Conditions: Ankylosing Spondylitis
Keywords: Ankylosing Spondylitis secukinumab AIN457H SpondyloArthritis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study was to assess the clinical efficacy, safety and tolerability of secukinumab subcutaneous injections up to 52 weeks in Japanese patients with active AS despite current or previous non-steroidal anti-inflammatory drugs (NSAIDs) and/or anti-tumor necrosis factor (TNF) α therapy. Efficacy and safety data were used to support the registration of secukinumab in Japan for the treatment of active AS.

Detailed description:

Arms:
arm 1: A screening (SCR) epoch running 4-10 weeks before baseline (BSL) was used to assess eligibility followed by 52 weeks of treatment. The treatment periods consist of Treatment period 1 (BSL to Week 24) and Treatment period 2 (Week 24 to Week 52). After Week 52 follows a post-treatment follow-up until Week 60. A follow-up visit was done at 12 weeks after last study treatment administration for all patients, regardless of whether they completed the entire study as planned (Week 60) or discontinue prematurely.

Interventions: intervention 1: Secukinumab 150 mg provided in 1.0 mL pre-filled syringes (PFSs) for sc injection.
Intervention descriptions: intervention 1: Baseline, 1, 2, 3, 4 week. After 4 week, administered every 4 weeks.

Protocol document:
Prot_000.pdf: 
Development - General Medicine
AIN457/Secukinumab
CAIN457H1301 / NCT02750592
An open-label, phase III, study of subcutaneous 
secukinumab to assess efficacy, safety and tolerability at 
up to 52 weeks in Japanese patients with active Ankylosing 
Spondylitis
Authors:
 
Document type:
Clinical Trial Protocol
EUDRACT number:
NA
Version number:
v00 (Original protocol)
Development phase:
III
Release date:
26-Nov-2015
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0, November, 2013


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................13
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................20
2
Study objectives.................................................................................................................21
2.1
Primary objective(s)...............................................................................................21
2.2
Secondary objectives .............................................................................................21
21
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.2
Rationale of study design.......................................................................................23
3.3
Rationale of dose/regimen, route of administration and duration of treatment.....23
3.4
Rationale for choice of comparator .......................................................................24
3.5
Purpose and timing of interim analyses/design adaptations..................................24
3.6
Risks and benefits..................................................................................................24
4
Population..........................................................................................................................25
4.1
Inclusion criteria ....................................................................................................25
4.2
Exclusion criteria...................................................................................................26
5
Treatment...........................................................................................................................28
5.1
Protocol requested treatment .................................................................................28
5.1.1
Investigational treatment.......................................................................28
5.1.2
Additional study treatment....................................................................29
5.2
Treatment arms......................................................................................................29
5.3
Treatment assignment, randomization...................................................................29
5.4
Treatment blinding.................................................................................................29
5.5
Treating the patient................................................................................................29
5.5.1
Patient numbering .................................................................................29
5.5.2
Dispensing the investigational treatment ..............................................29
5.5.3
Handling of study treatment..................................................................29
5.5.4
Instructions for prescribing and taking study treatment........................30


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5.5.5
Permitted dose adjustments and interruptions of study treatment ........31
5.5.6
Rescue medication ................................................................................31
5.5.7
Concomitant treatment..........................................................................31
5.5.8
Prohibited Treatment.............................................................................32
5.5.9
Discontinuation of study treatment .......................................................33
5.5.10
Withdrawal of consent ..........................................................................34
5.5.11
Loss to follow-up ..................................................................................35
5.5.12
Emergency breaking of assigned treatment code..................................35
5.5.13
Study completion and post-study treatment..........................................35
5.5.14
Early study termination.........................................................................35
6
Visit schedule and assessments .........................................................................................35
6.1
Information to be collected on screening failures..................................................39
6.2
Patient demographics/other baseline characteristics .............................................39
6.3
Treatment exposure and compliance .....................................................................39
6.4
Efficacy..................................................................................................................39
6.4.1
Assessment in SpondyloArthritis International Society Criteria 
(ASAS)..................................................................................................40
6.4.2
Patient’s global assessment of disease activity (VAS) .........................41
6.4.3
Patient’s assessment of inflammatory back pain intensity (VAS)........41
6.4.4
Bath Ankylosing Spondylitis Functional Index (BASFI).....................41
6.4.5
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........41
6.4.6
Bath Ankylosing Spondylitis Metrology Index (BASMI linear)..........42
 
42
6.4.8
High Sensitivity C-reactive protein (hsCRP)........................................42
42
42
43
6.4.12
Appropriateness of efficacy assessments..............................................43
6.5
Safety.....................................................................................................................44
6.5.1
T-SPOT test or PPD skin test................................................................44
6.5.2
Chest x-ray or MRI ...............................................................................45
6.5.3
Physical examination ............................................................................45
6.5.4
Vital signs..............................................................................................45
6.5.5
Height and weight .................................................................................45
6.5.6
Laboratory evaluations..........................................................................45
6.5.7
Immunogenicity (IG) ............................................................................46


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6.5.8
Electrocardiogram (ECG) .....................................................................47
6.5.9
Pregnancy and assessments of fertility .................................................47
6.5.10
Local tolerability (Injection site reactions) ...........................................47
6.5.11
Tolerability of secukinumab .................................................................47
6.5.12
Appropriateness of safety measurements..............................................47
6.6
Other assessments..................................................................................................47
6.6.1
Health-related Quality of Life...............................................................48
50
6.6.3
HLA-B27...............................................................................................50
6.6.4
Resource utilization...............................................................................50
6.6.5
Pharmacokinetics (PK)..........................................................................50
7
Safety monitoring..............................................................................................................51
7.1
Adverse events.......................................................................................................51
7.2
Serious adverse events...........................................................................................52
7.2.1
Definition of SAE .................................................................................52
7.2.2
SAE reporting........................................................................................53
7.3
Liver safety monitoring .........................................................................................54
7.4
Renal safety monitoring.........................................................................................54
7.5
Pregnancy reporting...............................................................................................54
8
Data review and database management.............................................................................55
8.1
Site monitoring ......................................................................................................55
8.2
Data collection.......................................................................................................55
8.3
Database management and quality control............................................................56
8.4
Data Monitoring Committee..................................................................................56
8.5
Adjudication Committee........................................................................................56
9
Data analysis......................................................................................................................56
9.1
Analysis sets ..........................................................................................................57
9.2
Patient demographics and other baseline characteristics.......................................57
9.3
Treatments .............................................................................................................57
9.4
Analysis of the primary variable(s) .......................................................................58
9.4.1
Variable(s).............................................................................................58
9.4.2
Statistical model, hypothesis, and method of analysis..........................58
9.4.3
Handling of missing values/censoring/discontinuations.......................58
9.4.4
Supportive analyses...............................................................................58
9.5
Analysis of secondary variables ............................................................................58
9.5.1
Secondary efficacy variables.................................................................58
59


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9.5.3
Safety variables .....................................................................................59
9.5.4
Resource utilization...............................................................................60
9.5.5
Pharmacokinetics ..................................................................................60
9.5.6
Pharmacogenetics/pharmacogenomics .................................................61
9.5.7
PK/PD ...................................................................................................61
9.6
Interim analyses.....................................................................................................61
9.7
Sample size calculation..........................................................................................61
10 Ethical considerations........................................................................................................61
10.1
Regulatory and ethical compliance........................................................................61
10.2
Informed consent procedures.................................................................................62
10.3
Responsibilities of the investigator and IRB/IEC..................................................62
10.4
Publication of study protocol and results...............................................................62
11 Protocol adherence ............................................................................................................63
11.1
Protocol Amendments ...........................................................................................63
12 References .........................................................................................................................63
13 Appendices ........................................................................................................................66
13.1
Appendix 1: Clinically notable laboratory values .................................................66
13.2
Appendix 2: Blood collection logs ........................................................................67
13.3
Appendix 3: Modified New York criteria .............................................................68
13.4
Appendix 4: Assessment of SpondyloArthritis International Society criteria 
(ASAS) ..................................................................................................................69
13.4.1
Bath Ankylosing Spondylitis Functional Index (BASFI).....................69
13.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........69
13.4.3
Bath Ankylosing Spondylitis Metrology Index (BASMI)....................70
72
13.6
Appendix 6: Guidelines for administering the questionnaires for patient 
reported outcomes..................................................................................................73


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List of tables
Table 5-1
Prohibited treatment..............................................................................33
Table 6-1
Assessment schedule.............................................................................36
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria......................66
Table 13-2
Blood collection log for immunogenicity .............................................67
Table 13-3
Blood collection log for pharmacokinetics ...........................................67
List of figures
Figure 3-1
Study design..........................................................................................23


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List of abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase/serum glutamic pyruvic transaminase
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society
AST/SGOT
aspartate aminotransferase/serum glutamic oxaloacetic transaminase
ASQoL
Ankylosing Spondylitis Quality of Life
ATC
anatomical therapeutic chemical classification system
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BMD
bone mineral density
BME
bone marrow edema
BSL
baseline
CD
crohn disease
COX
cyclo-oxigenase
CPO
country pharma organization
CRO
contract research organization
CRP (hsCRP)
(high sensitivity) C-reactive protein
CT
computerized tomography 
CV
coefficient of variation
DMARD
disease modifying anti-rheumatic drug
DXA
dual energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EMA/EMEA
European Medicines Agency


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FAS
full analysis set
GCP
good clinical practice
GGT
gamma glutamyl transpeptidase
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IBD
inflammatory bowel disease
IEC/EC
Independent Ethics Committee
IFN
interferon
IFU
instructions for use
IG
immunogenicity
IL
interleukin
IN
Investigator Notification
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine system
i.v.
intravenous(ly)
kg
kilogram
LDL
low density lipoprotein
LLN
lower limit normal
LLOQ
lower limit of quantification
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram


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MRI
magnetic resonance imaging
MTX
methotrexate
NSAIDs
non-steroidal anti-inflammatory drugs
PD
phamacodynamics
PFS
pre-filled syringe
PG
pharmacogenetics
PK
pharmacokinetics
PoC
proof- of- concept
PPD
purified protein derivative
PRO
patient reported outcome
PsA
psoriatic arthritis
OC/RDC
Oracle clinical/remote data capture
OPG
osteoprotegerin
PCS
Physical Component Summary
PRN
pro re nata
QoL
quality of life
RA
rheumatoid arthritis
RBC
red blood cell
RANKL
receptor activator of nuclear factor kappa-B ligand
RU
Resource Utilization 
SAE
serious adverse event
SCR
screening
s.c.
subcutaneous(ly)
SD
standard deviationSMQ
SpA
spondyloarthritis
SUSAR
suspected unexpected serious adverse reaction 
t.i.d.
ter in die, three times a day
TBL
total bilirubin
TNF/TNFα
tumor necrosis factor
TNFα-IR
TNFα inhibitor inadequate responder
ULN
upper limit normal
VAS
Visual Analog Scale


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VEs 
vertebral edges
WBC
white blood cell
WHO
World Health Organization
WoCBP
women of child-bearing potential


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Glossary of terms
Assessment
A procedure used to generate data required by the study
DMARD
Disease Modifying Anti-rheumatic Drug; In this study this term refers 
only to non-biologics.
Enrollment
Point/ time of patient entry into the study; the point at which informed 
consent must be obtained (i.e., prior to starting any of the 
procedures described in the protocol)
Epoch
The planned stage of the subjects’ participation in the study. Each 
epoch serves a purpose in the study as a whole. Typical epochs are: 
determination of subject eligibility, wash-out of previous treatments, 
exposure of subject to treatment or to follow-up on subjects after 
treatment has ended. Study ‘epoch’ will be referred to study period 
in the protocol
Rescue medication
Any new therapeutic intervention or a significant change to ongoing  
therapy made because a subject is experiencing either no benefit 
from participation in the trial or worsening/ exacerbation of their 
disease
Inadequate response to TNFα
Active disease despite stable treatment with anti-TNFα for at least 3 
months at a stable dose or for at least one dose in the case of lack 
of tolerance
Investigational drug
The drug whose properties are being tested in the study; this 
definition is consistent with US CRF 21 Section 312.3 and is 
synonymous with ‘investigational new drug’ or ‘investigational 
medicinal product’
Investigational treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new treatment.”
This includes any placebos, any active controls, as well as approved 
drugs used outside of their indication/approved dosage or tested in a 
fixed combination.
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or 
allowed by the protocol when used within approved 
indication/dosage
Loading regimen
A series of 4 weekly subcutaneous doses of secukinumab, given at 
baseline (BSL), Weeks 1, 2, and 3, prior to initiating subcutaneous 
maintenance dosing given every 4 weeks starting at Week 4
Medication number
A unique identifier on the label of each investigational / study drug 
package
Premature subject withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study treatment administration and assessments; at 
this time all study treatment administration is discontinued


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Re-Screening
A subject who qualified for all or most eligibility criteria but could not 
be entered within the screening epoch can be considered for re-
screening only once
Stop study participation
Point/time at which the subject came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study drug/ treatment
Any treatment administered to the subject as part of the required 
study procedures; includes investigational treatment and any control 
drugs
Study/investigational treatment 
discontinuation
Point/time when subject permanently stops taking study treatment 
for any reason; may or may not also be the point/time of premature 
subject withdrawal
Subject number
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each subject in the study
Variable
Information used in the data analysis; derived directly or indirectly 
from data collected using specified assessments at specified time 
points


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Protocol summary 
Protocol number
CAIN457H1301
Title
An open-label, phase III, study of subcutaneous secukinumab to assess 
efficacy, safety and tolerability at up to 52 weeks in Japanese patients 
with active Ankylosing Spondylitis
Brief title
Study of efficacy and safety of secukinumab in Japanese patients with
active Ankylosing Spondylitis
Sponsor and Clinical 
Phase
Novartis
Phase III
Investigation type
Drug; Biologic
Study type
Interventional
Purpose and rationale
To assess the clinical efficacy, safety and tolerability of secukinumab  
subcutaneous injections up to 52 weeks in Japanese patients with active 
AS despite current or previous NSAID and/or anti-TNFα therapy. Efficacy 
and safety data will be used to support the registration of secukinumab in 
Japan for the treatment of active AS. 
Primary Objective(s) 
To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to 
baseline in Japanese patients with active AS based on the proportion of 
patients 
achieving 
an 
ASAS(Assessment 
of 
SpondyloArthritis 
International Society criteria) 20 response.
Secondary Objectives

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the proportion of patients achieving 
an ASAS 40 response.

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the proportion of patients achieving 
Bath Ankylosing Spondylitis Disease Activity (BASDAI) 50 
response.

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the change from baseline of high 
sensitivity C-Reactive Protein (hsCRP)

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the proportion of patients meeting 
the ASAS 5/6 response criteria

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the change from baseline in total 
BASDAI

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the change from baseline in SF-36 
PCS

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the change from baseline in 
ASQoL

To assess the efficacy of secukinumab 150 mg s.c. at Week 16 
relative to baseline based on the proportion of patients achieving 
an ASAS partial remission

To assess the pharmacokinetics of secukinumab in Japanese 


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patients

To assess the development of immunogenicity against 
secukinumab

To assess overall safety and tolerability of secukinumab by vital 
signs, clinical laboratory values and adverse events (AEs)
monitoring
Study design
This is a multicenter, open-label, single arm study.
Population
This study population consist of 30 male and female patients aged at 
minimum 18 at time of consent, with moderate to severe AS fulfilling the 
Modified New York criteria for ankylosing.
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following 
criteria:

Patient must be able to understand and communicate with the 
investigator and comply with the requirements of the study and 
must give a written, signed and dated informed consent before 
any study assessment is performed

Male or non-pregnant, non-lactating female patients at least 18 
years of age

Diagnosis of moderate to severe AS with prior documented 
radiologic evidence (x-ray or radiologist’s report) fulfilling the 
Modified New York criteria for AS with active AS assessed by 
BASDAI ≥4 (0-10) and spinal pain as measured by VAS≥4 cm 
(BASDAI question #2) at Baseline

Patients should have been on NSAIDs at the highest 
recommended dose for at least 3 months prior to baseline with 
an inadequate response or failure to respond, or less than 3 
months if therapy had to be withdrawn due to intolerance, 
toxicity or contraindications 

Patients who are regularly taking NSAIDs (including COX-1 or 
COX-2 inhibitors) as part of their AS therapy are required to be 
on a stable dose for at least 2 weeks before baseline

Patients who have been on a TNFα inhibitor (not more than one) 
must have experienced an inadequate response to previous or 
current treatment given at an approved dose for at least 3 
months prior to baseline or have been intolerant to at least one 
administration of an anti-TNFα agent 

Patients who have previously been on a TNFα inhibitor will be 
allowed entry into study after appropriate wash-out period prior 
to baseline:

8 weeks for Remicade® (infliximab) – with a terminal half-
life of 8.0-9.5 days (i.v. infusion)

10 weeks for Humira® (adalimumab) – with a terminal half-
life of 10-20 days (average 2 weeks) (s.c. route)

Patients taking systemic corticosteroids have to be on a stable 
dose of ≤10 mg/day prednisone or equivalent for at least 2 
weeks before baseline
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion 
in this study. No additional exclusions may be applied by the investigator, 
in order to ensure that the study population will be representative of all 
eligible patients.


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


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hormone vaginal ring or transdermal hormone 
contraception

Placement of an intrauterine device (IUD) or intrauterine 
system (IUS)
In case of use of oral contraception women should have 
been stable on the same pill for a minimum of 3 months 
before taking study treatment.
Women are considered post-menopausal and not of child 
bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical 
profile (e.g., age appropriate, history of vasomotor 
symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered 
not of child bearing potential.

Active ongoing inflammatory diseases other than AS that might 
confound the evaluation of the benefit of secukinumab therapy, 
including inflammatory bowel disease or uveitis

Underlying metabolic, hematologic, renal, hepatic, pulmonary, 
neurologic, endocrine, cardiac, infectious or gastrointestinal 
conditions which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at 
unacceptable risk for participation in an immunomodulatory 
therapy

Significant medical problems or diseases, including but not 
limited to the following: uncontrolled hypertension 
(≥160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or 
very poor functional status unable to perform self-care

History of clinically significant liver disease or liver injury as 
indicated by abnormal liver function tests such as SGOT (AST), 
SGPT (ALT), alkaline phosphatase, or serum bilirubin. The
Investigator should be guided by the following criteria:

Any single parameter may not exceed 2 x upper limit of 
normal (ULN). A single parameter elevated up to and 
including 2 x ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to 
enrollment/randomization, to rule out lab error.

If the total bilirubin concentration is increased above 2 x 
ULN, total bilirubin should be differentiated into the direct 
and indirect reacting bilirubin.

History of renal trauma, glomerulonephritis, or patients with one 
kidney only, or a serum creatinine level exceeding 1.5 mg/dl
(132.6 µmol/L)

Screening total WBC count < 3,000/µl, or platelets < 100,000/µl 
or neutrophils 1,500/µl or hemoglobin < 8.5 g/dl (85 g/L)

Active systemic infections during the last two weeks (exception: 
common cold) prior to baseline

History of ongoing, chronic or recurrent infectious disease or 
evidence of tuberculosis infection as defined by either a positive 
PPD skin test (the size of induration will be measured after 48-


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72 hours, and a positive result is defined as an induration of 
≥5 mm or according to local practice/guidelines) or a positive T-
SPOT test as indicated in the assessment schedule in Table 6-
1. Patients with a positive test may participate in the study if 
further work up (according to local practice/guidelines) 
establishes conclusively that the patient has no evidence of 
active tuberculosis. If presence of latent tuberculosis is 
established, then treatment according to local country guidelines 
must have been initiated

Known infection with HIV, hepatitis B or hepatitis C at screening 
or baseline

History of lymphoproliferative disease or any known malignancy 
or history of malignancy of any organ system within the past 5 
years (except for basal cell carcinoma or actinic keratoses that 
have been treated with no evidence of recurrence in the past 3 
months, carcinoma in situ of the cervix or non-invasive 
malignant colon polyps that have been removed)

Current severe progressive or uncontrolled disease which in the 
judgment of the clinical investigator renders the patient 
unsuitable for the trial

Inability or unwillingness to undergo repeated venipuncture (e.g., 
because of poor tolerability or lack of access to veins)

Any medical or psychiatric condition which, in the Investigator’s 
opinion, would preclude the participant from adhering to the 
protocol or completing the study per protocol

Donation or loss of 400 mL or more of blood within 8 weeks 
before dosing

History or evidence of ongoing alcohol or drug abuse, within the 
last six months before baseline

Plans for administration of live vaccines during the study period 
or 6 weeks prior to baseline
Investigational 
and 
reference therapy
Secukinumab 150 mg s.c.
Efficacy assessments

Assessment of SpondyloArthritis International Society criteria 
(ASAS)


Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

 
 


 and hsCRP


Safety assessments

T-SPOT test or PPD skin test

Chest x-ray or MRI

Physical examination

Vital signs


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
Height and weight

Laboratory evaluations

Hepatitis B, C and/ or HIV serology

Immunogenicity

Electrocardiogram

Pregnancy and assessment of fertility

Local tolerability (Injection site reactions)

Tolerability of secukinumab
Other assessments

Health-related Quality of Life


HLA-B27

Pharmacokinetics
Data analysis
The primary efficacy variable is the proportion of patients who achieve an 
ASAS 20 at Week 16. The analysis of the efficacy variable will be based 
on the FAS.A frequency table with the number and percentage of patients 
achieving an ASAS 20 at Week 16 will be presented.
Key words
Ankylosing 
spondylitis, 
chronic 
inflammatory 
disease, 
Japanese, 
secukinumab, AIN457


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1
Introduction
1.1
Background
Ankylosing spondylitis (AS) is a chronic inflammatory disease which belongs to a group of
conditions known as spondyloarthritides. It is mainly characterized by involvement of the
axial skeletons and the sacroiliac joints, but also affects peripheral joints, entheses and 
extraarticular organs. A significant proportion of patients may present with associated 
extraarticular manifestations such as uveitis, psoriasis, inflammatory bowel disease (IBD),
cardiovascular and pulmonary abnormalities. Generalized osteoporosis as well as regional
osteopenia are common in AS patients and predispose them to non-traumatic fractures in spite
of young age and gender (male). The presence of the HLA-B27 antigen is strongly associated
with AS: 90%-95% of patients with AS have European ancestry and carry this marker.
Prevalence of AS is about 1.1% of the population in European countries, however in Japan,
AS prevalence is about 0.0065% (Hukuda et al. 2001). AS is associated with significant 
disability, and thus constitutes a major burden to the patients.
The first-line drug treatment of mild AS consists of non-steroidal anti-inflammatory drugs 
(NSAIDs), although there is no evidence that this class of medication alters the disease course 
or prevents the progression of disability. Treatment with tumor necrosis factor (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 only be 
suppressed but not completely abolished. Results reported in the ASSERT study, the largest 
study ever conducted on Magnetic Resonance Imaging (MRI) evaluation of spinal lesions in 
AS, demonstrated a near complete resolution of inflammatory lesions at the 24 week time 
point with anti-TNF therapy (Braun et al. 2006). However, in other reports AS inflammatory 
bone lesions depicted by MRI did not completely disappear under TNF antagonist therapy 
over a six-month study period. The bone lesions persisted despite full clinical remission, 
which suggests that the inflammatory process was still remaining (Zochling et al. 2007). 
Similarly, residual bone marrow edema (BME) as determined by MRI may represent a 
persistent inflammatory process in rheumatoid arthritis (RA) patients (Brown et al. 2006) and 
psoriatic arthritis (PsA) patients (Anandarajah et al. 2008) despite clinical remission. 
Structural damage could be significant and usually irreversible, with both osteoproliferative 
and osteodestructive changes observed on imaging studies. Classic radiographic findings 
include syndesmophytes, with progression to total spinal fusion in some cases. Radiographs of 
the sacroiliac joint often show sclerosis, erosion, and eventually fusion.
Together, these observations indicate that other treatments are needed to treat patients who do 
not respond to TNF blockers and/or who have incomplete resolution of inflammatory changes 
as evidenced on MRI studies. Current treatment options for patients with intolerance or 
inadequate response to anti-TNFα agents treatment are limited due to slow onset of activity 
and safety concerns. Interleukin (IL)-17 antagonism by secukinumab represents a novel 
approach to interfere with the chronic inflammatory process by selectively targeting the 


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cytokine of the unique subset of helper Th17 cells, as well as other cells that play a role in 
inflammation.
Assuming a potential role of Th17 cells in the inflammatory infiltrate in AS, it can be
speculated that locally disturbed homeostasis of osteoclastogenic and osteoblastogenic
mechanisms characteristic of Spondyloarthritis (SpA) might be amenable to correction via IL-
17 antagonism.
Animal data suggest that IL-17 blockade reduces receptor activator of nuclear factor kappa-B 
ligand (RANKL) dependent osteoclastogenesis upstream of TNFα (Koenders et al. 2005). 
Serum sRANKL levels and sRANKL/Osteoprotegerin (OPG) ratios are up-regulated in 
patients with AS and have relationship with bone mineral density (BMD) and radiological 
changes (Kim et al. 2006).
Notably secukinumab showed good efficacy in patients with AS based upon result of the 
Proof of Concept study (CAIN457A2209) and phase III
studies (CAIN457F2305, 
CAIN457F2310). Study CAIN457A2209 suggested that secukinumab demonstrated high 
efficacy, achieving an ASAS 20 response at Week 6 in 59% of the patients on secukinumab 
versus 24% on placebo, and was well-tolerated (Baeten et al. 2013). At week 94, patients had 
sustained clinical responses as 87% of the inflammatory vertebral edges (VEs) at baseline 
resolved under treatment as seen in MRI assessments (Baraliakos et al. 2015). In 
CAIN457F2305 and CAIN457F2310, in a mixed population of both TNF-naive and TNF-IR 
patients, ASAS20 response at Week 16 was 60.8% for IV-150 mg vs 28.7% for placebo 
(CAIN457F2305) and 61.1% for 150 mg s.c. vs 27.0% for placebo (CAIN457F2310) 
respectively. ASAS40 response rates were around 40% on secukinumab 150 mg.
Based on these  clinical study results, marketing applications have been submitted to the US, 
EU and more than 10 other countries for the use in patients with moderate to severe active AS. 
These applications are all under review by the Health Authorities.In Japan, biologics which 
have been approved for treatment of AS are two anti-TNFα agents, adalimumab and 
infliximab. There is no effective treatment for patients who have an inadequate response to 
anti-TNFα. In consideration of these circumstances, a development program of secukinumab 
for AS has also been projected in Japan.
This local Japan study is planned as a registration study to support the data of the global phase 
III program in AS and collect experience data of treatment for Japanese AS patients.
Secukinumab is approved in Japan for psoriasis and psoriatic arthritis at 300 mg s.c.
1.2
Purpose
The purpose of this phase III study is to assess the clinical efficacy, safety and tolerability of 
secukinumab subcutaneous injections up to 52 weeks in Japanese patients with active AS 
despite current or previous NSAID and/or anti-TNFα therapy. Efficacy and safety data will be 
used to support the registration of secukinumab in Japan for the treatment of active AS.


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2
Study objectives
2.1
Primary objective(s)
To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline in Japanese 
patients with active AS based on the proportion of patients achieving an ASAS(Assessment of 
SpondyloArthritis International Society criteria) 20 response.
2.2
Secondary objectives
1. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving an ASAS 40 response.
2. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving Bath Ankylosing Spondylitis Disease Activity 
(BASDAI) 50 response.
3. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline of high sensitivity C-Reactive Protein (hsCRP)
4. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients meeting the ASAS 5/6 response criteria
5. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline in total BASDAI
6. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline in SF-36 PCS
7. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline in ASQoL
8. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving an ASAS partial remission
9. To assess the pharmacokinetics of secukinumab in Japanese patients
10. To assess the development of immunogenicity against secukinumab
11. To assess overall safety and tolerability of secukinumab by vital signs, clinical laboratory 
values and adverse events (AEs) monitoring


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3
Investigational plan
3.1
Study design
This multicenter study uses an open-label, single arm design. A screening (SCR) epoch
running 4-10 weeks before baseline (BSL) will be used to assess eligibility followed by 52 
weeks of treatment. The treatment periods consist of Treatment period 1 (BSL to Week 24) 
and Treatment period 2 (Week 24 to Week 52). After Week 52 follows a post-treatment 
follow-up until Week 60. A follow-up visit is to be done at 12 weeks after last study treatment 
administration for all patients, regardless of whether they complete the entire study as planned 
(Week 60) or discontinue prematurely.
Secukinumab 150 mg s.c. will be administered once weekly at BSL, Weeks 1, 2, 3 and 4, 
followed by dosing every four weeks starting at Week 4.
In total, approximately 30 patients whose eligibility is confirmed will enter the treatment 
period. At each study treatment visit patients will receive secukinumab 150 mg s.c. up to 
Week 48.
Rescue medication will not be allowed until Week 16. However, patients who are deemed not 
to be benefiting from the study treatment by the investigator or for any reason on their own 
accord will be free to discontinue participation in the study at any time (Section 5.5.6).
Subjects who complete the 1 year trial may be eligible to enter an extension study when it will 
be planned.


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Figure 3-1
Study design
↓  AIN457 administration (150 mg s.c.) via PFS
3.2
Rationale of study design
As mentioned in Section 1.1, clinical study results (CAIN457F2305, CAIN457F2310) 
demonstrated the efficacy and safety of the drug in patients with moderate to severe active AS.
However, there is no experience for secukinumab in Japanese patients with AS. Because of 
the very low prevalence of AS in Japan (0.0065%), it is very difficult to implement a large 
placebo controlled confirmation study in Japan and an open label design was chosen. It is 
expected that approximately 30 patients will be enrolled in this study based on feasibility 
assessments.
No clinically relevant differences in secukinumab PK are observed between Japanese and 
non-Japanese healthy volunteers (CAIN457A1101). Based on population PK analyses, only 
body weight had a relevant impact in the model. The impact of other covariates including race 
on exposure is considered to be not clinically relevant. The difference in weight between the 
global AS population (78.1 ± 14.2 kg) and the Japanese AS population (65.6 ± 14.1 kg) 
(Remicade i.v. 100 application dossiers for marketing authorizations [Approved on 5-Feb-
2010]) was similar to that between the global psoriasis population (88.6 ± 23.6 kg) and 
Japanese psoriasis population (74.4 ± 16.6 kg) (Cosentyx s.c. 150 mg application dossiers for 
marketing authorizations [Approved on 26-Dec-2014]). Based on this, it is assumed that
secukinumab AS phase III results can be used as pivotal data for Japan.
A similar study design had been used in a previous clinical trial for the use of anti-TNFα 
inhibitors for AS patients in Japan (Kobayashi et al. 2012). The secukinumab Japan local 
study is planned for a registration in Japan to support data of the global phase III studies and 
collect experience data of treatment for Japanese AS patients. The study will include 
secukinumab only to collect as many data on the efficacy and safety as possible from a limited 
number of Japanese AS patients.
3.3
Rationale of dose/regimen, route of administration and duration 
of treatment
In 2 pivotal phase III trials (CAIN457F2305 with IV loading, CAIN457F2310 with SC 
loading),the efficacy of the secukinumab 150 mg sc regimen demonstrated consistent efficacy 
across multiple endpoints, with clinically meaningful improvements in AS measures of signs 
and symptoms, objective measures of inflammation, physical function, and patient-reported 
quality of life. In contrast, the 75 mg sc regimen did not achieve statistical significance for 
any of the pre-defined hierarchical endpoints in Study CAIN457F2310. The magnitude of 
treatment effect for the 150 mg s.c.
loading and maintenance regimen in Study 


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CAIN457F2310 was the same as observed for the i.v. loading regimens in Study 
CAIN457F2305, but without the high peak exposures associated with iv loading in that study. 
This suggests little to no added benefit from increasing the dose (or exposure) above 150 mg 
s.c., at least in the initial treatment epoch (16 weeks). Based on these data, secukinumab was 
submitted to obtain the indication for AS in US and EU as following posology;
Secukinumab is recommended for adult patients with active AS. The recommended dose is 
150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2, and 3 followed by
monthly dosing starting at Week 4.
Population PK models were built upon secukinumab concentration data from studies 
conducted in psoriasis, PsA and AS patient populations. Various covariates to explain inter-
patient variability in exposure, such as body weight, age, gender, race (Non-Asian vs. Asian 
including Japanese), and baseline disease severity were evaluated in the model to assess any 
differences among subgroups that might affect secukinumab PK and ultimately its clinical 
efficacy. Only body weight has a relevant impact in the model, and the relationship between 
body weight and exposure is near-linear.
No clinically relevant differences in secukinumab PK are observed between the various 
autoimmune diseases studied (Psoriasis, RA, AS, PsA, crohn disease (CD), AS, non-
infectious uveitis). PK is also similar when compared between healthy volunteers and 
psoriasis patients. Based on these data, dose and regimen are selected in this study as 
supported by the results from the global phase III studies.
3.4
Rationale for choice of comparator
This study has no comparator and all patients will receive secukinumab 150 mg.
3.5
Purpose and timing of interim analyses/design adaptations
A primary end point analysis will be performed after all patients have completed Treatment 
Period 1 (Week 24 visit) to support regulatory filing. Additional analyses may be performed 
to support Health Authority interactions, as necessary.
3.6
Risks and benefits
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure (IB).
As of June 2015, approximately 12000 patients have been enrolled in both completed and 
ongoing studies with secukinumab, with over 9600 having received active drug at doses 
ranging from single and/or multiple doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg 
s.c. across various indications (plaque psoriasis, RA, AS, PsA, multiple sclerosis, uveitis, 
Crohn’s disease, dry eye, polymyalgia rheumatica).
The risk profile of secukinumab in AS is informed by the safety experience from arthritides 
and psoriasis trials. Based on the pooled analysis, infections, neutropenia and hypersensitivity 
are identified as safety risks with secukinumab. Detailed information on the safety profile of 
secukinumab can be found in the "Reference Safety Information" of the IB. In the phase III 
AS studies CAIN457F2305 and CAIN457F2310 in 590 patients, the most common side 


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effects were nasopharyngitis, diarrhea, headache, upper respiratory tract infection and 
dyslipidemia. However, these side effects were also seen in patients who received placebo. In 
the submission dossier for chronic plaque psoriasis and psoriatic arthritis, a comparable safety 
profile between Japanese and non-Japanese patients was observed.
From the standpoint of the overall risk benefit assessment, the current trial with secukinumab 
is justified.
4
Population
The study population will be comprised of the following patients who have passed screening 
assessments, comply with inclusion / exclusion criteria and have provided written consent:
Male and female patients aged at minimum 18 at time of consent, with moderate to severe AS 
fulfilling the Modified New York criteria for ankylosing spondylitis (described in Appendix 3) 
with prior documented radiological evidence (x-ray or radiologist’s report).
Patients must have a history of active AS, a BASDAI ≥4 (0-10) and spinal pain as measured 
by visual analogue scale (VAS) ≥4 cm, on a scale of 0-10 cm (BASDAI question #2).
Patients included must have active disease despite current or previous NSAIDs or TNFα 
inhibitor therapy.
Patients can be re-screened only once. This is a Japan local study and it is expected that 
approximately 38 patients will be screened and 30 patients will be enrolled.
A screening failure rate of 20% is anticipated. Enrollment will stop as soon as the target 
number of patients is reached.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study assessment is performed
2. Male or non-pregnant, non-lactating female patients at least 18 years of age
3. Diagnosis of moderate to severe AS with prior documented radiologic evidence (x-ray or 
radiologist’s report) fulfilling the Modified New York criteria for AS with active AS 
assessed by BASDAI ≥4 (0-10) and spinal pain as measured by VAS ≥4 cm (BASDAI 
question #2) at Baseline
4. Patients should have been on NSAIDs at the highest recommended dose for at least 3 
months prior to baseline with an inadequate response or failure to respond, or less than 3 
months if therapy had to be withdrawn due to intolerance, toxicity or contraindications 
5. Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their AS therapy are required to be on a stable dose for at least 2 weeks before baseline
6. Patients who have been on a TNFα inhibitor (not more than one) must have experienced 
an inadequate response to previous or current treatment given at an approved dose for at 
least 3 months prior to baseline or have been intolerant to at least one administration of an 
anti-TNFα agent 


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7. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after appropriate wash-out period prior to baseline:
a. 8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. 
infusion)
b. 10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days
(average 2 weeks) (s.c. route)
8. Patients taking systemic corticosteroids have to be on a stable dose of ≤10 mg/day 
prednisone or equivalent for at least 2 weeks before baseline
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Chest x-ray or MRI with evidence of ongoing infectious or malignant process, obtained 
within 3 months of screening and evaluated by a qualified physician
2. Patients with total ankylosis of the spine 
3. Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone,  
morphine)
4. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or 
IL-17 receptor
5. Use of any investigational drug and/or devices within 4 weeks of baseline, or a period of 5 
half-lives of the investigational drug, whichever is longer
6. History of hypersensitivity to the study drug or its excipients or to drugs of similar 
chemical classes
7. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before 
baseline
8. Any intramuscular corticosteroid injection within 2 weeks before baseline
9. Patients previously treated with any biological immunomodulating agents except for those 
targeting TNFα
10. Previous treatment with any cell-depleting therapies including but not limited to anti-
CD20, investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-
CD19)
11. 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 
12. 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.

Effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception


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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository

Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for example 
hormone vaginal ring or transdermal hormone contraception

Placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
13. Active ongoing inflammatory diseases other than AS that might confound the evaluation 
of the benefit of secukinumab therapy, including inflammatory bowel disease or uveitis
14. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, 
cardiac, infectious or gastrointestinal conditions which in the opinion of the investigator 
immunocompromises the patient and/or places the patient at unacceptable risk for 
participation in an immunomodulatory therapy
15. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or very poor functional status 
unable to perform self-care
16. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests such as SGOT (AST), SGPT (ALT), alkaline phosphatase, or serum 
bilirubin. The Investigator should be guided by the following criteria:

Any single parameter may not exceed 2 x upper limit of normal (ULN). A single 
parameter elevated up to and including 2 x ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to enrollment/randomization, to rule 
out lab error.

If the total bilirubin concentration is increased above 2 x ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin. 
17. 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)
18. 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)


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19. Active systemic infections during the last two weeks (exception: common cold) prior to 
baseline
20. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis 
infection as defined by either a positive 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 T-SPOT test as indicated in the 
assessment schedule in Table 6-1. Patients with a positive test may participate in the study 
if further work up (according to local practice/guidelines) establishes conclusively that the 
patient has no evidence of active tuberculosis. If presence of latent tuberculosis is 
established, then treatment according to local country guidelines must have been initiated
21. Known infection with HIV, hepatitis B or hepatitis C at screening or baseline
22. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for basal cell carcinoma or actinic 
keratoses that have been treated with no evidence of recurrence in the past 3 months, 
carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been 
removed)
23. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial
24. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins)
25. 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
26. Donation or loss of 400 mL or more of blood within 8 weeks before dosing
27. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
baseline
28. Plans for administration of live vaccines during the study period or 6 weeks prior to 
baseline
5
Treatment
5.1
Protocol requested treatment
5.1.1
Investigational treatment
Novartis/CRO will supply the following study treatments:

Investigational Treatment:

Secukinumab 150 mg provided in a 1 mL PFS (one PFS for 150 mg dose)
Patients will be instructed by site staff on how to self-administer the s.c. injection using the 
PFS containing the liquid formulation of secukinumab, based on the Instructions for Use 
(IFU). The s.c. investigational drug will be administered by the patient into the appropriate 
injection site of the body under the supervision of the site staff. 
Site staff will administer the injection to subjects who are not able or feel insecure to self-
administer the PFS injection.


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The study medication will be labeled as follows:

Secukinumab PFS will be labeled as: AIN457 150 mg/1 ml
For detailed instructions on storage of the investigational treatments, please refer to 
Section 5.5.4.
5.1.2
Additional study treatment
No additional treatment beyond investigational treatment is requested for this trial.
5.2
Treatment arms
This trial is an open label, one arm study.  All patients will be treated with secukinumab 
150 mg.
5.3
Treatment assignment, randomization
At baseline, all eligible patients will receive secukinumab 150 mg s.c. in open-label fashion. 
Patients will receive all secukinumab doses as described in Section 3.1 at the study site, 
according to the assessment schedule in Table 6-1.
5.4
Treatment blinding
Not applicable.
5.5
Treating the patient
5.5.1
Patient numbering
Upon signing the informed consent form, the patient is assigned the next sequential number as 
given by the investigator using the next blank CRF book available from the electronic data 
capture (EDC) system.
If an enrolled patient fails to be treated for any reason, the reason will be entered on the 
Screening Study Disposition CRF.
5.5.2
Dispensing the investigational treatment
Each study site will be supplied by Novartis with secukinumab 150 mg PFS.
5.5.3
Handling of study treatment
5.5.3.1
Handling of investigational treatment
Investigational treatment must be received by a designated person at the study site, handled 
and stored safely and properly, and kept in a secured location to which only the investigator 
and designees have access. Upon receipt, all investigational treatment should be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance.


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Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the investigational treatment but no 
information about the patient.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by 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 investigational treatment, packaging, drug and a copy of the completed 
drug accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
5.5.3.2
Handling of other study treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Study treatment (150 mg secukinumab) will be administered s.c. by 1 mL PFS throughout the 
study as 150 mg / 1 mL secukinumab.
Administration of study treatment will be allowed to occur via self-injection at the study site 
through Week 48. Administration of study treatment must occur after the study assessments 
for the visits that have been completed. The PFS with the ready-to-use study treatment 
solution will be provided by the site staff to the patient. Detailed instructions on the self-
administration of the study treatment will be described in the IFU for secukinumab and 
provided to each patient.
If the patient is not comfortable self-injecting the study treatment, then the site can administer 
it for the patient.
At the BSL visit, patients will be instructed by the site staff, utilizing the IFU, on how to self-
inject using a PFS. Patients will be asked to raise any questions and then to proceed with self-
injection.
At the Week 1 visit, patients will be asked to refer to the IFU and to proceed directly with 
self-injection of the study drug (i.e., no prior retraining) for the remainder of the trial. 
However, if the patient is not comfortable self-injecting the study treatment, then the site staff 
may administer it for the patient. Any event related to self-injection should be reported 
appropriately.
Administration of investigational treatment should occur after sample collection for PK 
assessments at visits specified in Table 6-1.
The investigator should promote compliance by instructing the patient to attend the study 
visits as scheduled and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to attend a study visit as scheduled.


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5.5.5
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments are not permitted. Study treatment interruption is although 
not permitted with the following exceptions: Study treatment interruption is only permitted if, 
in the opinion of the investigator, a patient is deemed to be at a significant safety risk unless 
administration of investigational treatment is temporarily interrupted. In such cases study 
treatment should be interrupted only during the time that this risk is present and ongoing. 
Study treatment can be restarted at the next scheduled visit after resolution of the safety risk.
The effect of secukinumab on live vaccines is unknown; therefore live vaccines should not be
administered during participation in the study. In case a live vaccine has been administered
due to a medical urgency, study treatment should be interrupted for 12 weeks. Any study 
treatment interruption must be recorded on the corresponding eCRF page.
5.5.6
Rescue medication
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a patient is experiencing either no benefit from participation in 
the trial or worsening/exacerbation of their disease. Rescue medication must not be used 
before completion of Week 16 assessments. Although no patient will be restricted from 
receiving necessary rescue medications for lack of benefit or worsening of disease, if rescue 
with prohibited biologics (as described in Section 5.5.8) occurs, patients will be discontinued 
from the study. Efficacy will be assessed in detail at every study visit, and patients who are 
deemed not to be benefiting from the study treatment based on safety and efficacy 
assessments (see Section 5.5.9) or for any reason on their own accord will be free to 
discontinue participation in the study at any time. Changes in NSAID concomitant therapy are 
permitted as per investigator’s clinical judgment after all Week 16 assessments are completed. 
Please see Section 5.5.7, Section 5.5.8 and Section 5.5.9 for further details.
Any use of rescue medication must be recorded in the Prior/Concomitant medications eCRF 
page.
5.5.7
Concomitant treatment
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded.
Guidelines for the use of specific medications are provided below:
Methotrexate
Patients taking MTX (≤25 mg/week) must be on a stable dose for at least 4 weeks before 
baseline and maintained stable until Week 52.
Folic acid
Patients on MTX must be taking folic acid supplementation before baseline and during the 
trial to minimize the likelihood of MTX associated toxicity.


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Sulfasalazine
Patients taking sulfasalazine (≤3 g/day) must be on a stable dose for at least 4 weeks before 
baseline and maintained stable until Week 52.
Leflunomide wash-out with cholestyramine
In case of leflunomide treatment, a drug wash-out of 8 weeks has to be performed. However, 
another wash-out procedure might be considered. Cholestyramine could be given orally to 
wash-out the drug at a dose of 8 g t.i.d. Cholestyramine reduced plasma levels of the active 
leflunomide metabolite by approximately 40% in 24 hours and by 49% to 65% in 48 hours in 
three healthy volunteers. The administration of cholestyramine is recommended in patients 
who require a drug elimination procedure. If a patient receives the dose of 8 g t.i.d. for 11 
days, he/she could be safely randomized 4 weeks after the beginning of the 11 days treatment 
epoch.
Systemic corticosteroids
Treatment with systemic corticosteroids is permitted if the dose was stable within the 2 weeks 
preceding baseline, up to a maximum daily dosage of 10 mg prednisone equivalent. 
Corticosteroid dose reductions below 10 mg prednisone equivalent are permitted after Week 
16, although the corticosteroid dose should not be reduced rapidly.
Any change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding eCRF page.
Intra-articular corticosteroids are not permitted within the 4 weeks preceding baseline 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) and acetaminophen/paracetamol
Patients on regular use of NSAIDs or paracetamol/acetaminophen should be on stable dose 
for at least 2 weeks before baseline to allow inclusion in the study.
NSAIDs, low strength opioids or paracetamol/acetaminophen PRN can be taken during the 
study; however, patients should refrain from any intake during at least the 24 hours before a 
visit with disease activity assessment.
After the Week 16 assessments are completed, a change in the NSAID intake regimen is 
permitted.
Any change of the NSAID/paracetamol/acetaminophen treatment during the trial should be 
recorded on the corresponding eCRF page
5.5.8
Prohibited Treatment
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of the washout 
period unless otherwise specified below.


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Live vaccines should not be given until 12 weeks after last study treatment administration.
Table 5-1
Prohibited treatment
Prohibited treatments
Washout period 
(before BSL)
Etanercept*
4 weeks
Infliximab*
8 weeks
Adalimumab, golimumab, certolizumab*
10 weeks
Unstable dose of MTX or sulfasalazine
(until Week 52)
4 weeks
Other DMARD (except MTX or sulfasalazine)
4 weeks
Leflunomide
8 weeks
Leflunomide with Cholestyramine washout
4 weeks
Unstable dose of NSAIDs (COX1 or COX2 inhibitors)
(until Week 16)
2 weeks
Systemic corticosteroids > 10 mg prednisone equivalent**
(until Week 16)
2 weeks
Intra-articular steroid injections
(until Week 16)
4 weeks
Any investigational treatment or participation in any interventional 
trial
4 weeks or 5 half-lives
(whichever is longer)
Analgesics other than paracetamol/acetaminophen or low strength 
opioids PRN
4 weeks
Live vaccinations
6 weeks
* These agents fall under the category of biologic immunomodulators and are prohibited medications. 
Administration of these agents requires study discontinuation (see Section 5.5.9).
** See details about corticosteroid management in Section 5.5.7.
5.5.9
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time.
They may be considered discontinued if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason.
If premature discontinuation occurs for any reason, the investigator must make every effort to 
determine the primary reason for a patient’s premature discontinuation from the study and 
record this information on the appropriate Study Phase Completion eCRF.
Patients who discontinue study should undergo an end of treatment visit (corresponds to the 
last visit for the patient’s current period of treatment: e.g., Week 24, Week 52) at 4 weeks 
after last study treatment and then also return after an additional 8 weeks for a final follow-up 
visit, corresponding to Week F60 (12 weeks after last study treatment; see Table 6-1). The 


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final follow-up visit should be performed before any new treatment is initiated. For patients 
who are lost to follow-up (i.e., those patients whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw from the study), the 
investigator should show "due diligence" by documenting in the source documents steps taken 
to contact the patient, e.g., dates of telephone calls, registered letters, etc.
Patients who are prematurely discontinued from the study will not be replaced.
Study treatment must be discontinued under the following circumstances:

Withdrawal of informed consent

Emergence of the following adverse events:
a. Any severe or serious adverse event that is not compatible with administration of 
study medication, including adverse events that require treatment with prohibited co-
medication
b. Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
invasive malignant colon polyps which are being or have been removed
c. Life-threatening infection
d. Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the patient at a safety risk for continuation in the 
study (A general guidance on clinically notable laboratory values is provided in 
Appendix 1).
e. Pregnancy
f.
Use of any biologic immunomodulating agent except secukinumab
g. Any protocol deviation that results in a significant risk to the patient’s safety
In addition to these requirements for study treatment discontinuation, the investigator should 
discontinue study treatment for a given patient if there is a lack of improvement or worsening 
of their symptoms, or if on balance, he/she thinks that continuation would be detrimental to 
the patient’s well-being. 
5.5.10
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contacts and does not allow analysis of already obtained biologic material.
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information. Study
treatment must be discontinued and no further assessments conducted. All biological material 
that has not been analyzed at the time of withdrawal must not be used. Further attempts to 
contact the patient are not allowed unless safety findings require communicating or follow-up.


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5.5.11
Loss to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw, the investigator should show "due diligence" by contacting the 
patient, family or family physician as agreed in the informed consent and by documenting in 
the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
5.5.12
Emergency breaking of assigned treatment code
Not applicable.
5.5.13
Study completion and post-study treatment 
A patient will be considered to have completed the study if he/she received a maximum of 48
weeks of study treatment and upon completion of the scheduled study assessments and 
procedures up to and including Week F60.
Information on the patient’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the appropriate Study Phase Completion 
eCRF page.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic treatment. In case of a biologic 
treatment, a waiting period of 12 weeks after the last study treatment before initiating the 
treatment is recommended.
5.5.14
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and treated for a prematurely withdrawn patient. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The 
investigator will be responsible for informing the Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed.
Patients should be seen for all visits on the designated day or as close to it as possible.
At a minimum, patients will be contacted for safety evaluations during the 30 days following 
the last study visit. Documentation of attempts to contact the patient should be recorded in the 
source documentation


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Table 6-1
Assessment schedule
Screening1
Treatment period 1
Treatment period 2
Post-
treatment 
follow-up
Week
SV1 
−10 to 
−4
SV2
≤ −4
BSL
1
2
3
4
8
12
16
20
24*
28
32
36
40
44
48
52*
F60*
Obtain informed consent
X
Inclusion/Exclusion criteria2
X
X
X
Relevant medical history/ current medical 
condition2
X
X
X
Prior medication
X
X
X
AS assessment and history of extra-axial 
involvement3
X
Demography
X
Cardiovascular medical history
X
Smoking history
X
Physical Exam4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Height
X
Weight
X
X
X
X**
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PPD skin test5 or T-SPOT test
X
Chest x-ray or MRI4, 6
S
Hematology, blood chemistry, urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test
X
Hepatitis B, C and/ or HIV serology***4
S
Urine pregnancy test
X
X
X
X
X
X
X
X
ECG
X
X
X**
X
X
Administration of s.c. study treatment via PFS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK assessments (at predose)
X
X
X
X
X
X


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Screening1
Treatment period 1
Treatment period 2
Post-
treatment 
follow-up
Week
SV1 
−10 to 
−4
SV2
≤ −4
BSL
1
2
3
4
8
12
16
20
24*
28
32
36
40
44
48
52*
F60*
Concomitant medication / non-drug therapy
X
Updated as necessary
Adverse events/SAEs (including injection site 
reactions)7
X
Update as necessary
Patient’s global assessment of disease 
activity (VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s assessment of back pain intensity 
(VAS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Spinal mobility (BASMI Linear + chest 
expansion)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ASQoL
X
X
X
X
X
X
X
X
SF-36
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
X
X
X
X
X
X
X
HLA-B27
X
Immunogenicity
X
X
X
X
X
Lipids8
X
X
X
X**
X
Cardiovascular panel
X
X
X
X


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Screening1
Treatment period 1
Treatment period 2
Post-
treatment 
follow-up
Week
SV1 
−10 to 
−4
SV2
≤ −4
BSL
1
2
3
4
8
12
16
20
24*
28
32
36
40
44
48
52*
F60*
Treatment period 1 completion form
X
Treatment period 2 completion form
X
Post-treatment follow-up completion form
X
1 If the patient’s washout period ≤ 4 weeks, Screening visit 1 (SV1) and Screening visit 2 (SV2) can be performed on the same day.
2 Eligibility and relevant medical history assessments are conducted at SV1, SV2 and BSL. The data for all three visits should be recorded on the corresponding eCRFs 
available at SV1
3 Extra-axial involvement as uveitis, psoriasis, inflammatory bowel disease, dactylitis, enthesitis, peripheral arthritis
4 These assessments are source documentation only and will not be entered into the eCRF.
5 A PPD skin test can be performed at any time during the screening period, but it must be read within 72 hours and before baseline.
6 A chest x-ray or MRI is required if it was not performed and evaluated within 3 months prior to screening. The x-ray should be performed after it is certain the patient 
meets inclusion/exclusion criteria in order to minimize unnecessary exposure to radiation. The x-ray may be replaced by a MRI assessment.
7 AEs/SAEs occurring after the patient has signed the informed consent must be captured on the appropriate eCRF page.
8 Sample must be obtained in the fasting state.
* For all patients who discontinue the study, the investigator should ensure that the patient completes an end of treatment visit (corresponds to the last visit for the 
patient’s current treatment period) 4 weeks after last study treatment to complete assessments shown for Week 24 (Treatment period 1) or Week 52 (Treatment period 2) 
in Table 6-1, and also returns after an additional 8 weeks for a final follow-up visit, F60 in Table 6-1 (12 weeks after last study treatment). The final visit should be
performed before any new treatment is initiated. 
**Assessment for weight, Lipid and ECG at week 24 should be done only for patients who discontinue during treatment period 1.
*** Hepatitis B and/or hepatitis C and/or HIV serology testing should be performed during screening epoch prior to initiation of therapy. These assessments will be 
documented in source records only and will not be entered into the eCRF.


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


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

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

 
 


 and hsCRP


6.4.1
Assessment in SpondyloArthritis International Society Criteria (ASAS)
The 
ASAS 
response 
measures 
consist 
of 
the 
following 
assessment 
domains 
(Sieper et al. 2009):
Main ASAS domains:
1. Patient’s global assessment of disease activity measured on a VAS scale
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale
Additional assessment domains:
5. Spinal mobility represented by the  BASMI lateral spinal flexion assessment
6. C-reactive protein (acute phase reactant)
6.4.1.1
ASAS Response Criteria (ASAS 20)
The ASAS Response Criteria (ASAS 20) is defined as an improvement of ≥20% and ≥1 unit 
on a scale of 10 in at least three of the four main domains and no worsening of ≥20% and 
≥1 unit on a scale of 10 in the remaining domain.
6.4.1.2
ASAS Response Criteria (ASAS 40)
The ASAS 40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 
in at least three of the four main domains and no worsening at all in the remaining domain.
6.4.1.3
ASAS 5/6 improvement criteria
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five domains.
6.4.1.4
ASAS partial remission criteria
The ASAS partial remission criteria are defined as a value not above 2 units in each of the 
domains 1 to 4 on a scale of 10.


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6.4.2
Patient’s global assessment of disease activity (VAS)
The patient’s global assessment of disease activity will be performed using a 100 mm visual 
analog scale (VAS) ranging from not severe to very severe, after the question "How active 
was your disease on average during the last week?”.
6.4.3
Patient’s assessment of inflammatory back pain intensity (VAS)
The patient’s assessment of inflammatory back pain will be performed using a 100 mm VAS 
ranging from no pain to unbearable pain, after the questions “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?”. For ASAS calculation the total back 
pain will be used.
6.4.4
Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those patients with AS. The ten questions were chosen with a major input from patients 
with AS. The first 8 questions consider activities related to functional anatomy. The final 
2 questions assess the patients’ ability to cope with everyday life. A 100 mm VAS is used to 
answer the questions. The mean of the ten scales gives the BASFI score – a value between 0 
and 10.
6.4.5
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem), which is used to answer 6 questions pertaining to the 5 major symptoms of AS:
1. Fatigue
2. Spinal pain
3. Joint pain / swelling
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)
5. Morning stiffness duration
6. Morning stiffness severity
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken (questions 5 and 6). The resulting 0 to 10 score is added to the 
scores 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 disease, and patients 
with scores of 4 or greater are usually good candidates for either a change in their medical 
therapy or for enrollment in clinical trials evaluating new drug therapies directed at AS. 
BASDAI is a quick and simple index taking between 30 seconds and 2 minutes to complete.
6.4.5.1
BASDAI 50
The BASDAI 50 is defined as an improvement of at least 50% in the BASDAI compared to
baseline.


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6.4.6
Bath Ankylosing Spondylitis Metrology Index (BASMI linear)
The BASMI is a validated instrument that uses the minimum number of clinically appropriate 
measurements that assess accurately axial status, with the goal to define clinically significant 
changes in spinal movement. Parameters include:
1. Lateral spinal flexion
2. Tragus-to-wall distance
3. Lumbar flexion (modified Schober)
4. Maximal intermalleolar distance
5. Cervical rotation angle
Additionally, the following assessments should be taken:
6. Chest expansion
7. Occiput-to-wall distance
Detailed information on the assessments is described in the Appendix 4.
6.4.8
High Sensitivity C-reactive protein (hsCRP)
This assessment will be performed in order to identify the presence of inflammation, to 
determine its severity, and to monitor response to treatment.


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6.4.12
Appropriateness of efficacy assessments
The efficacy outcome measures used in this study are the standard measures used across AS 
trials and are required for filing.


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6.5
Safety

T-SPOT test or PPD skin test

Chest x-ray or MRI

Physical examination

Vital signs

Height and weight

Laboratory evaluations

Hepatitis B, C and/ or HIV serology

Immunogenicity

Electrocardiogram

Pregnancy and assessment of fertility

Local tolerability (Injection site reactions)

Tolerability of secukinumab
All blood draws and safety assessments should be done prior to study treatment 
administration. Appropriate safety assessments (e.g., evaluation of AEs and SAEs including 
injection site reactions) should be repeated after the dose is administered.
6.5.1
T-SPOT test or PPD skin test
Either a T-SPOT test or a PPD skin test must be performed at screening. Patients with a 
positive test may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the patient has no evidence of active 
tuberculosis, or if presence of latent tuberculosis is established then treatment according to 
local country guidelines must have been initiated.
T-SPOT test
An interferon (IFN-γ) response assay using the IFN-γ ELISPOT (T-SPOT) test must be 
performed for all patients at the screening Visit. Details about sample processing are 
described in the central laboratory manual
PPD skin test
A PPD skin test is to be performed at screening and read before BSL to determine the 
patient’s eligibility for the trial. The test dose is bioequivalent to 5 tuberculin units of standard 
PPD injected intradermally, usually into the volar surface of the forearm. The site is cleaned 
and the PPD extract is then injected into the most superficial layer under the skin. If given 
correctly, the injection should raise a small wheal of about 5 mm, which resolves within 10-
15 minutes.
Because the reaction (induration) will take 48-72 hours to develop, the patients must return to 
the investigators’ site within that time for a proper evaluation of the injection site. This will 
determine whether the patient has had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration 
≥5 mm (or according to local practice/guidelines) is interpreted as a positive result.


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6.5.2
Chest x-ray or MRI
A chest x-ray or MRI at screening (or within 3 months prior to screening) is performed to rule 
out the presence of a pulmonary malignancy of infectious process, in particular tuberculosis. 
Information for chest X-ray or MRI examinations must be included in the source 
documentation at the study site.
6.5.3
Physical examination
The physical examination will include the examination of general appearance, skin, neck, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological system.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF which meet 
the definition of an AE must be recorded in the Adverse Event eCRF and if SAE criteria are 
met also as a SAE.
6.5.4
Vital signs
This will include blood pressure and pulse rate measurements after 5 minutes rest in sitting 
position.
If possible, vital signs assessments should be performed by the same study site staff member 
using the same validated device throughout the study.
6.5.5
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing) (both without shoes) will be measured.
If possible, body weight assessments should be performed by the same study site staff 
member using the same scale throughout the study.
6.5.6
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected listed below (except 
urinalysis). Details on the collection, shipment of samples and reporting of results by the 
central laboratory are provided in the laboratory manual. For the identification of clinically 
notable values, see Appendix 1. All patients with laboratory tests containing clinically 
significant abnormal values are to be followed until the values return to normal ranges or until 
a valid reason, other than treatment related AE, is defined.
6.5.6.1
Hematology
Hemoglobin, platelet, red blood cell (RBC), white blood cell (WBC) and differential white 
blood cell counts will be measured at scheduled visits.


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6.5.6.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid.
6.5.6.3
Lipid panel
A lipid profile, including high density lipoprotein (HDL), low density lipoprotein (LDL), 
cholesterol and, triglycerides will be measured from a fasting blood sample.
A cardiovascular profile including lipoprotein(a), apolipoprotein B, apolipoprotein A-1, and 
adiponectin will be measured from a fasting blood sample.
6.5.6.4
Hepatitis B, C and/ or HIV serology
Hepatitis B and/or hepatitis C and/or HIV serology testing will be performed during screening
epoch prior to initiation of therapy. The result of this assessment will be documented in source 
records only and will not be entered into the eCRF.
6.5.6.5
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. The urinalysis results for standard parameters such as protein, glucose, blood 
and, WBCs will be recorded in the appropriate eCRF page.
6.5.7
Immunogenicity (IG)
Blood samples for immunogenicity (anti-AIN457 antibodies) will be taken pre-dose at the 
scheduled time points as indicated in Table 6-1. The Immunogenicity Sample Log can be 
found in the Appendix 2.
The actual sample collection date and exact time will be entered on the Immunogenicity blood 
collection eCRF page. Sampling problems will be noted in the Comments section of the eCRF.
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein.
IG 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 pre-printed labels will be provided by the central laboratory to the sites.
Analytical method
An electrochemiluminescence method will be used for the detection of potential anti-
secukinumab antibody formation. The detailed method to assess immunogenicity will be 
described in the bioanalytical raw data of the study and in the respective Bioanalytical Data 
Report.


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6.5.8
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as indicated in Table 6-1. All ECGs must be 
performed on the ECG machines provided for the study.
All ECGs will be independently reviewed. Instructions for the collection and transmission of 
the ECGs to the independent reviewer will be provided in the ECG investigator manual.
Clinically relevant abnormalities noted before the baseline ECG should be recorded on the 
relevant medical history/Current medical conditions eCRF page for the baseline ECG.
Clinically relevant abnormalities noted after the baseline ECG should be reported as AE 
(Section 7.1).
6.5.9
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test 
(serum pregnancy test) performed at the screening visit 2 and local urine pregnancy tests as 
indicated in Table 6-1. A positive urine pregnancy test requires immediate interruption of 
study drug until serum β-hCG is performed and found to be negative.
6.5.10
Local tolerability (Injection site reactions)
The local tolerability at the site of s.c. injection of the study treatment will be assessed in case 
of any local reaction, until this has disappeared.
The assessment of pain, redness, swelling, induration, hemorrhage and itching will be 
performed by a physician and will be recorded on the Adverse Events eCRF, including the 
severity (mild, moderate, severe) and the duration.
6.5.11
Tolerability of secukinumab
Tolerability will be assessed by adverse events, laboratory values, injection site reaction and 
immunogenicity.
6.5.12
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in AS. This study involves exposure to radiation from a possible chest X-ray. The 
radiation exposure by these procedures is not necessary for medical care but is intended for 
research purposes only.
The amount of radiation in this study is about 0.1 mSv for the X-ray procedure and is based 
on effective doses for various diagnostic radiological procedures reported in the literature 
(Mettler et al. 2008). This exposure is comparable to the natural radiation an average person 
receives in 10 days. This radiation exposure is considered ‘minimal’ (Stabin et al. 2009). 
Therefore, the radiation exposure in this study involves minimal risk and is necessary to 
ensure patient safety.
6.6
Other assessments

Health-related Quality of Life



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
HLA-B27

Pharmacokinetics
6.6.1
Health-related Quality of Life
The impact of AS on various aspects of patient's health-related quality of life (QoL) will be 
assessed by the following instruments:

SF-36

ASQoL



All questionnaires will be available in Japanese.
All questionnaires will be completed at the scheduled study visit prior to the patient seeing the 
investigator for any other clinical assessment or evaluation. The patient should be given 
sufficient instruction, space, time and privacy to complete the questionnaires. The study 
coordinator should check each questionnaire for completeness and encourage the patient to 
complete any missing responses. Guidelines for administering the PRO questionnaires can be 
found in Appendix 6. A detailed training manual relating to the administrative procedures of 
the questionnaires will be provided to the sites.
Completed questionnaires will be reviewed and examined by the investigator, before the 
clinical examination, for responses that may indicate potential adverse events (AEs) or serious 
adverse events (SAEs). The investigator should review not only the responses to the questions 
in the questionnaires but also for any unsolicited comments written by the patient. If AEs or 
SAEs are confirmed, then the physician must record the events as per instructions given in 
Section 7 of the protocol. Investigators should not encourage the patients to change the 
responses reported in the completed questionnaires.
The language in which each of the questionnaires to be completed will also be captured the 
first time a questionnaire is administered.
6.6.1.1
Medical Outcome Short Form Health Survey (SF-36) Version 2 (Acute 
Form)
The SF-36 is a widely used and extensively studied instrument to measure health-related 
quality of life among healthy patients and patients with acute and chronic conditions. It 
consists of eight subscales that can be scored individually: Physical Functioning, Role-
Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and 
Mental Health (Ware and Sherbourne 1992). Two overall summary scores, the Physical 
Component Summary (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.


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The purpose of the SF-36 in this study is to assess the health-related QoL of patients. Given 
the acute nature of this disease, version 2, with a 1-week recall period, will be used in this 
study.
6.6.1.2
Ankylosing Spondylitis Quality of Life (ASQoL)
The ASQoL is a self-administered questionnaire designed to assess health-related quality of 
life in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a 
dichotomous yes/no response option. A single point is assigned for each "yes" response and 
no points for each "no" response resulting in overall scores that range from 0 (least severity) 
to 18 (highest severity). As such, lower score indicate better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment," and the measure requires approximately 6 minutes to complete.
The purpose of the ASQoL is to assess the disease specific QoL of patients in this study.


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6.6.3
HLA-B27
A blood sample to analyze Human Leukocyte Antigen-B27 (HLA-B27) will be obtained from 
all patients at baseline.
Details on the collection, handling and shipment of the sample to the central laboratory will be 
provided to investigators in the laboratory manual.
6.6.4
Resource utilization 
No measures of Healthcare Resource Utilization (RU) will be collected in the study.
6.6.5
Pharmacokinetics (PK)
PK samples will be obtained for all patients. Secukinumab concentrations will be assessed in 
serum. The PK samples will be collected pre-dose at scheduled visits as indicated in Table 6-1. 
The Pharmacokinetics Sample Log can be found in the Appendix 2. All blood samples will be 
taken by direct venipuncture in a forearm vein.
The actual sample collection date and exact time will be entered on the PK blood collection 
summary page in the eCRF.


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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.
Analytical methods
An ELISA method will be used for bioanalytical analysis of secukinumab in serum, with an 
anticipated lower limit of quantification (LLOQ) of 80 ng/mL. The detailed method 
description to assess secukinumab concentration will be described in the bioanalytical raw 
data of the study and in the respective Bioanalytical Data Report.
7
Safety monitoring
7.1
Adverse events
AE is any untoward medical occurrence (i.e., any unfavorable and unintended sign [including 
abnormal laboratory findings], symptom or disease) in a subject or clinical investigation 
subject after providing written informed consent for participation in the study. Therefore, an 
AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
patient and identifying adverse events. Alert ranges for labs and other test abnormalities are 
included in Appendix 1.
Adverse events should be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information.

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities


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
its relationship to the study treatment (no/yes)

its duration (start and end dates), or if the event is ongoing, an outcome of not 
recovered/not resolved should be reported.

whether it constitutes a serious adverse event (SAE)

action taken regarding study treatment

whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the patient informed 
consent and should be discussed with the patient during the study as needed.
The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
7.2
Serious adverse events
7.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes)

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the patient’s 
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
is medically significant, i.e. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 7.2.2.
7.2.2
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 if there are post-treatment follow-up visits with no required procedures must be 
reported to Novartis within 24 hours of learning of its occurrence. Any SAEs experienced 
after the 30 days period should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department. The telephone and fax number of the contact persons in the local 
department of Drug Safety and Epidemiology, specific to the site, are listed in the investigator 
folder provided to each site. The original copy of the SAE Report Form and the fax 
confirmation sheet must be kept with the case report form documentation at the study site.
Follow-up information should be provided using a new paper SAE Report Form stating that 
this is a follow-up to a previously reported SAE


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Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
patient continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.
7.3
Liver safety monitoring
There has been no safety signal for liver toxicity with secukinumab to date in over 9600 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the liver. Standard liver function tests will be obtained at 
regular intervals, but special measures for liver safety monitoring are not planned. For further 
information on standard liver function tests, see Appendix 1.
7.4
Renal safety monitoring
There has been no safety signal for nephrotoxicity with secukinumab to date in over 9600 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the kidney. All patients with laboratory tests containing 
clinically significant abnormal values (see Appendix 1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined. Standard renal function tests (blood urea nitrogen, serum creatinine) 
will be obtained at regular intervals, but special measures for renal safety monitoring are not 
planned.
7.5
Pregnancy reporting
All pre-menopausal women who are not surgically sterile will have a urine pregnancy test. A 
positive urine pregnancy test requires immediate interruption of study drug until serum β-hCG 
is performed and found to be negative.
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis/CRO within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. The study drug must be discontinued, though the 
patient may stay in the study, if she wishes to do so. All assessments that are considered as a 
risk during pregnancy must not be performed. The patient may continue all other protocol 
assessments.


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Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis/CRO Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis/CRO study drug of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.
8
Data review and database management
8.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of patient records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.  Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis CRA organization, 
Additionally, a central analytics organization may analyse data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 


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database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
8.3
Database management and quality control
Novartis staff review the data entered into the CRFs by investigational staff for completeness 
and accuracy and instruct the site personnel to make any required corrections or additions. 
Queries are sent to the investigational site using an electronic data query. Designated 
investigator site staff is required to respond to the query and confirm or correct the data. If the 
electronic query system is not used, a paper Data Query Form will be faxed to the site. Site 
personnel will complete and sign the faxed copy and fax it back to Novartis staff that will 
make the correction to the database. The signed copy of the Data Query Form is kept at the 
investigator site.
Concomitant 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. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
ECG readings will be processed centrally and the results will be sent electronically to 
Novartis.
Patient reported outcome data will be entered into an electronic device by the patient. The 
system will be supplied by a vendor(s), who will also manage the database. The database will 
be sent electronically to Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and made available for data analysis. Any changes to the database after that time can 
only be made after written agreement by Novartis Development management.
8.4
Data Monitoring Committee
Not required.
8.5
Adjudication Committee
Not required.
9
Data analysis
Summary statistics for continuous variables will include the number of patients (N), mean, 
standard deviation, minimum, median, maximum (lower quartile, upper quartile, if 
appropriate). Summary statistics for discrete variables will be presented in contingency tables 
and will include absolute and relative frequencies. The 95% confidence interval will be 
provided for efficacy variables as appropriate.


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9.1
Analysis sets
The following analysis sets will be used in this study:
Full analysis set (FAS): The FAS will be comprised of all patients who entered into the
treatment periods.
Safety set: The safety set includes all patients who took at least one dose of study treatment
during the treatment periods.
9.2
Patient demographics and other baseline characteristics
Demographics and baseline characteristics
Summary statistics will be presented for demographic and baseline characteristic variables for 
the safety set. 
Medical history
Any significant prior or active medical condition at the time of signing informed consent will
be coded using the MedDRA dictionary. These medical conditions will be summarized by
primary system organ class and preferred term for the safety set. Summaries for 
cardiovascular medical history and ankylosing spondylitis medical history will be presented
as well.
9.3
Treatments
Study treatment
The analysis of study treatment data will be based on the safety set. The number of injections 
will be summarized. The duration of exposure to study treatment will also be summarized. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g. any 
exposure, ≥1 week, ≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, etc.) will be presented.
Duration of exposure is defined as the time from first dose of study treatment to the end of 
treatment period. The end of treatment period will be defined as the last dose plus 84 days or 
last visit whichever occurs earlier. i.e., for patients who discontinued or have their last visit 
earlier than last dose plus 84 days, the end of study treatment exposure will be the date of the 
last study visit.
Prior and concomitant medication
Prior and concomitant medications will be summarized in separate tables. Prior medications
are defined as treatments taken and stopped prior to first dose of study treatment. Any
medication given at least once between the day of first dose of study treatment and within 84 
days after last dose will be a concomitant medication, including those which were started pre-
baseline and continued into the treatment periods.
Medications will be presented in alphabetical order, by Anatomical Therapeutic chemical 
classification (ATC) system codes and grouped by anatomical main group. Tables will show 
the overall number and percentage of patients receiving at least one treatment of a particular 
ATC code and at least one treatment in a particular anatomical main group.


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Significant prior and concomitant non-drug therapies and procedures will be summarized by
primary system organ class and MedDRA preferred term.
The number and percentage of patients receiving prior and concomitant ankylosing
spondylitis therapy will be presented as well.
9.4
Analysis of the primary variable(s)
9.4.1
Variable(s)
The primary efficacy variable is the proportion of patients who achieve an ASAS 20 at 
Week 16. The analysis of the efficacy variable will be based on the FAS.
9.4.2
Statistical model, hypothesis, and method of analysis
A frequency table with the number and percentage of patients achieving an ASAS 20 at 
Week 16 will be presented.
With a small number of patients in this study, the efficacy results will be presented in a
descriptive manner. Neither statistical model nor statistical hypothesis is defined.
9.4.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS 20/40 response and other binary efficacy variables will be handled as 
follows:
1. Patients who drop out of the trial for any reason will be considered non-responders 
from the time they drop out 
2. Patients who do not have the required data to compute response (e.g. ASAS 
components) at baseline and at the specific time point will be classified as non-
responders.
Missing values for continuous efficacy variables will not be imputed. Summary statistics will 
be presented based on all data available at the analysis visits.
9.4.4
Supportive analyses
For binary efficacy variables, the percentage will be calculated based on the number of 
patients with an assessment at the analysis visits (observed case analysis).
9.5
Analysis of secondary variables
9.5.1
Secondary efficacy variables 
All secondary efficacy variables will be summarized using the FAS.
ASAS 40 at Week 16
A frequency table with the number and percentage of patients achieving an ASAS 40 at 
Week 16 will be presented.


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BASDAI 50 at Week 16
A frequency table with the number and percentage of patients achieving a BASDAI 50 at 
Week 16 will be presented.
hsCRP at Week 16
For the change in hsCRP at Week 16, since evidence from the literature would suggest that 
the data is not normally distributed (Huffman et al. 2006), summary statistics will be provided 
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. Summary statistics for the observed values and the change from 
baseline at Week 16 will be presented. 
ASAS 5/6 at Week 16
A frequency table with the number and percentage of patients achieving an ASAS 5/6 at 
Week 16 will be presented.
Total BASDAI at Week 16
Summary statistics for the observed values and the change from baseline at Week 16 will be 
presented.
SF-36 PCS at Week 16
Summary statistics for the observed values and the change from baseline at Week 16 will be 
presented.
ASQoL at Week 16
Summary statistics for the observed values and the change from baseline at Week 16 will be 
presented.
ASAS partial remission at Week 16
A frequency table with the number and percentage of patients achieving an ASAS partial 
remission at Week 16 will be presented.
9.5.3
Safety variables
All safety evaluations will be performed on the Safety set.


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Adverse events
Treatment emergent AEs (events started after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity after dosing based on
preferred term and within last dose + 84 days) will be summarized.
AEs will be summarized by presenting the number and percentage of patients having any AE, 
having an AE in each primary system organ class and having each individual AE (preferred 
term).
Summaries will also be presented for AEs by severity. Separate summaries will be presented
for AEs possibly related to study treatment, death, serious adverse events, AEs leading to 
discontinuation and AEs reading to temporary dose interruption. Adverse events will also be 
summarized by SMQ.
As appropriate, the incidence of AEs will be presented per 100 patient years of exposure.
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests
(hematology, serum chemistry and urinalysis).
For hematology and serum chemistry, descriptive statistics for the change from baseline to 
each analysis visit will be presented. Change from baseline will only be summarized for 
patients with both baseline and post baseline. For each parameter, the maximum change from 
baseline will be analyzed analogously. Shift tables of baseline to the most extreme post 
baseline value will also be presented based on normal ranges for all parameters.
For urinalysis, frequency tables will be presented by analysis visit.
In addition, incidence rates of newly occurring or worsening clinically notable abnormalities 
will be presented for particular parameters.
Vital signs and ECG
Vital signs and ECG measurements will be summarized by presenting descriptive statistics for 
the change from baseline to each analysis visit. Change from baseline will only be 
summarized for patients with both baseline and post baseline.
Incidence rates of newly occurring or worsening clinically notable abnormalities will also be 
presented for particular parameters.
Immunogenicity
A patient listing of immunogenicity (anti-AIN457 antibodies) will be presented.
9.5.4
Resource utilization
Not applicable.
9.5.5
Pharmacokinetics
All patients with concentration data will be included in the pharmacokinetic data analysis.


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Pharmacokinetic variables
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. In addition to mean, standard
deviation (SD), coefficient of variation (CV), median and quartiles, the geometric mean and
geometric coefficient of variation (CV), and n(log) will be presented.
Statistical methods for pharmacokinetic analyses
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 pharmacokinetic samples from previous studies. The modeling approach will be
further detailed in a modeling plan.
9.5.6
Pharmacogenetics/pharmacogenomics
Not Applicable.
9.5.7
PK/PD
An indirect response model, driven by study treatment concentration, will be used to 
characterize the time course of efficacy response. Further details of the modeling approach 
will be specified in a modeling plan.
9.6
Interim analyses
An interim analysis on the efficacy and safety data will be performed after all patients have 
completed the Treatment Period 1 (Week 24 visit) in order to support regulatory filing.
Additional analyses may be performed to support Health Authority interactions, as necessary.
9.7
Sample size calculation
With a very low prevalence of AS in Japan (0.0065%), it is expected that approximately 30 
patients will be enrolled in this study based on the feasibility assessment. With 30 patients and 
assuming an ASAS 20 response rate of 60% at Week 16 (F2310), the estimated lower limit of 
95% confidence interval for the ASAS 20 response rate in Japanese population treated with 
secukinumab 150 mg s.c. will be approximately 42.5%, which is well above the upper limit of 
the 95% confidence interval for the response rate of control group derived in F2310 (ASAS
20 response: 28.4%, CI: 18.1-38.7).
10
Ethical considerations
10.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese Ministry of 
Health, Labor, and Welfare), and with the ethical principles laid down in the Declaration of 
Helsinki.


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10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study or longer if required by locally approved prescribing information. If 
there is any question that the patient will not reliably comply, they should not be entered in 
the study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.


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11
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the CSR.
11.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 Safety Monitoring should be followed.
12
References
References are available upon request.
Anandarajah AP, Schwarz EM, Totterman S, et al. (2008) The effect of etanercept on 
osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic 
arthritis. Ann Rheum Dis; 67:296-301.
Baeten D, Baraliakos X, Braun J, et al. (2013) Anti-interleukin-17A monoclonal antibody 
secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-
controlled trial. Lancet; 382(9906):1705-13.
Baraliakos X, Landewe 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; 64:730-4.
Baraliakos X, Borah B, et al. (2015) Long-term effects of secukinumab on MRI findings in 
relation to clinical efficacy in subjects with active ankylosing spondylitis: an observational 
study. Ann Rheum Dis; 0:1-5.
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.
Braun J, Brandt J, Listing J, et al. (2002) Treatment of ankylosing spondylitis with 
infliximab:A randomized controlled multicenter trial. Lancet; 359:1187-93.


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Braun J, Landewé R, Hermann KG, et al. (2006) Major reduction in spinal inflammation in 
patients with ankylosing spondylitis after treatment with infliximab. Arthritis Rheum; 
54:1646-52.
Brown AK, Quinn MA, Karim Z, et al. (2006) Presence of significant synovitis in rheumatoid 
arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: 
evidence from an imaging study may explain structural progression. Arthritis Rheum; 
54:3761-73.
 
Cosentyx s.c. 150 mg application dossiers for marketing authorizations (Approved on 26-Dec-
2014) http://www.pmda.go.jp/drugs/2014/P201400171/index.html
 
 
Hukuda S, Minami M, Saito T, et al. (2001) Spondyloarthropathies in Japan: nationwide 
questionnaire survey performed by the Japan Ankylosing Spondylitis Society. J Rheumatol; 
28(3):554-9.
 
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.
Kim HR, Lee SH, Kim HY (2006) Elevated serum levels of soluble receptor activator of 
nuclear factors-kappaB ligand (sRANKL) and reduced bone mineral density in patients with 
ankylosing spondylitis. Rheumatology (Oxford); 45(10):1197-200.
Kobayashi S, Harigai M, Mozaffarian N, et al. (2012) A multicenter, open-label, efficacy, 
pharmacokinetic, and safety study of adalimumab in Japanese patients with ankylosing 
spondylitis. Mod Rheumatol; 22(4):589-97.
Koenders MI, Lubberts E, Oppers-Walgreen B, et al. (2005) Blocking of interleukin-17 
during reactivation of experimental arthritis prevents joint inflammation and bone erosion by 
decreasing RANKL and interleukin-1. Am J Pathol; 167:141-9.
 
McHorney CA, Ware JE and Raczek AE C (1992) The MOS 36-Item Short-Form Health 
Survey (SF-36). Medical Care; 31: 247-263.
Mettler FA, Huda W, Yoshizumi TT, et al. (2008) Effective doses in Radiology and 
Diagnostic Nuclear Medicine – A catalog. Radiology; 248:254-63.


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Remicade i.v. 100 application dossiers for marketing authorizations (Approved on 5-Feb-
2010) http://www.pmda.go.jp/drugs/2010/P201000023/index.html
Sieper J, Rudwaleit M, Baraliakos X, et al. (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis; 
68 Suppl 2:ii1-44.
Stabin M, Marcus C, Siegel J (2009) New tool for nuclear medicine patient release 
calculations. J Nucl Med; 50:14N.
Ware JE and Donald Sherbourne C (1992) The MOS 36-Item Short-Form Health Survey (SF-
36). Medical Care; 30: 473-483.
 
Zochling J, Baraliakos X, Hermann KG, et al. (2007) Magnetic resonance imaging in 
ankylosing spondylitis. Curr Opin Rheumatol; 19:346-52.


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13
Appendices
13.1
Appendix 1: Clinically notable laboratory values
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests.
Clinically notable values will be forwarded to Novartis/CRO at the same time that they are 
sent to investigators. Any action based on these laboratory values should be discussed with 
Novartis/CRO personnel.
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria
Final Harmonization
Laboratory Variable
Notable Criteria
Standard Units
SI Units
LIVER FUNCTION AND RELATED VARIABLES
SGOT (AST)
> 3 x ULN
> 3 x ULN
SGPT (ALT)
> 3 x ULN
> 3 x ULN
Bilirubin
> 2 x ULN
> 2 x ULN
Alkaline phosphatase
> 2.5 x ULN
> 2.5 x ULN
RENAL FUNCTION, METABOLIC AND ELECTROLYTE VARIABLES
Creatinine (serum)
>2 x ULN
> 2 x ULN
HEMATOLOGY VARIABLES
Hemoglobin
20 g/L decrease from baseline
Platelet Count
< 100 x 10E9/L
White blood cell count
< 0.8 x LLN
Neutrophils
< 0.9 x LLN


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13.2
Appendix 2: Blood collection logs
Table 13-2
Blood collection log for immunogenicity
Week
Timepoint
Volume
IG Sample 
number
BSL
0 (pre-dose)
2 ml
201
Week 16
0 (pre-dose)
2 ml
202
Week 24
0 (pre-dose)
2 ml
203
Week 52
672 h (post-dose)
2 ml
204
Week 60
2016 h (post-dose)
2 ml
205
Table 13-3
Blood collection log for pharmacokinetics
Week
Timepoint
Volume
PK Sample 
number
PK collection 
number
BSL
0 (pre-dose)
2 ml
101
1
Week 4
0 (pre-dose)
2 ml
102
2
Week 16
0 (pre-dose)
2 ml
103
3
Week 24
0 (pre-dose)
2 ml
104
4
Week 52
672 h (post-dose)
2 ml
105
5
Week 60
2016 h (post-dose)
2 ml
106
5
Unscheduled*
2 ml
100x**
NA
* Unscheduled blood sample is obtained based on the decision of investigators.
** Unscheduled blood samples will be uniquely, sequentially numbered 1001, 1002,…


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


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13.4
Appendix 4: Assessment of SpondyloArthritis International 
Society criteria (ASAS)
The 
ASAS 
response 
measures 
consist 
of 
the 
following 
assessment 
domains 
(Sieper et al. 2009).
Main ASAS domains:
1. Patient’s global assessment of disease activity measured on a VAS scale
2. Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale
3. Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale
4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale
Additional assessment domains:
5. Spinal mobility represented by the BASMI lateral spinal flexion assessment
6. C-reactive protein (acute phase reactant)
13.4.1
Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those subjects with AS. The ten questions were chosen with a major input from subjects 
with AS. The first 8 questions consider activities related to functional anatomy. The final 2 
questions assess the subjects’ ability to cope with everyday life. A 10 cm visual analog scale 
is used to answer the questions. The mean of the ten scales gives the BASFI score – a value 
between 0 and 10.
13.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to 
the 5 major symptoms of AS:
1. How would you describe the overall level of fatigue/tiredness you have experienced?
2. How would you describe the overall level of AS neck, back or hip pain you have had?
3. How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had?
4. How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure?
5. How would you describe the overall level of morning stiffness you have had from the 
time you wake up?
6. How long does your morning stiffness last from the time you wake up?
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (questions 5 and 6) is taken. The mean of questions 5 and 6 is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 


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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).
13.4.3
Bath Ankylosing Spondylitis Metrology Index (BASMI)
Cervical rotation
Cervical rotation is measured twice with the subject supine on plinth, head in neutral position, 
forehead horizontal (if necessary, with the head on a pillow or foam block, which must be 
documented for future reassessments). A goniometer (preferably a gravity goniometer) is 
placed centrally on the forehead. Subject rotates head as far as possible to the right, keeping 
shoulders still; ensure no neck flexion or side flexion occurs. The angle between the sagittal 
plane and the new plane after rotation is recorded. The higher reading of two assessments is 
recorded in degrees. The same procedure is repeated twice for the left side. Record the mean 
of the higher reading from the right side and the higher reading from the left side.
Tragus to wall distance
Tragus to wall distance is measured twice with the subject’s heels and back rested against the 
wall. The chin should be at usual carrying level and the subject takes maximal effort to touch 
the head against the wall. The distance between the tragus and the wall is assessed on each 
side, and an average of the two distances from each side is calculated. The procedure is 
repeated, and the shorter of the two average assessments is reported.
Spinal lateral flexion (lumbar lateral flexion)
Subject stands with heels and buttocks touching the wall, knees straight, shoulders back, and 
hands by the side. The subject bends to the right side as far as possible, without lifting the left 
foot/heel or flexing the right knee and maintaining a straight posture with heels, buttocks, and 
shoulders against the wall. The distance from the third fingertip to the floor when subject 
bends to the side is subtracted from the distance when subject stands upright. The higher of 
two tries is recorded. The maneuver is repeated on the left side. Record the mean of the larger 
difference from the right side and the larger difference from the left side. 
Lumbar flexion (modified Schober index)
Subject is standing erect. Set marks in upright position 5 cm below and 10 cm above 
lumbosacral junction (spinal section of a line joining the dimples of Venus). Measure the 
difference between the distance between marks in a standing position (15 cm) versus a 
forward flexed position when the subject bends forward as far as possible, keeping the knees 
straight. The procedure is repeated, and the higher difference of the two tries is reported.
Maximal intermalleolar distance
Subject is lying down with the legs separated as far as possible with knees straight and toes 
pointing upwards. Alternatively, the subject stands and separates the legs as far as possible. 
Distance between medial malleoli is measured, and the higher of the two readings is recorded.


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Chest expansion
Chest expansion is measured with the subject’s hands resting on or behind the head. The 
measurement is taken at the fourth intercostal level anteriorly. The difference between 
maximal inspiration and expiration in cm (to the nearest 0.1 cm) is recorded twice, and the 
higher difference of the two tries is reported.
Occiput-to-wall distance
Occiput to wall distance is measured twice with the subject’s heels and back rested against the 
wall. The chin should be at usual carrying level, and the subject takes maximal effort to touch 
the head against the wall. The distance between the occiput and the wall is assessed, and the 
shorter of the two readings is reported.


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13.6
Appendix 6: Guidelines for administering the questionnaires for 
patient reported outcomes
Before trial start
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the trial 
and identify any items where a patient’s response might highlight issues of potential concern.
For example, one question in the SF-36 asks ‘How much of the time in the past 4 weeks- have 
you felt downhearted and blue?’ If a patient responds ‘most or all of the time’, then the study 
coordinator should inform the study investigator.
Before completion
1. 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 forms
3. Questionnaire should be administered before the clinical examination
During completion
1. Administrator may clarify the questions but should not influence the response
2. Only one response for each question
3. Also see “Addressing Problems and Concerns”
After completion
1. Check for completeness and not for content*
2. Check for multiple responses that were made in error
*However, any response which may directly impact or reflect the patient’s medical condition 
(e.g., noting of depression) should be communicated by the study coordinator to the 
investigator).
Addressing problems and concerns
Occasionally a patient may have concerns or questions about the questionnaires administered. 
Guidance related to some of the most common concerns and questions are given below.
The patient does not want to complete the questionnaire(s)
Tell the patient that completion of the questionnaire(s) is voluntary. The goal is to better 
understand the physical, mental and social health problems of patients. Emphasize that such 
information is as important as any other medical information and that the questionnaire(s) is 
simple to complete. Suggest that the questionnaire(s) may be different from anything the 
respondent has filled in the past. If the patient still declines, retrieve the questionnaires. 
Record the reason for the decline and thank the patient.


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The patient is too ill or weak to complete the questionnaire(s)
In these instances, the coordinator may obtain patient responses by reading out loud each 
question, followed by the corresponding response categories, and entering the patient’s 
response. No help should be provided to the patient by any person other than the designated 
study coordinator. The coordinator should not influence patient responses. The study 
coordinator cannot translate the question into simpler language and has to be read verbatim.
The patient wants someone else to complete the questionnaire(s)
In no case should the coordinator or anyone other than the patient provide responses to the 
questions. Unless specified in the study protocol, proxy data are not an acceptable substitute 
for patient self-report. Patients should be discouraged from asking a family member or friend 
for help in completing a questionnaire.
The patient does not want to finish completing the questionnaire(s)
If non-completion is a result of the patient having trouble understanding particular items, ask 
the patient to explain the difficulty. Re-read the question for them verbatim but do not 
rephrase the question. If the respondent is still unable to complete the questionnaire, accept it 
as incomplete. Thank the patient.
The patient is concerned that someone will look at his/her responses
Emphasize that all responses are to be kept confidential. Point out that their names do not 
appear anywhere on the questionnaire, so that their results will be linked with an ID number 
and not their name. Tell the patient that his/her answers will be pooled with other patients’ 
answers and that they will be analyzed as a group rather than as individuals. Tell the patient 
that completed forms are not routinely shared with treating staff and that their responses will 
only be seen by you (to check for completeness) and by the investigator. Any response which 
may directly impact on or reflect their medical condition (e.g., noting of severe depression) 
will be communicated by the coordinator to the physician.
The patient asks the meaning of a question/item
While completing the questionnaire, some patients might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the patient by rereading the 
question for them verbatim. If the patient asks to interpret the meaning of an item, do not try 
to explain it, but suggest that he/she use his/her own interpretation of the question. Patients 
should answer the questions based on what they think the questions mean.
General information about all questionnaire(s):
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. The questionnaires should be completed by the patients in a quiet area free 
from disturbance, and before any visit assessments. Patients should receive no help from 
family members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 


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Confidential
Page 75
Clinical Trial Protocol (v00)
Protocol No. CAIN457H1301
per question, then this should be brought to patient. Incomplete questions should not be 
accepted without first encouraging the patient to complete unanswered questions.
The investigator must complete the patient/visit information on the electronic device and 
ensure that the center number, patient’s number and initials are identical to the Case Record 
Form. As there are no source data for this questionnaire, the data queries will be restricted to 
patient/visit information.

SAP_001.pdf: 
Clinical Development
AIN457/Secukinumab
CAIN457H1301 / NCT02750592
An open-label, phase III, study of subcutaneous 
secukinumab to assess efficacy, safety and tolerability at 
up to 52 weeks in Japanese patients with active Ankylosing 
Spondylitis
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final (for Week 52 and 60 analysis)
Release date:
6-Feb-2018
Number of pages:
43
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
6-Feb-
2018
Before 
Week 
52 
DBL
New version for 
week 52 and 60 
analysis
This is a statistical analysis plan
(SAP) for week 52 and 60 analysis. 
This SAP was developed based on 
SAP amendment 3 for week 24 
analysis.


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................10
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................12
2.1.2
Analysis visit windows .........................................................................12
2.2
Analysis sets ..........................................................................................................15
2.2.1
Subgroup of interest ..............................................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Demographics and other baseline characteristics .................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................17
2.4.1
Study treatment / compliance................................................................17
2.4.2
Prior and concomitant therapies............................................................17
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................19
2.6
Analysis of the key secondary objective ...............................................................19
2.6.1
Key secondary endpoint........................................................................19
2.6.2
Statistical hypothesis, model, and method of analysis..........................19
2.6.3
Handling of missing values/censoring/discontinuations.......................19
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.7.1
Secondary endpoints .............................................................................20
2.7.2
Statistical hypothesis, model, and method of analysis..........................21
2.7.3
Handling of missing values/censoring/discontinuations.......................22
2.8
Safety analyses.......................................................................................................22
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................24
2.8.3
Laboratory data .....................................................................................24
2.8.4
Other safety data ...................................................................................27


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2.9
Pharmacokinetic endpoints....................................................................................28
2.10
PD and PK/PD analyses.........................................................................................29
2.11
Patient-reported outcomes .....................................................................................29
2.12
Biomarkers.............................................................................................................32
32
2.14
Interim analysis......................................................................................................38
3
Sample size calculation .....................................................................................................38
4
Change to protocol specified analyses ..............................................................................38
5
Appendix ...........................................................................................................................39
5.1
Imputation rules.....................................................................................................39
5.1.1
Study drug.............................................................................................39
5.1.2
AE date imputation ...............................................................................39
5.1.3
Concomitant medication date imputation .............................................39
5.2
AEs coding/grading ...............................................................................................40
5.3
Laboratory parameters derivations ........................................................................40
5.4
Statistical models...................................................................................................40
5.4.1
Primary analysis....................................................................................40
5.4.2
Key secondary analysis.........................................................................41
5.4.3
Secondary analysis................................................................................41
5.4.4
Safety analysis.......................................................................................41
5.5
Rule of exclusion criteria of analysis sets..............................................................42
6
Reference...........................................................................................................................42


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List of abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase/serum glutamic pyruvic transaminase
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society
AST/SGOT
aspartate aminotransferase/serum glutamic oxaloacetic transaminase
ASQoL
Ankylosing Spondylitis Quality of Life
ATC
anatomical therapeutic chemical classification system
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index 
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMI
Bath Ankylosing Spondylitis Metrology Index
BMD
bone mineral density
BME
bone marrow edema
BSL
baseline
CD
crohn disease
COX
cyclo-oxigenase
CPO
country pharma organization
CRO
contract research organization
CRP (hsCRP)
(high sensitivity) C-reactive protein
CSR
Clinical Study report
CT
computerized tomography 
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DMARD
disease modifying anti-rheumatic drug
DXA
dual energy x-ray absorptiometry
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EMA/EMEA
European Medicines Agency


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FAS
full analysis set
GCP
good clinical practice
GGT
gamma glutamyl transpeptidase
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
IB
investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IBD
inflammatory bowel disease
IEC/EC
Independent Ethics Committee
IFN
interferon
IFU
instructions for use
IG
immunogenicity
IL
interleukin
IN
Investigator Notification
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine system
i.v.
intravenous(ly)
kg
kilogram
LDL
low density lipoprotein
LLN
lower limit normal
LLOQ
lower limit of quantification
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Regulatory Activities


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mg
milligram
MRI
magnetic resonance imaging
MTX
methotrexate
NSAIDs
non-steroidal anti-inflammatory drugs
OC/RDC
Oracle clinical/remote data capture
OPG
osteoprotegerin
PCS
Physical Component Summary
PD
phamacodynamics
PFS
pre-filled syringe
PG
pharmacogenetics
PK
pharmacokinetics
PoC
proof- of- concept
PPD
purified protein derivative
PRN
pro re nata
PRO
patient reported outcome
PsA
psoriatic arthritis
QoL
quality of life
RA
rheumatoid arthritis
RANKL
receptor activator of nuclear factor kappa-B ligand
RAP
Reporting and Analysis Process
RBC
red blood cell
RU
Resource Utilization 
SAE
serious adverse event
SAP
Statistical Analysis Plan
SCR
screening
s.c.
subcutaneous(ly)
SD
standard deviationSMQ
SOC
System Organ Class
SpA
spondyloarthritis
SUSAR
suspected unexpected serious adverse reaction 
t.i.d.
ter in die, three times a day
TBL
total bilirubin


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TFLs
Tables, Figures, Listings
TNF/TNFα
tumor necrosis factor
TNFα-IR
TNFα inhibitor inadequate responder
ULN
upper limit normal
VAS
Visual Analog Scale
VEs 
vertebral edges
WBC
white blood cell
WHO
World Health Organization
WoCBP
women of child-bearing potential


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1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to describe the implementation of the 
statistical analysis planned in the data analysis section 9 of the clinical study protocol. The 
statistical methodology is described below and any deviation from the protocol are documented. 
Additional detailed information regarding the analysis methodology is contained in the 
Appendix section.
The analysis results of this SAP will be presented in the clinical study report (CSR) and first 
interpretable results (FIR) output. 
Study reference documents and versions available at the time of finalization of this SAP are 
listed in Table 1-1.
Table 1-1
Study reference documents and versions available at the time of 
finalization of this Statistical Analysis Plan (SAP)
Name of study reference documents
Version
Study protocol
v00(26-Nov-2015)
Standard TFLs
eRAP tool v2.0 and eRAP GenMed 
Lib_v1.2_31Mar2015G or later
eCRS (Case retrieval sheets)
The definition in the eCRS will be updated 
continuously. The latest one at the interim and 
final analyses will be used and the version of the 
eCRS used for the analyses will be described in a 
footnote in tables.
1.1
Study design
This multicenter study uses an open-label, single arm design. A screening (SCR) period running 
4-10 weeks before baseline (BSL) will be used to assess eligibility followed by 52 weeks of 
treatment. The treatment periods consist of Treatment period 1 (BSL to week 24) and Treatment 
period 2 (week 24 to week 52). Week 52 follows a post-treatment follow-up until Week 60. A 
follow-up visit is to be done 12 weeks after last study treatment administration for all patients, 
regardless of whether they complete the entire study as planned or discontinue prematurely.
Secukinumab 150 mg s.c. once weekly at BSL, Weeks 1, 2, 3 and 4, followed by dosing every 
four weeks starting at Week 4.
In total, approximately 30 patients whose eligibility is confirmed will enter the treatment period. 
At each study treatment visit patients will receive secukinumab 150 mg s.c. up to Week 48.
Rescue medication will not be allowed until Week 16. However, patients who are deemed not 
to be benefiting from the study treatment by the investigator or for any reason on their own 
accord will be free to discontinue participation in the study at any time.
The primary efficacy variable is the proportion of patients who achieve the Ankylosing 
SpondyloArthritis International Society Response Criteria (ASAS 20) at Week 16.


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An interim analysis on the efficacy and safety data was performed after all patients have 
completed Treatment Period 1 (Week 24 visit), and will be performed after all patients have 
completed Treatment Period 2 (Week 52 visit). Additional analyses may be performed to 
support Health Authority interactions, as necessary.
1.2
Study objectives and endpoints
The primary objective is to assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative 
to baseline in Japanese patients with active AS based on the proportion of patients achieving an 
ASAS(Assessment of SpondyloArthritis International Society criteria) 20 response.
The secondary objectives are as follows:
1. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving an ASAS 40 response.
2. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving Bath Ankylosing Spondylitis Disease Activity 
(BASDAI) 50 response.
3. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline of high sensitivity C-Reactive Protein (hsCRP)
4. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients meeting the ASAS 5/6 response criteria
5. To assess the efficacy of secukinumab 150 mg s.c at Week 16 relative to baseline based 
on the change from baseline in total BASDAI
6. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline in SF-36 PCS
7. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the change from baseline in ASQoL
8. To assess the efficacy of secukinumab 150 mg s.c. at Week 16 relative to baseline based 
on the proportion of patients achieving an ASAS partial remission
9. To assess the pharmacokinetics of secukinumab in Japanese patients
10. To assess the development of immunogenicity against secukinumab
11. To assess overall safety and tolerability of secukinumab by vital signs, clinical laboratory 
values and adverse events (AEs) monitoring


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2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis. SAS (version 9.4 or later) in GPSII will be used for all 
analyses in this SAP.
Summary statistics for continuous variables will include the number of patients (N), mean, 
standard deviation, minimum, median, maximum (lower quartile, upper quartile, if appropriate).  
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. The 95% confidence interval will be provided for 
efficacy variables as appropriate.
The cut-off date of the interim analysis at the applicable Week (e.g., Week 52) will be defined 
as the date of the last patient visit at the Week. All available data up to the cut-off date will be 
used in the interim analysis. The analysis results for efficacy variables by week will be presented
only up to the applicable week(e.g., in case the Week 52 interim analysis, efficacy results at 
Week 60 will NOT be presented), while all available results from safety variables will be 
presented.


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2.1.1
General definitions
Study treatment is defined as Secukinumab 150mg in the rest of this document.
In general, a baseline value refers to he last measurement made prior to administration of the 
first dose of study treatment. Baseline assessments scheduled for and captured on day 1 will be 
considered baseline measurements regardless of the time of assessment.
The first day of administration of study treatment (first dose) is defined as Study Day 1 or Day 
1.  All other study days will be labeled relative to Day 1.  For event dates on or after Day 1, 
study day for a particular event date is calculated as [Date of event] – [Date of first dose]+1, 
i.e., Day 2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively. For the dates 
before Day 1, study day for an event date is calculated as [Date of event] – [Date of first dose], 
i.e., Day -1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration 
of an event will be calculated as (Event end date – Event start date + 1). The descriptor ”Day 
0“ will not be used.
2.1.2
Analysis visit windows
Analysis visit windows will be used for the data that is summarized by visit; they are based on 
the study evaluation schedule and comprise a set of days around the nominal visit day.  For any 
assessment, there are the protocol defined scheduled visits around which visit windows will be 
created to cover the complete range of days within the study. These visit windows apply to 
measurements taken at every visit. For assessments collected less often different visit windows 
will be applied as detailed below.
The analysis visit windows depend on the visit schedule for the assessments and are shown in
Table 2-1. 
The analysis visit will be used for listing of visit and period.
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 conventions in 
Table 2-2 will be used to determine the appropriate measurement to be summarized in the event 
of multiple measurements within a visit window.


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Table 2-1
Analysis visit windows
Analysis 
Visit
Wee
k
Sche
duled 
Day
Visit window (Day)
Variables
assessed 
everyVisit
weight, 
ECG
Vital 
signs, 
LAB
PK
ASQoL,
SF-36
Immunog
enicity
Lipids
Cardiova
scular
panel
Baseline
BSL
1
to 1
to 1
to 1
to 1
to 1
to 1
to 1
to 1
Week 1
1
8
2-11
2-11
Week 2
2
15
12-18
12-18
Week 3
3
22
19-25
19-25
Week 4
4
29
26-43
26-43
2-71
2-43
Week 8
8
57
44-71
44-71
44-71
2-85
Week 12
12
85
72-99
72-99
72-99
Week 16
16
113
100-127
2-239
100-127
72-141
100-141
2-141
86-239
2-141
Week 20
20
141
128-155
128-155
Week 24
24
169
156-183
156-183
142-267
142-267
142-267
142-267
Week 28
28
197
184-211
184-239
Week 32
32
225
212-239
Week 36
36
253
240-267
Week 40
40
281
268-295
240-323
Week 44
44
309
296-323
Week 48
48
337
324-351
Week 52
52
365
352-393
240-393
324-393
268-393
268-393
268-393
240-393
268-393
Week 60
60
421
394-449
CRF visit
CRF visit
394-449
394-449
394-449
-
-
Variables assessed every visit: Patient’s global assessment of disease activity (VAS), Patient’s assessment of back pain intensity (VAS), BASFI, 
BASDAI, Spinal mobility (BASMI Linear + chest expansion), 
, hsCRP


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Note that safety assessments in Week F60 in the post treatment follow-up period will NOT be mapped to Week 1 – Week 52 of Analysis Visits
Table 2-2
Rules for flagging variables
Timing of measurement
Type of data
Rule
Baseline
All data
The last measurement made prior to administration of the first dose of study treatment. Baseline 
assessments scheduled for and captured on day 1 will be considered baseline measurements 
regardless of the time of assessment. In case several measurements are taken on day 1 after the 
first dose of study treatment, the first one will be used.
Post-baseline efficacy
All data
The measurement closest to the target will be used. In the event two measurements are taken 
equally apart (e.g. 1 before target date and 1 after) the first one will be used.
Post-baseline safety
Summary visit 
information (e.g. lab, 
ECG, etc.)
Post-baseline safety 
Notable abnormalities 
(e.g. lab)
The most extreme measurement in the window will be used.  Note this means a patient can have a 
notably high and notably low measurement within a window.


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2.2
Analysis sets
The following analysis sets will be used in this study:
Full analysis set (FAS): The FAS will be comprised of all patients who entered into the 
treatment periods.
Safety set: The safety set includes all patients who took at least one dose of study treatment
during the treatment periods.
Note that patients not exposed to study drug at any visit (DVSPID = TRT01) will be excluded 
from the Safety set.
2.2.1
Subgroup of interest
Table 2-3 displays the subgroup of interest and endpoints evaluated based on the subgroups.
Table 2-3
Subgroup of interest and endpoints evaluated
Subgroup of interest
Endpoints

Previous use of TNF-alpha inhibitors

Primary and all secondary endpoints

Crude incidence of AE, SAE by SOC 
and PT

hsCRP value (≤10 mg/L, >10mg/L) 
at baseline

Primary and all secondary endpoints

hsCRP value (≤5 mg/L, > 5 mg/L) at 
baseline

Primary and selected secondary 
endpoint (ie, ASAS20 and ASAS 40)

Age (< 65 yr, ≥65 yr)

Gender

Weight (< 70 kg, 70 – 90 kg, > 90 kg)

Primary and selected secondary 
endpoint (ie, ASAS20 and ASAS 40)

Crude incidence of AE, SAE by SOC 
and PT
Note that the threshold value for subgroup analysis of hsCRP (≤10 mg/L, >10mg/L), age, and 
weight is same as the one in CTD Clinical Overview of Secukinumab in Ankylosing Spondylitis
in EU and US.


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
The  number of patients who entered the screening period will be presented. In addition, the 
reasons for screen failures will be provided.
The number and percentage of patients in the safety set who completed treatment periods, and 
Post-treatment follow-up, and who discontinued the study prematurely (including the reason 
for discontinuation) will be presented.
For each protocol deviation (PD), the number and percentage of patients for whom the PD 
applies will be tabulated for entire period (i.e., all PDs will be presented.) in the safety set.
2.3.2
Demographics and other baseline characteristics
The following common background and demographic variables will be summarized:
Continuous variables:

Age at the time of informed consent

Height 

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2
For BMI, height and body weight of the last value prior to baseline is used. If there is no weight 
recorded prior to taking of study drug, BMI will be missing.
Categorical variables:

Age categories (<65 years, 65 years and older, 75 years and older)

Gender

Race

Ethnicity

Smoking status at baseline
Baseline disease characteristics will also be summarized for the following variables:
Patient’s global assessment of disease activity and other ASAS components, hsCRP, 
, TNF  
alpha inhibitor inadequate responder, number and previous use (yes/no) of TNF-alpha inhibitor, 
use (yes/no) and separate dose of methotrexate (mg/week), sulfasalazine (g/day) and systemic 
corticosteroids (mg/day) at baseline, time since first diagnosis of AS (years), time since onset 
of inflammatory back pain (years), HLA-B27, 
, BASDAI (Total and #2), BASMI 
(linear), BASMI components (all seven in original units).
Calculation method for dose of systemic corticosteroids is described in 2.4.2.


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Unless otherwise specified, summary statistics will be presented for continuous variables and 
for all patients (total) in the safety set. The number and percentage of patients in each category 
will be presented for categorical variables for all patients (total) in the safety set.
2.3.3
Medical history
Any condition entered on the Relevant medical history / current medical conditions CRF will
be coded using the MedDRA dictionary. They will be summarized by system organ class (SOC) 
and preferred term (PT) of the MedDRA dictionary. Summaries for cardiovascular
medical history and ankylosing spondylitis medical history will also be provided on the safety 
set.
Smoking history will be summarized on the safety set.
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 injections 
will be summarized. The duration of exposure to study treatment will also be summarized. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g., any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented. 
In general, duration of exposure is defined as the time from first dose of study treatment to the 
end of treatment period. The end of treatment period will be defined as the last dose plus 84 
days or last visit (including Week F60 in the Post-treatment follow-up period), whichever 
occurs earlier, i.e., for patients who discontinued or have their last visit earlier than last dose 
plus 84 days, the end of study treatment exposure will be the date of the last study visit.
Duration of exposure (days)= (last visit date or last dose date + 84 days whichever comes earlier) 
−first dose date + 1
Duration of exposure (years) = duration of exposure (days) / 365.25
2.4.2
Prior and concomitant therapies
Prior and concomitant medications will be summarized in separate tables based on the safety 
set. Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of study treatment 
and within 84 days after last dose will be a concomitant medication, including those which were 
started pre-baseline and continued into the treatment periods.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of patients receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group.
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 


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treatment and within 84 days after last dose will be concomitant surgeries and procedures, 
including those which were started pre-baseline and continued into the period where study 
treatment is administered.
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term on the safety set.
The number and percentage of patients receiving prior and concomitant ankylosing spondylitis 
therapy (disease-specific therapy) will be presented by category for medication preferred term 
on the safety set. The category is “Topical glucocorticoids”, “Systemic glucocorticoids”, 
“Nonsteroidal anti-inflammatory drugs”, “Tumour necrosis factor alpha inhibitor”, and “Other 
ankylosing spondylitis medication”.  Glucocoriticoids in the eCRF page will be devided into 
two; Topical one and Systemic one based on whether the Route (CMROUTE in SDTM) is 
Topical or not. The category for NSAIDs will be specified based on whether the data is from 
the NSAIDs CRF page or not.
At a minimum, methotrexate, sulfasalazine and systemic corticosteroid intake at baseline (Day 
1) will be presented based on the amount taken per time unit, e.g. mg/day. Since different 
steroids have different strengths the following multiplication factors will be used to convert a 
dose in mg into a prednisone equivalent dose in mg:
Cortisone (0.20), hydrocortisone (0.25), prednisolone (1.0), triamcinolone (1.25), 
methylprednisolone (1.25), dexamethasone (6.67), betamethasone (8.33) (corticosteroid 
converter website).
The reported dose and frequency of intake will be converted into the desired units. If the 
frequency is missing or specified as ‘per needed’, ‘unknown’, ‘once’, ‘other’ or if the dose or 
dose unit is missing, then the medication will not be part of the presentation.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The primary efficacy variable is the proportion of patients who achieve an ASAS 20 at Week 
16. The analysis of the efficacy variable will be based on the FAS.
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


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4. Inflammation represented by mean duration and severity of morning stiffness, represented 
by the average of the last 2 questions on the 6-question BASDAI as measured by VAS 
scale
Additional assessment domains:
5. Spinal mobility represented by the  BASMI lateral spinal flexion assessment
6. C-reactive protein (acute phase reactant)
The ASAS Response Criteria (ASAS 20) is defined as an improvement of ≥ 20% and ≥ 1 unit 
on a scale of 10 in at least three of the four main domains and no worsening of ≥ 20% and ≥ 1 
unit on a scale of 10 in the remaining domain.
The  ASAS20 response will be evaluated in subgroups based on previous use of TNF-alpha 
inhibitors,hsCRP value (≤10 mg/L, >10mg/L, and ≤5 mg/L, > 5 mg/L) at baseline, age (< 65 
yr, ≥ 65 yr), gender,  weight (< 70 kg, 70 – 90 kg, > 90 kg) at baseline.
2.5.2
Statistical hypothesis, model, and method of analysis
A frequency table with the number and percentage of patients achieving an ASAS 20 at Week 
16 will be presented. Because of the small number of patients in this study, the efficacy results 
will be presented in a descriptive manner. Neither statistical model nor statistical hypothesis is 
defined.
2.5.3
Handling of missing values/censoring/discontinuations
Missing data for ASAS 20 up to Week 52 will be handled as follows:
1. Patients who drop out of the trial for any reason will be considered non-responders from 
the time they drop out 
2. Patients who do not have the required data to compute response (e.g. ASAS 
components) at baseline and at the specific time point will be classified as non-
responders.
2.5.4
Supportive analyses
For binary efficacy variables, the percentage will be calculated based on the number of patients 
with an assessment at the analysis visits in the FAS (observed case analysis).
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
Not applicable
2.6.2
Statistical hypothesis, model, and method of analysis
Not applicable
2.6.3
Handling of missing values/censoring/discontinuations
Not applicable


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2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
ASAS 40 at Week 16
The ASAS 40 response is defined as an improvement of ≥40% and ≥2 units on a scale of 10 
in at least three of the four main domains and no worsening at all in the remaining domain.
Total BASDAI and BASDAI 50 at Week 16
The BASDAI consists of a 0 through 10 scale (1 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 (called enthesitis, or inflammation of tendons and 
ligaments) 
5. Morning stiffness duration 
6. Morning stiffness severity 
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (Q5 and Q6 above) is taken. The resulting 0 to 50 score is divided by 5 to 
give a final 0 – 10 BASDAI score (total BASDAI). Scores of 4 or greater suggest suboptimal 
control of disease, and patients with scores of 4 or greater are usually good candidates for either 
a change in their medical therapy or for enrollment in clinical trials evaluating new drug 
therapies directed at AS. BASDAI is a quick and simple index taking between 30 secs and 2 
mins to complete.
At least 4 questions should be non-missing to calculate the BASDAI score. Otherwise, the 
BASDAI score will be regarded as missing (Haywood 2002). If both Q5 and Q6 are missing or 
one of Q1 to Q4 is missing the total sum should be divided by 4 instead of 5. If two of Q1 to 
Q4 is missing and both Q5 and Q6 are not missing the sum should be divided by 3.
The BASDAI50 is defined as a 50% improvement over the initial total BASDAI (Braun, 2003;
Rudwaleit, 2004).
hsCRP at Week 16
This assessment will be performed in order to identify the presence of inflammation, to 
determine its severity, and to monitor response to treatment.
ASAS 5/6 at Week 16
The ASAS 5/6 improvement criteria is an improvement of ≥20% in at least five domains.


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SF-36 PCS at Week 16
See Section 2.11 Patient-reported outcomes.
ASQoL at Week 16
See Section 2.11 Patient-reported outcomes.
ASAS partial remission at Week 16
The ASAS partial remission criteria is defined as a value not above 2 units in each of the 
domains 1 to 4 on a scale of 10.
Pharmacokinetics of secukinumab in Japanese patients
See Section 2.9 Pharmacokinetic endpoints.
2.7.2
Statistical hypothesis, model, and method of analysis
Given the small number of patients in this study, the efficacy results will be presented in a 
descriptive manner. Neither statistical model nor statistical hypothesis is defined.
ASAS 40 at Week 16
A frequency table with the number and percentage of patients achieving an ASAS 40 at Week 
16 will be presented.
BASDAI 50 at Week 16
A frequency table with the number and percentage of patients achieving a BASDAI 50 at Week 
16 will be presented.
hsCRP at Week 16
For the change in hsCRP at Week 16, since evidence from the literature would suggest that the 
data is not normally distributed (Huffman, 2006), summary statistics will be provided 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. Summary statistics for the observed values and the change from baseline 
at Week 16 will be presented. 
ASAS 5/6 at Week 16
A frequency table with the number and percentage of patients achieving an ASAS 5/6 at Week 
16 will be presented.
Total BASDAI at Week 16
Summary statistics for the observed values and the change from baseline at Week 16 will be 
presented.


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SF-36 PCS at Week 16
See Section 2.11 Patient-reported outcomes.
ASQoL at Week 16
See Section 2.11 Patient-reported outcomes.
ASAS partial remission at Week 16
A frequency table with the number and percentage of patients achieving an ASAS partial 
remission at Week 16 will be presented.
Pharmacokinetics of secukinumab in Japanese patients
See Section 2.9 Pharmacokinetic endpoints.
2.7.3
Handling of missing values/censoring/discontinuations
These handlings for binary efficacy variables up to Week 52 will be the same as described in 
2.5.3. For binary efficacy variables, the observed case analysis (the percentage calculated based 
on the number of patients with an assessment at the analysis visits in the FAS) is also performed 
as the supportive analysis.
Missing values for continuous efficacy variables will not be imputed. Summary statistics will 
be presented based on all data available at the analysis visits.
2.8
Safety analyses
Summaries will be performed for entire treatment period in the Safety set.
2.8.1
Adverse events (AEs)
Only treatment emergent adverse events are summarized. However all AEs are included in the 
listing with flags for treatment emergent. Non-treatment emergent adverse events may be 
summarized separately upon request.
Treatment emergent adverse events are defined as events started after the first dose of study 
medication or events present prior to the first dose of study medication but increased in severity 
after dosing based on preferred term and within last dose + 84 days.
The crude incidence of treatment emergent adverse events will be summarized by primary 
system organ class and preferred term. Confidence intervals for the crude rate will be derived 
as described in 5.4.4. In addition, exposure time-adjusted rates (incidence  rate) including 95% 
confidence intervals will be provided for entire treatment period described below.

Primary SOC level for AE

Primary SOC and PT level for SAE


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
Level 1 for risks and SMQ
AEs will be summarized by presenting the number and percentage of patients having any AE, 
having an AE in each primary system organ class and having each individual AE (preferred 
term). AEs reported will be presented in descending frequency according to its incidence in all 
patients 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 patient
reported more than one adverse event with the same preferred term, the adverse event with the 
greatest severity will be presented. If a patient reported more than one adverse event within the 
same primary system organ class, the patient will be counted only once with the greatest severity 
at the system organ class level, where applicable.
Separate summaries will be presented for AEs possibly related to study treatment, death, serious 
adverse events (SAEs), SAEs possibly related to study treatment, AEs leading to 
discontinuation and AEs leading to temporary dose interruption.
Adverse events will also be reported separately by SMQ according to MedDRA, using a narrow 
search. The MedDRA version used for reporting the study will be described in a footnote.
In addition, crude incidence of AEs will be derived by 3 months intervals (only the first 
occurrence will be counted in case of multiple occurrences.)
For SAEs occurred during screening a listing will be prepared for all patients screened including 
screening failures.
MedDRA version used is the latest one at the analysis performed and will be specified in the 
subsequent SAP by clinical database lock as applicable.
Based upon the clinical information disclosure requirements of ClinicalTrials.gov and EudraCT, 
two required tables on treatment-emergent adverse events which are not serious adverse events 
with an incidence greater than 5% and on treatment-emergent serious adverse events and SAE 
suspected to be related to study treatment will be provided by system organ class and preferred 
term in the safety set population.
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


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
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block, e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
Safety topics of interest, such as risks defined in the Safety Profiling Plan (SPP), Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are defined 
in the Program Case Retrieval Sheet.
The crude incidence and exposure-adjusted incidence rates (only for level 1) will be 
summarized. In addition, listings will be provided presenting which patients experienced which 
risk.
The version of the Case Retrieval Sheet used for the analyses will be described in a footnote. 
This includes MedDRA version and Customized MedDRA Query (CMQ) and Novartis 
MedDRA Query (NMQ) dictionary date.
2.8.2
Deaths
A listing for deaths will be presented. The listing will include trial period when death occured, 
and whether the death is on treatment, post-treatment follow-up, or screening will be identified.
2.8.3
Laboratory data
The general guideline for laboratory summaries(including Vital sign and ECGs) are as below:

All the summary of lab outputs (newly occurring notables, maximum changes, shift 
tables, by visit summary statistics) will consider the "on-treatment" data, i.e., all 
assessments within last dose plus 84 days.
Follow up visit summary: using CRF visits (including early discontinued patients), i.e., 
not applying visit window and cut-off day 84. Summary of follow up visit outputs will
be provided. The listing will provide follow up visit records.

All records are displayed in the listing with the on-treatment flag, i.e.,  occurred within 
last dose plus 84 days- yes or no.
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, clinical chemistry, and urinalysis). In addition to the individual laboratory 
parameters the ratios “total cholesterol / HDL” and “apolipoprotein B / apolipoprotein A1” will 
be derived and summarized.
For urinalysis, frequency tables will be presented.
Descriptive summary statistics for the change from baseline to each study visit will be presented. 
These descriptive summaries will be presented by laboratory test and treatment group. Change 


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from baseline will only be summarized for patients with both baseline and post baseline values 
and will be calculated as:
change from baseline = post baseline value – baseline value
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 patient’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. If appropriate, the shifts to the most extreme laboratory test value within entire 
treatment period 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 2-3: 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.
Table 2-4
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.0 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased 
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Platelet count
decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell 
decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count 
decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased*
>1 - 1.5 x baseline; 
>ULN - 1.5 x ULN
>1.5 - 3.0 x 
baseline; >1.5 - 3.0 x 
ULN
>3.0 baseline; 
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Glucose increased 
(Hyperglycemia ) 
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
>13.9 - 27.8 mmol/L
>27.8 mmol/L
Glucose decreased 
(Hypoglycemia)
<LLN - 3.0 mmol/L
<3.0 - 2.2 mmol/L
<2.2 - 1.7 mmol/L
<1.7 mmol/L
Cholesterol high
>ULN - 7.75 mmol/L
>7.75 - 10.34 mmol/L
>10.34 - 12.92 mmol/L
>12.92 mmol/L
Hypertriglyceridemia
1.71 - 3.42 mmol/L
>3.42 - 5.7mmol/L
>5.7 - 11.4 mmol/L
>11.4 mmol/L
*Note: for “creatinine increased” the baseline criteria do not apply


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Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during entire treatment period analyzed. Of note, 
baseline will be defined as last assessment prior to first dosing in initial treatment phase. Patients 
with abnormal laboratory values will be listed and values outside the normal ranges will be 
flagged.
Summaries for newly occurring or worsening clinically notable lipid abnormalities will also be 
provided cumulatively for each of the following parameters and categories:

HDL:

<=LLN

<0.8 x LLN

LDL, cholesterol, triglycerides:

>=ULN 

>1.5 x ULN 

>2.5 x ULN
Newly occurring or worsening liver enzyme abnormalities will also be summarized based on 
the event criteria given in Table 2-4:


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Table 2-5
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
TBL
>1.5xULN, >2xULN, >3xULN,
ALP
>2xULN, >3xULN. >5xULN
ALT or AST & 
TBL
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST & 
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law laboratory 
criteria)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result 
in severe DILI.
Notes:
1) In studies which enroll patients with pre-existing liver disease, baseline LFT may be increased 
above ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the 
abnormality criteria
2) In case an Adjudication Committee is in place it may be meaningful to summarize all abnormalities 
classed as e.g., definitely/probably (depending on the categories used) related to study treatment
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 patient with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN.
Individual patient data listings will be provided for patients with newly occurring or worsening 
abnormal laboratory data. Data of patients with newly occurring or worsening liver enzyme 
abnormalities will be listed in an additional listing.
Box plots will be presented for selected laboratory parameters: WBC, neutrophils, and liver
(ALP, AST, ALT, bilirubin) and lipid (cholesterol, HDL, LDL, triglycerides) parameters.
2.8.4
Other safety data
2.8.4.1
ECG 
Summaries of ECG are presented for all “on-treatment” data (see section 2.8.3).
The following quantitative variables may be summarized: ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, and corrected QT interval (QTc). Both Bazett (QTcB) and 
Fridericia (QTcF) corrections will be presented for QTc. 
QTc will summarized by computing the number and percentage of patients with:


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
QTc > 500 msec 

QTc > 480 msec

QTc > 450 msec

QTc changes from baseline > 30 msec

QTc changes from baseline > 60 msec

PR > 250 msec
Summary statistics will be presented for ECG variables by visit.
In addition, shift tables comparing baseline ECG interpretation (normal, abnormal, not available, 
total) with the worst on study interpretation (normal, abnormal, not available, total) will be 
provided.
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by-
patient listing of all quantitative ECG parameters.  
2.8.4.2
Vital signs
Summaries of vital signs are presented for all “on-treatment” data (see section 2.8.3).
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. Change from baseline will only be summarized for patients with both 
baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of patients with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table below.
Table 2-6
Criteria fornotable 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
Data of patients with newly occurring notable vital signs abnormalities will be listed in an 
additional listing.
2.8.4.3
Immunogenicity
A patient listing of immunogenicity (anti-AIN457 antibodies) will be presented.
2.9
Pharmacokinetic endpoints
All patients with concentration data will be included in the pharmacokinetic data analysis.


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Pharmacokinetic variables
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. In addition to mean, standard deviation 
(SD), coefficient of variation (CV), median and quartiles, the geometric mean and geometric 
coefficient of variation (CV) and n(log) will be presented. The formula for derivingthe 
geometric mean and CV (%) is as following:

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 at pre-dose and minutes
pre-dose will be listed. All data will be listed.
Statistical methods for pharmacokinetic analyses
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 
pharmacokinetic samples from previous studies. The modeling approach will be further detailed 
in a modeling plan. Results will be reported separately.
2.10
PD and PK/PD analyses
An indirect response model, driven by study treatment concentration, will be used to 
characterize the time course of efficacy response. Further details of the modeling approach will 
be specified in a modeling plan. Results will be reported separately.
2.11
Patient-reported outcomes
The following patient-reported outcomes will be summerized. In general, the derived scores 
will be calculated when all variables for calculating the scores are non-missing otherwise 
specified.
For binary efficacy variables, analyses with the non-rensponder imputation described in 2.5.3
and with observed case will be performed.
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 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-


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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. SF-36 scoring will be done by an independent vendor.
The following variables will be evaluated:

SF-36 domain scores (based on a scale of 0-100).

SF-36 PCS and MCS scores (norm-based scores).

SF-36 PCS and MCS responder (improvement of ≥ 2.5 points, Lubeck 2004)
ASQoL
The ASQoL is a self-administered questionnaire designed to assess health-related quality of life 
in adult patients with Ankylosing Spondylitis. The ASQoL contains 18 items with a 
dichotomous yes/no response option. A single point is assigned for each "yes" response and no 
points for each "no" response resulting in overall scores that range from 0 (least severity) to 18 
(highest severity). As such, lower score indicate better quality of life. Items include an 
assessment of mobility/energy, self-care and mood/emotion. The recall period is "at the 
moment," and the measure requires approximately 6 minutes to complete.
At least 15 answered questions are required to be able to calculate ASQoL using mean 
imputation, 18*(sum of answered)/(number answered) (Doward, 2003)


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2.12
Biomarkers
Not applicable.


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2.14
Interim analysis
An interim analysis on the efficacy and safety data has been performed after all patients have 
completed the Treatment Period 1 (Week 24 visit), and will be performed after all patients have 
completed the Treatment Period 2 (Week 52 visit), in order to support regulatory filing. 
Additional analyses may be performed to support Health Authority interactions, as necessary.
3
Sample size calculation
With a very low prevalence of AS in Japan (0.0065%), it is expected that approximately 30 
patients will be enrolled in this study based on the feasibility assessment. With 30 patients and 
assuming an ASAS20 response rate of 60% at week 16 (F2310), the estimated lower limit of 
95% confidence interval for the ASAS20 response rate in Japanese population treated with 
secukinumab 150 mg s.c. will be approximately 42.5%, which is well above the upper limit of 
the 95% confidence interval for the response rate of control group derived in F2310 (ASAS20 
response: 28.4%, Confidential Interval: 18.1-38.7).
4
Change to protocol specified analyses
There is no change.


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5
Appendix
5.1
Imputation rules
5.1.1
Study drug
In case of missing date of study treatment, the date of the visit in which the missing date occurs 
will be imputed.
5.1.2
AE date imputation
The following table explains the notation used in the logic matrix. Please note that missing start
dates will not be imputed.
Note, it may happen that the imputed AE start is after AE end date.
Table 5-1
Convention for imputation rule for AE start date
Day
Month
Year
Partial adverse event start date
Not used
MON
YYYY
Treatment start date (TRTSDT)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
Table 5-2
Imputation algorithm for AE start date
MON missing
MON < TRTM
MON = TRTM
MON > TRTM
YYYY missing
NA
YYYY < TRTY
01JULYYYY
15MONYYYY
YYYY = TRTY
TRTSDT + 1
15MONYYYY
TRTSDT + 1
01MONYYYY
YYYY > TRTY
01JANYYYY
01MONYYYY
AE end date will not be imputed.
5.1.3
Concomitant medication date imputation
The following table explains the notation used in the logic matrix for the partial start date of the 
concomitant medication (CMD). Please note that missing start dates will not be imputed.
Note, it may happen that the imputed CMD start date is after CMD end date.
Table 5-3
Convention for imputation rule for concomitant medication start date
Day
Month
Year
Partial concomitant medication
(CMD) Start Date 
Not used
MON
YYYY
Treatment Start Date (TRTSDT)
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.


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Table 5-4
Imputation algorithm for concomitant medication start date
MON missing
MON < TRTM
MON = TRTM
MON > TRTM
YYYY missing
NA
YYYY < TRTY
01JULYYYY
15MONYYYY
YYYY = TRTY
*
15MONYYYY
*
01MONYYYY
YYYY > TRTY
01JANYYYY
01MONYYYY
* if CRF pages specify the date is prior to TRTSDT, then TRTSDT -1: otherwise TRTSDT + 1.
Concomitant medication end date will not be imputed.
5.2
AEs coding/grading
Please see section 2.8.1.
5.3
Laboratory parameters derivations
Normal ranges for differential count of leukocytes (absolute value) will be as follows:
Table 5-5
Normal ranges for differential counts of leukocytes
Laboratory test name
(Low, High) (Unit)
Basophils (absolute)
(0.0, 0.2) (x 10E3/uL)
Eosinophils (absolute)
(0.0, 0.7) (x 10E3/uL)
Lymphocytes (absolute)
(1.0, 4.0) (x 10E3/uL)
Monocytes (absolute)
(0.1, 0.9) (x 10E3/uL)
Neutrophils (absolute)
(1.6, 7.4) (x 10E3/uL)
5.4
Statistical models
5.4.1
Primary analysis
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  as (1 −α/2)-quantile of the standard normal distribution (SAS: z = PROBIT(1 −α/2),  n
as total number of patients (i.e. number of patients in the denominator), and p as estimated crude 
incidence (number of patients with event /  n) it is  q = 1 −p
Then the lower limit is
























2
2
2
2
1
4
1
2
1
2
,0
max
100
z
n
nq
p
n
z
z
z
np
L


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and the upper limit is
























2
2
2
2
1
4
1
2
1
2
,1
min
100
z
n
nq
p
n
z
z
z
np
U
.
In addition, if L > p then L = p and if U < p then U = p.
5.4.2
Key secondary analysis
Not applicable.
5.4.3
Secondary analysis
See Section 5.4.1 Primary analysis.
5.4.4
Safety analysis
Crude incidence and related risk estimates 
Crude incidence and 100*(1 −α)% confidence interval
For n patients, 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 patients 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)
as Section 5.4.1.
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.
Exposure adjusted incidence rate and 100*(1 −α)% confidence interval
It will be assumed that for each of n patients in a clinical trial the time tj (j = 1,... , n) to the first 
occurrence of a certain treatment emergent event is observed, or if the event was not 
experienced, the (censored) time to the end of the treatment period or last dose plus 84 days 
whichever occur earlier. 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 patients 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):


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Lower confidence limit:
T
c
L
D
2
,2
/
5.0


   for D > 0, 0 otherwise,
Upper confidence limit:  
T
c
U
D 2
2
,2
/
1
5.0




where  
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.5
Rule of exclusion criteria of analysis sets 
No exclusion criteria will be defined.
6
Reference
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International ASAS consensus statement for the use of anti-tumour necrosis factor agents in 
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Corticosteroid converter (data retrieved October 30, 2015):
http://www.globalrph.com/steroid.cgi
 
 
Doward LC, Spoorenberg A, Cook SA, et al. (2003) Development of the ASQoL: a quality of 
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Garwood F (1936). Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453.
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Koch GG, Tangen CM, Jung JW, et al. (1998) Issues for covariance analysis of dichotomous 
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