfasalazine) and ts-DMARDs 
including apremilast, tofacitinib, 
etc. 
4 weeks 
Discontinue investigational 
treatment 
Leflunomide 
8 weeks 
Discontinue investigational 
treatment 
Leflunomide with 
cholestyramine washout# 
4 weeks 
Discontinue investigational 
treatment 
Any investigational treatment or 
participation in any 
interventional trial 
4 weeks or 5 half-lives 
(whichever is longer) 
Discontinue investigational 
treatment 
Unstable dose of NSAIDs 
(including selective COX-1 and 
COX-2 inhibitors) 
2 weeks 
Dose adjustments allowed after 
Week 16 
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis. 
Analgesics other than NSAIDs, 
paracetamol/acetaminophen, 
and low strength opioids PRN+ 
2 weeks 
Discontinue investigational 
treatment 


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Medication 
Washout period 
(before randomization) 
Action 
(after randomization) 
Systemic corticosteroids > 10 
mg prednisone equivalent (until 
Week 16)* 
2 weeks 
If administered due to a 
medical urgency unrelated to 
the patient’s arthritis, study 
treatment should be interrupted 
until the steroid is discontinued. 
If not administered for a 
medical urgency or for use 
related to the patient’s arthritis, 
then discontinuation of 
investigational treatment may 
be required on a case by case 
basis 
Unstable dose of systemic 
corticosteroids ≤ 10 mg 
prednisone equivalent (until 
Week 16)* 
2 weeks 
Discontinue investigational 
treatment (Dose adjustments 
allowed after Week 16) 
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis. 
Intra-articular corticosteroids 
injections (until Week 16)* 
4 weeks 
Discontinue investigational 
treatment 
Intramuscular or intravenous 
corticosteroid treatment 
4 weeks 
Discontinuation of 
investigational treatment may 
be required on a case by case 
basis 
Live vaccinations 
6 weeks 
If administered due to a 
medical urgency, study 
treatment should be interrupted 
for 4 months. If administered 
not for a medical urgency then 
discontinue investigational 
treatment 
* See details about corticosteroid management in Section 6.2.1. 
+ Regular dosing with low strength opioids is not permitted. 
#In case of leflunomide treatment, a drug wash-out of 8 weeks must be performed. Another wash-out 
procedure might also be considered. Cholestyramine could be given orally to wash-out the drug at a 
dose of 8 g t.i.d. Cholestyramine reduced plasma levels of the active leflunomide metabolite by 
approximately 40 % in 24 hours and by 49 % to 65 % in 48 hours in three healthy volunteers. The 
administration of cholestyramine is recommended in subjects who require a drug elimination 
procedure. If a subject receives 8 g t.i.d. for 11 days he/she can be safely randomized 4 weeks after 
the beginning of the 11-day treatment period. 
6.2.3 
Rescue medication 
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the trial or worsening / exacerbation of his/her disease. 
Rescue medication should not be used before completion of Week 16 assessments (see Table 
8-1). Although no subject will be restricted from receiving necessary rescue medications for 


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lack of benefit or worsening of disease, if rescue with prohibited biologics (as described in 
Section 6.2.2) occurs prior to completion of Week 16 assessments, subjects will be discontinued 
from study treatment and enter into the follow-up period after an end of treatment visit. Efficacy 
will be assessed in detail at every study visit, and subjects who are deemed not to be benefiting 
from the study treatment based upon safety and efficacy assessments by the investigator or for 
any reason on their own accord will be free to discontinue participation in the study at any time. 
Changes in concomitant therapy with NSAIDs are permitted after Week 16 assessments as per 
investigator’s clinical judgment. After Week 16, the dose and regimen of other concomitant 
medications may be adjusted slowly at the investigator’s discretion and recorded appropriately 
on the CRF page. 
Any use of rescue medication must be recorded in the Prior/Concomitant medications eCRF. 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Once assigned to a subject, the Subject No. will not be reused. Upon signing the informed 
consent form, the subject is assigned to the next sequential Subject No. available.  
6.3.2 
Treatment assignment, randomization 
At BSL visit, all eligible subjects will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The investigator or his/her delegate will contact the IRT 
after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the subject. The randomization number will not be communicated to any of the 
site staff. 
Starting at Week 16, subjects who have been randomized to placebo at baseline will receive 
secukinumab 3 mg/kg i.v. up to Week 48. Although the investigator, site personnel and subjects 
are unblinded to current treatment assignment after Week 16 (as all subjects will be on 
secukinumab 3 mg/kg i.v starting at Week 16), original treatment assignment, as per baseline 
randomization, will remain blinded to the subject, investigator, and site personnel until after 
final database lock and analyses. 
All efficacy and safety assessments should be done prior to calling IRT. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 


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numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment. 
The subjects will be stratified at randomization according to disease condition (i.e. AS or nr-
axSpA). Not more than 20% of randomized subjects will be TNF- IR to ensure a representative 
subject population for the assessment of efficacy and safety. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
This is a double-blind, randomized treatment trial. 
Subjects, investigators, investigator staff and persons performing the assessments, will remain 
blind to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data are kept strictly confidential until the time of 
unblinding and will not be accessible by anyone else involved in the study with the exception 
of the bioanalyst, (2) the identity of the treatments will be concealed by the use of study 
treatment in form of vials, filled with secukinumab or placebo that are identical in appearance.  
The bioanalyst will have access to the randomization list to facilitate analysis of the PK 
 
 (i.e. to avoid the unnecessary analysis of placebo samples). Whenever 
needed or requested by the clinical team, the bioanalyst will share information from PK 
measurements before clinical database lock in a blinded fashion with the pharmacokineticist. 
Starting at Week 16, subjects who have been randomized to placebo at baseline will start 
receiving secukinumab 3 mg/kg i.v. every four weeks up to Week 48. Although subjects, 
investigators, investigator staff and persons performing the assessments are unblinded to current 
treatment assignment after Week 16 (as all patients will be on secukinumab 3 mg/kg i.v. at 
Week 16), original treatment assignment, as per baseline randomization, will remain blinded to 
subjects, investigator staff and persons performing the assessments until after final database 
lock and analyses. 
Unblinding will occur in the case of subject emergencies (see Section 6.6.3) and at the 
conclusion of the study. 
Unblinding of the Global core CTT members will also occur at the time of the primary analysis 
database lock (see Section 12.7). 
The hsCRP results from samples collected during the treatment period will be revealed to sites 
only after the database lock and analyses are completed. The hsCRP results from samples 
collected during the treatment period 1 will be revealed to Global core CTT members at the 
time of the primary interim analysis database lock. 
6.5 
Dose escalation and dose modification 
Dose modifications of the investigational study drug are not permitted. 


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6.5.1 
Dose escalation guidelines 
With the proposed i.v. regimen anticipated to provide exposures of secukinumab similar to the 
Cavg and Cmax achieved with 300 mg s.c. and Ctrough consistently above those achieved by 150 
mg s.c., dose escalations will not be provisioned for in this study.  
6.5.1.1 
Starting dose 
The starting dose at BSL for the active arm in the study will be secukinumab 6 mg/kg. The 
placebo group will receive as starting dose at BSL an appropriate infusion volume matching 
secukinumab 6 mg/kg. 
6.5.2 
Dose modifications 
Study treatment interruptions are not permitted with the following exceptions: 
• If, in the opinion of the investigator, a subject is deemed to be placed at a significant 
safety risk unless dosing is temporarily interrupted. In such cases study treatment should 
be interrupted only during the time that this risk is present and ongoing. Study treatment 
can be restarted at the next scheduled visit after resolution of the safety risk. 
• If any prohibited medication described in Table 6-1 requires the interruption of the study 
treatment. 
Study treatment interruptions must be recorded on the corresponding Dosage Administration 
Record eCRF page and all assessments should be completed as scheduled. 
6.5.3 
Follow-up for toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant abnormal laboratory value, must be followed up in accordance with what 
is clinically indicated per the investigator until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrist, etc., should be consulted as deemed necessary. 
6.5.3.1 
Follow up on potential drug-induced liver injury (DILI) cases 
An increase in transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis. 


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Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment, and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, TBIL, direct and 
indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted. 
4. Obtain PK sample as close as possible to last dose of secukinumab. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should reported as SAE using the term 
“potential drug-induced liver injury.” All events should be followed up with the outcome clearly 
documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator should promote compliance by instructing the subject to attend the study visits 
as scheduled and by stating that compliance is necessary for the subject’s safety and the validity 
of the study. The subject should be instructed to contact the investigator if he/she is unable for 
any reason to attend a study visit as scheduled. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in Section 6.5.2 or discontinuation of study treatment is required as described in 
Section 9.1.1. Compliance will also be assessed by a Novartis monitor using information 
provided by the authorized site personnel. 
All dates and times of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page.  
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with secukinumab, as detailed in pharmacokinetics section (see Section 8.5.5). 


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6.6.2 
Recommended treatment of adverse events 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject 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 subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide to the subject: 
• protocol number 
• study drug name 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact the 
investigator's backup in cases of emergency, or when he/she is unavailable, to ensure that un-
blinding can be performed at any time. 
Study drug must be discontinued after emergency unblinding. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (see Section 6.1.1). 
Detailed instructions for storage, handling and administration of the study treatment are 
included in the Pharmacist Manual. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 


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6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
The following non-study treatment will be monitored specifically: 
• Stable doses of MTX, sulfasalazine and/or NSAIDS and acetaminophen/paracetamol as 
applicable (see Section 6.2.1) 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 


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informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject. 
Women of child-bearing potential must 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 requirements. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
Subjects will be asked to complete optional questionnaires to provide feedback on their clinical 
trial experience. 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) or as close to the designated day/time as possible. 
The study treatment should not be administered within less than 14 days after the previous 
administration. 
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for an end of treatment 
visit 4 weeks after the last study treatment, at which time all of the assessments listed for the 
final visit will be performed (corresponding to the last visit for the subject’s current period of 
treatment (treatment period 1 or 2): i.e., Week 16 or Week 52). At this final visit, all dispensed 
investigational product should be reconciled, and the adverse event and concomitant 
medications recorded on the CRF. A follow-up visit is to be done 8 weeks after the end of 
treatment visit, for all subjects, regardless of whether they complete the entire study as planned 
or discontinue prematurely. 
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. 
For Patient Report Outcomes (PROs) Section 16.5 provides guidance for completion of the 
questionnaires. 


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Table 8-1 
Assessment Schedule 
Period 
Screening 
Extension 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-
up 
Visit Name 
Screening 
visit 11 
Screening 
visit 2 
Baseline 
(BSL) 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 24 
Wee
k 25 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48 
Wee
k 52 Week 60 
Days 
-70 to -29 
-28 to -1 
- 
28 
56 
84 
112 
140 
168 
175 
196 
224 
252 
280 
308 
336 
364 
420 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion 
criteria2,3 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical conditions2 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
axSpA and nr-axSpA 
assessment and 
history of extra-axial 
involvement4,5 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X-ray (sacroiliac 
joints)6 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MRI (sacroiliac 
joints)6 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Cardiovascular 
medical history 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Smoking history 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical 
Examination8 
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 


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Period 
Screening 
Extension 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-
up 
Visit Name 
Screening 
visit 11 
Screening 
visit 2 
Baseline 
(BSL) 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 24 
Wee
k 25 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48 
Wee
k 52 Week 60 
Days 
-70 to -29 
-28 to -1 
- 
28 
56 
84 
112 
140 
168 
175 
196 
224 
252 
280 
308 
336 
364 
420 
Body Height 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight & BMI9 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
X 
Vital Signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PPD skin test or 
QuantiFERON TB-
Gold test10 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Chest X-ray or 
MRI11,12 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis and HIV 
Screen12,13 
  
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology 
  
X 
X 
X 
X 
X 
X 
  
X 
  
  
X 
  
X 
  
  
X 
X 
Clinical Chemistry 
  
X 
X 
X 
X 
X 
X 
  
X 
  
  
X 
  
X 
  
  
X 
X 
Urinalysis 
  
X 
X 
X 
X 
X 
X 
  
X 
  
  
X 
  
X 
  
  
X 
X 
Pregnancy Test 
(serum)14 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test 
(urine)14,15 
  
  
S 
S 
S 
S 
S 
S 
S 
  
S 
S 
S 
S 
S 
S 
S 
S 
12-Lead ECG 
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PK blood collection 
  
  
X16 
X16 
X16 
  
X17 
  
X16 
X 
  
  
  
  
  
X16 
X 
X 
Study drug 
administration 
  
  
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
  
  


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Period 
Screening 
Extension 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-
up 
Visit Name 
Screening 
visit 11 
Screening 
visit 2 
Baseline 
(BSL) 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 24 
Wee
k 25 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48 
Wee
k 52 Week 60 
Days 
-70 to -29 
-28 to -1 
- 
28 
56 
84 
112 
140 
168 
175 
196 
224 
252 
280 
308 
336 
364 
420 
Prior and 
Concomitant 
Medication and Prior 
or Concomitant non-
drug 
therapies/procedures  
X 
Update as necessary 
Wash-out evaluation / 
instructions 
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events/SAEs 
(including injection 
site reactions)18 
X 
Update as necessary 
Patient’s global 
assessment of 
disease activity (VAS) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient’s assessment 
of back pain intensity 
(VAS) 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASFI 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BASDAI 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36  
  
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
X 
  
ASQoL 
  
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
X 
  


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Period 
Screening 
Extension 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-
up 
Visit Name 
Screening 
visit 11 
Screening 
visit 2 
Baseline 
(BSL) 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 24 
Wee
k 25 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48 
Wee
k 52 Week 60 
Days 
-70 to -29 
-28 to -1 
- 
28 
56 
84 
112 
140 
168 
175 
196 
224 
252 
280 
308 
336 
364 
420 
PSQI 
  
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
X 
X 
  
High sensitivity C-
Reactive protein 
(hsCRP) 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
  
X 
  
X 
  
  
X 
X 
HLA-B27 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Lipid profile19 
  
  
X 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
X 
  
Cardiovascular panel 
  
  
X 
  
  
  
X 
  
X 
  
  
  
  
  
  
  
X 
  
Trial Feedback 
Questionnaire (TFQ) 
  
  
X 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
X 
Treatment period 1 
completion form  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
Treatment period 2 
completion form 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Follow-up completion 
form 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 


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Period 
Screening 
Extension 
Screening 
Treatment Period 1 
Treatment Period 2 
Follow-
up 
Visit Name 
Screening 
visit 11 
Screening 
visit 2 
Baseline 
(BSL) 
Wee
k 4 
Wee
k 8 
Wee
k 12 
Wee
k 16 
Wee
k 20 
Wee
k 24 
Wee
k 25 
Wee
k 28 
Wee
k 32 
Wee
k 36 
Wee
k 40 
Wee
k 44 
Wee
k 48 
Wee
k 52 Week 60 
Days 
-70 to -29 
-28 to -1 
- 
28 
56 
84 
112 
140 
168 
175 
196 
224 
252 
280 
308 
336 
364 
420 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 If the subject’s washout period ≤ 4 weeks, Screening visit 1 (SV1) and Screening visit 2 (SV2) can be performed on the same day. 
2 Eligibility and relevant medical history assessments are conducted at SV1, SV2 and BSL. The data for all three visits should be recorded on the 
corresponding eCRFs available at SV1. 
3 A copy of the x-ray or radiologist’s report must be kept in the source documentation. 
4 Extra-axial involvement such as uveitis, psoriasis, inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis. 
5 The "modified New York criteria for AS" eCRF page will have to be completed for axSpA and nr-axSpA subjects. 
6 Only applicable for nr-axSpA subjects. 
 
8 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion 
criteria are not met are captured on the Inclusion/Exclusion eCRF.  After the baseline visit, the investigator should do an abbreviated physical exam 
focusing on relevant clinical areas. 
9 BMI calculated at Baseline 
10 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. 
11 A chest x-ray or MRI is required if it was not performed and evaluated within 3 months prior to screening. The x-ray should be performed after it is 
certain the subject meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The x-ray may be replaced by an MRI 
assessment. 
12 These assessments are source documentation only and will not be entered into the eCRF. However, data regarding to which inclusion/exclusion 
criteria are not met are captured on the Inclusion/Exclusion eCRF. 
13 Hepatitis B and/or hepatitis C and/or HIV serology testing to be performed during screening period only if required as per local medical practice or 
local regulations prior to initiation of therapy. These assessments will be documented in source records only and will not be entered into the eCRF. 
14 Pregnancy tests will be conducted for women of child bearing potential. 
15 Kits will be provided by the central laboratory and the test is to be performed locally. 
16 At pre- and post-dose. 
17 At pre-dose. 
18 AEs / SAEs occurring after the subject has signed the informed consent must be captured on the appropriate eCRF page. 
19 Sample must be obtained fasting. 
 
 


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8.1 
Screening 
Screening will be flexible in duration based on the time required to wash out prior anti-
rheumatic medications and have a duration between 4 and 10 weeks, during which time the 
subject will sign the ICF, be evaluated for eligibility and allowed sufficient time for potential 
medication washout, in addition to all other assessments indicated in Table 8-1. 
Screening will consist of two consecutive visits. During the first screening visit, initial 
assessments will be performed as outlined in Table 8-1. At that visit the duration of the washout 
period will be determined. The second screening visit will be performed as follows: 
• If the washout period is ≤ 4 weeks the investigator should proceed directly to visit 2 on the 
same day and complete all assessments 
• If the washout period is more than 4 weeks, the subject will be instructed to initiate 
necessary washout regimen and return for visit 2 in the next 4 weeks prior to 
randomization (i.e., in all cases, Visit 2 should not happen earlier than 4 weeks prior to 
randomization). 
If subjects do not have a chest X-ray available within 3 months of screening, the X-ray should 
be performed after it is certain the subject meets inclusion/exclusion criteria in order to 
minimize unnecessary exposure to radiation.The X-ray assessment may be replaced by an MRI 
assessment. 
All subjects evaluated at visit 1 and 2 for Inclusion/Exclusion criteria should not be screen failed 
on the basis of a medication requiring washout, unless the subject will be unable to complete 
the washout in the appropriate time frame before randomization. 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure subjects. No 
other data will be entered into the clinical database for subjects who are screen failures, unless 
the subject experienced a serious adverse event during the screening phase (see SAE 
Section 10.1.2 for reporting details). The CRF for adverse events (AEs) should be completed 
for any Serious Adverse Events (SAEs) that occurred during the screening period. Adverse 
events that are not SAEs will be followed by the investigator and collected only in the source 
data.  
If the subject fails to be randomized, the IRT must be notified within 2 days of the screen fail 
that the subject was not randomized. 
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
Subjects who are prematurely withdrawn from the study will not be replaced. 


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8.1.2 
Re-screening 
If a subject re-screens for the study, the subject must sign a new ICF and be issued a new subject 
number prior to any screening assessments being conducted under the new subject number. For 
all re-screened subjects, the investigator/qualified site staff will record if the subject was re-
screened on the re-screening CRF and the original screening number the subject was issued 
prior to the current screening number. The date of the new informed consent signature must be 
entered in the Informed Consent eCRF corresponding to the new subject number. For re-
screening, all screening assessments must be performed per protocol, except the tuberculosis 
(TB) work up (if applicable). If the date of the TB work up is less than 12 weeks from the 
projected baseline date, then it is not required that the TB work up be repeated; however, the 
re-screened subject must repeat PPD skin test or the QuantiFERON TB-Gold performed by the 
central laboratory. 
8.2 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristics data to be collected on all subjects and to be 
recorded in the eCRF include: 
• Age, sex, race, ethnicity and source of subject referral 
• Relevant axSpA and general medical history/current medical condition data until the start 
of study treatment, history of extra-axial involvement (uveitis, psoriasis, inflammatory 
bowel disease, dactylitis, enthesitis, peripheral arthritis), number and type of previous 
DMARDs used, date of diagnosis of axSpA, previous axSpA 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. 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
8.3 
Efficacy 
• Assessment of SpondyloArthritis International Society (ASAS) response criteria; 
ASAS40, ASAS20, ASAS 5/6 and ASAS partial remission 
• Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
 
 
• Bath Ankylosing Spondylitis Functional Index (BASFI) 
• Patient’s global assessment of disease activity (VAS) 
• Patient’s assessment of back pain intensity (VAS) 
 
 
• Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute Form) 
• Ankylosing Spondylitis Quality of Life (ASQoL) 
• High sensitivity C-Reactive Protein (hsCRP) 
 
 


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• Ankylosing Spondylitis Disease Activity Score (ASDAS)-C-Reactive Protein (CRP) and 
ASDAS response categories 
 
 
 
 
• Sleep improvement (
 sleep PROs) 
8.3.1 
Assessment of SpondyloArthritis International Society criteria (ASAS) 
The ASAS response measures consist of the following assessment domains (Sieper et al 2009). 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale 
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale 
Additional assessment domains: 
 
2. C-reactive protein (acute phase reactant) 
8.3.1.1 
ASAS Response Criteria-40% (ASAS40) 
ASAS40 response is defined as a ≥40% improvement and an absolute improvement from 
baseline of ≥20 units (range 0–100) in ≥ 3 of the following 4 domains: back pain [10 cm visual 
analogue scale (VAS)], patient global assessment of disease activity (10 cm VAS), physical 
function (BASFI; range 0–100) and inflammation (mean score of items 5 and 6 of the BASDAI; 
both 10 cm VAS) without any worsening in the remaining domain. 
8.3.1.2 
ASAS Response Criteria-20% (ASAS20) 
The ASAS Response Criteria (ASAS20) is defined as an improvement of ≥20% and ≥1 unit on 
a scale of 10 in at least three of the four main domains and no worsening of ≥20% and ≥1 unit 
on a scale of 10 in the remaining domain. 
8.3.1.3 
ASAS 5/6 improvement criteria 
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five of all six 
domains. 
8.3.1.4 
ASAS partial remission criteria 
The ASAS partial remission is defined as a value not above 2 units in each of the four main 
domains on a scale of 10. 


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8.3.2 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
BASDAI consists of a 0 through 10 scale (0 indicating no problem and 10 indicating the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS: 
1. Fatigue 
2. Spinal pain 
3. Peripheral joint pain / swelling 
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments) 
5. Morning stiffness duration 
6. Morning stiffness severity 
To give each symptom equal weight, the mean (average) of the two scores relating to morning 
stiffness is taken into account (questions 5 and 6). The resulting 0 to 10 score is added to the 
scores for questions 1 through 4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 
10 BASDAI score. Scores of 4 or greater suggest suboptimal control of the disease and subjects 
with scores of 4 or greater are usually good candidates for either a change in their medical 
therapy or enrollment in clinical trials evaluating new drug therapies directed at AS. BASDAI 
is a quick and simple index taking between 30 seconds and 2 minutes to complete. 
 
 
 
8.3.4 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The Bath Ankylosing Spondylitis Functional Index is a set of 10 questions designed to 
determine the degree of functional limitation in subjects with AS. The questions were chosen 
on the basis of predominant input from subjects with AS. The first 8 questions consider 
activities related to functional anatomy. The final 2 questions assess the subjects’ ability to cope 
with everyday life. A 0 through 10 scale (captured as a continuous VAS) is used to answer the 
questions. The mean of the ten scales gives the BASFI score – a value between 0 and 10. 
8.3.5 
Patient’s global assessment of disease activity (VAS) 
The patient’s global assessment of disease activity will be performed using a 100 mm VAS 
ranging from none to very severe in response to the question "How active was your disease on 
average during the last week?”. 
8.3.6 
Patient’s assessment of back pain intensity (VAS) 
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from no 
pain to unbearable pain in response to the question “Based on your assessment, please indicate 
what is the amount of back pain at night that you experienced during the last week?” and 
“Based on your assessment, please indicate what is the amount of back pain at any time that 
you experienced during the last week?”  For ASAS calculation the total back pain will be used. 


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8.3.8 
Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute 
Form) 
The Medical Outcome Short Form Health Survey is a widely used and extensively studied 
instrument to measure health-related quality of life among healthy patients and patients with 
acute and chronic conditions. It consists of eight subscales that can be scored individually: 
Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, 
Role-Emotional, and Mental Health (Ware and Sherbourne 1992). Two overall summary 
scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) 
also can be computed (McHorney et al 1993). The SF-36 has proven useful in monitoring 
general and specific populations, comparing the relative burden of different disease, 
differentiating the health benefits produced by different treatments, and in screening individual 
patients. 
The purpose of the SF-36 in this study is to assess the health-related quality of life (HRQoL) of 
patients. Given the acute nature of this disease, version 2, with a 1-week recall period, will be 
used in this study. 
8.3.9 
Ankylosing Spondylitis Quality of Life (ASQoL) 
The Ankylosing Spondylitis Quality of Life is a self-administered questionnaire designed to 
assess health-related quality of life in adult patients with Ankylosing Spondylitis. The ASQoL 
contains 18 items with a dichotomous yes/no response option. A single point is assigned for 
each "yes" response and no points for each "no" response, resulting in overall scores that range 
from 0 (least severity) to 18 (highest severity). As such, lower scores indicate better quality of 
life. Items include an assessment of mobility/energy, self-care and mood/emotion. The recall 
period is "at the moment". 
The purpose of the ASQoL is to assess the disease specific QoL of patients in this study. 


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8.3.10 
High Sensitivity C-reactive protein (hsCRP) 
This assessment will be performed in order to identify the presence of inflammation, to 
determine its severity and to monitor the response to treatment. 
Since the results of this test may unblind the study personnel to treatment groups, results from 
the central lab will be provided for screening and baseline only. The hsCRP results from 
samples collected during the treatment period will be revealed following database lock only. 
8.3.13 
ASDAS-CRP and ASDAS response categories 
The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess 
disease activity in AS. 
ASDAS-CRP will be utilized to assess the disease activity status. Parameters used for the 
ASDAS include: total back pain (BASDAI question 2), the patient global assessment of disease 
activity, peripheral pain/swelling (BASDAI question 3), duration of morning stiffness 
(BASDAI question 6) and C-reactive protein (CRP) in mg/L (Lukas et al 2009). 
Disease activity states: inactive disease, moderate disease activity, high disease activity, and 
very high disease activity. The 3 values selected to separate these states are: <1.3 between 
inactive disease and moderate disease activity; <2.1 between moderate disease activity and high 
disease activity; and >3.5 between high disease activity and very high disease activity. Selected 
cutoffs for improvement scores are a change ≥1.1 unit for “minimal clinically important 
improvement” and a change ≥2.0 units for “major improvement” (Machado et al 2011). 


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8.3.16 
Sleep improvement 
To measure improvement in sleep and reduction in nocturnal awakening, subjective sleep PROs 
 Pittsburg Sleepness Quality Index; PSQI) will be used 
 
 
8.3.16.2 Sleep PROs 
Patients with AS also report chronic and extensive sleep disturbance due to pain and stiffness 
during the night (Leverment et al 2017). Often patients get out of bed and walk around during 
the night to reduce pain and stiffness, which can lead to daytime fatigue (Rudwaleit et al 2006). 
In patients with AS, poor quality sleep is strongly correlated with increased pain, lower quality 
of life, higher depressed mood, higher disease activity and reduced physical function 
(Batmaz et al 2013). Additionally, there is a general lack of data to investigate associations 
between sleep disturbance and daytime fatigue levels in AS. 
To study the effect of secukinumab on AS related sleep disturbance, the subjective sleep PRO’s 
in Section 8.3.16.2.1 and Section 8.3.16.2.2 will be used. 


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8.3.16.2.2 
Pittsburgh Sleep Quality Index (PSQI) 
The Pittsburgh Sleep Quality Index is a self-report questionnaire that assesses sleep quality over 
a 1-month time interval. Consisting of 19 items, the PSQI measures several different aspects of 
sleep, offering seven component scores and one composite score. The component scores consist 
of subjective sleep quality, sleep latency (i.e., how long it takes to fall asleep), sleep duration, 
habitual sleep efficiency (i.e., the percentage of time in bed that one is asleep), sleep 
disturbances, use of sleeping medication, and daytime dysfunction. 
Each item is weighted on a 0–3 interval scale. The global PSQI score is then calculated by 
totaling the seven component scores, providing an overall score ranging from 0 to 21, where 
lower scores denote a healthier sleep quality. 
The PSQI is self-administered and to be completed as per the assessment schedule on an 
electronic device. 
8.3.17 
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are standard measures used across all axSpA 
trials and are required for regulatory filing. 
8.4 
Safety 
Evaluation of all AEs and SAEs including injection site reactions, electrocardiograms (ECGs), 
physical examination, vital signs and laboratory assessments will occur.
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. 
• Physical examination 
• Vital signs 
• Height and weight 
• QuantiFERON TB-Gold test or PPD skin test 
• Hepatitis and human immunodeficiency virus (HIV) screen 
• Laboratory evaluations (Hematology, clinical chemistry, lipid panel, cardiovascular panel, 
urinalysis and pregnancy test) 
• Evaluation of AE/ SAE’s 
• Electrocardiogram 
• Local tolerability (Injection site reactions) 
• Pregnancy and assessment of fertility 
• Tolerability of secukinumab 
 
 
Table 8-3 
Assessments & Specifications 
Assessment 
Specification 


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Physical 
A complete physical examination of the subject 
will be performed according to the schedule 
defined in Table 8-1 and will include the 
examination of general appearance, hydration 
status, skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical 
history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be 
performed. Information for all physical 
examinations must be included in the source 
documentation at the study site. Clinically 
relevant findings that are present prior to signing 
informed consent form must be recorded on the 
appropriate CRF that captures medical history 
screen on the patient CRF. Significant findings 
that occur after signing informed consent form 
which meet the definition of an Adverse Event 
must be recorded as an adverse event. 
Vital signs 
Vital signs 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. 
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. 
8.4.1 
QuantiFERON TB-Gold test or PPD skin test 
Either a QuantiFERON TB-Gold test or a PPD skin test must be performed at screening visit 
2. Subjects with a positive test may participate in the study if further work up (according to 
local practice/guidelines), establishes conclusively that the subject 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 prior to enrollment. 
8.4.1.1 
A QuantiFERON TB-Gold test 
A QuantiFERON TB-Gold test is to be performed at the second screening visit and the results 
to be known prior to randomization to determine the subject’s eligibility for the trial. The test 
will be used to screen the subject population for latent tuberculosis infection. 
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual. 


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8.4.1.2 
PPD skin test 
A PPD skin test is to be performed at screening and read before randomization to determine the 
subject’s eligibility for the trial, if a QuantiFERON test is not performed. The test dose is 
bioequivalent to 5 tuberculin units of standard PPD injected intradermally, usually into the volar 
surface of the forearm. The site is cleaned and the PPD extract is then injected into the most 
superficial layer under the skin. If given correctly, the injection should raise a small wheal of 
about 5 mm, which resolves within 10-15 minutes. 
Because the reaction (induration), will take 48-72 hours to develop, the subjects must return to 
the study site within that time for evaluation of the injection site. This will determine whether 
the subject 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. 
8.4.2 
Hepatitis and human immunodeficiency virus (HIV) screen 
Screening for hepatitis and HIV is optional, based on the judgment of the investigator or if 
required by local regulations. If hepatitis testing is performed, testing will include hepatitis B 
surface antigen (HBsAg) and anti-HCV antibodies. If HIV testing is performed, positive HIV 
screening will be confirmed by a second technique available at the respective local laboratory, 
e.g., Western blot. 
8.4.3 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens listed below (except urinalysis). 
Details on the collection, shipment of samples and reporting of results by the central laboratory 
are provided in the laboratory manual. For the identification of clinically notable values, see 
Section 16.1. All subjects with laboratory tests containing clinically significant abnormal values 
are to be followed until the values return to normal ranges or until a valid reason, other than 
treatment related AE, is defined. 
Table 8-4 
Specifications of Laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hemoglobin, platelets, red blood cell (RBC), 
white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled 
visits. 
Chemistry 
Serum chemistries will include glucose, urea, 
creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, 
potassium, bicarbonate, calcium, phosphorus, 
total protein, albumin, and uric acid. 
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. 


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Lipid Panel 
A lipid profile including High Density Lipoprotein 
(HDL), Low Density Lipoprotein (LDL), total 
cholesterol, and triglycerides will be measured 
from a fasting blood sample. 
Cardiovascular panel 
A cardiovascular profile including lipoprotein (a), 
apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be done from a blood sample. 
Pregnancy Test 
Serum / Urine pregnancy test (refer to 
'Pregnancy and assessments of fertility' section) 
8.4.4 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed as indicated in Table 8-1. ECGs must be recorded 
after 10 minutes rest in the supine position to ensure a stable baseline. The preferred sequence 
of cardiovascular data collection during study visits is ECG collection followed by vital signs 
and blood sampling. The Fridericia QT correction formula (QTcF) should be used for clinical 
decisions. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant ECG findings must be discussed with the sponsor before randomization of the 
subject into the study. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate. 
8.4.5 
Local tolerability (Injection site reactions) 
Local tolerability at the site of i.v. injection of the study treatment will be assessed in case of 
any local reaction, and followed up until this has disappeared. 
The assessment of pain, redness, swelling, induration, hemorrhage and itching, including 
severity (mild, moderate, severe) and duration, will be performed by a physician and will be 
recorded on the Adverse Events eCRF. 
8.4.6 
Pregnancy and assessments of fertility 
The study treatment must not be given to pregnant women; therefore, effective methods of birth 
control must be used for women of childbearing potential (see exclusion criteria definitions, 
Section 5.2). 
A serum β-hCG test will be performed in all women at screening. All women who are not 
surgically sterile or post-menopausal (as defined in Section 5.2) at screening will have local 
urine pregnancy tests as indicated in Table 8-1. A positive urine pregnancy test requires 
immediate interruption of study treatment until serum β-hCG is performed and found to be 
negative. If positive, the subject must discontinue study treatment. 
8.4.7 
Tolerability of secukinumab 
Tolerability will be assessed by adverse events, laboratory values, injection site reaction 
 
. 


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8.4.9 
Other safety evaluations 
Chest X-ray or MRI 
A chest X-ray or MRI at screening visit 2 (except for subjects who have a valid chest X-ray or 
MRI done within 3 months prior to screening) is performed to rule-out the presence of a 
pulmonary malignancy or infectious process, in particular, tuberculosis. 
8.4.10 
Appropriateness of safety measurements 
The safety measures used in this study are reliable and relevant standard measures for a biologic 
in axSpA. A chest x-ray or MRI at screening (or within 3 months prior to screening) is 
performed to rule out the presence of a pulmonary malignancy or infectious process, in 
particular, pulmonary tuberculosis. The radiation exposure that results from the chest X-ray 
safety measurements are estimated to be far below 1 mSv (millisievert). For effective radiation 
doses under 3 mSv (300 mrem; 300 milliroentgen equivalent man), the risk is considered to be 
minimal. Therefore, the radiation exposure in this study involves minimal risk and is necessary 
to ensure adequate safety measures before the treatment with a biologic. 
The safety assessments selected are standard and adequate for this indication/subject 
population. 


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8.5 
Additional assessments 
The other assessments planned for the study are: 
• Quality of Life questionnaires/ Patient reported outcomes (PROs) 
• Trial Feedback Questionnaires 
 
 
• HLA-B27 
• Pharmacokinetics 
 
 
• Activity/Mobility improvement 
• Sacroiliac Joint X-ray 
• Sacroiliac Joint MRI 


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8.5.2 
Trial Feedback Questionnaires 
This trial will include an anonymized questionnaire, ‘Trial Feedback Questionnaire’ for 
subjects to provide feedback on their clinical trial experience. Individual subject level responses 
will not be reviewed by investigators. Responses would be used by the sponsor (Novartis) to 
understand where improvements can be made in the clinical trial process. This questionnaire 
does not collect data about the subject's disease, symptoms, treatment effect or adverse events 
and therefore would not be trial data. Should any spontaneous information be collected about 
AEs, this would be reported to the investigator. 
8.5.4 
HLA-B27 
A blood sample to analyze Human leukocyte antigen B27 (HLA-B27) will be obtained from all 
subjects as indicated in Table 8-1. 
Details on the collection, handling and shipment of the sample to the central laboratory will be 
provided to investigators in the laboratory manual 


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8.5.5 
Pharmacokinetics 
Pharmacokinetic (PK) samples will be collected at the visits defined in the assessment schedule 
(Table 8-1) and Table 8-3. 
All blood samples will be drawn by direct venipuncture in a forearm vein. 
The actual sample collection date and exact time will be entered on the PK blood collection 
summary eCRF. The reason for not taking blood samples will be captured in the eCRF. 
The bioanalyst will receive a copy of the randomization schedule to facilitate analysis of the 
PK samples. The bioanalyst will provide the samples’ concentration data to the team under 
blinded conditions. Bioanalyst will keep this information blinded until the interim clinical 
database lock. 
PK sample handling, labeling and shipment instructions: 
Laboratory manuals will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment. 
Tubes and labels will be provided by the central laboratory with study/sample type information 
pre-printed on the label. 
Table 8-6 
PK sample log 
Week 
Timepoint 
PK sample number* 
PK collection number 
BSL 
0 h (pre-dose) 
1 
1 
BSL 
0.5 h 
2 
1 
Week 4 
0 h (pre-dose) 
3 
2 
Week 4 
0.5 h 
4 
2 
Week 8 
0 h (pre-dose) 
5 
3 
Week 8 
0.5 
6 
3 
Week 16 
0 h (pre-dose) 
7 
4 
Week 24 
0 h (pre-dose) 
8 
5 
Week 24 
0.5 h 
9 
5 
Week 25 
anytime 
10** 
5 
Week 48 
0 h (pre-dose) 
11 
6 
Week 48 
0.5 h 
12 
6 
Week 52 
anytime 
13** 
6 
Week 60 
anytime 
14** 
6 
* If a PK sample is collected at an unschedule visit, the sample number will follow the pattern: 1001, 
1002, etc. 
** Post-dose time point for sample number 10 refers to the dose given at Week 24. Post-dose time 
points for sample numbers 13 and 14 refer to the last dose given at Week 48. 
PK analytical methods  
An ELISA method will be used for the bioanalytical analysis of AIN457 in serum, with an 
anticipated lower limit of quantification (LLOQ) of 80 ng/mL. The detailed method description 
to assess the Secukinumab concentration will be described in the Bioanalytical Data Report 
(BDR). 


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Concentrations below the LLOQ will be reported as “zero” and missing data will be labeled as 
such in the BDR. 


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8.5.7 
Activity/Mobility improvement 
This study will also investigate the association between treatment with i.v. secukinumab and 
daytime activity patterns by using relevant components of PRO's (BASDAI, 
 
amongst others) 
 


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8.5.8 
Sacroiliac Joint X-ray 
For eligibility purpose, an SIJ X-ray will be obtained from nr-axSpA as defined in the 
assessment schedule (Table 8-1) and according to the imaging acquisition guidelines provided 
by the central imaging laboratory. The X-ray images should be transferred to the central 
imaging laboratory following acquisition. The central imaging laboratory will conduct 
independent review for all sacroiliac X-rays in this trial to determine eligibility of patients with 
nr-axSpA. 
8.5.9 
Sacroiliac Joint MRI 
For eligibility purpose, an SIJ MRI will be obtained from nr-axSpA subjects as defined in the 
assessment schedule (Table 8-1) and according to the imaging acquisition guidelines provided 
by the central imaging laboratory. The MRI images should be transferred as anonymized 
electronic files to the central imaging laboratory following acquisition. The central imaging 
laboratory will conduct independent review for all sacroiliac MR imaging in this trial. 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
The following circumstances require study treatment discontinuation: 
• Withdrawal of informed consent (WoC) 
• Emergence of the following adverse events: 
a. Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with an unacceptable 
co-medication 
b. Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed 
c. Life-threatening infection 
d. Severe hypersensitivity reaction or anaphylactic reaction 
• Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the subject at a safety risk for continuation in the study 
(A general guidance on clinically notable laboratory values is provided in Section 16.1.) 
• Pregnancy 
• Use of any biologic immunomodulating agent except secukinumab 
• Any protocol deviation that results in a significant risk to the subject’s safety 


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In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given subject if there is a lack of improvement or worsening 
of their symptoms, or if on balance, he/she thinks that continuation would be detrimental to the 
subject’s well-being. 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). Where possible, they 
should return for the assessments indicated in the Assessment Schedule. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
Section 9.1.3. This contact should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
Subjects who prematurely discontinue or withdraw during a specific treatment period should 
return, 4 weeks after the last study treatment, for the final visit within that treatment period (i.e., 
Week 16 for treatment period 1 or Week 52 for treatment period 2), as well as return for the 
follow-up visit (i.e.,Week 60) 12 weeks after the last study treatment, see Table 8-1. The final 
visit should be performed before any new treatment is initiated. 
For subjects who are lost to follow-up (i.e. those subjects whose status is unclear because they 
fail to appear for study visits without stating an intention to withdraw), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the 
subject, e.g. dates of telephone calls, registered letters, etc. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code Section 6.6.3. 
9.1.1.1 
Replacement policy 
Subjects who are prematurely withdrawn from the study will not be replaced by newly enrolled 
subjects. 
9.1.2 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 


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In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until his/her 
scheduled end of study visit would have been occured. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible and treated as a prematurely withdrawn 
subject. The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the subject’s interests. The 
investigator or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
A subject will be considered to have completed the study if he/she received a maximum of 52 
weeks of study treatment and upon completion of the scheduled study assessments and 
procedures up to and including visit Week 60. 


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Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation will be recorded on the appropriate Study Phase Completion eCRF page. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing medical care. This 
medical care may include initiating another treatment outside of the study as deemed 
appropriate by the investigator. This treatment may be any non-biologic DMARD. In case of a 
biologic treatment, a waiting period of 3 months before initiating the treatment is 
recommended.  
If, at study completion, the investigator determines that a patient could benefit from continued 
secukinimab treatment, the physician may request access from Novartis, at no cost to the 
patient, if not commercially available and accessible. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2 ): 
1. The severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 


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underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown) 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Section 16.1. 


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10.1.2 
Serious adverse events (SAEs) 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• 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 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 


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10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any SAEs experienced from the 30 day period after the last study visit only reported to Novartis 
if the investigator suspected a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one must 
be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements on 
investigator's signature can be found in the investigator folder provided to each site. 
If the SAE is previously not documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
10.1.4 
Pregnancy reporting 
Pregnancies 
To ensure subject safety, each pregnancy occurring after signing the informed consent 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 and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 


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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure subject 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 (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Table 16-1 in Section 16.6 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-1 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 


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of liver events are outlined in Table 16-2. Repeat liver chemistry tests (i.e. ALT, AST, TBL, 
PT/INR, ALP and G-GT) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF.  
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 9.1.1), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• Investigations which can be based on investigator’s discretion: serology tests, imaging 
and pathology assessments, hepatologist’s consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug 
use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Renal safety monitoring 
To date, there has been no safety signal for nephrotoxicity with secukinumab in over 27,000 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the kidney. All subjects with laboratory tests resulting in 
clinically significant abnormal values (see Section 16.1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined. Standard renal function tests (blood urea nitrogen, serum creatinine) will 
be obtained at regular intervals, but special measures for renal safety monitoring are not 
planned. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 


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The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment (s) dispensed to the subject 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 data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
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. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed byindependent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, 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. 


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The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file.  The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods 
The primary endpoint analysis will be performed after all subjects complete Week 16 as 
described in Section 12.7 and the final analysis will be conducted on all subject data at the time 
the study ends. Any data analysis carried out independently by the investigator should be 
submitted to Novartis before publication or presentation. 
Summary statistics for continuous variables will generally include the number of subjects (N), 
minimum, lower quartile, mean, standard deviation (SD), median, upper quartile, and 
maximum. For categorical or binary variables, the number and percent of subjects in each 
category will be presented. P-values presented will be two-sided unless otherwise specified. 
Inferential efficacy comparisons with placebo will be performed on the first 16 weeks of 
treatment. 
Data analyses will be presented by treatment group. Efficacy and safety data for the 16-week 
placebo-controlled period and the entire treatment period as appropriate will be presented by 
the following two treatment groups. Subjects may be included in more than one treatment group 
for some analyses (e.g., exposure adjusted adverse events over the entire treatment period). 
These treatment groups represent the regimens to which subjects will be eligible to be 
randomized: 
• Secukinumab i.v. regimen 
• Placebo regimen 
Note that the treatment groups above for a subject may differ depending on the time period of 
the analysis and whether one assesses the subject for efficacy or safety (see Section 12.1 for 
details).  
12.1 
Analysis sets 
The following analysis sets will be used in this study: 


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Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized subjects are treated as screen failures. 
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be evaluated according to the treatment assigned to at randomization. 
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. 
12.2 
Subject demographics and other baseline characteristics 
Demographics and baseline characteristics 
The following common background and demographic variables will be summarized: 
• Gender, age, race, ethnicity, weight, height, and BMI. 
Baseline disease characteristics will also be summarized for the following variables: 
• Patient’s global assessment of disease activity and other ASAS components, hsCRP (mg/L 
and >ULN), 
, prior use (yes/no) of TNF-alpha inhibitors, use (yes/no) and 
separate dose of MTX (mg/week), sulfasalazine (g/day) and systemic corticosteroids 
(mg/day) at randomization, time since first diagnosis of axSpA (years), modified New York 
criteria for AS, HLA-B27, 
, total back pain (VAS), nocturnal back pain (VAS), total 
BASDAI score, spinal pain (BASDAI question #2) 
 
. 
Medical history 
A history of axSpA with focus on previous extra-articular involvement and past therapies for 
axSpA will be obtained and summarized by treatment group. Any other significant prior or 
active medical condition at the time of signing informed consent will be recorded and coded 
using the MedDRA dictionary. These medical conditions will be summarized by primary 
system organ class and preferred term. 
To establish a baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether or not a subject currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not occur for 
that subject. 


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12.3 
Treatments 
Study treatment 
The analysis of study treatment data will be based on the safety set. The number of visits with 
active and placebo i.v. infusions 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, ≥ 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. 
Prior surgeries and procedures are defined as surgeries and procedures done prior to first dose 
of study treatment. Any surgeries and procedures done between the day of first dose of study 
treatment and within the date of the last study visit will be a concomitant surgeries and 
procedures, including those which were started pre-baseline and continued into the period 
where study treatment is administered. 
The number and percentage of subjects receiving prior and concomitant axSpA 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 axSpA therapies previously.
 
12.4 
Analysis of the primary endpoint(s) 
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 12.5.1. 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy variable is response to treatment according to the ASAS40 criteria at 
Week 16 in patients with active axSpA (AS and nr-axSpA). The analysis of the primary variable 
will be based on the FAS population. 


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12.4.2 
Statistical model, hypothesis, and method of analysis 
The estimand for primary endpoint is defined as follows: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
axSpA population (AS and nr-axSpA) 
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving ASAS40 response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: difference in proportions of responders between the 
secukinumab and placebo arms 
The statistical hypothesis for ASAS40 being tested is that there is no difference in the proportion 
of subjects fulfilling the ASAS40 criteria at Week 16 in the secukinumab i.v. regimen versus 
placebo regimen. 
Let p0 denote the proportion of ASAS40 responders at Week 16 for placebo regimen and p1 
denote the proportion of ASAS40 responders at Week 16 for secukinumab i.v. regimen. 
In statistical terms, H1: p1= p0, HA1: p1≠ p0, i.e., 
H1: secukinumab i.v. regimen is not different to placebo regimen with respect to ASAS40 
response at Week 16 
The primary analysis will be conducted via logistic regression with treatment and stratification 
factor (disease condition) as factors and weight as a covariate. Difference in marginal response 
proportions with p-value and 95% confidence interval (CI) will be presented comparing 
secukinumab i.v. regimen to placebo. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Missing data for ASAS40 response and other binary efficacy variables (e.g., ASAS 5/6, etc.) 
for data up to Week 16 will be handled as follows: 
1. Patients who drop out of the trial for any reason will be considered as non-responders 
from the time they drop out through Week 16 
2. Patients who do not have the required data to compute responses (e.g., ASAS 
components) at baseline and at the specific timepoint will be classified as non-responders 
at the specific timepoint. 
Patients who are unblinded prior to the scheduled time point will be considered non-responders 
from the time of unblinding up to Week 16. The primary analysis will use the non-responder 
imputation. 
Continuous variables (e.g., ASAS components) will be analyzed using a mixed-effects model 
repeated measures (MMRM) which is valid under the missing at random (MAR) assumption. 
As such, single-point imputation of missing data will not be performed (e.g., LOCF). For 
analyses of these parameters, if all post-baseline values are missing then these missing values 
will not be imputed and this patient will be removed from the analysis of the corresponding 
variable, i.e., it might be that the number of patients providing data to an analysis is smaller 
than the number of patients in the FAS. 


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12.4.4 
Sensitivity and Supportive analyses 
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. These analyses will center on the 
deviations in model assumptions and the treatment of missing data. 
In order to determine the robustness of the logistic regression model used for the primary 
analysis, ASAS40 response at Week 16 will also be evaluated using a non-parametric 
ANCOVA model (Koch et al 1998) with the same independent variables as the logistic 
regression model. In addition, further logistic regression models may be conducted which 
explore the impact of other baseline or disease characteristics (and respective interactions with 
treatment group) on response. 
The impact of missing data on the analysis results of ASAS40 will be assessed as well by 
repeating the logistic regression model using different ways to handle missing data. 
These may include, but are not limited to: 
• Multiple imputation 
• Observed data analysis 
• Tipping point analysis 
12.5 
Analysis of secondary endpoints 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below. Secondary efficacy variables will be analyzed using the FAS population. Handling of 
missing data for secondary variables included in the testing strategy will be the same as for the 
primary variable. 
Estimand definition for the secondary variables 
Estimand definition for the secondary binomial variables (e.g., ASAS 5/6, etc.) is the following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
axSpA population 
B. Variable: composite of remaining on the study and on randomized treatment through 16 
weeks and achieving variable response at 16 weeks 
C. Intercurrent event: the intercurrent event is captured through the variable definition 
D. Population-level summary: difference in proportions of responders between the treatment 
conditions 
The estimand of binary variables is (secukinumab vs placebo) obtained from a logistic 
regression model at week 16 in the FAS population. In the analysis, patients dropping out or 
being unblinded before week 16 or having missing response data at week 16 are considered as 
non-responders. 


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Estimand definition for the secondary continuous variables (e.g., BASDAI, etc.) is the 
following: 
A. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
axSpA population 
B. Variable: change from baseline in the variable of interest 
C. Intercurrent event: had no intercurrent events occured before week 16 
D. Population-level summary: difference in variable means between the treatment conditions 
The estimand of continuous variables at week 16 is (secukinumab vs placebo) obtained from 
MMRM in the FAS population assuming patients dropping out or having missing data at week 
16 are missing-at-random. MAR imputation will be implemented through an MMRM or 
multiple imputation model. 
ASDAS-CRP major improvement at Week 16 
Response at Week 16 to ASDAS-CRP major improvement criteria will be evaluated using a 
logistic regression model with treatment, stratification factor (disease condition) as factors and 
weight and baseline score as a covariate. 
BASDAI at Week 16 
Between-treatment differences in the change from baseline in BASDAI will be evaluated using 
MMRM with treatment group, stratification factor (disease condition) and analysis visit as 
factors and baseline BASDAI score and weight as continuous covariates. Treatment by analysis 
visit and baseline BASDAI score by analysis visit will be included as interaction terms in the 
model. An unstructured covariance structure will be assumed for the model. 
ASAS 5/6 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (disease condition) as factors and 
weight as a covariate. 
BASFI at Week 16 
Between-treatment differences in the change from baseline in BASFI will be evaluated using 
MMRM with treatment group, stratification factor (disease condition) and analysis visit as 
factors and baseline BASFI score and weight as continuous covariates. Treatment by analysis 
visit and baseline BASFI score by analysis visit will be included as interaction terms in the 
model. An unstructured covariance structure will be assumed for the model. 
SF-36 PCS at Week 16 
See Section 12.5.7 Patient Reported Outcomes. 


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ASQoL at Week 16 
Summary statistics of observed data by visit and change from baseline in ASQoL will be 
provided for each treatment regimen. Between-treatment differences will be evaluated using 
MMRM. Treatment group, stratification factor (disease condition) and analysis visit will be 
included as categorical factors and baseline ASQoL scores and weight as continuous covariates. 
Treatment by analysis visit and baseline ASQoL scores by analysis visit will be included as 
interaction terms in the model. An unstructured covariance structure will be assumed for the 
model. 
hsCRP at Week 16 
For the change in hsCRP, since evidence from the literature would suggest that the data are not 
normally distributed (Huffman et al 2006), analysis will be performed on the loge ratio of the 
treatment value vs baseline value (calculated by dividing the post-baseline value by the baseline 
value and then applying the loge transformation) to normalize the distribution of hsCRP at each 
analysis visit. Between-treatment differences in the change in hsCRP relative to baseline will 
be evaluated using MMRM with treatment group, stratification factor (disease condition) and 
analysis visit as factors and loge baseline hsCRP and weight as continuous covariates. 
Treatment by analysis visit and loge baseline hsCRP by analysis visit will be included as 
interaction terms in the model. An unstructured covariance structure will be assumed for the 
model. The estimate and the 2-sided 95% confidence intervals obtained from the model will be 
back transformed to the original scale. 
ASAS20 at Week 16 
The proportion of patients meeting the response criteria will be evaluated using a logistic 
regression model with treatment group, stratification factor (disease condition) as factors and 
weight as a covariate. 
ASDAS-CRP inactive disease at Week 16 
Response at Week 16 to ASDAS-CRP inactive disease criteria will be evaluated using a logistic 
regression model with treatment, stratification factor (disease condition) as factors and weight 
and baseline score as a covariate. 
ASAS partial remission at Week 16 
Response at Week 16 to ASAS partial remission criteria will be evaluated using a logistic 
regression model with treatment, stratification factor (disease condition) as factors and weight 
as a covariate. 
PSQI at Week 16 
Summary statistics of observed data by visit and change from baseline in total PSQI score will 
be provided for each treatment regimen. Between-treatment differences will be evaluated using 
MMRM. Treatment group, stratification factor (disease condition) and analysis visit will be 
included as categorical factors and baseline PSQI scores and weight as continuous covariates. 
Treatment by analysis visit and baseline PSQI scores by analysis visit will be included as 


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interaction terms in the model. An unstructured covariance structure will be assumed for the 
model. 
Testing Strategy 
The following null hypotheses will be included in the testing strategy, and type-I-error will be 
set such that a family-wise type-I-error of 5% is kept: 
Primary objective: 
H1: secukinumab i.v. regimen is not different to placebo regimen with respect to signs and 
symptoms (ASAS40 response) in axSpA patients at Week 16 
Secondary objectives: 
H2: secukinumab i.v. regimen is not different to placebo regimen with respect to ASDAS-CRP 
major improvement in axSpA patients at Week 16 
H3: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in total BASDAI in axSpA patients at Week 16 
H4: secukinumab i.v. regimen is not different to placebo regimen with respect to ASAS 5/6 
response in axSpA patients at Week 16 
H5: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in BASFI in axSpA patients at Week 16 
H6: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in SF-36 PCS in axSpA patients at Week 16 
H7: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in ASQoL in axSpA patients at Week 16 
H8: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in hsCRP in axSpA patients at Week 16 
H9: secukinumab i.v. regimen is not different to placebo regimen with respect to ASAS20 
response in axSpA patients at Week 16 
H10: secukinumab i.v. regimen is not different to placebo regimen with respect to ASDAS-CRP 
inactive disease in axSpA patients at Week 16 
H11: secukinumab i.v. regimen is not different to placebo regimen with respect to ASAS partial 
remission in axSpA patients at Week 16 
H12: secukinumab i.v. regimen is not different to placebo regimen with respect to change from 
baseline in PSQI in axSpA patients at Week 16 


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Figure 12-1 
Testing strategy 
 
The family-wise error will be set to α=5% and it will be controlled with the proposed sequential 
testing strategy as described in Figure 12-1. The primary hypothesis (H1) for the primary 
objective (ASAS40 at Week 16) for secukinumab i.v. regimen versus placebo will be tested at 
α-level. If the hypothesis H1 is rejected then the whole α will be passed to the next hypothesis 
(H2) which will be tested at α-level. This procedure will continue (pending rejection of the null 
hypotheses) until H12 is rejected. 
Of note, in the description above, rejection of a hypothesis refers to rejection of the two-sided 
hypothesis; however the level of a rejected hypothesis is only passed on according to the 
sequence for the test of another hypothesis if the treatment effect is in favor of secukinumab. 
12.5.2 
Safety endpoints 
Adverse events 
Treatment-emergent adverse events (i.e., events started after the first dose of study treatment or 
events present prior to the first dose of study treatment but increased in severity based on 
preferred term and on or before last dose + 84 days) will be summarized. 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of 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. 
As appropriate, the incidence of AEs will be presented per 100 subject years of exposure 
(exposure-adjusted incidence rates). 
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. 


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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 and serum chemistry). 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 normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented by visit as well as for most extreme values post-baseline. 
 
 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. 
12.5.3 
Pharmacokinetics 
All subjects with concentration data will be included in the PK data analysis. 
Pharmacokinetic variables 
The following PK parameter will be determined: Cmin,ss. Cmin,ss will be determined using 
Phoenix software. Individual serum concentrations in µg/mL will be listed. All concentrations 
below the limit of quantification or missing data will be labeled as such in the concentration 
data listings. Concentrations below the limit of quantification will be treated as zero in summary 
statistics for concentration data only. 
During modeling of the PK of secukinumab, the broad principles outlined in the 
FDA Guidance for Industry: Population Pharmacokinetics will be followed. 


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Statistical methods for pharmacokinetic analyses 
Summary statistics by visit/time will be provided for the above mentioned parameter and will 
include arithmetic and geometric means, SD, median, minimum and maximum. Individual 
concentrations will be listed by subject. 
12.5.7 
Patient Reported Outcomes (PROs) 
Patient reported outcomes will be evaluated based on FAS unless otherwise specified. 
BASDAI 
The following variables will be evaluated: 
• BASDAI 
 
 
For BASDAI, see Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s) for details. 


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BASFI 
See Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s). 
 
 
Patient’s assessment of back pain intensity (VAS) 
Summary statistics of observed data by visit and change from baseline in patient’s assessment 
of back pain intensity will be provided for each treatment. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100) 
• SF-36 PCS 
 (norm-based scores) 
• SF-36 PCS 
 (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change in SF-36 summary scores (PCS 
), summary statistics will be provided 
using observed data for each treatment regimen. 
For the responder analyses, the proportion of responders will be descriptively summarized along 
with its 95% CI for each randomized treatment based on observed data. 
The SF-36 domain scores will be summarized by treatment. 
ASQoL 
See Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s). 


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PSQI 
See Section 12.5.1 Efficacy and/or Pharmacodynamic endpoint(s). 


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The secukinumab i.v. regimen will be compared for primary and secondary variables as part of 
the regular statistical models (e.g., logistic regression and MMRM). 
For binary variables, the proportion of responders for these endpoints (e.g., achieving ASAS20) 
may be summarized along with its 95% CI for each randomized treatment based on observed 
data. Details will be provided in the statistical analysis plan. 
Between-treatment comparisons for binary variables in the FAS population (e.g., ASAS20, 
ASAS40, ASDAS inactive disease, etc.) at individual analysis visits will be evaluated in a 
logistic regression model with treatment group, stratification factor (disease condition) as 
factors and baseline score (if appropriate) and weight as covariates. Difference in marginal 


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response proportions with p-value and 95% CI will be presented for treatment comparison up 
to Week 16. 
For continuous variables, summary statistics may be provided for the variables using the 
observed data or change from baseline for each treatment regimen. Summary statistics include 
N, mean, SD, minimum, lower quartile, median, upper quartile and maximum. Details will be 
provided in the statistical analysis plan. 
Continuous variables (e.g., change from baseline in ASDAS) will be evaluated using MMRM 
with treatment regimen, stratification factor (disease condition) 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. Variables such as hsCRP whose distribution is not 
anticipated to be normal will be transformed and analyzed on the loge scale and back 
transformed prior to presentation. 
12.7 
Interim analyses 
The primary endpoint analysis will be performed after all subjects complete Week 16 in order 
to support regulatory filing. As the primary analysis is scheduled at Week 16, no adjustment 
will be made to the testing strategy to control family-wise type I error rate for this analysis. 


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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
An overall type I error (2-sided) of 5% will be used to control type I error. Secukinumab i.v. 
regimen will be tested versus placebo with respect to the primary endpoint (ASAS40 response 
at Week 16). A sample size of 250 axSpA patients (200 AS patients and 50 nr-axSpA patients) 
per group is deemed appropriate to achieve adequate power for the primary and secondary 
endpoints for this study. 
An ASAS40 response rate of about 28.2% for the AS population in the placebo group at week 
16 was reported in a published phase III study (CAIN457F2320). The ASAS40 response to 
secukinumab 150 mg is estimated to be 44.9% in the AS population based on the lower bound 
of the 90% confidence interval of risk difference from the meta-analysis of 3 phase III studies 
(CAIN457F2310, CAIN457F2320 and CAIN457F2308). With 250 patients per treatment group 
(200 AS patients and 50 nr-axSpA patients), there would be approximately 96% power to detect 
a treatment difference of 16.7% in ASAS40 response rates between secukinumab and placebo 
in the evaluation of the primary efficacy hypothesis at Week 16 (Chi Square test, NQuery 7.0). 
The overall sample size will be 500 patients (400 AS patients and 100 nr-axSpA patients) for a 
randomization ratio of 1:1. 
12.8.2 
Secondary endpoint(s) 
The estimated power with the chosen sample size for secondary efficacy endpoints based on 
the pooled results of the same phase III studies (CAIN457F2310, CAIN457F2320 and 
CAIN457F2308) are summarized in Table 12-1 for binary endpoints and Table 12-2 for 
continuous endpoints.  
Table 12-1 
Summary of power for binary secondary endpoints 
Endpoint 
Response Rate 
Power 
  
Secukinumab(N = 200 
AS + 50 nr-axSpA) 
Placebo (N = 200 AS + 
50 nr-axSpA) 
  
ASAS 5/6 
44.2% 
19.5% 
99% 
ASDAS-CRP major 
improvement 
27.8% 
6.4% 
99% 
ASAS20 
59.0% 
38.4% 
99% 
ASDAS-CRP inactive 
disease 
13.6% 
3.5% 
97% 
ASAS partial remission 
15.2% 
5.5% 
92% 
Table 12-2 
Summary of power for continuous endpoints 
Endpoint 
Mean change from baseline 
Common 
standard 
deviation 
Power 
  
Secukinumab(N = 
200 AS + 50 nr-
axSpA) 
Placebo (N = 200 
AS + 50 nr-
axSpA) 
  
hsCRP1 
-0.79 
0.09 
0.867 
99% 
BASDAI 
-2.61 
-1.48 
2.241 
99% 
BASFI 
-2.14 
-1.13 
2.253 
99% 


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SF-36 PCS 
6.87 
3.99 
6.898 
99% 
ASQoL 
-4.46 
-2.56 
4.714 
99% 
PSQI2 
-1 
0 
3.9 
81% 
1 hsCRP is in log scale 
2 Source: mean change from baseline is from Karatas et al 2018 (AS study, median was used) and 
common standard deviation is from Taylor-Gjevre et al 2011 (RA study, largest standard deviation was 
used).  
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines 
for Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g. 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 


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13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
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. 
14.1 
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 required for subject 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
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Baraliakos X, Braun J (2015) Non-radiographic axial spondyloarthritis and ankylosing 
spondylitis: what are the similarities and differences? RMD Open; 1(suppl 1):e000053. 
Baraliakos X, Landewé R, Hermann KG, et al (2005) Inflammation in ankylosing spondylitis: 
a systematic description of the extent and frequency of acute spinal changes using magnetic 
resonance imaging. Ann. Rheum. Dis; 64(5):730-4.  
Baraliakos X, Listing J, Fritz C, et al (2011) Persistent clinical efficacy and safety of 
infliximab in ankylosing spondylitis after 8 years--early clinical response predicts long-term 
outcome. Rheumatology (Oxford); 50(9):1690-9. 
Batmaz İ, Sarıyıldız MA, Dilek B, et al (2013) Sleep quality and associated factors in 
ankylosing spondylitis: relationship with disease parameters, psychological status and quality 
of life. Rheumatol. Int; 33(4):1039-45. 
 
Braun J, Brandt J, Listing J, et al (2002) Treatment of active ankylosing spondylitis with 
infliximab: a randomised controlled multicentre trial. Lancet p; 359(9313):1187-93. 
Cella DF, Tulsky DS, Gray G, et al (1993) The Functional Assessment of Cancer Therapy 
scale: development and validation of the general measure. J. Clin. Oncol; 11(3):570-9. 
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. 
EMA 2017 Guideline on the Clinical Investigation of Medicinal Products for the Treatment of 
Axial Spondyloarthritis. 
FDA Guidance for Industry: Population Pharmacokinetics. 
https://www.fda.gov/media/71364/download. 
Gladman DD (2007) Axial disease in psoriatic arthritis. Curr Rheumatol Rep; 9(6):455-60. 
Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, et al (2003) Assessment of enthesitis 
in ankylosing spondylitis. Ann. Rheum. Dis; 62(2):127-32. 
Huffman KM, Samsa GP, Slentz CA, et al (2006) Response of high-sensitivity C-reactive 
protein to exercise training in an at-risk population. Am. Heart J; 152(4):793-800.  
Karatas G, Bal A, Yuceege M, et al (2018) Evaluation of sleep quality in patients with 
ankylosing spondylitis and efficacy of anti-TNF-α therapy on sleep problems: A 
polisomnographic study. Int J Rheum Dis; 21(6):1263-1269. 


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Koch GG, Tangen CM, Jung JW, et al (1998) Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Stat Med; 17(15-16):1863-92. 
Leverment S, Clarke E, Wadeley A, et al (2017) Prevalence and factors associated with 
disturbed sleep in patients with ankylosing spondylitis and non-radiographic axial 
spondyloarthritis: a systematic review. Rheumatol. Int; 37(2):257-271. 
Lubeck DP (2004) Patient-reported outcomes and their role in the assessment of rheumatoid 
arthritis. Pharmacoeconomics; 22(2 Suppl 1):27-38. 
Lukas C, Landewé R, Sieper J, et al (2009) Development of an ASAS-endorsed disease 
activity score (ASDAS) in patients with ankylosing spondylitis. Ann. Rheum. Dis; 68(1):18-
24. 
Machado PM, Landewé RB, van der Heijde DM (2011) Endorsement of definitions of disease 
activity states and improvement scores for the Ankylosing Spondylitis Disease Activity Score: 
results from OMERACT 10. J. Rheumatol; 38(7):1502-6. 
McHorney CA, Ware JE, Raczek AE (1993) The MOS 36-Item Short-Form Health Survey 
(SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental 
health constructs. Med Care; 31(3):247-63. 
Rudwaleit M, Feldtkeller E, Sieper J (2006) Easy assessment of axial spondyloarthritis (early 
ankylosing spondylitis) at the bedside. Ann. Rheum. Dis; 65(9):1251-2. 
Rudwaleit M, van der Heijde D, Landewé R, et al (2009) The development of Assessment of 
SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part 
II): validation and final selection. Ann. Rheum. Dis; 68(6):777-83.  
Said-Nahal R, Miceli-Richard C, Berthelot JM, et al (2000) The familial form of 
spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude 
Génétique des Spondylarthropathies. Arthritis Rheum; 43(6):1356-65. 
Sieper J, Rudwaleit M, Baraliakos X, et al (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann. Rheum. 
Dis; 68 Suppl 2:1-44. 
Sieper J, van der Heijde D (2013) Review: Nonradiographic axial spondyloarthritis: new 
definition of an old disease? Arthritis Rheum; 65(3):543-51. 
Song IH, Weiß A, Hermann KG, et al (2013) Similar response rates in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis after 1 year of treatment 
with etanercept: results from the ESTHER trial. Ann. Rheum. Dis; 72(6):823-5. 
Taylor-Gjevre RM, Gjevre JA, Nair BV, et al (2011) Improved Sleep Efficiency after Anti-
Tumor Necrosis Factor α Therapy in Rheumatoid Arthritis Patients. Ther Adv Musculoskelet 
Dis; 3(5):227-33. 


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Wallis D, Haroon N, Ayearst R, et al (2013) Ankylosing spondylitis and nonradiographic 
axial spondyloarthritis: part of a common spectrum or distinct diseases? J. Rheumatol; 
40(12):2038-41. 
Ware JE, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care; 30(6):473-83. 
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J 
Pain Symptom Manage; 13(2):63-74. 
van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for 
ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis 
Rheum; 27(4):361-8. 
 


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16 
Appendices 
16.1 
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 at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel.  
Table 16-1 
Safety Analyses: Expanded Limits and Notable Criteria 
  
  
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 


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16.2 
Appendix 2: 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. 
16.3 
Appendix 3: ASAS, BASFI 
 
The ASAS response measures consist of the following assessment domains (Sieper et al 2009). 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale 
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale  
Additional assessment domains: 
 
2. C reactive protein (acute phase reactant)Bath Ankylosing Spondylitis Functional 
Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those subjects with AS. The ten questions were chosen with a major input from subjects with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the subjects’ ability to cope with everyday life. A 10cm visual analog scale is used to 
answer the questions. The mean of the ten scales gives the BASFI score – a value between 0 
and 10.
 


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.Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI) 
The BASDAI consists of a zero through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS: 
1. How would you describe the overall level of fatigue/tiredness you have experienced? 
2. How would you describe the overall level of AS neck, back or hip pain you have had? 


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3. How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had? 
4. How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure? 
5. How would you describe the overall level of morning stiffness you have had from the 
time you wake up? 
6. How long does your morning stiffness last from the time you wake up? 
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (questions 5 and 6) is taken. The resulting 0 to 10 number is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical trials evaluating new drug therapies directed at Ankylosing 
Spondylitis. BASDAI is a quick and simple index (taking between 30 seconds and 2 minutes to 
complete. 


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16.5 
Appendix 5: Guidelines for administering the PRO 
questionnaires 
All questionnaires will be available, where possible, in the local languages of the participating 
countries. 
All questionnaires will be completed on an electronic device at the scheduled study visit prior 
to the subject seeing the investigator for any clinical assessment or evaluation. The subject 
should be given sufficient instruction, space, time and privacy to complete the questionnaire. 
The study coordinator should check the questionnaire for completeness and encourage the 
subject to complete any missing responses. A detailed training manual relating to the 
administrative procedures of the questionnaires will be provided to the sites. 
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires, but also any unsolicited comments written by the subject. If AEs or SAEs are 
confirmed, then the physician must record the events. Investigators should not encourage the 
subjects to change the responses reported in the completed questionnaires. 
The language in which each of the questionnaires to be completed will also be captured the first 
time a questionnaire is administered. 
Before trial begin 
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial and 
identify any items where a subject’s response might highlight issues of potential concern. For 
example, one question in the SF-36 asks ‘How much of the time in the past 4 weeks- have you 
felt downhearted and blue?’ If a subject responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator. 
Before completion 
1. Subjects should be provided with the correct questionnaire 
• at the appropriate visits, and 
• in the appropriate language 
2. Subjects should have adequate space and time to complete the questionnaires 
3. Questionnaire should be administered before the clinical examination 
During completion 
1. Administrator may clarify the questions but should not influence the response 


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2. Only one response for each question 
3. Also see ‘Addressing Problems and Concerns’ 
After completion 
1. Check for completeness and not for content* 
2. Check for multiple responses that were made in error**  
3. Data should be transcribed from the completed questionnaire to the appropriate web 
portal** 
4.  File completed questionnaire in the patient study files** 
* However, any response which may directly impact or reflect the subject’s medical 
condition (e.g. noting of depression) should be communicated by the study coordinator to 
the investigator). 
** Only applicable if a paper PRO questionnaire(s) is utilized as a backup should there be 
a failure with the electronic device. 
Addressing Problems and Concerns 
Occasionally a subject may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below. 
The patient does not want to complete the questionnaire(s) 
Tell the subject that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental, and social health problems of subjects. Emphasize that this 
information is as important as any of the other medical information, and that the 
questionnaire(s) is simple to complete. Suggest that the questionnaire(s) may be different from 
anything the respondent has filled in the past. If the subject still declines, retrieve the 
questionnaires. Record the reason for the decline, and thank the subject. 
The patient is too ill or weak to complete the questionnaire(s) 
In these instances, the coordinator may obtain subject responses by reading out loud each 
question, followed by the corresponding response categories, and entering the subject’s 
response. No help should be provided to the subject by any person other than the designated 
study coordinator. The coordinator should not influence subject responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim. 
The patient wants someone else to complete the questionnaire(s) 
In no case should the coordinator or anyone other than the subject provide responses to the 
questions. Unless specified in the study protocol proxy data are not an acceptable substitute for 
subject self-report. Subjects should be discouraged from asking a family member or friend for 
help in completing a questionnaire. 
The patient does not want to finish completing the questionnaire(s) 
If non-completion is a result of the subject having trouble understanding particular items, ask 
the subject to explain the difficulty. Re-read the question for them verbatim, but do not rephrase 
the question. If the respondent is still unable to complete the questionnaire, accept it as 
incomplete. Thank the subject. 


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The patient is concerned that someone will look at his/her responses 
Emphasize that all responses are to be kept confidential. Point out that their names do not appear 
anywhere on the questionnaire, so that their results will be linked with an ID number and not 
their name. Tell the subject that his/her answers will be pooled with other subjects’ answers and 
that they will be analyzed as a group rather than as individuals. Tell the subject that completed 
forms are not routinely shared with treating staff, and that their responses will only be seen by 
you (to check for completeness), and possibly the investigator. Any response which may 
directly impact on or reflect their medical condition (e.g. noting of severe depression) will be 
communicated by the coordinator to the physician. 
The patient asks the meaning of a question/item 
While completing the questionnaire, some subjects might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the subject by rereading the 
question for them verbatim. If the subject asks to interpret the meaning of an item, do not try to 
explain it, but suggest that he/she use his/her own interpretation of the question. Subjects should 
answer the questions based on what they think the questions mean. 
General information about all questionnaire(s): 
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. The questionnaires should be completed by the patients in a quiet area free 
from disturbance, and before any visit assessments. Patients should receive no help from family 
members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
per question, then this should be brought to patient. Incomplete questions should not be accepted 
without first encouraging the patient to complete unanswered questions. 
The investigator must complete the patient/visit information on the electronic device and ensure 
that the center number, patient’s number and initials are identical to the Case Record Form. As 
there are no source data for this questionnaire, the data queries will be restricted to patient/visit 
information. 
16.6 
Appendix 6: Liver event and laboratory trigger definitions and 
follow-up requirements 
Table 16-3 
Liver Events 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 


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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 * 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 
TBL: total bilirubin; ULN: upper limit of normal 
Table 16-4 
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 appropriate eCRF 
pages 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete appropriate eCRF 
pages 
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 appropriate eCRF 
pages 
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 appropriate eCRF 
pages 
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 
> 3 × ULN accompanied by 
symptomsb 
Discontinue the study drug 
immediately 
Hospitalize if clinically 
appropriate 
Establish causality 
Complete appropriate eCRF 
pages 
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 appropriate eCRF 
pages 
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 appropriate eCRF 
pages 
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 appropriate eCRF 
pages 
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially indicative of 
a liver toxicity* 
Consider study drug 
interruption or discontinuation 
Hospitalization if clinically 
appropriate 
Establish causality 
Complete appropriate eCRF 
pages 
Investigator discretion 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms 


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Criteria 
Actions required 
Follow-up monitoring 
TBL: total bilirubin; ULN: upper limit of normal 
a Elevated 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 
c Resolution 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. 
 

SAP_001.pdf: 
Clinical Development 
Secukinumab (AIN457) 
CAIN457P12301 / NCT04156620
A randomized, double-blind, placebo-controlled, parallel 
group, phase III multicenter study of intravenous 
secukinumab to compare efficacy at 16 weeks with placebo 
and to assess safety and tolerability up to 52 weeks in 
subjects with active Ankylosing Spondylitis or non-
radiographic axial SpondyloArthritistudy  
Statistical Analysis Plan (SAP) 
Author: 
, Trial Statistician 
Document type: 
SAP Documentation  
Document status: 
Final 
Release date: 
12-Jan-2023
Number of pages: 
45 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Page 2 of 45 
SAP 
 
Study No. CAIN457P12301 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for update 
Outcome for 
update 
Section and 
title 
impacted 
(Current) 
04-Nov-2022 
Initial version 
Creation of final version  
This SAP is created for 
the Final DBL.  
Analyses that are specific 
for Week 16 DBL and will 
not be repeated in the 
Final DBL are removed, 
e.g., inferential analyses, 
baseline information, etc.  
 
 
  
 
 
 
N/A - First 
version 
NA 
05-Dec-2022 
Ammendment 
1 
 
 
 
   
 
 
 
 
 
 
 
 
Duration 
of 
exposure 
updated for patients who 
discontinue treatment, to 
be consistent within the 
program.      
 
 
 
 
 


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SAP 
 
Study No. CAIN457P12301 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 5 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
1.2.1 
Primary objective .................................................................................... 9 
1.2.2 
Secondary objectives ............................................................................... 9 
 
 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Treatment groups .................................................................................. 12 
2.2.2 
Subgroup of interest .............................................................................. 12 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 13 
2.3.2 
Background and demographic characteristics ....................................... 13 
2.3.3 
Medical history...................................................................................... 13 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 13 
2.4.1 
Study treatment / compliance ................................................................ 13 
2.4.2 
Prior, concomitant and post therapies ................................................... 14 
2.5 
Analysis of the primary objective .......................................................................... 14 
2.6 
Analysis of secondary objectives .......................................................................... 14 
 
 15 
 
 15 
 
 16 
2.8 
Safety analyses....................................................................................................... 16 
2.8.1 
Adverse events (AEs) ............................................................................ 17 
2.8.2 
Laboratory data ..................................................................................... 18 
2.8.3 
Other safety data ................................................................................... 21 
2.9 
Pharmacokinetic endpoints .................................................................................... 22 
2.10 
PD 
 analyses ........................................................................................ 23 
 
 23 
2.11 
Patient reported outcomes (PROs) ........................................................................ 25 
 
 26 


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SAP 
 
Study No. CAIN457P12301 
 
 
 26 
2.14 
Interim analysis ...................................................................................................... 27 
3 
Sample size calculation ..................................................................................................... 27 
4 
Change to protocol specified analyses .............................................................................. 28 
5 
Appendix ........................................................................................................................... 28 
5.1 
Description of efficacy variables ........................................................................... 28 
5.2 
Description of health-related quality of life variables ........................................... 35 
5.3 
Visit Windows ....................................................................................................... 38 
5.4 
Statistical methodology and assumptions .............................................................. 42 
5.4.1 
Analysis of continuous data .................................................................. 42 
5.4.2 
Analysis of binary and categorical data ................................................ 42 
5.4.3 
Crude incidence and related risk estimates ........................................... 43 
5.4.4 
Exposure adjusted incidence rate and related risk estimates ................ 44 
6 
Reference ........................................................................................................................... 44 
 


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SAP 
 
Study No. CAIN457P12301 
 
List of tables 
Table 2-1 
Overview of analyses on some safety endpoints................................... 18 
Table 2-2 
CTCAE grades for laboratory parameters to be analyzed .................... 19 
Table 2-3 
Liver-related events ............................................................................... 21 
Table 2-4 
Criteria for notable vital sign abnormalities .......................................... 22 
Table 3-1 
Summary of power for binary secondary endpoints ............................. 27 
Table 3-2 
Summary of power for continuous endpoints ....................................... 28 
 
 31 
 
 33 
 
 34 
Table 5-4 
Analysis visit windows ......................................................................... 39 
Table 5-5 
Rules for flagging variables .................................................................. 41 
Table 5-6 
Examples for calculating exposure time for incidence rates (IR) ......... 44 
 
 


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SAP 
 
Study No. CAIN457P12301 
 
List of abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AS 
Ankylosing spondylitis 
ASAS 
Assessment of SpondyloArthritis International Society 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
ASQoL 
Ankylosing Spondylitis Quality of Life 
AST 
Aspartate Aminotransferase 
axSpA 
Axial spondyloarthritis 
BASDAI 
Bath Ankylosing Spondylitis Disease Activity Index  
BASFI 
Bath Ankylosing Spondylitis Functional Index 
 
 
BMI 
Body Mass Index 
BSL 
Baseline 
CRF 
Case Report/Record Form (paper or electronic) 
CRP 
C-Reactive Protein 
CSR 
Clincial Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMARD 
Disease Modifying Anti-rheumatic Drug 
 
 
 
  
 
 
 
 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GGT 
Gamma Glutamyl Transferase 
H 
Hour 
HDL 
High Density Lipoprotein 
HLA 
Human Leukocyte Antigen  
hsCRP 
high sensitivity C-Reactive Protein 
i.v. 
Intravenous 
 
 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
LDL 
Low Density Lipoprotein 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
kg 
MAR 
kilogram(s) 
Missing At Random 
 
 


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MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
milligram(s) 
MI 
Multiple Imputation 
MMRM 
Mixed effect Model for Repeated Measurements 
MTX 
Methotrexate 
nr-axSpA 
non-radiographic axial spondyloarthritis 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PCS 
Physical Component Summary 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRN 
as needed 
PRO 
Patient Reported Outcome 
PSQI 
Pittsburgh Sleep Quality Index 
PT 
Preferred term 
q4w 
Every 4 weeks 
QoL 
Quality of Life  
RMP 
Risk Management Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SF-36 
Medical Outcome Short Form (36) Health Survey  
SF-36 PCS 
Short Form-36 Physical Component Summary 
SOC 
System Organ Class 
SMQ 
Standardized MedDRA Query 
SpA 
Spondyloarthritis 
 
 
TBL 
Total Bilirubin 
TNF-IR  
TNFα Inhibitor Incomplete Responder 
TNF/TNFα 
Tumor Necrosis Factor  
ULN 
Upper Limit of Normal 
VAS 
Visual Analog Scale  
vs 
Versus 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction 
Data will be analyzed by Novartis according to the data analysis Section 12 of the clinical study 
protocol. The statistical methodology is described below and any deviations from the protocol 
are documented. Additional detailed information regarding the analysis methodology is 
contained in the Appendix section. 
1.1 
Study design 
This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-
group design to study the efficacy, safety, and tolerability of treatment with intravenous 
secukinumab (initial dose of 6 mg/kg followed thereafter with 3 mg/kg administered every four 
weeks starting at Week 4) in subjects with active axSpA. The study population consists 
of approximately 400 subjects with active AS and approximately 100 subjects with active nr-
axSpA, despite current or previous NSAID, conventional DMARD and / or TNF inhibitor 
therapy, or intolerance to these therapies. A screening (SCR) period of up to 10 weeks will be 
used to assess eligibility, followed by randomization to 52 weeks of study treatment.  
At baseline, subjects with active AS and nr-axSpA will be randomized to one of the two 
treatment groups: 
• Group 1: approximately 200 AS subjects and approximately 50 nr-axSpA subjects; These 
subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline (BSL) visit), 
followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at 
Week 4 through Week 48 (exposure through Week 52). 
• Group 2: approximately 200 AS subjects and approximately 50 nr-axSpA subjects; These 
subjects will receive i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , 
followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four 
weeks through Week 48 (exposure through Week 52). 
This study will consist of 4 periods totaling 70 weeks: the screening period (up to 10 weeks), 
the treatment period 1 (total duration of 16 weeks) and the treatment period 2 (total duration of 
36 weeks) followed by the safety follow up period of 8 weeks after the end of treatment visit 
(i.e., Week 52). 
The subjects will be stratified at randomization according to disease condition (i.e., AS or nr-
axSpA). No more than 20% TNF Inhibitor Incomplete Responders (TNF-IR) subjects will be 
enrolled in the study. Starting at Week 16, all subjects will switch to open-label intravenous 
secukinumab, including all placebo subjects. 
No subject will be on placebo treatment after Week 16, because axSpA is considered a chronic 
disease with no ‘true’ and lasting placebo response. However, all subjects and investigators/site 
staff will remain blinded to the original randomized treatment group assignment (secukinumab 
treatment vs placebo). Study treatment will continue up to Week 52. An end of treatment visit 
(i.e., Week 52) is to be done 4 weeks after last study treatment administration and a post 
treatment follow-up visit (i.e., Week 60) is to be done 8 weeks after the end of treatment visit 
for all subjects (regardless of whether they complete the entire study as planned or discontinue 
prematurely). All i.v. infusions will be performed at the study site and site personnel will 
administer the infusions to subjects. 


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Rescue medication is not allowed until Week 16. However, subjects who are deemed by the 
investigator not to be benefiting from the study treatment based on safety and efficacy 
assessments or for any reason of their own accord will be free to discontinue participation in 
the study at any time. The study will have a primary endpoint analysis at Week 16. Therefore, 
the primary analysis will be performed with Week 16 data once the last subject has completed 
the Treatment Period 1. 
The primary endpoint analysis will be performed after all subjects complete Week 16 in order 
to support regulatory filing. As the primary analysis is scheduled at Week 16, no adjustment 
will be made to the testing strategy to control family-wise type I error rate for this analysis. 
1.2 
Study objectives and endpoints 
1.2.1 
Primary objective 
The primary objective is to demonstrate that the efficacy of i.v. secukinumab at Week 16 is 
superior to placebo in subjects with active axSpA (AS and nr-axSpA) based on the proportion 
of subjects achieving an ASAS40 (Assessment of SpondyloArthritis International Society 
criteria) response. 
1.2.2 
Secondary objectives 
1. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving Ankylosing Spondylitis Disease Activity Score 
(ASDAS)-C-Reactive Protein (CRP) major improvement  
2. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline in total Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI)  
3. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects meeting the ASAS 5/6 response criteria  
4. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline of Bath Ankylosing Spondylitis Functional Index (BASFI) 
5. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline in Short Form-36 Physical Component Summary (SF-36 PCS) 
6. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline in Ankylosing Spondylitis Quality of Life (ASQoL) scores 
7. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline in high sensitivity C-Reactive Protein (hsCRP)  
8. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving an ASAS20 response 
9. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving Ankylosing Spondylitis Disease Activity Score 
(ASDAS)-C-Reactive Protein (CRP) inactive disease  
10. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the proportion of subjects achieving ASAS partial remission 


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11. To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo based 
on the change from baseline in Pittsburgh Sleep Quality Index (PSQI)  
12. Overall safety and tolerability of i.v. secukinumab compared to placebo as assessed by 
physical exams, vital signs, laboratory assessments and adverse event monitoring 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
To support the submission, tables and figures will be generated for overall axSpA population. 
Listings will be generated for overall axSpA population and will be sorted by disease condition 
(AS and nr-axSpA), except for the listing of randomization allocation to treatment which will 
be sorted by the randomization number.  
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile and maximum. Summary statistics for discrete variables 
will be presented in the number and percent of subjects in each category. 
Data analyses will be presented by treatment regimen. Efficacy and safety data for the placebo-
controlled period (or the entire treatment period as appropriate) will be presented by the 
following 2 treatment groups. Subjects may be included in more than one treatment group for 
some analyses (e.g., exposure-adjusted adverse events over the entire treatment period). The 2 
treatment groups represent the regimens subjects will be eligible to be randomized to for the 
first 16 weeks of the study. 
• Secukinumab regimen: approximately 200 AS subjects and approximately 50 nr-axSpA 
subjects; These subjects will receive secukinumab 6 mg/kg i.v. at randomization (Baseline 
(BSL) visit), followed by the administration of secukinumab 3 mg/kg i.v. every four weeks 
starting at Week 4 through Week 48 (exposure through Week 52). 
• Placebo regimen: approximately 200 AS subjects and approximately 50 nr-axSpA subjects; 
These subjects will receive  i.v. placebo at randomization (BSL visit), Weeks 4, 8, and 12 , 
followed by the administration of secukinumab 3 mg/kg i.v. at Week 16 and every four 
weeks through Week 48 (exposure through Week 52). 
Note that the treatment groups above for a subject may differ depending on the time period of 
the analysis and whether one assesses the subject for efficacy or safety. 
Comparative efficacy data 
Comparative efficacy analyses (i.e., inferential efficacy comparisons with placebo) will focus 
on the time period when both active drug and the placebo are given in a manner suitable for 
making comparisons (e.g., double-blind). For AIN457P12301, this is the first 16-weeks of 
treatment. Comparative efficacy will be performed based on the Full Analysis Set (FAS) 
population using the randomized treatment. Data collected after Week 16 will generally be 
summarized descriptively on the FAS population using treatment sequence. 
Efficacy data following treatment switch 
Data will also be presented after Week 16, by a combination of the ‘original’ and ‘switch’ 
treatment groups and will be referred to as treatment sequence. These treatment sequences 
represent the treatment combinations the subjects experience over the course of the entire trial 


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in case of switch (e.g., placebo patients who are reassigned to secukinumab 3 mg/kg i.v. at 
Week 16). 
All listings will be presented by treatment sequence. 
2.2 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set.  
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized patients are treated as screen failures.   
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be evaluated according to the treatment assigned to at randomization, but actual stratum, if 
stratified randomization is used.  
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 
Treatment groups 
The summaries by treatment will primarily be performed by the randomized treatment but also 
by combination of randomized treatment and switch treatment. For some safety summaries (e.g., 
exposure-adjusted) the ‘switch’ treatment may be summarized separately. 
• Randomized treatment: 
• AIN457 6 mg/kg - 3 mg/kg i.v. 
• Placebo     
• Treatment sequence: 
• AIN457 6 mg/kg - 3 mg/kg i.v. 
• Placebo - AIN457 3 mg/kg i.v. 
• Placebo Not Switch 
• Switch treatments (for placebo patients who cross-over): 
• AIN457 3 mg/kg i.v. (will only be counted under Any AIN457) 
2.2.2 
Subgroup of interest 
The primary and secondary endpoints will be analyzed by disease condition (AS and nr-axSpA). 
Analyses by previous use of TNF-α inhibitor may also be provided for overall axSpA 
population.   


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of subjects screened will be presented. In addition, the reasons for screen failures 
will be provided. The number and percentage of subjects in the randomized set who completed 
the study periods and who discontinued the study prematurely (including the reason for 
discontinuation) will be presented at the end of each treatment period (Week 16 and Week 52) 
and follow-up period, if appropriate, for each treatment group and all subjects. 
For each protocol deviation (PD), the number and percentage of subjects for whom the PD 
applies will be tabulated. Protocol deviations due to COVID-19 will be reported in separate 
categories. 
Additional analysis due to COVID-19 might be provided, e.g., summary of participants missed 
visit and/or treatment due to COVID-19. 
2.3.2 
Background and demographic characteristics 
Data on background and demographic characteristics have been summarized in the Week 16 
Clincial Study Report (CSR) and will not be reproduced for the Final Analysis.   
2.3.3 
Medical history 
Data on medical history and smoking history have been summarized in Week 16 CSR and will 
not be reproduced for the Final Analysis. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The analysis of study treatment data will be based on the safety set. The number of active and 
placebo i.v. infusions 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, ≥ 4 weeks, ≥ 8 
weeks, etc.) will be presented. 
Duration of exposure will be defined as the time from first dose of study treatment to the time 
of treatment switch (for subjects who switch from placebo to open-label secukinumab) or 
minimum of (last dose of the treatment + 84 days) and (last visit date). Patients who switch 
treatment during the study (e.g., from placebo to open-label secukinumab treatment at Week 
16) will have exposure to both medications using the appropriate start and stop dates.  
Duration of exposure (years) = duration of exposure (days) / 365.25 
Duration of exposure (100 subject years) = duration of exposure (years) / 100 
The analyses of duration of exposure described above will be done for the entire study treatment 
period. 


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2.4.2 
Prior, concomitant and post therapies 
Prior medications have been summarized in the Week 16 CSR and will not be reproduced for 
the Final Analysis. 
Any medication given at least once between the day of first dose of randomized study treatment 
and within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the period where study treatment is administered. 
Concomitant medications will be presented in alphabetical order, by Anatomical Therapeutic 
Classification (ATC) codes and grouped by anatomical main group (the 1st level of the ATC 
codes). Tables will show the overall number and percentage of subjects receiving at least one 
treatment of a particular ATC code and at least one treatment in a particular anatomical main 
group. 
Significant concomitant non-drug therapies and procedures will be summarized by primary 
system organ class and MedDRA preferred term. 
Any non-drug therapies and procedures done between the day of first dose of study treatment 
and within 84 days after last dose will be defined as concomitant non-drug therapies and 
procedures, including those which were started pre-baseline and continued into the period 
where study treatment is administered. 
The number and percentage of subjects receiving concomitant axSpA therapy will be presented 
by randomized treatment group and the total duration of previous exposure to axSpA therapies. 
 
 
Prior or concomitant medications will be identified by comparing recorded or imputed start and 
end dates of medication taken to the reference start date. 
2.5 
Analysis of the primary objective 
The primary efficacy variable is response to treatment according to the ASAS40 criteria at 
Week 16 in patients with active axSpA (AS and nr-axSpA).  
The analysis of primary variable at Week 16 will not be reproduced for the Final Analysis. 
2.6 
Analysis of secondary objectives 
The secondary efficacy variables include, 
• response to treatment at Week 16 according to the ASDAS-CRP major improvement 
criteria 
• change from baseline in BASDAI at Week 16 
• response to treatment at Week 16 according to the ASAS 5/6 criteria 
• change from baseline in total BASFI score at Week 16 
• change from baseline in SF-36 PCS at Week 16 
• change from baseline in ASQoL at Week 16 
• change from baseline in hsCRP at Week 16 
• response to treatment at Week 16 according to the ASAS20 criteria 


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• response to treatment at Week 16 according to the ASDAS-CRP inactive disease criteria  
• response to treatment at Week 16 according to the ASAS partial remission 
• change from baseline in PSQI at Week 16 
The analysis of secondary variables at Week 16 will not be reproduced for the Final Analysis.  


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2.8 
Safety analyses 
Summaries may performed separately for the entire treatment period.  The analyses of the 
follow-up period will be limited to summaries for treatment-emergent adverse events, serious 
adverse events and risks based on adverse events. 
Safety analyses will be performed on treatment received or actual treatment as described below: 


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The actual treatment or treatment received for summaries of safety data will differ to the 
treatment assigned at randomization only if a subject received the wrong treatment during the 
entire study. 
For those subjects who received not the treatment randomized, i.e., who received erroneously 
the wrong treatment at least once, an additional AE listing will be prepared displaying which 
events occurred after the treatment errors. 
In addition for subjects who discontinue study treatment but continue with study participation, 
an additional AE listing will be prepared displaying which events occurred after the study 
treatment discontinuation. 
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 on or before last dose date + 84 days) will be summarized 
by primary system organ class and preferred term. Confidence intervals for the crude rate will 
be derived as described in Section 5.4.3. In addition, exposure time-adjusted incidence rates 
including 95% confidence intervals will be provided for the entire treatment period (see Section 
5.4.4). A graphical display of the crude incidence rates and exposure-adjusted rates will be 
presented for all AEs and serious AEs by system organ class. 
Adverse events reported will be presented in descending frequency according to its incidence 
in the secukinumab group starting from the most common event. Summaries (crude incidences 
only) will also be presented for AEs by severity and for study treatment related AEs. If a 
particular AE ‘severity’ is missing, this variable will be listed as missing and treated as missing 
in summaries. If a subject reported more than one adverse event with the same preferred term, 
the adverse event with the greatest severity will be presented. If a subject reported more than 
one adverse event within the same primary system organ class, the subject will be counted only 
once with the greatest severity at the system organ class level, where applicable.  
Separate summaries will be provided for adverse events suspected to be related to study drug, 
deaths, serious adverse events, and adverse events leading to discontinuation and adverse events 
requiring concomitant medication. 
Adverse events will also be reported separately by Standardized MedDRA Query (SMQ) 
according to MedDRA, using a narrow search. The MedDRA version used for reporting the 
study will be described in a footnote. 
A listing of non-treatment emergent adverse events will be provided. These adverse events 
occurred before the first dose of the study treatment.  The crude incidence rate will be provided 
without treatment information. 
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures. 
An overview of the safety analyses which will be performed for treatment emergent AEs, labs 
and vital signs for each analysis period is described in Table 2-1.  


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Table 2-1 
Overview of analyses on some safety endpoints 
Analysis 
period 
AEs & SAEs 
AEs by 
severity 
Study drug 
related AEs 
AEs-SMQ 
Risk 
Notables for 
(vitals), lab 
criteria 
Day 1 – 
Week 16 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
Entire 
Treatment  
 
• crude 
incidence 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
 
• crude 
incidence 
 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
• exposure 
time 
adjusted 
incidence 
• crude 
incidence 
 
Exposure-adjusted incidence rates will be done for the following: 
• Primary SOC level for AE and SAE  
• Level 1 for Risks and SMQ analyses 
• PT level for AE and SAE  
Algorithms for date imputations will be provided in Programming Datasets Specifications. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment/treatment emergent adverse events which are not serious adverse events with an 
incidence greater than x% and on on-treatment/treatment emergent serious adverse events 
and SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population. Here threshold value x is set to 2 (%), but it may be 
updated following review of the dry run outputs. 
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 
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.8.2 
Laboratory data 
The summary of lab data will only include treatment emergent data, which are defined as those 
lab assessments after the first dose of study treatment and on or before last dose + 84 days. 
Reported laboratory assessments with either a less than or greater than sign (“<” or “>”) will be 
used for analysis after removal of the sign and conversion to standard unit. These laboratory 
data will be displayed in listings using the standard unit with the reported sign (“<” or “>”). 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, chemistry and urinalysis). In addition to the individual laboratory parameters the 


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ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will be derived and 
summarized. 
For urinalysis, frequency tables will be presented. 
Descriptive summary statistics for the change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test and treatment group. Change 
from baseline will only be summarized for subjects with both baseline and post baseline values 
and will be calculated as: 
change from baseline = post baseline value – baseline value 
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline, if appropriate for each study phase, will be analyzed analogously.  
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. If appropriate, the shifts to the most extreme laboratory test value within a treatment 
phase (either initial or entire) will be presented as well (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. 
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-2: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase 
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), glucose, cholesterol, triglycerides (TG). 
These summaries will be split into hematology and chemistry for study level reports and the 
pooled summary of clinical safety. 
Table 2-2 
CTCAE grades for laboratory parameters to be analyzed 
CTCAE v4.03 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
HGB decreased 
(Anemia) 
<LLN – 100 g/L 
<100 – 80 g/L 
<80 g/L 
See note below 
Platelet count 
decreased 
<LLN – 75.0 × 10e9 /L 
<75.0 - 50.0 × 10e9 /L 
<50.0 – 25.0 × 10e9 /L 
<25.0 × 10e9 /L 
White blood cell 
decreased 
<LLN - 3.0 × 10e9 /L 
<3.0 - 2.0 × 10e9 /L 
<2.0 - 1.0 × 10e9 /L 
<1.0 × 10e9 /L 
Neutrophil count 
decreased 
<LLN - 1.5 × 10e9 /L 
<1.5 - 1.0 × 10e9 /L 
<1.0 - 0.5 × 10e9 /L 
<0.5 × 10e9 /L 
Lymphocyte count 
decreased 
<LLN - 0.8 × 10e9/L 
<0.8 - 0.5 × 10e9 /L 
 
<0.5 - 0.2 × 10e9 /L 
<0.2 × 10e9 /L 
Creatinine increased* 
 
>1 - 1.5 × baseline;  
>ULN - 1.5 × ULN 
>1.5 - 3.0 × 
baseline; >1.5 - 3.0 x 
ULN 
>3.0 baseline;  
>3.0 - 6.0 × ULN 
>6.0 × ULN 
TBL increased 
>ULN - 1.5 × ULN 
>1.5 - 3.0 × ULN 
>3.0 - 10.0 × ULN 
>10.0 × ULN 
GGT increased 
>ULN - 2.5 × ULN 
>2.5 - 5.0 × ULN 
>5.0 - 20.0 × ULN 
>20.0 × ULN 
ALT increased 
>ULN - 3.0 × ULN 
>3.0 - 5.0 × ULN 
>5.0 - 20.0 × ULN 
>20.0 × ULN 
AST increased 
>ULN - 3.0 × ULN 
>3.0 - 5.0 × ULN 
>5.0 - 20.0 × ULN 
>20.0 × ULN 
ALP increased 
>ULN - 2.5 × ULN 
>2.5 - 5.0 × ULN 
>5.0 - 20.0 × ULN 
>20.0 × 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 


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CTCAE v4.03 Term 
Grade 1    
Grade 2    
Grade 3    
Grade 4    
Glucose decreased 
(Hypoglycemia) 
<LLN - 3.0 mmol/L 
<3.0 - 2.2 mmol/L 
<2.2 - 1.7 mmol/L 
<1.7 mmol/L 
Cholesterol high 
>ULN - 7.75 mmol/L 
>7.75 - 10.34 mmol/L 
>10.34 - 12.92 mmol/L 
>12.92 mmol/L 
Hypertriglyceridemia 
1.71 - 3.42 mmol/L 
>3.42 - 5.7mmol/L 
>5.7 - 11.4 mmol/L 
>11.4 mmol/L 
Note: Grade 4 Hemoglobin events are defined as life-threatening anemia events and will not be displayed in the table, as a 
numerical range is not provided in the CTCAE. 
*Note: for “creatinine increased” the baseline criteria do not apply. 
 
 
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase (either initial or entire) 
analyzed. Of note, baseline will be defined as last assessment prior to first dosing in initial 
treatment phase. Subjects with abnormal laboratory values will be listed and values outside the 
normal ranges will be flagged. 
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories: 
• HDL: 
• <=LLN 
• <0.8 × LLN 
• LDL, cholesterol, triglycerides: 
• >=ULN  
• >1.5 × ULN  
• >2.5 × ULN 
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 2-3: 


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Table 2-3 
Liver-related events 
Parameter 
Criterion 
ALT 
>3×ULN; >5×ULN; >8×ULN;>10×ULN, >20×ULN 
AST 
>3×ULN; >5×ULN; >8×ULN >10×ULN; >20×ULN 
ALT or AST 
>3×ULN; >5×ULN; >8×ULN >10×ULN; >20×ULN 
TBL 
>1.5×ULN, >2×ULN, >3×ULN, 
ALP 
>2×ULN, >3×ULN. >5×ULN 
ALT or AST & 
TBL 
ALT or AST>3×ULN & TBL >2×ULN; 
ALT or AST >5×ULN & TBL >2×ULN; 
ALT or AST >8×ULN & TBL >2×ULN; 
ALT or AST >10×ULN & TBL >2×ULN 
ALP & TBL 
ALP >3×ULN & TBL >2×ULN 
ALP >5×ULN & TBL >2×ULN 
ALT or AST & 
TBL & ALP 
ALT or AST>3×ULN & TBL >2×ULN & ALP <2×ULN (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 >3×ULN & TBL >2×ULN & ALP ≥2×ULN may not result 
in severe DILI. 
Notes: 
In studies which enroll subjects with pre-existing liver disease, baseline LFT may be increased above 
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality 
criteria 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42×ULN is counted for 
ALT >3×ULN and ALT>5×ULN. 
Individual subject data listings will be provided for subjects with abnormal laboratory data. 
Data of subjects with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing. 
Boxplots over time will be presented for selected laboratory parameters (neutrophils, liver and 
lipid parameters). 
Individual subject data listing will be provided for hematology. 
2.8.3 
Other safety data 
2.8.3.1 
Vital signs 
The summary of vital signs will only include treatment emergent data, which are defined as 
those vital sign measurements after the first dose of study treatment and on or before last dose 
+ 84 days. 
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed. These descriptive summaries will be 
presented by vital sign and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post-baseline values and will be calculated as: 


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change from baseline = post-baseline value – baseline value 
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-4: 
Table 2-4 
Criteria for notable vital sign abnormalities 
Vital sign (unit) 
Notable abnormalities 
Systolic blood pressure (mmHg) 
>= 140 mmHg or < 90 mmHg 
Diastolic blood pressure (mmHg) 
>=90 mmHg or <60 mmHg 
Pulse (bpm) 
> 100 bpm or <60 bpm 
 
 
  
2.8.3.3 
Compound specific safety evaluation 
Safety topics of interest, such as risks defined in the Risk Management Plan (RMP) or topics of 
interest regarding signal detection or routine analysis are defined in the Program Case Retrieval 
Sheet that is stored in CREDI at the path Cabinets/CREDI Projects/A/AIN457A/Integrated 
Medical Safety. 
The crude incidence and exposure-adjusted incidence rates for RMP risks will be summarized. 
In addition, listings will be provided presenting which subjects experienced which risk.   
Important note: For the evaluation of RMP risks primary and secondary system organ classes 
of the MedDRA dictionary will be considered. 
2.9 
Pharmacokinetic endpoints   
During modeling of the PK of secukinumab, the broad principles outlined in the 
[FDA Guidance for Industry: Population Pharmacokinetics] will be followed. 
All completed subjects with quantifiable pharmacokinetic (PK) measurements will be included 
in the PK data analysis. Serum concentrations will be expressed in mass per volume units. All 
concentrations below the limit of quantification as well as missing data will be labeled as such 
in the concentration data listings. PK concentrations will be summarized by visit and treatment 
group. In addition to mean, standard deviation (SD), coefficient of variation (CV), median and 
quartiles, the geometric mean and geometric coefficient of variation (CV), minimum and 
maximum, as well as n and n(log) will be presented. The formula for deriving the geometric 
mean and CV (%) is as follows:  
• CV (%) = (SD/mean)*100, 
• geometric mean=exp((sum of log transformed data) / number of non-missing data points 
after log transformation), 
• geometric CV = sqrt(exp(variance of log-transformed data)-1)*100. 
In addition, sample number, concentration, sample date, sample time and elapsed time from 
first dose (in days) will be listed by treatment sequence. 
Values below lower limit of quantification/below detection limit will be imputed by 0. 


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Pharmacokinetic data of the study treatment will be analyzed with a population-
pharmacokinetic mixed effects model. The analysis will be based on a pooled data set, including 
PK samples from previous studies. The modeling approach will be further detailed in a 
modeling plan. Results will be reported separately. 
2.10 
PD 
 analyses 


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2.11 
Patient reported outcomes (PROs) 
Patient reported outcomes will be evaluated based on FAS unless otherwise specified. 
BASDAI 
The following variables will be evaluated: 
• BASDAI 
 
 
For BASDAI, summary statistics of observed data by visit and change from baseline in 
BASDAI will be provided for each treatment. 
 
 
BASFI 
See Section 5.1 Description of efficacy variables for details. 
Patient’s global assessment of disease activity (VAS) 
Summary statistics of observed data by visit and change from baseline in patient’s global 
assessment of disease activity will be provided for each treatment. 
Patient’s assessment of back pain intensity (VAS) 
Summary statistics of observed data by visit and change from baseline in patient’s assessment 
of back pain intensity will be provided for each treatment. 
SF-36 
The following variables will be evaluated: 
• SF-36 domain scores (based on a scale of 0-100) 
• SF-36 PCS 
 (norm-based scores) 
• SF-36 PCS 
 (improvement of ≥ 2.5 points, Lubeck 2004) 
For the change from baseline in SF-36 summary scores (PCS 
), summary statistics 
will be provided using observed data for each treatment regimen. 
For the responder analyses, the proportion of responders will be descriptively summarized along 
with its 95% CI for each randomized treatment based on observed data. 
The SF-36 domain scores will be summarized by treatment. 
ASQoL 
Summary statistics of observed data by visit and change from baseline in ASQoL will be 
provided for each treatment. 


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PSQI 
Summary statistics of observed data by visit and change from baseline in PSQI score will be 
provided for each treatment. 
 
 
 


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2.14 
Interim analysis 
The primary endpoint analysis was performed after all subjects completed Week 16 or 
discontinued earlier in order to support regulatory filing.  
The investigators, site personnel and monitors continue to remain blinded to the treatment each 
subject received at randomization until all patients have completed the study (Week 60 Follow-
up) and the final database lock has occurred. Additional analyses may be performed to support 
interactions with health authorities, as necessary. 
3 
Sample size calculation 
An overall type I error (2-sided) of 5% will be used to control type I error. Secukinumab i.v. 
regimen will be tested versus placebo with respect to the primary endpoint (ASAS40 response 
at Week 16). A sample size of 250 axSpA patients (200 AS patients and 50 nr-axSpA patients) 
per group is deemed appropriate to achieve adequate power for the primary and secondary 
endpoints for this study. 
An ASAS40 response rate of about 28.2% for the AS population in the placebo group at week 
16 was reported in a published phase III study (CAIN457F2320). The ASAS40 response to 
secukinumab 150 mg is estimated to be 44.9% in the AS population based on the lower bound 
of the 90% confidence interval of risk difference from the Meta-analysis of 3 phase III studies 
(CAIN457F2310, CAIN457F2320 and CAIN457F2308). With 250 patients per treatment group 
(200 AS patients and 50 nr-axSpA patients), there would be approximately 96% power to detect 
a treatment difference of 16.7% in ASAS40 response rates between secukinumab and placebo 
in the evaluation of the primary efficacy hypothesis at Week 16 (Chi Square test, NQuery 7.0). 
The overall sample size will be 500 patients (400 AS patients and 100 nr-axSpA patients) for a 
randomization ratio of 1:1. 
The estimated power with the chosen sample size for secondary efficacy endpoints based on 
the pooled results of the same phase III studies (CAIN457F2310, CAIN457F2320 and 
CAIN457F2308) are summarized in Table 3-1 for binary endpoints and Table 3-2 for 
continuous endpoints.  
 
Table 3-1 
Summary of power for binary secondary endpoints 
Endpoint 
Response Rate 
Power 
  
Secukinumab(N = 200 
AS + 50 nr-axSpA) 
Placebo (N = 200 AS + 
50 nr-axSpA) 
  
ASAS 5/6 
44.2% 
19.5% 
99% 
ASDAS-CRP major 
improvement 
27.8% 
6.4% 
99% 
ASAS20 
59.0% 
38.4% 
99% 
ASDAS-CRP inactive 
disease 
13.6% 
3.5% 
97% 
ASAS partial remission 
15.2% 
5.5% 
92% 


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Table 3-2 
Summary of power for continuous endpoints 
Endpoint 
Mean change from baseline 
Common 
standard 
deviation 
Power 
  
Secukinumab(N = 
200 AS + 50 nr-
axSpA) 
Placebo (N = 200 
AS + 50 nr-
axSpA) 
  
hsCRP1 
-0.79 
0.09 
0.867 
99% 
BASDAI 
-2.61 
-1.48 
2.241 
99% 
BASFI 
-2.14 
-1.13 
2.253 
99% 
SF-36 PCS 
6.87 
3.99 
6.898 
99% 
ASQoL 
-4.46 
-2.56 
4.714 
99% 
PSQI2 
-1 
0 
3.9 
81% 
1 hsCRP is in log scale 
2 Source: mean change from baseline is from Karatas et al 2018 (AS study, median was used) and 
common standard deviation is from Taylor-Gjevre et al 2011 (RA study, largest standard deviation was 
used).  
4 
Change to protocol specified analyses 
No change from protocol specified analysis was made. 
5 
Appendix 
5.1 
Description of efficacy variables 
Assessment of Spondyloarthritis International Society criteria (ASAS) response 
criteria 
The ASAS response measures consist of the following assessment domains (Sieper 2009) 
Main ASAS domains: 
1. Patient’s global assessment of disease activity measured on a VAS scale 
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale. For ASAS response analyses, the total back pain will be 
used. 
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale 
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale (at least one question is needed) 
Additional assessment domains: 
 
2. C-reactive protein (acute phase reactant) 
ASAS40 


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The ASAS40 response is defined as a ≥ 40% improvement and an ≥ 2 units on a scale of 10 in 
at least three of the following 4 domains: back pain, patient global assessment of disease activity, 
physical function (BASFI) and inflammation (mean score of items 5 and 6 of the BASDAI) 
without any worsening in the remaining domain. 
ASAS20 
The ASAS20 response is defined as an improvement of ≥ 20% and ≥ 1 unit on a scale of 10 in 
at least three of the four main domains and no worsening of ≥ 20% and ≥ 1 unit on a scale of 
10 in the remaining domain. 
ASAS 5/6 
The ASAS 5/6 improvement criteria is an improvement of ≥ 20% in at least five domains. 
ASAS partial remission  
The ASAS partial remission is defined as a value not above 2 units in each of the four main 
domains on a scale of 10. 
 ASDAS-CRP, ASDAS Inactive disease, clinically important and 
major improvement 
The 
 ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) will be 
utilized to assess the disease activity status. Parameters used for the ASDAS include: total back 
pain (BASDAI question 2), the patient global assessment of disease activity (ASAS component 
1), peripheral pain/swelling (BASDAI question 3), duration of morning stiffness (BASDAI 
question 6) and C-reactive protein (CRP) in mg/liter (
) 
(Sieper 2009, Lukas 2009).  
The ASDAS formulas are as follows: 
ASDAS-CRP = 0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral 
pain/swelling + 0.058 × duration of morning stiffness + 0.579 × ln(CRP +1) 
 
 
CRP is in mg/liter, 
; the range of other variables is from 0 to 10; ln represents 
the natural logarithm; √ represents the square root. If any of the ASDAS components are 
missing, ASDAS will not be calculated. 
Disease activity states: inactive disease, moderate disease activity, high disease activity, and 
very high disease activity. The 3 values selected to separate these states are < 1.3 between 
inactive disease and moderate disease activity, < 2.1 between moderate disease activity and 
high disease activity, and > 3.5 between high disease activity and very high disease activity. 
Selected cutoffs for improvement scores are a change ≥ 1.1 unit for “minimal clinically 
important improvement” and a change ≥ 2.0 units for “major improvement” (Machado 2011). 
Separate states will be calculated for ASDAS-CRP 
. 


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ASAS components 
Patient’s global assessment of disease activity (VAS) 
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question "How active was 
your disease on average during the last week?”.  
Patient’s assessment of total back pain and nocturnal back pain intensity (VAS) 
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from no 
pain to unbearable pain, after the question “Based on your assessment, please indicate what is 
the amount of back pain at any time that you experienced during the last week?” and “Based 
on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?”. 
Bath Ankylosing Spondylitis Functional Index (BASFI) 
The BASFI is a set of 10 questions designed to determine the degree of functional limitation in 
those subjects with AS. The ten questions were chosen with a major input from subjects with 
AS. The first 8 questions consider activities related to functional anatomy. The final 2 questions 
assess the subjects’ ability to cope with everyday life. A 100 mm VAS is used to answer the 
questions. The mean of the ten questions gives the BASFI score – a value between 0 and 10. In 
the case that some of the BASFI questions are missing, then the average of the non-missing 
items is used (Braun 2009, van Tubergen 2001). 
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
The gold standard for measuring and evaluating disease activity in AS is the BASDAI. The 
BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst problem), 
which is used to answer 6 questions pertaining to the 5 major symptoms of AS: 
1. Fatigue 
2. Spinal pain  
3. Joint pain / swelling  
4. Areas of localized tenderness  
5. Morning stiffness severity  
6. Morning stiffness duration  
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken and is then added to the sum of the first 4 questions. The resulting 0 
to 50 score is divided by 5 to give a final 0 – 10 BASDAI score. Scores of 4 or greater suggest 
suboptimal control of disease, and subjects with scores of 4 or greater are usually good 
candidates for either a change in their medical therapy or for enrollment in clinical trials 
evaluating new drug therapies directed at. BASDAI is a quick and simple index taking between 
30 secs and 2 mins to complete. At least 4 questions should be non-missing to calculate the 
BASDAI score. Otherwise, BASDAI score will be missing (Haywood 2002). If both Q5 and 
Q6 are missing or one of Q1 to Q4 is missing, then the total sum should be divided by 4 instead 


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of 5. If two of Q1 to Q4 is missing and both Q5 and Q6 are not missing, then the sum should 
be divided by 3. 
High Sensitivity C-reactive protein (hsCRP) 
This assessment will be performed in order to identify the presence of inflammation, to 
determine its severity and to monitor the response to treatment. 


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5.2 
Description of health-related quality of life variables 
Ankylosing Spondylitis Quality of Life (ASQoL)  
The ASQoL is a self-administered questionnaire designed to assess health-related quality of life 
in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a 
dichotomous yes/no response option. A single point is assigned for each "yes" response and no 
points for each "no" response resulting in overall scores that range from 0 (least severity) to 18 
(highest severity). As such, lower score indicates better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment," and the measure requires approximately 6 minutes to complete. 
At least 15 answered questions are required to be able to calculate ASQoL using mean 
imputation, (sum of answered)/(number answered)*18 (Doward 2003). 
SF-36 
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy subjects and patients with acute and 
chronic conditions. It consists of eight subscales (domains) that can be scored individually: 
Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, 
Role- Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 
burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients. The eight domains are based on a scale from 0-100 while 
PCS and MCS are norm-based scores with a mean of 50 and a standard deviation of 10. 
Quality metric uses weighted maximum likelihood estimation, a modified version of item 
response theory (IRT) to estimate scale scores when a respondent is missing multiple 
items.  The PCS summary score measure requires scores for seven scales, one of which must 
be the PF scale and the MCS score also requires scores for seven scales, one of which must be 
the MH scale.  Only one item is needed for each of the multi-item domains.  


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Pittsburgh Sleep Quality Index (PSQI) 
The Pittsburgh Sleep Quality Index is a self-report questionnaire that assesses sleep quality over 
a 1-month time interval. Consisting of 19 items under 9 questions, the PSQI measures several 
different aspects of sleep, offering seven component scores and one composite score. The 
component scores consist of subjective sleep quality (1 item), sleep latency (2 items, i.e., how 
long it takes to fall asleep), sleep duration (1 item), habitual sleep efficiency (3 items, i.e., the 
percentage of time in bed that one is asleep), sleep disturbances (9 items), use of sleeping 
medication (1 item), and daytime dysfunction (2 items). 
Of the 19 items, items 1-4 have free entry responses asking for usual bedtime and wake up time, 
number of minutes to fall asleep, and hours slept per night. Items 5-17 have 4-point Likert scale 
responses relating to frequency of specified sleep problems. Item 18 has a 4-pont Likert scale 
response relating to overall assessment of sleep quality (“very good”, “fairly good”, “fairly bad”, 
or “very bad”). Item 19 has a 4-point Likert response scale relating to respondent's overall 


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assessment of “enthusiasm to get things done” (“no problem at all”, “only a very slight problem”, 
“somewhat of a problem”, or “a very big problem”). 
Each item is weighted on a 0-3 interval scale. In scoring the PSQI, seven component scores are 
derived, each scored 0 (no difficulty) to 3 (severe difficulty). The global PSQI score is then 
calculated by totaling the seven component scores, providing an overall score ranging from 0 
to 21, where lower scores denote a healthier sleep quality and higher scores indicate worse sleep 
quality. 
Questions 1 through 9 are not allowed to be missing.  If these questions are missing then any 
scores calculated using missing questions are also missing.   
5.3 
Visit Windows 
Baseline and post-baseline definitions 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. A post-baseline value refers to a measurement taken after the first 
dose of study treatment.  
Analysis visit windows 
Analysis visit windows will be used for the data that is summarized by visit; they are based on 
the study visit and 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, 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 5-4 
Analysis visit windows 
Analysis 
Visit 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group 7 
Group 8 
Group 9 
Group 
10 
Group 
11 
Group 
12 
Group 
13 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Week 4 
29 
2-43 
2-43 
2-43 
 
 
2-43 
2-43 
2-43 
2-43 
2-43 
2-43 
2-43 
 
 
Week 8 
57 
44-71 
44-71 
44-71 
2-85 
 
44-71 
44-71 
44-71 
44-71 
44-71 
44-71 
44-85 
 
 
Week 12 
85 
72-99 
72-99 
72-99 
 
 
72-99 
72-99 
72-99 
72-99 
72-99 
72-99 
 
 
 
Week 16 
113 
100-127 
100-127 
100-127 
86-141 
2-141 
100-127 
100-127 
100-141 
100-141 
100-127 
100-127 
86-141 
2-239 
2-239 
Week 20 
141 
128-155 
128-155 
128-155 
 
 
128-239 
128-155 
 
 
128-155 
128-155 
 
 
 
Week 24 
169 
156-173 
156-183 
156-183 
142-267 
142-267 
 
156-197 
142-197 
142-197 
156-183 
156-183 
142-253 
 
 
Week 25 
176 
174-187 
 
 
 
 
 
 
 
 
 
 
**  
 
 
Week 28 
197 
188-211 
184-211 
184-211 
 
 
 
 
 
 
184-211 
184-211 
 
 
 
Week 32 
225 
212-239 
212-239 
212-239 
 
 
 
198-253 
198-253 
198-253 
212-239 
212-239 
 
 
 
Week 36 
253 
240-267 
240-267 
240-267 
 
 
 
 
 
 
240-267 
240-267 
 
 
 
Week 40 
281 
268-295 
268-295 
268-295 
 
 
 
254-323 
254-323 
254-323 
268-295 
268-295 
 
 
 
Week 44 
309 
296-323 
296-323 
296-323 
 
 
 
 
 
 
296-323 
296-323 
 
 
 
Week 48 
337 
324-351 
324-351 
324-351 
 
 
240-351 
 
 
 
324-351 
324-379 
*** 
 
 
Week 52 
365 
352-393 
324-393 
352-435 
268-435 
268-435 
352-435 
324-393 
324-393 
324-393 
352-393 
 
352-393 
240-393 
240-435 
Week 60 
421 
394-435 
394-435 
 
 
 
 
394-435 
394-435 
394-435 
394-435 
380-435 
394-435 
394-435 
 
Group 1: Patient’s global assessment of disease activity (VAS), Patient’s assessment of back pain intensity (VAS), BASFI, BASDAI, Vital signs 
 
Group 3: SF-36, ASQoL, 
, 
 Lipids  
Group 4: 
, 
, Cardiovascular panel 
Group 5: 
, PSQI, 
 
 
Group 7: hsCRP 


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Analysis 
Visit 
Target 
Day 
Analysis 
Visit 
Window 
Group 1 
Group 2 
Group 3 
Group 4 
Group 5 
Group 6 
Group 7 
Group 8 
Group 9 
Group 
10 
Group 
11 
Group 
12 
Group 
13 
Group 8: hematology, blood chemistry, urinalysis 
Group 9: Urine pregnancy test 
Group 10: Weight 
Group 11: PK 
 
 
* The first day of administration of randomized study treatment (first dose) is defined as Day 1. 
** For Week 25 visit window, if the patient visited at week 24, then any visit at day range between 7-14 days after week 24 visit will be counted as Week 25; Otherwise, if 
the patient missed the visit of week 24, please use the range of 254-267 to count the visit into week 25. 
*** For Week 48 visit window, if the patient visited week 25 as defined above, then any day after week 25 visit up to day 351 would be counted as Week 48. 


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The following rules are used to determine the window for an applicable visit post baseline: 
“Lower limit” = “upper limit of prior applicable visit” + 1. “Upper limit” = “target day of current 
visit” + integer part of (“target day of next applicable visit” – “target day of current visit”)/2. 
Lower limit of the first applicable visit is always Day 2. 
The mapping described above applies to all visits (not just scheduled visits).  Repeat and/or 
unscheduled visits (which will be numbered in the database according to new NCDS standards) 
will be mapped for analysis purposes in the same way as scheduled visits. This leaves the 
possibility, then, for multiple measurements within an analysis window. The following 
conventions will be used to determine the appropriate measurement to be summarized in the 
event of multiple measurements within a visit window. 
Table 5-5 
Rules for flagging variables 
Timing of measurement 
Type of data 
Rule 
Baseline 
All data 
The last measurement made prior to administration of the first dose of study 
treatment – note this may include measurements taken on the day of 
randomization (e.g., lab). Baseline assessments scheduled for and captured on 
Day 1 will be considered baseline measurements regardless of the time of 
assessment. If a patient did not receive any dose of study treatment then the 
randomization date will be used. 
Only the date part will be considered if there is only one assessment on Day 1 
but if there are multiple assessments on Day 1, then the following rules will 
apply: 
1. If time of assessment exist, 
• 
select the last available measurement prior to the reference start 
date/time considering time 
• 
if no measurement prior to the reference start date/time then 
considering time select the earliest measurement post reference start 
date/time 
2. If time of assessment does not exist the measurement from the lowest 
CRF visit number will be used. 
Post-baseline efficacy 
All data 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 
day after) the first one will be used. If the patient switches from placebo to AIN 
within the window the following rules apply: 
1. 
If the analysis visit window is ≤ week 16, then 
• 
If available, the closest measurement to the target date which is on 
or before the switch date will be used 
• 
If there are no data on or before the switch then the closest 
measurement after the switch to target will be used 
2. 
If the analysis visit window is > week 16, then 
• 
If available, the closest measurement to the target date which is 
after the switch date will be used 
• 
If there are no data after the switch then the closest to target before 
or on the switch date will be use 
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be use 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
Post-baseline safety 
Summary visit 
information (e.g., 
lab, etc.) 
The measurement closest to the target day will be used. In the event two 
measurements are taken equally apart (e.g., 1 day before target date and 1 
day after) the first one will be used. If the patient switches from placebo to AIN 
within the window the following rules apply: 
1. 
If the analysis visit window is ≤ week 16, then 


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Timing of measurement 
Type of data 
Rule 
• 
If available, the closest measurement to the target date which is on 
or before the switch date will be used 
• 
If there are no data on or before the switch then the closest 
measurement after the switch to target will be used 
2. 
If the analysis visit window is > week 16, then 
• 
If available, the closest measurement to the target date which is 
after the switch date will be used 
• 
If there are no data after the switch then the closest to target before 
or on the switch date will be use 
Cases where the same parameter is recorded more than once on the same 
date will be handled as follows: 
• 
If time of completion exists the earliest measurement will be used 
• 
If time does not exist the measurement from the lowest CRF visit 
number will be used 
• 
If CRF visit number is the same the average value will be used 
Post-baseline safety  
Notable 
abnormalities 
(e.g., lab) 
The most extreme measurement in the window will be used. Note this means 
a patient can have a notably high and notably low measurement within a 
window 
5.4 
Statistical methodology and assumptions 
5.4.1 
Analysis of continuous data 
5.4.1.1 
Summary statistics for continuous data 
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile and maximum) will be provided for continuous data by visit and treatment group.  
5.4.2 
Analysis of binary and categorical data 
5.4.2.1 
Summary statistics for binary and categorical data 
Summary statistics for discrete variables will be presented in contingency tables and will 
include count and frequency in each category. If applicable, confidence intervals will be derived 
as well based on the score method including continuity correction (Newcombe 1998): 
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z = PROBIT(1-α/2), n as 
total number of subjects (i.e., number of subjects in the denominator), p as estimated crude 
incidence (number of subjects with event / n) and q = 1-p 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
×
=
2
2
2
2
1
4
1
2
1
2
,0
max
100
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
×
=
2
2
2
2
1
4
1
2
1
2
,1
min
100
z
n
nq
p
n
z
z
z
np
U
. 


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In addition, if L > p then L = p and if U < p then U = p. 
For binary response variables the placebo-adjusted response rates including 95% confidence 
interval will be derived. 
SAS code for risk difference: 
proc freq data=; 
        tables response* treatment / riskdiff; 
run; 
Note the response value should be sorted with ‘1’ ahead of ‘0’. 
5.4.3 
Crude incidence and related risk estimates  
5.4.3.1 
Crude incidence and 100*(1-α)% confidence interval 
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event. 
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 1998).  
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z = PROBIT(1-α/2), n as 
total number of subjects (i.e., number of subjects in the denominator), p as estimated crude 
incidence (number of subjects with event / n) and q=1-p. 
Then the lower limit is 
(
)
(
)










+
+
+
−
−
−
−
+
=
2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
 
and the upper limit is 
(
)
(
)










+
−
+
−
+
+
+
+
=
2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
. 
In addition, if L > p then L = p and if U < p then U = p. 
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson, 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses. 


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5.4.4 
Exposure adjusted incidence rate and related risk estimates 
5.4.4.1 
Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain event is observed, or if the event was not experienced, the (censored) 
time to the end of the observation period. The sequence of first occurrences of an event will be 
modeled to follow approximately a Poisson process with constant intensity θ. The rate 
parameter θ will be estimated as λ=D/T, where 
∑
=
=
n
j
jt
T
1
 and D is the number of subjects with 
at least one event. Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson 
variable with parameter θT and observed value D can be obtained based on (Garwood 1936), 
from which an exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai 
1993; Ulm 1990): 
Lower confidence limit   
T
c
L
D
2
,
2
/
5
.
0
α
=
 for D>0, 0 otherwise, 
Upper confidence limit 
T
c
U
D
2
2
,
2
/
1
5
.
0
+
−
=
α
 
Where cα,k is the αth quantile of the Chi-square distribution with k degrees of freedom. 
The example below shows how this should be handled for cases where subjects switch treatment. 
In particular for summarizing ‘Any AIN’ as a group, one should take into consideration the 
sequence of treatments while calculating exposure time for subjects.   
Table 5-6 
Examples for calculating exposure time for incidence rates (IR) 
1st treatment / total 
exposure time 
2nd treatment / total 
exposure time 
AE event onset (in days 
from study start) 
Exposure for IR 
Placebo / 100 days 
AIN457 150 mg / 200 days 
Day 50 (during 1st 
treatment) 
Day 110 (10 days into 2nd 
treatment) 
Placebo:  50 days 
AIN457 150 mg: 10 days 
Any AIN: 10 days 
6 
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Doward LC, Spoorenberg A, Cook SA, et al. (2003) Development of the ASQoL: a quality of 
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