A Randomized, Partially-blinded Study of Secukinumab to Demonstrate Reduction of Radiographic Progression Versus GP2017 (Adalimumab Biosimilar) at 104 Weeks and to Assess the Long Term Safety, Tolerability and Efficacy up to 2 Years in Patients With Active Ankylosing Spondylitis
Phase: PHASE3
Conditions: Ankylosing Spondylitis
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 2 ...........................................................................................................................11
Amendment 1 ...........................................................................................................................12
Protocol summary..............................................................................................................14
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................19
2.1
Primary objective...................................................................................................19
2.2
Secondary objectives .............................................................................................19
20
3
Investigational plan ...........................................................................................................21
3.1
Study design...........................................................................................................21
3.2
Rationale for study design .....................................................................................22
3.3
Rationale for dose/regimen, route of administration and duration of treatment....23
3.4
Rationale for choice of comparator .......................................................................23
3.5
Purpose and timing of interim analyses/design adaptations..................................24
3.6
Risks and benefits..................................................................................................24
4
Population..........................................................................................................................25
4.1
Inclusion criteria ....................................................................................................26
4.2
Exclusion criteria...................................................................................................26
5
Treatment...........................................................................................................................29
5.1
Study treatment......................................................................................................29
5.1.1
Investigational and control drugs..........................................................29
5.1.2
Additional treatment..............................................................................30
5.2
Treatment arms......................................................................................................30
5.3
Treatment assignment and randomization.............................................................30
5.4
Treatment blinding.................................................................................................31
5.5
Treating the subject................................................................................................31
5.5.1
Subject numbering ................................................................................31
5.5.2
Dispensing the study drug.....................................................................32

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5.5.3
Handling of study and additional treatment..........................................32
5.5.4
Instructions for prescribing and taking study treatment........................33
5.5.5
Permitted dose adjustments and interruptions of study treatment ........34
5.5.6
Rescue medication ................................................................................34
5.5.7
Concomitant medication .......................................................................35
5.5.8
Prohibited medication ...........................................................................36
5.5.9
Emergency breaking of assigned treatment code..................................37
5.6
Study completion and discontinuation...................................................................37
5.6.1
Study completion and post-study treatment..........................................37
5.6.2
Discontinuation of study treatment .......................................................38
5.6.3
Withdrawal of informed consent...........................................................39
5.6.4
Loss to follow-up ..................................................................................39
5.6.5
Early study termination by the sponsor.................................................39
6
Visit schedule and assessments .........................................................................................40
6.1
Information to be collected on screening failures..................................................46
6.2
Subject demographics/other baseline characteristics.............................................46
6.3
Treatment exposure and compliance .....................................................................46
6.4
Efficacy..................................................................................................................47
6.4.1
X-ray .....................................................................................................47
6.4.2
MRI .......................................................................................................47
6.4.3
Assessment of SpondyloArthritis International Society criteria 
(ASAS)..................................................................................................48
6.4.4
High sensitivity C-reactive protein (hsCRP).........................................49
6.4.5
ASDAS-CRP and ASDAS response categories....................................49
6.4.6
Appropriateness of efficacy assessments..............................................50
6.5
Safety.....................................................................................................................50
6.5.1
Tuberculosis screening..........................................................................50
6.5.2
Physical examination ............................................................................51
6.5.3
Vital signs..............................................................................................51
6.5.4
Height and weight .................................................................................52
6.5.5
Laboratory evaluations..........................................................................52
52
6.5.7
Chest X-ray or MRI ..............................................................................53
6.5.8
Electrocardiogram (ECG) .....................................................................53
6.5.9
Pregnancy and assessments of fertility .................................................53
6.5.10
Local tolerability (injection site reactions) ...........................................53

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6.5.11
Tolerability of investigational treatments .............................................54
6.5.12
Appropriateness of safety measurements..............................................54
54
54
56
6.6.3
HLA-B27...............................................................................................56
56
57
7
Safety monitoring..............................................................................................................58
7.1
Adverse events.......................................................................................................58
7.2
Serious adverse events...........................................................................................59
7.2.1
Definition of SAE .................................................................................59
7.2.2
SAE reporting........................................................................................60
7.3
Liver safety monitoring .........................................................................................61
7.4
Renal safety monitoring.........................................................................................61
7.5
Reporting of study treatment errors including misuse/abuse ................................61
7.6
Pregnancy reporting...............................................................................................62
8
Data review and database management.............................................................................62
8.1
Site monitoring ......................................................................................................62
8.2
Data collection.......................................................................................................63
8.3
Database management and quality control............................................................63
64
64
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Subject demographics and other baseline characteristics......................................65
9.3
Treatments .............................................................................................................66
9.4
Analysis of the primary variable(s) .......................................................................67
9.4.1
Variable(s).............................................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................68
9.4.4
Sensitivity analyses ...............................................................................68
9.5
Analysis of secondary variables ............................................................................68
9.5.1
Efficacy variables..................................................................................68
71
9.5.3
Safety variables .....................................................................................72

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74
75
75
75
75
9.7
Sample size calculation..........................................................................................75
10 Ethical considerations........................................................................................................76
10.1
Regulatory and ethical compliance........................................................................76
10.2
Informed consent procedures.................................................................................76
10.3
Responsibilities of the investigator and IRB/IEC..................................................77
10.4
Publication of study protocol and results...............................................................77
10.5
Quality Control and Quality Assurance.................................................................77
11 Protocol adherence ............................................................................................................78
11.1
Protocol amendments.............................................................................................78
12 References .........................................................................................................................78
13 Appendices ........................................................................................................................81
13.1
Appendix 1: Clinically notable laboratory values and vital signs .........................81
13.2
Appendix 2: Blood collection log..........................................................................81
13.3
Appendix 3: Modified New York criteria .............................................................82
13.4
Appendix 4: Assessment of SpondyloArthritis International Society criteria 
(ASAS) ..................................................................................................................83
13.4.1
Bath Ankylosing Spondylitis Functional Index (BASFI).....................83
13.4.2
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ........83
13.5
Appendix 5: modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) ....84
13.6
Appendix 6: Guidelines for administering the questionnaires for patient 
reported outcomes..................................................................................................84
List of tables
Table 5-1
Prohibited medication ...........................................................................36
Table 6-1
Assessment schedule – Part 1: Screening to Week 52..........................41
Table 6-2
Assessment schedule – Part 2: Week 54 to Week 104 and Follow-
up visits F112 and F120........................................................................44
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................62
Table 13-1
Safety Analyses: Expanded Limits and Notable Criteria......................81
81

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82
List of figures
Figure 3-1
Study design..........................................................................................22
Figure 9-1
Testing strategy for the second family after both H1 and H2 have 
been rejected..........................................................................................70

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List of abbreviations
AE
adverse event
ALT/SGPT
alanine aminotransferase/ serum glutamic pyruvic transaminase
ANCOVA
analysis of covariance
AS
ankylosing spondylitis 
ASAS
Ankylosing SpondyloArthritis International Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASspiMRI-a
Ankylosing Spondylitis Spine Magnetic Resonance Imaging - activity
AST/SGOT
aspartate aminotransferase/ serum glutamic oxaloacetic transaminase
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BMI
body mass index
BSL
baseline
CFR
US Code of Federal Regulations 
CI
Confidence interval
CRF
case report/record form (paper or electronic)
CRO
contract research organization
CRP (hsCRP)
(high sensitivity) C-reactive protein
CSR
clinical study report 
CTC
Common Terminology Criteria
DMARD
disease modifying anti-rheumatic drug
ECG
electrocardiogram
EDC
electronic data capture
ELISA
enzyme-linked immuno sorbent assay
EMA
European Medical Agency
FAS
full analysis set
FDA
Food and Drug Administration
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GP2017
GP2017 (adalimumab biosimilar)
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICF
informed consent form
ICH
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC/EC
Independent Ethics Committee
IFU
Instructions for Use

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IL
interleukin
IN
Investigator Notification
IRB
Institutional Review Board
IRT
interactive response technology
i.v.
Intravenous(ly)
LDL
low density lipoprotein
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
millimeter of mercury
MRI
magnetic resonance imaging/image
mSASSS
modified Stoke Ankylosing Spondylitis Spinal Score
MTX
methotrexate
NSAID
non-steroidal anti-inflammatory drug
PFS
pre-filled syringe 
PPD
purified protein derivative 
PRN
pro re nata
PRO
patient reported outcome(s)
PsA
psoriatic arthritis
RBC
red blood cell
SAE
serious adverse event
s.c.
subcutaneous(ly)
SCR
screening
SI
sacroiliac
SmPC
Summary of Product Characteristics
SpA
spondyloarthritides
STIR
short tau inversion recovery
SUSAR
suspected unexpected serious adverse reactions
SV
screening visit
TD
study treatment discontinuation
TNF/TNFα
Tumor Necrosis Factor/ Tumor Necrosis Factor alpha
ULN
upper limit of normal
VAS
visual analog scale
WBC
white blood cell
WHO
World Health Organization 
 

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WoC
withdrawal of consent

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Glossary of terms
Cohort 
A specific group of subjects fulfilling certain criteria
Control drug
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g., 
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (e.g., prior to starting any of the procedures 
described in the protocol)
Investigational drug
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.”
Medication pack number
A unique identifier on the label of each investigational drug package
Subject ID 
A unique number assigned to each subject upon signing the informed 
consent 
Period
The subdivisions of the trial design (e.g., Screening, Treatment, 
Follow-up) which are described in the Protocol. Periods define the 
study phases and will be used in clinical trial database setup and 
eventually in analysis
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. These data include subject 
identifier information, study information and biological samples
Randomization number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Study drug/ treatment
Any single drug or combination of drugs administered to the subject as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy
Study Treatment 
Discontinuation (TD)
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data

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Amendment 2
Amendment rationale
This protocol amendment is issued to align the blinding strategy between subjects, investigators, 
site and sponsor personnel. 
As per the original study design:

Subjects, investigators, site personnel, persons performing the assessments and monitors 
are unblinded to the study drug received. Secukinumab or GP2017 is supplied in an open 
label fashion (Section 5.4). 

Subjects, investigators, site personnel, persons performing the assessments, monitors and 
the Sponsor (with the exception of the bioanalyst) are blinded to secukinumab dose (150 
mg, 300 mg). Designated Sponsor personnel involved in study conduct and the statistical 
analysis plan have been blinded to treatment group, GP2017 or secukinumab.
Due to the difference in blinding strategy between the site staff, monitors and the designated 
Sponsor personnel, accidental unblinding incidences with respect to study drug allocation of 
secukinumab vs GP2017 are occurring at an increasing rate, despite preventative measures. This 
is due to ongoing data review whereby information such as dosing frequency or therapy on 
study completion has to be regarded as potentially unblinding.
Therefore, in this amendment, the blinding strategy will be aligned between subjects, 
investigators, site personnel and the Sponsor. The designated Sponsor personnel will become 
unblinded to treatment group (GP2017 or secukinumab).  
The dose of secukinumab (150 mg or 300 mg) will remain blinded, in a double blind fashion, 
for all (Section 5.4) in order to minimize the potential bias in the assessment and analysis of a 
potential dose-related response.
Patient flow through the study is not affected in any way by this amendment.
Primary and radiographic secondary endpoints will remain unaffected, as the images are scored 
by central imaging experts, who will remain fully blinded to study drug, secukinumab dose, and 
time point for efficacy. 
There are no changes to informed consent forms or electronic database.
The ECG analysis in Section 9.5.3 was revised to reflect the protocol assessment table, which 
does not include post-baseline ECG collection.
Section 9.5.1 was modified to align with Amendment v.01 language.
Typographical errors were also corrected in Section 9.4.2.
At the time of this amendment, enrollment has been completed and all subjects have completed 
Week 52. 

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

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Protocol summary
Protocol number
AIN457K2340
Title
A randomized, partially-blinded, active-controlled multicenter study of 
secukinumab to demonstrate reduction of radiographic progression versus 
GP2017 (adalimumab biosimilar) at 104 weeks and to assess the long term 
safety, tolerability and efficacy up to 2 years in patients with active 
ankylosing spondylitis
Brief title
Study of the effect of secukinumab on radiographic progression in 
ankylosing spondylitis as compared to GP2017 (adalimumab biosimilar) 
Sponsor and Clinical 
Phase
Novartis
Phase IIIb
Investigation type
Drug
Study type
Interventional 
Purpose and rationale
The purpose of this study is to demonstrate the impact on progression of 
structural damage in the spine as measured by the mSASSS in patients 
with AS. Data from this study will be used to support the submission of an 
AS label extension to include a claim on radiographic progression.
Primary Objective(s) 
The primary objective of this study is to demonstrate the proportion of 
subjects on each secukinumab dose with no radiographic progression as 
measured by mSASSS at Week 104 is superior to subjects on GP2017 
(adalimumab biosimilar).
Secondary Objectives
Objective 1: To demonstrate the change from baseline in mSASSS in 
subjects on each secukinumab dose is superior to GP2017 (adalimumab 
biosimilar) at Week 104.
Objective 2: To demonstrate the proportion of subjects with a 
syndesmophyte at baseline with no new syndesmophytes at Week 104 on 
each secukinumab dose is superior to GP2017 (adalimumab biosimilar). 
Objective 3: To evaluate the Berlin sacroiliac (SI) joint edema score in 
subjects on each secukinumab dose at Week 104 versus GP2017 
(adalimumab biosimilar) (in a subset of subjects at selected sites). 
Objective 4: To evaluate the ASspiMRI-a Berlin modification score in 
subjects on each secukinumab dose at Week 104 versus GP2017 
(adalimumab biosimilar) (in a subset of subjects at selected sites).
Objective 5: To evaluate ASAS 20 response, ASAS 40 response, ASAS 
partial remission and ASDAS inactive disease in subjects on secukinumab 
at Week 104.
Objective 6: Overall safety and tolerability of secukinumab.
Study design
This is a multicenter, randomized, partially-blinded, active-controlled, 
parallel-group study.
Population
Male or female patients at least 18 years of age with AS fulfilling the 
Modified New York criteria for classification of ankylosing spondylitis, and 
with moderate to severely active disease despite previous or current 
NSAIDs/non-biologic DMARDs and with no prior history of biologic 
DMARDs (including anti-TNFα agent) therapy. 

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Key Inclusion criteria
Patients must have active AS, despite previous or current NSAIDs/ non-
biologic DMARDs therapy, as measured by total BASDAI ≥ 4 on a scale of 
0-10, spinal pain as measured by BASDAI question #2 ≥ 4 (0-10) and total 
back pain as measured by visual analog scale (VAS) ≥ 40 mm (0-100 mm). 

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 radiologic evidence 
(centrally read X-ray) fulfilling the Modified New York criteria for AS 
(Appendix 3) 

Active AS assessed by total BASDAI ≥ 4 (0-10) at Baseline

Spinal pain as measured by BASDAI question #2 ≥ 4 (0-10) at 
Baseline

Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at 
Baseline

hsCRP ≥ 5 mg/L OR presence of at least 1 syndesmophyte on 
centrally read spinal X-ray

Patients should have been on NSAIDs at the highest tolerated dose 
for at least 8 weeks prior to randomization with an inadequate 
response or failure to respond, or less than 8 weeks if therapy had to 
be withdrawn due to intolerance, toxicity or contraindications 

Patients who are regularly taking NSAIDs (including COX-1 or COX-2 
inhibitors) as part of their AS therapy are required to be on a stable 
dose for at least 2 weeks before randomization 

Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 g/day) are
allowed to continue their medication and must have taken it for at 
least 3 months and have to be on a stable dose for at least 4 weeks 
prior to randomization

Patients on MTX must be on stable folic acid supplementation before 
randomization

Patients who are on a DMARD other than MTX or sulfasalazine must 
discontinue the DMARD 4 weeks prior to randomization

Patients taking systemic corticosteroids have to be on a stable dose 
of ≤ 10 mg/day prednisone or equivalent for at least 2 weeks before 
randomization
Key Exclusion criteria

Patients with total ankylosis of the spine

Chest X-ray or chest MRI with evidence of ongoing infectious or 
malignant process obtained within 3 months prior to screening and 
evaluated by a qualified physician 

Previous exposure to secukinumab, adalimumab or any other 
biological immunomodulating agent, including those targeting IL-17, 
IL-17 receptor or TNFα

Patients taking high potency opioid analgesics (e.g., methadone, 
hydromorphone, morphine, oxycodone)

Use of any investigational drug and/or devices within 4 weeks of 
randomization, or a period of 5 half-lives of the investigational drug, 
whichever is longer 

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
Any intramuscular corticosteroid injection within 2 weeks before 
randomization

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 human chorionic gonadotropin 
(hCG) laboratory test 

Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
effective methods of contraception during dosing of study treatment 
and minimum 16 weeks or longer if local label requires it after the last 
dose (e.g. 20 weeks for secukinumab, 5 months for adalimumab in 
EU). 

Active ongoing inflammatory diseases other than AS that might 
confound the evaluation of the benefit of secukinumab or 
adalimumab 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 (≥ 160/100 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. 

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)

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 central laboratory 
tuberculosis screening 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 human immunodeficiency virus (HIV), hepatitis 
B or hepatitis C at screening or randomization

History of lymphoproliferative disease or any known malignancy or 
history of malignancy of any organ system within the past 5 years 
(except for basal cell carcinoma or actinic keratoses that have been 

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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)
Study treatment
AIN457 secukinumab
GP2017 (adalimumab biosimilar)
Efficacy assessments

X-ray of the cervical and thoraco-lumbar spine assessed by modified 
Stoke Ankylosing Spondylitis Spinal Score (mSASSS)

MRI of the spine and SI joints assessed by ASspiMRI-a Berlin 
modification score and Berlin SI joint edema score

Assessment of SpondyloArthritis International Society criteria (ASAS)

Patient’s global assessment of disease activity (VAS)

Patient’s assessment of back pain intensity (VAS)

Bath Ankylosing Spondylitis Functional Index (BASFI)

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

hsCRP

ASDAS response categories
Key safety 
assessments

Evaluation of adverse events/ serious adverse events

Tuberculosis central laboratory test or local PPD skin test

Chest X-ray or MRI

Physical examination

Vital signs

Height and weight

Laboratory evaluations

Pregnancy and assessment of fertility

Local tolerability (injection site reactions)

Tolerability of study treatment
Other assessments
Data analysis
The primary endpoint in the study is no radiographic progression (change 
from baseline ≤ 0.5) at Week 104. The statistical hypothesis tests 
secukinumab 150 mg s.c. or 300 mg s.c. versus GP2017 40 mg as the 
primary endpoint at Week 104 using the full analysis set.
Key words
ankylosing spondylitis, secukinumab, GP2017, adalimumab biosimilar, 
mSASSS, ASAS 20

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1
Introduction
1.1
Background 
Ankylosing spondylitis (AS) is a chronic inflammatory disease which belongs to a group of 
conditions known as spondyloarthritides (SpA). It is mainly characterized by involvement of 
the axial skeleton and sacroiliac (SI) joints, but also affects peripheral joints, entheses and extra-
articular organs. A significant proportion of patients may present with associated extra-articular 
manifestations such as uveitis, psoriasis, inflammatory bowel disease (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 human leukocyte antigen is strongly associated with AS: 
90–95% of patients with AS who have European ancestry carry this marker. AS affects up to 
1.1% of the population, is associated with significant morbidity and disability, and thus 
constitutes a major socio-economic burden. 
First-line medication of mild AS consists of non-steroidal anti-inflammatory drugs (NSAIDs). 
Treatment of NSAID-refractory AS is hampered by the lack of efficacy of virtually all standard 
disease modifying anti-rheumatic drugs (DMARDs), including methotrexate (MTX). Tumor 
necrosis factor (TNF) blocking agents were successfully added to the armamentarium to treat 
AS (Braun 2002) and subsequently demonstrated prolonged efficacy up to eight years of follow-
up (Baraliakos 2011). However, upon discontinuation of TNF blockers the disease relapses 
quickly (Baraliakos 2005), indicating that the inflammatory process may have only been 
inhibited but not completely abolished. 
Secukinumab, a human monoclonal antibody that inhibits the effector function of IL-17A, has 
been previously shown to be better than placebo in improving the signs and symptoms of AS. 
In the Phase III MEASURE 1 and MEASURE 2 studies of 590 patients with AS, secukinumab 
significantly improved key clinical domains of disease versus placebo, including signs and 
symptoms, physical functioning, and quality of life (Baeten 2015).
Secukinumab as well as a number of anti-TNFs including adalimumab are approved for 
treatment of patients with active AS (Cosentyx® and Humira® package inserts and SmPCs). 
Results on signs and symptoms with both secukinumab and adalimumab have demonstrated 
good response along with rapid reduction of SI-joint and spinal inflammation as evidenced by 
MRI. 
One of the key features of AS contributing to long term disability is the process of structural 
remodeling in the axial skeleton and the SI-joints. This process as evidenced by SI and spinal 
radiography typically begins with subchondral sclerosis in the SI-joints along with squaring and 
marginal sclerosis of the vertebral bodies. Over time SI joint erosions occur and vertebral body 
syndesmophytes form, ultimately leading to spinal fusion (Sieper 2009). The process is slow, 
progresses over 10 – 15 years and includes both osteoproliferative as well as absorptive 
processes. 
Studies evaluating the effects of the anti-TNF agents adalimumab, etanercept and infliximab on 
radiographic damage in patients with AS did not demonstrate inhibition of radiographic 
progression after approximately 2 years of therapy compared to a historical cohort. The 
comparisons to the historical cohorts that had been treated with NSAIDs only have shown a 

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mean modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) progression of 0.8-0.9 
over 2 years, regardless of anti-TNF or NSAID treatment (van der Heijde 2008a, van der Heijde 
2008b, van der Heijde 2009).
Two-year spinal X-ray data from the secukinumab pivotal study MEASURE 1 suggest that IL-
17A inhibition may have the potential to decrease spinal structural progression as evidenced by 
a mean mSASSS change after 2 years of therapy of ~ 0.3. This speaks to the potential of 
secukinumab to influence the long-term structural progression in the spine of patients with AS 
(Braun 2016).
However, a need exists for comparative studies to assess how different mechanisms of action 
can reverse or slow down structural progression. This will be the first study comparing an anti-
IL17A treatment with an anti-TNF agent in AS. This study will provide critical scientific 
evidence that will improve evidence-based decision making in the treatment of patients with 
AS and play an important role in filling the current data gap between clinical research and day-
to-day clinical practice on the therapeutic utility of biologic therapy in patients with active AS.
As of 25-Jun-2016, over 13,000 healthy subjects and patients have been enrolled into clinical 
studies with secukinumab, of whom approximately 9,600 have received at least one dose of 
secukinumab. Overall, secukinumab studies have investigated various indications (Rheumatoid
Arthritis (RA), AS, Psoriatic Arthritis (PsA), psoriasis, multiple sclerosis, uveitis, Crohn’s 
disease, dry eye syndrome, polymyalgia rheumatica) at doses ranging from single and multiple 
doses of 0.1 mg/kg to 30 mg/kg i.v. and 25 mg to 300 mg s.c. As of Jan-2016, secukinumab has 
been approved for the treatment of AS in the European Union, the US and multiple other 
countries. Full safety results from completed studies for AS, PsA and psoriasis show that 
secukinumab generally is safe and well tolerated. Please refer to the Investigator’s Brochure 
(IB) for a more detailed review of the risk:benefit profile of secukinumab which supports the 
clinical development for the treatment of AS patients with secukinumab.
1.2
Purpose 
The purpose of this study is to demonstrate the impact on progression of structural damage in 
the spine as measured by the mSASSS in patients with AS. Data from this study will be used to 
support the submission of an AS label extension to include a claim on radiographic progression.
2
Study objectives and endpoints
2.1
Primary objective
To demonstrate the proportion of subjects on secukinumab (150 mg s.c. or 300 mg s.c.) with no 
radiographic progression as measured by mSASSS at Week 104 is superior to subjects on 
GP2017 (adalimumab biosimilar 40 mg s.c.). 
2.2
Secondary objectives
1. To demonstrate the change from baseline in mSASSS in subjects on secukinumab (150 
mg s.c. or 300 mg s.c.) is superior to GP2017 (adalimumab biosimilar 40 mg s.c.) at Week 
104.

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Two follow-up visits are to be completed after last administration of study treatment for all 
subjects, regardless of whether they complete the entire study as planned or discontinue 
prematurely.
Figure 3-1
Study design
3.2
Rationale for study design
The subject population will be described in more detail in the Section 4 below.
The randomized, partially-blinded, active-controlled, parallel-group design used in this study is 
based on the primary focus of this study, which is to demonstrate the ability of secukinumab to 
slow structural spinal progression over time relative to current standard of care for AS. The 
primary objective is based on mSASSS scoring of spinal X-rays obtained at baseline and Week 
104, which will be conducted in a fully blinded fashion in this study with a partially-blinded 
design. Spinal structural progression in AS is known to be a slow process. Thus, the length of 
the study is required to be 2 years in order to detect radiographic changes and fully demonstrate 
the potential impact of therapy. 
Evaluations of mSASSS scoring for the primary objective will be conducted by three 
independent readers who will be blinded to the subject name, subject initials, exam date, order 
of image acquisition, investigator site identifiers, study treatment group, and all other efficacy 
and safety assessments. As previously noted, a partially-blinded design will not bias the analysis 
of the primary or secondary radiographic endpoints, which are not subject or physician reported 
outcomes.
Adalimumab is a commonly used anti-TNF agent in AS and confers similar efficacy to 
secukinumab in terms of signs and symptoms (van der Heijde 2006). Radiographic progression 
data for AS subjects on adalimumab for up to 2 years are published and provide statistical 

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assumptions for the powering of the primary endpoint (van der Heijde 2009). Thus, adalimumab 
is well suited as the active comparator in this study.
While the GP2017 (adalimumab biosimilar) treatment group will be supplied with unblinded 
study medication, the secukinumab treatment groups will be blinded to the dose of secukinumab 
through the use of a blinded placebo injection in the 150 mg s.c. group. The blinding of the 
secukinumab treatments (150 mg or 300 mg) will allow for an evaluation of a potential dose-
response of the 150 mg and 300 mg secukinumab doses on both efficacy and safety outcomes.   
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The secukinumab dosing regimens in this study are based upon the currently approved dose for 
AS, which is 150 mg s.c. every 4 weeks (with or without a loading dosage of 150 mg at Weeks 
0, 1, 2, 3, and 4; country dependent), as well as the 300 mg s.c. dose, which is approved for 
PsA. 
Notably, 300 mg s.c. administered monthly is an approved dose for secukinumab in both 
psoriasis and in PsA, and the safety profile for 300 mg s.c. every 4 weeks is comparable to 150 
mg s.c. every 4 weeks (Langley 2014, Mease 2015). The higher dose of secukinumab confers 
an additional benefit in other disease conditions (e.g., psoriasis and PsA). This study will 
evaluate whether a higher dose of secukinumab will have an effect on subjects with AS with 
respect to structural spinal progression. While it will be known if the subject is receiving 
secukinumab or GP2017, the dose of secukinumab will be blinded. This will allow an 
assessment of the effect of 150 mg and 300 mg in an unbiased manner, as no study has yet 
assessed both 150 mg or 300 mg s.c. in AS.
Based on the rationale above, this study will evaluate both secukinumab 150 mg and 300 mg 
s.c. doses for the treatment of adults with active AS compared with GP2017 (adalimumab 
biosimilar) s.c. injection. As a biosimilar to adalimumab, the dosing of GP2017 reflects that of 
Humira®. Adalimumab is approved for the treatment of AS at a recommended dose of 40 mg 
administered s.c. every other week, which matches the treatment regimen that subjects 
randomized to the GP2017 treatment group will receive. 
In summary, the secukinumab doses in this study are based on the approved AS dose and a 
well-characterized safety profile for both proposed secukinumab doses across the PsA, psoriasis 
and AS indications; the dose for the GP2017 active control is based on an approved dose 
demonstrating optimal efficacy and safety in subjects with AS.
Formulation to be used
This study will use secukinumab 150 mg/ 1 mL and placebo liquid in single-use pre-filled 
syringes (PFS). An investigational adalimumab biosimilar (GP2017) in the dose approved for 
AS (40 mg/ 0.8 mL) in a single-use PFS will be used.
3.4
Rationale for choice of comparator
An active comparator group is necessary to evaluate the structural benefit of secukinumab as 
compared to an approved standard of care therapy in AS. The randomized parallel-group 
controlled design is the most appropriate method to compare the two therapies and is consistent 

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autoimmune disorders and malignancies. In clinical trials of Humira®, allergic reactions overall 
(e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, 
urticaria) were observed in approximately 1% of subjects. The contraindications, precautions 
and warnings, as summarized in the Humira® SmPC apply also for the use of GP2017 
(adalimumab biosimilar). 
The immunogenicity potential, i.e. of eliciting anti-drug antibodies (ADA), is higher for 
adalimumab (up to 26%) than for secukinumab (< 1%). However, the presence of ADAs does 
not appear to be associated with development of adverse reactions for either secukinumab or 
adalimumab, although the development of ADAs has been associated with secondary treatment 
failure to adalimumab, but not to secukinumab (Cosentyx® package insert, Humira® package 
insert, Humira® SmPC).
Taking into account the individual risks as outlined above, the expected risk profile of 
secukinumab from its mechanism of action is anticipated to be similar or improved compared 
to the other approved inflammatory cytokine-targeting therapies. The expected safety profile 
for GP2017, as a biosimilar adalimumab, will also be expected to be similar to the reference 
safety profile of Humira® (Humira® package insert, Cosentyx® package insert). The risk to 
subjects in this study will be minimized by compliance with the eligibility criteria and study 
procedures, close clinical monitoring, and extensive guidance for the investigators provided by 
Novartis and in the current version of the IBs for secukinumab and GP2017. Based on the 
overall risk-benefit assessment, along with the fact that secukinumab and adalimumab are 
approved treatments for subjects with active AS, the current study evaluating secukinumab with 
investigational adalimumab biosimilar as the comparator is justified.
4
Population
The study population will consist of male and female patients (≥ 18 years old at the time of 
consent) with AS fulfilling the Modified New York criteria for classification of ankylosing 
spondylitis (described in Appendix 3), and with moderate to severely active disease despite 
previous or current NSAIDs/ non-biologic DMARDs and with no prior history of biologic 
DMARDs (including anti-TNFα agent) therapy.
Patients must have a history of active AS, as measured by the following three assessments:

total BASDAI ≥ 4 on a scale of 0-10

spinal pain as measured by BASDAI question #2 ≥ 4 (0-10) 

total back pain as measured by visual analog scale (VAS) ≥ 40 mm (0-100 mm)
The study aims to randomize approximately 837 patients at approximately 200 centers 
worldwide. Since a 25% screening failure rate is expected, approximately 1,116 patients will 
be screened. Enrollment will stop as soon as the target number of randomized subjects is 
reached. 
Patients may be re-screened only once, and no study-related re-screening procedure should be 
performed prior to written re-consent by the patient. Mis-randomization occurs when a patient 
who does not meet all eligibility criteria nevertheless receives a randomization number 
incorrectly; mis-randomized patients will not be re-screened.

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4.1
Inclusion criteria
Patients eligible for inclusion in this study must 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 radiologic evidence (centrally read X-ray) 
fulfilling the Modified New York criteria for AS (Appendix 3) 
4. Active AS assessed by total BASDAI ≥ 4 (0-10) at Baseline
5. Spinal pain as measured by BASDAI question #2 ≥ 4 (0-10) at Baseline
6. Total back pain as measured by VAS ≥ 40 mm (0-100 mm) at Baseline
7. hsCRP ≥ 5 mg/L OR presence of at least 1 syndesmophyte on centrally read spinal X-ray

Subjects are permitted to have one hsCRP re-test during the screening period.

Spinal X-rays obtained to confirm presence of syndesmophytes will be performed 
after hsCRP results are confirmed by the central lab to be < 5 mg/L and must be 
confirmed by the central imaging vendor prior to inclusion in the study.
8. Patients should have been on NSAIDs at the highest tolerated dose for at least 8 weeks  
prior to randomization with an inadequate response or failure to respond, or less than 8 
weeks if therapy had to be withdrawn due to intolerance, toxicity or contraindications 
9. 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 
randomization
10. Patients taking MTX (≤ 25 mg/week) or sulfasalazine (≤ 3 g/day) are allowed to continue 
their medication and must have taken it for at least 3 months and have to be on a stable 
dose for at least 4 weeks prior to randomization
11. Patients on MTX must be on stable folic acid supplementation before randomization
12. Patients who are on a DMARD other than MTX or sulfasalazine must discontinue the 
DMARD 4 weeks prior to randomization
13. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 10 mg/day 
prednisone or equivalent for at least 2 weeks before randomization
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients. 
1. Patients with total ankylosis of the spine
2. Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process 
obtained within 3 months prior to screening and evaluated by a qualified physician 
3. Previous exposure to secukinumab, adalimumab or any other biological 
immunomodulating agent, including those targeting IL-17,  IL-17 receptor or TNFα
4. Patients taking high potency opioid analgesics (e.g., methadone, hydromorphone,  
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5. Use of any investigational drug and/or devices within 4 weeks of randomization, or a 
period of 5 half-lives of the investigational drug, whichever is longer
6. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes
7. Any intramuscular corticosteroid injection within 2 weeks before randomization
8. 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)
9. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) laboratory test 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment and minimum 16 weeks or longer if local label requires it after 
the last dose (e.g., 20 weeks for secukinumab, 5 months for adalimumab in EU). Effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. 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 subject

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository 

Use of oral (estrogen and progesterone), 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 or 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 investigational drug.
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the ICF.
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), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 

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the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. 
11. Active ongoing inflammatory diseases other than AS that might confound the evaluation 
of the benefit of secukinumab or adalimumab therapy, including inflammatory bowel 
disease or uveitis
12. 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
13. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥ 160/100 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
14. 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.
15. 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)
16. Screening total WBC count < 3,000/µL, or platelets < 100,000/µL or neutrophils 
1,500/µL or hemoglobin < 8.5 g/dL (85 g/L)
17. Active systemic infections during the last two weeks (exception: common cold) prior to 
randomization
18. 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 ≥ 5mm or 
according to local practice/guidelines) or a positive central laboratory tuberculosis 
screening 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
19. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
screening or randomization
20. 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)
21. Current severe progressive or uncontrolled disease which in the judgment of the clinical 
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22. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins)
23. Inability or unwillingness to receive injections with PFS
24. 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
25. Donation or loss of 400 mL or more of blood within 8 weeks before randomization
26. History or evidence of ongoing alcohol or drug abuse, within the last 6 months before 
randomization
27. Patients who know they will be unable to complete 2 year study treatment period
28. Plans for administration of live vaccines during the study period or 6 weeks prior to 
randomization
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis will supply the following study drugs:
Investigational treatment:

Secukinumab 150 mg, liquid formulation in 1 mL PFS 
Reference treatment:

Placebo, liquid formulation in 1 mL PFS

GP2017 (adalimumab investigational biosimilar) 40 mg, liquid formulation in 0.8 mL 
PFS
If the subject opts for self-administration and/or home administration (at protocol specified time 
points, see Table 6-1 and Table 6-2), subjects or caregivers will be instructed by site staff on 
how to self-administer the s.c. injection using the PFS containing the liquid formulation of each 
study drug. Subjects receiving secukinumab will follow the Secukinumab Instructions for Use 
(IFU) document, and subjects receiving GP2017 will follow the GP2017 (adalimumab 
biosimilar) IFU document. The subject may elect to self-administer the PFS at home when they 
are not visiting the site for any other study related procedures. Site staff will administer the 
injection to subjects who are not able or feel insecure to self-administer the PFS injection.
The secukinumab 150 mg PFSs and placebo 1 mL PFSs will be provided in a double-blind 
fashion and have identical appearance.
GP2017 (adalimumab biosimilar) 40 mg PFSs will be provided as unblinded supplies. They 
have a different appearance from secukinumab 150 mg / placebo 1 mL.
The study medication will be labeled as follows:

Double-blind secukinumab and placebo PFS will be labeled as AIN457 150mg / 1 mL / 
Placebo

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
Open-label GP2017 (adalimumab biosimilar) PFS will be labeled as adalimumab 40 mg / 
0.8 mL
For detailed instructions on storage of the study drugs, please refer to Section 5.5.3.
5.1.2
Additional treatment
No additional treatment beyond investigational and reference treatments are included in this 
study.
5.2
Treatment arms
Subjects will be randomly assigned at the baseline visit to one of the following three treatment 
groups in a 1:1:1 ratio, with approximately 279 randomized subjects planned for each group.   

Group 1: secukinumab 150 mg

Group 2: secukinumab 300 mg

Group 3: GP2017 (adalimumab biosimilar) 40 mg
Subjects in both of the secukinumab dose groups will receive study treatment at BSL, Weeks 1, 
2, 3 and 4 followed by treatment every 4 weeks through Week 100. Subjects in the GP2017 
group will receive study treatment at BSL and every two weeks through Week 102. Subjects 
can self-administer all secukinumab / placebo and GP2017 doses as described in Section 3.1 at 
the study site or at home, according to the assessment schedule in Table 6-1 and Table 6-2.
5.3
Treatment assignment and randomization 
At baseline all eligible subjects will be randomized via an Interactive Response Technology 
(IRT) system to one of the treatment arms. The investigator or his/her delegate will contact the 
IRT after confirming that the subject fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the subject, which will be used to link the subject to a 
treatment arm and will specify a unique medication number for the first package of study drug 
to be dispensed to the subject. The randomization number will not be communicated to the 
caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and that the randomization of secukinumab doses is concealed 
from subjects and investigator staff. A subject randomization list will be produced by the IRT 
provider using a validated system that automates the random assignment of subject numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Drug Supply Management using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drug(s). 
The randomization scheme for subjects will be reviewed and approved by a member of the 
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contact the IRT and provide the requested identifying information for the subject to register 
them into the IRT. The site must select the CRF book with a matching Subject Number in the 
EDC system to enter data. 
If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the appropriate 
screening period CRF.
Subjects may be re-screened once and will receive a new Subject Number after they have been 
re-consented. Subjects who are mis-randomized cannot be re-screened.
5.5.2
Dispensing the study drug 
Each study site will be supplied with secukinumab study drug in packaging of identical 
appearance.  The GP2017 (adalimumab biosimilar) PFS will appear slightly different.
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label which corresponds to one of the 3 treatment arms. Investigator staff will 
identify the study drug package(s) to dispense to the subject by contacting the IRT and obtaining 
the medication number(s). Immediately before dispensing the package to the subject, 
investigator staff will detach the outer part of the label from the packaging and affix it to the 
source document (Drug Label Form) for that subject’s unique Subject Number. 
During the BSL visit or any of the scheduled on-site visits, if the subject opts for home 
administration (at protocol specified time points, see Table 6-1 and Table 6-2) the investigator 
or delegated site staff will dispense, via the IRT, an appropriate number of investigational 
treatment packages for the home self-administrations. The investigator staff will detach the 
outer part of the label and affix it to the source documentation (Drug Label Form). Detailed 
instructions on the self-administration of the study treatment will be described in the IFU 
provided to each subject and made available to the site staff and investigator. These instructions 
should be reviewed in detail by the subject and the site personnel.
5.5.3
Handling of study and additional treatment 
5.5.3.1
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must 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 Novartis.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of the drug accountability will be performed 
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to the subject. It should be recorded on the appropriate CRF(s) whether the subject self-
administered the study treatment at home or at the site and if a caregiver administered the 
treatment. 
Prior to self-administration at home, subjects should contact the investigator/site staff in case 
they are experiencing any AE/SAEs, or have any concerns. 
All dates and times of self-administrations by the subject during the study must be recorded on 
the appropriate CRF. Immediately before dispensing the package to the subject, site staff will 
detach the outer part of the label from the packaging and affix it to the source document (Drug 
Label Form) for that subject’s unique subject number.
5.5.5
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Study treatment interruption is also not 
permitted with the following exceptions:

Study treatment interruption is only permitted if, in the opinion of the investigator, a 
subject 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 or adalimumab on live vaccines is unknown; therefore live 
vaccines should not be administered during participation in the study. The elimination of 
adalimumab may take up to four months (Humira® SmPC); in case a live vaccine has been 
administered due to a medical urgency, study treatment should be interrupted for four 
months for a subject taking GP2017. The study treatment should be interrupted for 12 
weeks for a subject taking secukinumab.
Study treatment interruption or permanent discontinuation of study treatment will not affect the 
ability for the subject to remain in the study.
Any study treatment interruption must be recorded on the corresponding CRF.
5.5.6
Rescue medication
Rescue medication is defined as any new therapeutic intervention or a significant change to 
ongoing therapy made because a subject is experiencing either no benefit from participation in 
the study or worsening/exacerbation of their disease.
Although no subject will be restricted from receiving necessary rescue medications for lack of 
benefit or worsening of disease, if treatment with prohibited biologics (as described in Section 
5.5.8) is started, subjects may remain in the study but must discontinue study treatment. Efficacy 
and safety will be assessed at each on-site study visit, and subjects who are deemed by the 
investigator not to be benefiting from study treatment, or for any reason on the subject’s own 
accord, will be free to discontinue study participation at any time. Changes in NSAIDs, non-
biologic DMARDs and corticosteroid concomitant therapy are permitted as per investigator’s 
and subject’s clinical judgment. Please see Section 5.5.7, Section 5.5.8 and Section 5.6.2 for 
details.
Use of rescue medication must be recorded on the corresponding CRF.

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5.5.7
Concomitant medication 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded in the appropriate CRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis/CRO medical monitor 
before randomizing a subject or allowing a new medication to be started.
Guidelines for the use of specific medications are provided below:
Methotrexate
Subjects taking MTX (≤ 25 mg/week) must be on a stable dose for at least 4 weeks before 
randomization.
Folic acid
Subjects on MTX must be taking folic acid supplementation before randomization and during 
the study to minimize the likelihood of MTX associated toxicity.
Sulfasalazine
Subjects taking sulfasalazine (≤ 3 g/day) must be on a stable dose for at least 4 weeks before 
randomization.
Systemic corticosteroids
Treatment with systemic corticosteroids (e.g., oral, intramuscular, i.v., s.c.) is permitted if the 
dose is stable within the 2 weeks preceding randomization through Week 104, up to a maximum 
daily dosage of 10 mg prednisone equivalent. 
Higher-dose, time-limited corticosteroid courses (bursts) may be permitted for exacerbations of 
medical conditions unrelated to AS (e.g., asthma, chronic obstructive pulmonary disease 
(COPD), contact dermatitis) after randomization.  
Any change in the dose of systemic corticosteroids during the trial must be recorded on the 
corresponding CRF. 
Intra-articular corticosteroids are not permitted within the 4 weeks preceding randomization. 
After randomization, 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 Weeks 
16, 52 and 104. 

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Non-steroidal anti-inflammatory drugs (NSAIDs) (including COX-1 or COX-2 
inhibitors) and acetaminophen/paracetamol
Subjects regularly using NSAIDs, low strength opioids, or paracetamol/acetaminophen should 
be on stable dose for at least 2 weeks before randomization to allow inclusion in the study.
Subjects taking NSAIDs, low strength opioids or paracetamol/acetaminophen PRN within the 
2 weeks before randomization can continue to do so in the study; however, they have to refrain 
from any intake during the 24 hours before a visit with disease activity assessment. 
Any change of the NSAIDs, low strength opioids, or paracetamol/acetaminophen treatment 
during the trial should be recorded on the corresponding CRF.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-1 is NOT allowed after the start of the washout 
period through Week 104, unless otherwise specified below.
Live vaccines should not be given until 12 weeks after last study treatment administration of 
secukinumab. The elimination of adalimumab may take up to four months (Humira® SmPC); 
live vaccines should not be given until 16 weeks after last study treatment administration of 
GP2017.
Table 5-1
Prohibited medication
Medication
Washout period 
(before 
randomization)
Action
(after randomization, 
through Week 104)
Any immunomodulating biologic drugs, 
including but not limited to TNFα inhibitors, 
denosumab, secukinumab, or other biologic 
drug directly targeting IL-17 or IL-17 receptor 
No prior 
exposure
Discontinue study treatment
Any cell-depleting therapies including but not
limited to anti-CD20 or investigational agents
No prior 
exposure 
Discontinue study treatment
Any investigational treatment or participation 
in any interventional study
4 weeks or 5 
half-lives 
(whichever is 
longer)
Discontinue study treatment
Live vaccinations
6 weeks
Through Week 120, interrupt 
study treatment 12 weeks for 
secukinumab and 16 weeks for 
GP2017
Stable use of systemic corticosteroids > 10 
mg prednisone equivalent
2 weeks
Protocol deviation
Intra-articular corticosteroids
4 weeks
Dose adjustments permitted 
after randomization
Unstable dose of conventional synthetic 
DMARDs (e.g. MTX, sulfasalazine) 
4 weeks
Dose adjustments permitted 
after randomization; no more 
than 1 DMARD concomitantly
Non-biologic targeted synthetic DMARDs (e.g. 
JAK inhibitors) (van der Heijde 2016)
4 weeks 
Protocol deviation

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Medication
Washout period 
(before 
randomization)
Action
(after randomization, 
through Week 104)
Unstable dose of NSAIDs (COX1 or COX2 
inhibitors), paracetamol/acetaminophen or low 
strength opioids
2 weeks
Dose adjustments permitted 
after randomization
Analgesics (other than NSAIDs, 
paracetamol/acetaminophen or low strength 
opioids)
4 weeks
Protocol deviation
5.5.9
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis/CRO monitor for the site and the Study Team that the code 
has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
Study drug must be discontinued after emergency unblinding. Refer to Section 5.6.2 for 
Discontinuation of study treatment.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
A subject will be considered to have completed the study when the subject has completed the 
last visit planned in the protocol.
Information on the subject’s completion or discontinuation of the study and the reason for 
discontinuation of the study will be recorded on the corresponding CRF. 
In any case, the investigator or site staff must contact the IRT as soon as possible to record the 
subject’s study completion (Week F120) and/or discontinuation. 

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The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. This treatment may be any non-biologic DMARD. In case of a biologic treatment, 
a waiting period of 3 months for a subject previously on secukinumab and 4 months for a subject 
previously on GP2017 before initiating the treatment is recommended; elimination of 
adalimumab may take up to 4 months (Humira® SmPC).
5.6.2
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier than 
the protocol planned duration, and can be initiated by either the subject or the investigator. 
Subjects may voluntarily discontinue study treatment (refuse study treatment but continue with 
study participation) or completely discontinue from the study (no further study participation) 
for any reason, at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of study participation.
Study treatment must be discontinued under the following circumstances: 

Subject wish

Withdrawal of consent 

Pregnancy (see Section 6.5.9 and Section 7.6)

Any situation in which study participation might result in a safety risk to the subject

Emergence of the following adverse events:

Any severe or serious adverse event that in the judgement of the investigator, taking 
into account the subject’s overall status prevent the subject from continuing study 
treatment

Life-threatening infection

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevent the subject from continuing study 
treatment (A general guidance on clinically notable laboratory values is provided in 
Appendix 1.)

Use of any prohibited treatment as per recommendations in Table 5-1
The investigator must determine the primary reason for the subject’s premature discontinuation 
of study treatment and record this information on the appropriate CRF. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
Discontinuation of study treatment does not require the subject to be discontinued from the 
study and all ongoing visit assessments. Refer to Section 6 for the visit schedule and 
assessments.
If study drug discontinuation occurs because of treatment unblinding, please refer to Section 
5.5.9.   

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5.6.3
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow any further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.
5.6.4
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be considered as lost to follow-up until the time 
point of his/her scheduled end of study visit (Week F120) has passed.
5.6.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the subject 
must be seen as soon as possible and treated as a prematurely discontinued subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial.

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6
Visit schedule and assessments
Table 6-1 and Table 6-2 list all of the assessments and indicate with an “X” when the visits are 
performed.
Subjects must be seen for all visits on the designated day, or as close to it as possible. Missed 
or rescheduled visits will not lead to automatic discontinuation. 
Screening will be flexible in duration based on the time required to be evaluated for eligibility. 
Sufficient time is allowed for potential medication washout, in addition to all other assessments 
indicated in Table 6-1. Upon confirmation that all inclusion and exclusion criteria have been 
met, the subject may be randomized. The full 10-week screening window is not required.
Screening will consist of two consecutive visits. During Screening Visit 1 (SV1), initial 
assessments will be performed as outlined in Table 6-1, including the collection of hsCRP 
central laboratory test and SI joint X-rays. It is recommended that the subject should not proceed 
to Screening Visit 2 (SV2) until confirmation of sacroiliitis per the Modified NY AS Criteria 
grading from the centrally read SI joint X-rays (Appendix 3). One retest of the hsCRP lab result 
may be performed during the screening period. 
While the full screening window available is up to 10 weeks, SV2 should occur within the 4 
weeks prior to randomization.       
Subjects who prematurely discontinue the study treatment (secukinumab or GP2017) are 
encouraged to remain in the study to continue the study-related assessments until the completion 
of the study at Week F120. Every effort should be made to request the subjects to complete the 
final X-ray evaluations as part of the Week 104 visit assessments. Please refer to Section 5.6.2
for reasons for study treatment discontinuation.
Subjects who prematurely discontinue completely from the study for any reason should return 
for the final visit to conduct the Week 104 assessments (4 weeks after the last study treatment 
administration of secukinumab or 2 weeks after the last study treatment administration of 
GP2017), as well as return for the follow-up visits (Week F112 and F120). Every effort should 
be made to request discontinued subjects to complete the final X-ray and MRI evaluations as 
part of the Week 104 visit assessments, unless the last X-ray and/or MRI was taken within 12 
weeks prior to discontinuation.  
At the final visit, all dispensed investigational product should be reconciled and the adverse 
event and concomitant medications reconciled on the CRF.
If the subject refuses to return for these assessments or is unable to do so, every effort should 
be made to contact him/her or a knowledgeable informant by telephone to determine the reason.
Attempts to contact the subject should be recorded in the source documentation.

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6.1
Information to be collected on screening failures
Subjects who discontinue from the study prior to randomization are considered screen failures. 
If a subject discontinues before entering the partially-blinded treatment period at baseline, the 
IRT system must be notified within 2 days and the reason for not being randomized will be 
entered on the appropriate screening phase CRF. In addition, only the CRFs related to the 
following assessments should be completed: demography, informed consent, re-screening and 
inclusion/exclusion. The CRF for adverse events (AEs) should be completed for any Serious 
Adverse Events (SAEs) that occurred during the screening period. Adverse events that are not 
SAEs will be followed by the investigator and collected only in the source data. 
All subjects who have signed informed consent and are randomized into the Treatment Period 
of the study will have all AEs occurring after informed consent is signed recorded on the 
CRF capturing AEs, and SAEs if applicable, i.e. when SAE criteria are met.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgement, the test abnormality occurred prior to the informed consent 
signature. 
6.2
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data to be collected on all subjects and to be 
recorded in the CRF include: 

Age, sex, race, ethnicity

Relevant AS and general medical history/current medical condition data until the start of 
investigational treatment: targeted medical history events related to AS, such as the history 
of extra-axial involvement (uveitis, psoriasis, inflammatory bowel disease, dactylitis, 
enthesitis, peripheral arthritis), number of previous DMARDs used, date of diagnosis of 
AS, previous AS therapies, functional status class according to the New York criteria, 
cardiovascular medical history and smoking history
Where possible, diagnoses and not symptoms will be recorded. 
Investigators will have the discretion to record abnormal test findings on the CRF capturing 
medical history whenever in their judgment, the test abnormality occurred prior to the informed 
consent signature.
6.3
Treatment exposure and compliance
All dates and times of study treatment administration will be recorded on the appropriate CRF.
Drugs administered prior to start of treatment and other drugs/procedures continuing or started 
during the study treatment period will be entered in the appropriate CRF.
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons 
as described in Section 5.5.5. Compliance will be assessed by a field monitor using information 
provided by the subject and the authorized site personnel. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log.

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6.4
Efficacy

X-ray of the cervical, thoracic and lumbar spine assessed by modified Stoke Ankylosing 
Spondylitis Spinal Score (mSASSS)

X-ray of the SI joints

MRI of spine and SI joints (in a subset of subjects at selected sites)

Assessment of SpondyloArthritis International Society criteria (ASAS)

Patient’s global assessment of disease activity (VAS)

Patient’s assessment of back pain intensity (VAS)

Bath Ankylosing Spondylitis Functional Index (BASFI)

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

hsCRP

ASDAS-CRP and ASDAS response categories
All efficacy assessments should be performed prior to administration of study treatment. Details 
relating to the administration of all PROs are provided in Appendix 6. 
6.4.1
X-ray
X-rays will be obtained as defined in the schedule of assessments (Table 6-1 and Table 6-2) and 
according to the imaging acquisition guidelines provided by the central imaging lab. Prior to 
the first imaging assessment for the study, the center should be trained and qualified by the 
central imaging lab. The X-ray requirements include lateral views of the cervical and thoraco-
lumbar spine for mSASSS scoring (bottom 1/3 of C2 through top 1/3 of T1, inclusive) and 
anterio-posterior view of the pelvis including visibility of both SI joints. These images should 
be transferred to the central imaging lab following acquisition. Some X-rays may need to be 
repeated if deemed unacceptable by central review. In case of insufficient quality, the site will 
be advised and trained on any quality issues prior to the repeat X-ray, to keep any repeat X-rays 
to a minimum. The central imaging lab will conduct independent review for all spine and SI X-
rays in this study.
6.4.1.1
No radiographic progression in mSASSS
No radiographic progression in mSASSS is defined as a change from baseline in mSASSS at 
Week 104 of ≤ 0.5. While the primary analyses will be based on this definition, additional 
analyses using ≤ 0 and < 2 will be performed.
6.4.1.2
Syndesmophyte
A syndesmophyte will be defined as a score of ≥ 2 for any individual vertebral edge within 
evaluable vertebral units. A new syndesmophyte is defined as an individual vertebral edge with 
a score of 0 or 1 at baseline that changes to a score of 2 or 3 at Week 104.
6.4.2
MRI
MRI will be performed at selected sites in a subgroup of approximately 30% of all randomized 
subjects. MRI will be performed to assess SI and spinal inflammation using a scoring system 
for quantification of AS-related pathologies, to investigate whether these changes are affected 

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by treatment with secukinumab or GP2017. The images will be obtained as defined in the 
schedule of assessments (Table 6-1 and Table 6-2) and according to the imaging acquisition 
guidelines provided by the central imaging lab. The MRI for each subject will include T1 and 
STIR sequences of the sagittal spine (cervical, thoracic and lumbar) and oblique coronal of the 
pelvis including both SI joints. These MRI images should be transferred as anonymized 
electronic files to the central imaging lab following acquisition. The central imaging lab will 
conduct independent review for all spine and SI MRI imaging in this study.
6.4.3
Assessment of SpondyloArthritis International Society criteria (ASAS)
The ASAS response measures consist of the following assessment domains (Sieper 2009).
ASAS domains:

Patient’s global assessment of disease activity measured on a VAS scale

Patient’s assessment of back pain, represented by either total or nocturnal pain scores, 
both measured on a VAS scale

Function represented by BASFI average of 10 questions regarding ability to perform 
specific tasks as measured by VAS scale

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
6.4.3.1
ASAS Response Criteria 20% (ASAS 20)
ASAS 20 response is defined as an improvement of ≥ 20% and ≥ 1 unit on a scale of 10 in at 
least three of the four domains and no worsening of ≥ 20% and ≥ 1 unit on a scale of 10 in the 
remaining domain.
6.4.3.2
ASAS Response Criteria 40% (ASAS 40)
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 domains and no worsening at all in the remaining domain.
6.4.3.3
ASAS partial remission criteria
The ASAS partial remission criteria are defined as a value not above 2 units in each of the four 
domains on a scale of 10.
6.4.3.4
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?”.
6.4.3.5
Patient’s assessment of back pain intensity (VAS)
The patient’s assessment of back pain will be performed using a 100 mm VAS ranging from no 
pain to unbearable pain, after the question “Based on your assessment, please indicate what is 
the amount of back pain at any time that you experienced during the last week?” and “Based 

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on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?”.
6.4.3.6
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 0 through 10 scale (captured as a 
continuous VAS) is used to answer the questions. The mean of the ten scales gives the BASFI 
score – a value between 0 and 10.
6.4.3.7
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous VAS), which is used to answer 6 questions pertaining to the 
5 major symptoms of AS:
1. Fatigue
2. Spinal pain
3. Joint pain / swelling
4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)
5. Morning stiffness severity
6. Morning stiffness duration
To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness is taken. The mean of questions 5 and 6 is added to the scores from questions 
1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 BASDAI score. Scores of 
4 or greater suggest suboptimal control of disease, and subjects with scores of 4 or greater are 
usually good candidates for either a change in their medical therapy or for enrollment in clinical 
studies evaluating new drug therapies directed at AS. BASDAI is a quick and simple index 
taking between 30 seconds and 2 minutes to complete.
6.4.4
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.
6.4.5
ASDAS-CRP and ASDAS response categories
The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to assess 
disease activity in AS.
The ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score) will be utilized to assess 
the disease activity status. Parameters used for the ASDAS include spinal pain (BASDAI 
question 2), the patient’s global assessment of disease activity, peripheral pain/swelling 
(BASDAI question 3), duration of morning stiffness (BASDAI question 6) and C-reactive 
protein (CRP) in mg/L (Sieper 2009, Lukas 2009).

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Disease activity states are inactive disease, moderate disease activity, high disease activity, and 
very high disease activity. The 3 values selected to separate these states were < 1.3 between 
inactive disease and moderate disease activity, < 2.1 between moderate disease activity and 
high disease activity, and > 3.5 between high disease activity and very high disease activity. 
Selected cutoffs for improvement scores were a change ≥ 1.1 unit for “minimal clinically 
important improvement” and a change ≥ 2.0 units for “major improvement” (Machado 2011).
6.4.6
Appropriateness of efficacy assessments 
The efficacy outcome measures used in this study are the standard measures used across all 
ankylosing spondylitis studies.
This study involves exposure to radiation from X-rays of part of the thoracic, the cervical and 
lumbar spine and the SI joints. The radiation exposure from these procedures is not necessary 
for medical care but is intended for research purposes only. 
The amount of cumulative annual radiation in this study is about 3.4 mSv for the combined X-
ray procedures and is based on effective doses for various diagnostic radiological procedures 
reported in literature (Mettler 2008). This exposure is comparable to the natural radiation an 
average person receives in one year. The radiation dose between 3 mSv and 50 mSv is 
considered ‘minimal’ (Stabin 2009). Therefore, the radiation exposure in this study involves 
minimal risk and is necessary to obtain the research information desired.
6.5
Safety 

Tuberculosis screening

Physical examination

Vital signs

Height and weight

Laboratory evaluations

Chest X-ray or MRI

Electrocardiogram

Pregnancy and assessment of fertility

Local tolerability (injection site reactions)

Tolerability of investigational treatment
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
Tuberculosis screening
Either a central laboratory test or a locally performed skin test must be performed at the 
screening visit to screen the subject population for latent tuberculosis infection. The results must 
be known prior to randomization to determine the subject’s eligibility for the study. 

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Subjects with a positive test may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that 

the subject has no evidence of active tuberculosis

if presence of latent tuberculosis is established then treatment according to local country 
guidelines must have been initiated.
Central laboratory test for Tuberculosis screening
The test will be analyzed by the central laboratory. Details on the collection, processing and 
shipment of samples and reporting of results by the central laboratory are provided in the 
laboratory manual.
Local skin test for Tuberculosis screening
A PPD skin test is to be performed at screening and read before randomization to determine the 
subject’s eligibility for the study. The test dose is bioequivalent to 5 tuberculin units of standard 
PPD injected intradermally, usually into the volar surface of the forearm. The site is cleaned 
and the PPD extract is then injected into the most superficial layer under the skin. If given 
correctly, the injection should raise a small wheal of about 5 mm, which resolves within 10-15 
minutes.
Because the reaction (induration) will take 48-72 hours to develop, the subjects must return to 
the investigators’ site within that time for a proper evaluation of the injection site. This will 
determine whether the subject has had a significant reaction to the PPD test. A reaction is 
measured in millimeters of induration (hard swelling) at the site. A PPD skin induration ≥ 5 mm 
(or according to local practice/guidelines) is interpreted as a positive result.
6.5.2
Physical examination
The physical examination will include the examination of general appearance, skin, neck 
(including thyroid), 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. Clinically relevant findings that are present prior to signing informed consent must 
be included in the relevant medical history CRF. Significant findings made during a physical 
exam after signing the ICF which meet the definition of an AE must be recorded on the 
appropriate CRF capturing AEs and if SAE criteria are met, also as a SAE.
6.5.3
Vital signs 
This will include blood pressure and pulse rate measurements after 5 minutes rest in a sitting 
position.
If possible, vital sign assessments should be performed by the same study site staff member 
using the same validated device throughout the study.

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6.5.11
Tolerability of investigational treatments
Tolerability will be assessed by adverse events, laboratory values, injection site reaction 
 
.
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. 
The safety assessments selected are standard and adequate for this indication/subject population.
6.6
Other assessments

HLA-B27

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7
Safety monitoring 
7.1
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must 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

its relationship to any study treatment (no/yes) 

its duration (start and end dates), or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.

whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met.

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
action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 

no action taken (e.g. further observation only) 

study treatment interrupted/withdrawn

concomitant medication or non-drug therapy given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged (see Section 7.2 for definition 
of SAE)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must 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 Brochures (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the medicinal product that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification (IN) 
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the subject.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must 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)

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
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 subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject 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 subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to 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 subject 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 (please refer to Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
7.2.2
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 20 weeks following the last administration of study 
treatment or until the end of study visit (whichever is later) must be reported to Novartis 
safety/CRO within 24 hours of learning of its occurrence. Any SAEs experienced after this 
period should only be reported to Novartis if the investigator suspects a causal relationship to 
study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up information to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one must be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to each specific 
component of study treatment, (if study treatment consists of several components) complete the 
SAE Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the investigator folder provided to each site. 

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Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the subject continued or withdrew from study participation.
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 study 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 study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries.
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information.
7.3
Liver safety monitoring
There has been no safety signal for liver toxicity with secukinumab to date in approximately 
13,000 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 approximately 
13,000 patients and healthy subjects exposed, and from a mechanism of action standpoint there 
is no known effect of blocking IL-17A on the kidney. All subjects with laboratory tests 
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
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.

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Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the appropriate dose medication CRF irrespective of whether or not associated with an AE/SAE 
and reported to Safety only if associated with an SAE. Misuse or abuse will be collected and 
reported in the safety database irrespective of it being associated with an AE/SAE.
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error 
type
Document in study 
medication CRF 
(Yes/No)
Document in AE 
CRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes 
Yes, even if not 
associated with a SAE
7.6
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 subject safety, each pregnancy occurring after signing the informed consent 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 
subject 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 subject may continue all other protocol 
assessments.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. Any SAE experienced during the pregnancy and 
unrelated to the pregnancy must be reported on a SAE 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 data capturing tools with the investigators and their 
staff. During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The field monitor will visit the site to 
check the completeness of patient records, the accuracy of entries on the 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 the study medication 
specifications. Key study personnel must be available to assist the field monitor during these 

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visits.  Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis Clinical 
Teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the 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 subjects will be 
disclosed.
8.2
Data collection 
Designated investigator staff will enter the data required by the protocol into the CRFs using 
fully validated, secure web-enabled software that conforms to US CRF 21 Part 11 requirements. 
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 (CRFs) are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site.
The investigator is responsible for assuring that the data entered by the site personnel into the 
CRFs are complete, accurate and that entry and updates are performed in a timely manner. 
8.3
Database management and quality control 
Novartis personnel will review the data entered by investigator site staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
system. Designated investigator site staff are required to respond promptly to queries and to 
make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.

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9
Data analysis 
The analysis will be conducted on all subject data at the time the study ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
Summary statistics for continuous variables will generally include the number of subjects (N), 
minimum, lower quartile, mean, standard deviation median, upper quartile, and maximum. For 
categorical or binary variables, the number and percent of subjects in each category will be 
presented. P-values presented will be two-sided unless otherwise specified.
Data analyses will be presented by treatment regimen.  Efficacy and safety data will be 
presented by the following three treatment groups. 

Secukinumab 150 mg 

Secukinumab 300 mg 

GP2017 40 mg
9.1
Analysis sets
The following analysis sets will be used in this study:
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, mis-randomized subjects (mis-randomized in IRT) will be excluded 
from the randomized set. 
Mis-randomized subjects are defined as those subjects who were mistakenly randomized into 
the IRT prior to the site confirming all eligibility criteria had been met and to whom no study 
medication was given. Mis-randomized subjects are treated as screen failures.
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be evaluated according to the treatment assigned to at randomization. 
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. Subjects will be evaluated according to treatment received.
9.2
Subject demographics and other baseline characteristics
Demographics and baseline characteristics
The following common background and demographic variables will be summarized:

Gender, age, race, ethnicity, weight, height, and BMI.
Baseline disease characteristics will also be summarized for the following variables:

Patient’s global assessment of disease activity and other ASAS components, hsCRP, use 
(yes/no) and separate dose of MTX (mg/week), sulfasalazine (g/day) and systemic 
corticosteroids (mg/day) at randomization, time since first diagnosis of AS (years), modified 
New York criteria for AS, mSASSS, number of syndesmophytes, HLA-B27, total back pain 
(VAS), nocturnal back pain (VAS), total BASDAI score and spinal pain (BASDAI question 
#2).

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Medical history
A history of AS with focus on previous extra-articular involvement and past therapies for AS 
will be obtained. Any other significant prior or active medical condition at the time of signing 
informed consent will be recorded and coded using the MedDRA dictionary. These medical 
conditions will be summarized by primary system organ class and preferred term.
To establish a baseline level of cardiovascular risk, the number and percentage of subjects with 
pre-solicited cardiovascular risk factors will be summarized by treatment group. The number 
of cardiovascular risk factors that each subject has will also be summarized by treatment group. 
If it is unknown whether or not a subject currently or previously experienced a specific 
cardiovascular risk factor, it will be assumed that cardiovascular risk factor did not occur for 
that subject.
9.3
Treatments
Study treatment
The analysis of study treatment data will be based on the safety set. The number of visits with
injections received will be presented by treatment group. 
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number and percentage of subjects with cumulative exposure levels (e.g., any 
exposure, ≥ 2 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.
Prior and concomitant medication
Prior and concomitant medications will be summarized in separate tables by treatment group.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group.
Significant prior and concomitant non-drug therapies and procedures will be summarized by 
primary system organ class and MedDRA preferred term.
Prior surgeries and procedures are defined as surgeries and procedures done prior to first dose 
of study treatment. Any surgeries and procedures done between the day of first dose of study 
treatment and within the date of the last study visit will be a concomitant surgeries and 
procedures, including those which were started pre-baseline and continued into the period 
where study treatment is administered.
The number and percentage of subjects receiving prior and concomitant ankylosing spondylitis 
therapy will be presented by randomized treatment group as well as the reasons for stopping 

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their therapies (primary lack of efficacy, secondary lack of efficacy, lack of tolerability, other) 
and the total duration of exposure to ankylosing spondylitis therapies previously. NSAID use 
will be summarized.
9.4
Analysis of the primary variable(s)
Details of the testing strategy including primary and secondary endpoints are provided in 
Section 9.4.1 and Section 9.5.1.
9.4.1
Variable(s)
The primary efficacy objective is to demonstrate that the proportion of subjects on secukinumab 
(150 mg or 300 mg) with no radiographic progression is superior to GP2017 40 mg at Week 
104. The analysis of the primary objective will be based on the following estimand:

Population – defined through appropriate inclusion/exclusion criteria to reflect the 
targeted AS population

Variable – binary response variable indicating no radiographic progression, defined as a 
change from baseline in mSASSS at Week 104 of ≤ 0.5.

Intercurrent event – regardless of adherence to randomized treatment 

Population-level summary – difference in proportions of responders between the 
secukinumab and GP2017 arms
9.4.2
Statistical model, hypothesis, and method of analysis
The statistical hypothesis for no radiographic progression being tested is that there is no 
difference in the proportion of subjects with no radiographic progression at Week 104 in the 
secukinumab regimens versus GP2017 40 mg regimen.
Let pj denote the proportion of subjects with no radiographic progression at Week 104 for 
treatment regimens j, j=0, 1 or 2 where 

0 corresponds to GP2017 40 mg regimen,

1 corresponds to secukinumab 150 mg 

2 corresponds to secukinumab 300 mg
In statistical terms, Hj: pj = p0, HAj: pj≠p0,
H1: secukinumab 150 mg is not different to GP2017 regimen with respect to proportion of 
subjects with no radiographic progression at Week 104
H2: secukinumab 300 mg is not different to GP2017 regimen with respect to proportion of 
subjects with no radiographic progression at Week 104
The primary analysis will be conducted via logistic regression with treatment as factor and 
includes baseline mSASSS as covariate. Difference in marginal response proportions with p-
value and respective 95% confidence interval will be estimated from the logistic regression 
model. Analysis will be done on the FAS.

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9.4.3
Handling of missing values/censoring/discontinuations
Missing Week 104 data for a given subject will be imputed using an imputation model based 
on the observed data of subjects in the same randomized arm who also discontinued the study 
treatment but for whom Week 104 X-ray data is available (‘retrieved dropout approach’) and 
based on the observed data of the given subject (Baseline and Week 52). 
The potential sparsity of the retrieved data may preclude fitting the proposed imputation model 
to impute the subjects with missing X-ray data at Week 104. In this case, an alternative approach 
may be used if necessary, which will be detailed in the statistical analysis plan.
9.4.4
Sensitivity analyses 
Sensitivity analyses and supplementary analyses will be conducted in order to provide evidence 
that the results seen from the primary analysis are robust.
Sensitivity analyses may be conducted to determine the impact of missing data handling on the 
primary estimand by changing the covariate in the imputation model (e.g. using different ways 
of adjusting for baseline mSASSS, adding additional clinically relevant covariates).
Additional supplementary analyses may be conducted to examine different estimands which are 
also deemed clinically relevant. 
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The secondary efficacy variables and the method for adjusting for multiplicity are described 
below.  Handling of missing data for secondary variables included in the testing strategy will 
be the same as for the primary variable. All analysis will be done on the FAS.
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at Week 104
Change from baseline in mSASSS will be evaluated using ANCOVA model with treatment as 
a factor and baseline mSASSS as a covariate.
Estimand definition:

Population –  defined through appropriate inclusion/exclusion criteria to reflect the 
targeted AS population

Variable – mSASSS change from baseline at Week 104

Intercurrent event – regardless of adherence to randomized treatment

Population-level summary – difference in means between treatment
New syndesmophytes at Week 104
The proportion of subjects with no new syndesmophyte will be evaluated using a logistic 
regression model with treatment group as a factor and baseline mSASSS as a covariate.
Difference in marginal response proportions with p-value and respective 95% confidence 
interval will be estimated from the logistic regression model.
Estimand definition:

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
Population – defined through subjects with syndesmophyte at baseline, within the targeted 
AS population defined by inclusion/exclusion criteria

Variable – binary response variable indicating absence of new syndesmophyte at Week 
104. Absence of new syndesmophyte is defined as having individual vertebral score < 2 
for all interpretable locations which had no syndesmophyte at baseline

Intercurrent event – regardless of adherence to randomized treatment

Population-level summary – difference in proportion of absence of new syndesmophyte
between the secukinumab and GP2017 arms
MRI of spine and SI joints
MRI analysis will be based on a subgroup of subjects who have MRI performed on spine and 
SI joints at selected sites. 
The change from baseline to Week 104 in ASspiMRI-a Berlin modification score and Berlin SI 
joint edema score will be evaluated using a non-parametric ANCOVA model with treatment as 
factor and baseline score as covariate. Pairwise comparison will be performed for secukinumab 
(150 mg s.c. or 300 mg s.c.) versus GP2017. These will be assessed and analyzed outside the 
testing strategy.
If values are missing for baseline or post-baseline visit, the subject will be excluded from the 
analysis. 
Summary statistics of observed data by visit and change from baseline will be provided for each 
treatment regimen. Summary statistics include mean, standard deviation, minimum, lower 
quartile, median, upper quartile and maximum.
ASAS 20, ASAS 40, ASAS partial remission and ASDAS inactive disease at 
Week 104
Response at Week 104 to ASAS 20, ASAS 40, ASAS partial remission and ASDAS inactive 
disease will be evaluated using a logistic regression model with treatment group as a factor 
and baseline score (if appropriate) as a covariate. These will be assessed and analyzed outside 
the testing strategy.
Testing strategy
The following hypotheses will be included in the testing strategy, which controls the family-
wise two sided type-I-error at 5% level. The two primary hypotheses (H1 and H2) form the first 
family, which will be tested first at 5% level using the Hochberg (1988) procedure. The second 
family consists of the secondary hypotheses (H3 through H6), which will be tested only if both 
primary hypotheses have been rejected, and will be tested at 5% level using the graphical 
approach for sequentially rejective procedures (Bretz 2009) as illustrated in Figure 9-1:
Primary hypotheses:
H1: secukinumab 150 mg is not different to GP2017 40 mg with respect to proportion of 
subjects with no radiographic progression at Week 104
H2: secukinumab 300 mg is not different to GP2017 40 mg with respect to proportion of 
subjects with no radiographic progression at Week 104

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Secondary hypotheses:
H3: secukinumab 150 mg is not different to GP2017 40 mg with respect to change from baseline 
in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at Week 104
H4: secukinumab 300 mg is not different to GP2017 40 mg with respect to change from baseline 
in modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at Week 104
H5: secukinumab 150 mg is not different to GP2017 40 mg with respect to proportion of 
subjects with a syndesmophyte at baseline with no new syndesmophytes at Week 104
H6: secukinumab 300 mg is not different to GP2017 40 mg with respect to proportion of 
subjects with a syndesmophyte at baseline with no new syndesmophytes at Week 104
Figure 9-1
Testing strategy for the second family after both H1 and H2 have been 
rejected
The family-wise error rate will be controlled strongly at α=5% two-sided level with the 
proposed hierarchical testing strategy.  In the first family, the Hochberg procedure will reject 
H1 and H2, if both of them are significant at level α simultaneously. Otherwise, it will reject 
H1 if it is significant at level α/2, or reject H2 if it is significant at level α/2. Because H1 and 
H2 represent two doses of secukinumab versus GP2017, the correlation between the two test 
statistics will be positive. In this case, the type I error is controlled for the Simes test (Sarkar 
and Chang 1997) and, thus, the family-wise error rate is controlled strongly for the Hochberg 
procedure.
Once both primary hypotheses within the first family are rejected then the α will be passed to 
the second family starting with each of the hypotheses H3 and H4 tested simultaneously at α /2. 
Then based on the rejection of one or both (of H3 and H4), the next endpoint will be tested 
hierarchically for each dose (through H5 and/or H6), respectively. This procedure will continue 
(pending rejection of the null hypotheses) until H5 and/or H6 are/is rejected respectively, then 
the respective α/2 can be passed on to the other secukinumab regimen’s hierarchy of hypotheses 
in the second family (i.e. H3 or H4), if they are not already rejected at α/2. Of note, in the 
description above, rejection of a hypothesis refers to rejection of the two-sided hypothesis; 
however the level of a rejected hypothesis is only passed on according to the graphical 
procedure for the test of another hypothesis if the treatment effect is in favor of secukinumab.

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2016) and from a historical cohort where subjects took NSAIDs, a no progression rate of 66% 
for Secukinumab-treated subjects and 51% for NSAIDs-treated subjects at Week 104 were 
calculated.  Published data for anti-TNFs compared to a cohort of subjects who took NSAID 
showed no difference in change from baseline in mSASSS at Week 104 (van der Heijde 2009). 
Therefore, the 51% no progression rate calculated from the subjects who took NSAIDs will be 
used for GP2017.  Assuming 80% of subjects will complete the 2-year study treatment period 
and provide both baseline and Week 104 evaluable radiographic films with 66% no progression 
rate at Week 104 and assuming for subjects who discontinue study treatment with 51% no 
progression rate at Week 104, a new no progression rate of 63% for Secukinumab was 
calculated using the definition of the estimand. Therefore, no progression rate of 63% for 
secukinumab and 51% for GP2017 were used as assumptions to calculate the sample size using 
a two-group Chi-square test of equal proportion (nQuery Advisor 7.0). This calculated 
approximately 73% power at α=0.025 for each secukinumab dose, and the power to reject at 
least one of these hypotheses using the Hochberg procedure is 88% at an overall type I error of 
5%.
Analysis of an unpublished Phase III study showed a change from baseline in mSASSS at Week 
104 with a mean of 0.52 and standard deviation of 2.5 for Secukinumab subjects. With a sample 
size of 279 subjects in each treatment group, a treatment difference of 0.58 (i.e. assuming 
GP2017 have a mean of 1.1 and the same standard deviation) yields approximately 68% power 
at α = 0.025. 
Analysis of an unpublished Phase III study showed the 68% of the randomized subjects have 
syndesmophyte at baseline and for this subset the proportion of subjects with no new 
syndesmophyte at Week 104 is 70% for Secukinumab.  With a sample size of 190 subjects in 
each treatment group (about 68% of the planned randomized 279 subjects), a treatment 
difference of 15% (i.e. assuming GP2017 response rate of 55%) yields approximately 78% 
power at α = 0.025.
10
Ethical considerations
10.1
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21, and Japanese 
Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki.
10.2
Informed consent procedures 
Eligible subjects 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 subject. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 

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For trials using an Electronic Informed Consent system where a date/timestamp is automatically 
generated, the system-generated date/timestamp is sufficient; additional input of the date at the 
time of consent is not required by the subject.
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 must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study, and for a minimum 16 weeks or longer if local label requires it (e.g., 20 weeks for 
Secukinumab, 5 months for GP2017 in EU) after the last dose. If there is any question that the 
subject will not reliably comply, they must not be entered in the study.
The study includes an optional PG ICF which requires a separate signature if the subject agrees 
to participate. It is required as part of this protocol that the Investigator presents this option to 
the subject. The process for obtaining consent should be exactly the same as described above 
for the main informed consent.
Declining to participate in the PG assessments will in no way affect the subject’s ability to 
participate in the main research study.
10.3
Responsibilities of the investigator and IRB/IEC
Before initiating a study, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the study 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.
10.4
Publication of study protocol and results 
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.
10.5
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 

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responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance (CQA), a group independent from those involved 
in conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures, and are performed according to written 
Novartis processes.
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/subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstance, including 
incidental collection, is an investigator allowed to collect additional data or conduct any 
additional procedure for any purpose involving any investigational drugs under the protocol, 
other than for the purpose of the study. If despite this interdiction, any additional data, 
information, or observations would be incidentally collected, the investigator shall immediately 
disclose it to Novartis and not use it for any purpose other than the study, except for the 
appropriate monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
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 subjects may be implemented immediately provided the health authorities are subsequently 
notified by protocol amendment and the reviewing IRB/IEC is notified. Notwithstanding the 
need for approval of formal protocol amendments, the investigator is expected to take any 
immediate action required for the safety of any subject included in this study, even if this action 
represents a deviation from the protocol. In such cases, the reporting requirements identified in 
Section 7 Safety Monitoring must be followed.
12
References
References are available upon request.
Baeten D, Sieper J, Braun J, et al (2015) Secukinumab, an interleukin-IL17A inhibitor, in 
ankylosing spondylitis. N Eng J Med; 373:2534-48.

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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.

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
Limitation of motion of the lumbar spine in the sagittal and frontal planes.

Limitation of chest expansion relative to normal values correlated for age and sex.
Radiological criterion:

Sacroiliitis grade ≥ 2 bilaterally or grade 3–4 unilaterally.
Definite AS if the radiological criterion is associated with at least one clinical criterion.
13.4
Appendix 4: Assessment of SpondyloArthritis International 
Society criteria (ASAS)
The ASAS response measures consist of the following assessment domains (Sieper 2009).
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
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?

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To give each symptom equal weighting, the mean (average) of the two scores relating to 
morning stiffness (questions 5 and 6) is taken. The mean of questions 5 and 6 is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and subjects with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical studies evaluating new drug therapies directed at Ankylosing 
Spondylitis. BASDAI is a quick and simple index (taking between 30 seconds and 2 minutes to 
complete).
13.5
Appendix 5: modified Stoke Ankylosing Spondylitis Spine Score 
(mSASSS)
A total of 24 sites are scored on the lateral cervical and lumbar spine: the anterior corners of the 
vertebrae from lower border of C2 to upper border Th1 (inclusive) and from lower border of 
Th12 to upper border of S1 (inclusive). Each corner can be scored from 0 to 3, resulting in a 
range from 0 to 72 for the total mSASSS (Sieper 2009).
mSASSS scoring:

0 = normal

1 = sclerosis, squaring or erosion

2 = syndesmophyte

3 = bony bridge
13.6
Appendix 6: Guidelines for administering the questionnaires for 
patient reported outcomes
Before study start
Study coordinators should familiarize themselves with the PRO questionnaire(s) in the study 
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”

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

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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 nurse should read the questions and record the patient’s responses 
without influencing their answers. The information provided is strictly confidential and will be 
treated as such. If a patient has missed a question or given more than one response per question, 
then this should be brought to patient. Incomplete questions should not be accepted without first 
encouraging the patient to complete unanswered questions.
The investigator must complete the patient/visit information on the electronic device and ensure 
that the center number, patient’s number and initials are identical to the Case Record Form. As
there are no source data for this questionnaire, the data queries will be restricted to patient/visit 
information.