Clinical trial NCT03136861
Conditions: Spondyloarthritis
Keywords: axial spondyloarthritis ankylosing spondylitis non-radiographic axial spondyloarthritis inflammatory back pain spinal pain secukinumab AIN457
Sponsor: Novartis Pharmaceuticals
Start date: 2017-06-30; Completion date: 2019-02-15
Enrollment: 383 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study was to evaluate the efficacy and safety of secukinumab 150 mg compared to placebo in the early management (Baseline to Week 8) of spinal pain, disease activity, fatigue, and predictability of disease flares in patients with axial spondyloarthritis (axSpA) who had an inadequate response to prior non-steroidal anti-inflammatory drugs (NSAIDs). This study also explored the efficacy and safety of secukinumab 300 mg compared to secukinumab 150 mg from Week 8 to Week 24 in order to assess the potential additional benefits of dose escalation in patients with axSpA.

Detailed description:
The study consisted of 2 treatment periods: a double-blind, placebo-controlled period from Baseline to Week 8 (Treatment Period 1) and a double-blind secukinumab treatment period from Week 8 to Week 24 (Treatment Period 2).

At Baseline (Treatment Period 1), patients were randomized in a 3:1 ratio to either secukinumab 150 mg (Group A) or placebo (Group B). At Week 8 (Treatment Period 2), patients were re-randomized and re-assigned respectively to 1 of 5 treatment arms to receive either secukinumab 150 mg or secukinumab 300 mg.

Patients assigned to secukinumab 150 mg (Group A) at Baseline who were responders (i.e. spinal pain score \< 4) at Week 8 continued on the same dose until Week 24 under 1 treatment arm (Arm A1). Patients assigned to secukinumab 150 mg at Baseline who were non-responders at Week 8 were re-randomized to 1 of 2 treatment arms: secukinumab 150 mg (Arm A2) or secukinumab 300 mg (Arm A3) from Week 8 to Week 24.

Similarly, patients assigned to placebo (Group B) at Baseline were re-randomized to 1 of 2 treatment arms: secukinumab 150 mg (Arm B1) or secukinumab 300 mg (Arm B2) from Week 8 until Week 24.

Arms: arm 1: Treatment Period 1: Secukinumab 150 mg (1 x 1.0 mL) s.c. administered at Baseline, Week 1, 2, 3 and 4 arm 2: Treatment Period 1: Placebo (1 x 1.0 mL) s.c. administered at Baseline and Week 1, 2, 3 and 4 arm 3: Treatment Period 2: Secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered at Week 8, 12, 16 and 20 arm 4: Treatment Period 2: Secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered at Week 8, 12, 16 and 20 arm 5: Treatment Period 2: Secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20 arm 6: Treatment Period 2: Secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered at Week 8, 12, 16 and 20 arm 7: Treatment Period 2: Secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20
Interventions: intervention 1: AIN457 intervention 2: AIN457 Placebo
Intervention descriptions: intervention 1: anti IL-17a monoclonal antibody intervention 2: Placebo matching AIN457

Protocol documents:
Prot_001.pdf: 
Clinical Development - Medical Affairs Region Europe 
Secukinumab (AIN457) 
Clinical Trial Protocol CAIN457H3301 / NCT03136861
SKIPPAIN (Speed of onset of SecuKinumab-Induced relief 
from Pain in Patients with AxIal SpoNdyloarthritis)
A 24-week, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy and safety of 
secukinumab in controlling spinal pain in patients with 
axial spondyloarthritis
Document type:
Clinical Trial Protocol
EUDRACT number:
2017-000401-21
Version number:
00 (Original Protocol)
Clinical trial phase:
IIIb
Release date:
07-Feb-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.2 (July 2016)


Novartis
Confidential
Page 2
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................10
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Study objectives and endpoints .........................................................................................20
2.1
Objectives and related endpoints...........................................................................20
3
Investigational plan ...........................................................................................................22
3.1
Study design...........................................................................................................22
3.1.1
Treatment Period 1................................................................................22
3.1.2
Treatment Period 2................................................................................23
3.2
Rationale for study design .....................................................................................25
3.3
Rationale for dosing regimen, route of administration and duration of 
treatment ................................................................................................................26
3.4
Rationale for choice of comparator .......................................................................26
3.5
Rationale for re-randomization of patients............................................................27
3.6
Purpose and timing of interim analyses/design adaptations..................................27
3.7
Risks and benefits..................................................................................................27
4
Population..........................................................................................................................28
4.1
Inclusion criteria ....................................................................................................28
4.2
Exclusion criteria...................................................................................................29
5
Treatment...........................................................................................................................32
5.1
Study treatment......................................................................................................32
5.1.1
Investigational and control drugs..........................................................32
5.1.2
Additional treatment..............................................................................32
5.2
Treatment arms......................................................................................................32
5.3
Treatment assignment and randomization.............................................................33
5.4
Treatment blinding.................................................................................................34
5.5
Treating the patient................................................................................................34
5.5.1
Patient numbering .................................................................................34
5.5.2
Dispensing the study drug.....................................................................34


Novartis
Confidential
Page 3
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5.5.3
Handling of study and additional treatment..........................................35
5.5.4
Instructions for prescribing and taking study treatment........................36
5.5.5
Permitted dose adjustments and interruptions of study treatment ........37
5.5.6
Allowed treatment modifications and escape treatment .......................37
5.5.7
Concomitant medication .......................................................................37
5.5.8
Prohibited medication ...........................................................................39
5.5.9
Emergency breaking of assigned treatment code..................................40
5.6
Study completion and discontinuation...................................................................41
5.6.1
Study completion and post-study treatment..........................................41
5.6.2
Discontinuation of study treatment .......................................................41
5.6.3
Withdrawal of informed consent...........................................................42
5.6.4
Lost to follow-up...................................................................................43
5.6.5
Early study termination by the sponsor.................................................43
6
Visit schedule and assessments .........................................................................................43
6.1
Information to be collected on screening failures..................................................50
6.2
Patient demographics/other baseline characteristics .............................................50
6.2.1
Demographic data .................................................................................50
6.2.2
Baseline characteristics.........................................................................50
6.2.3
Electrocardiogram.................................................................................52
6.2.4
Other baseline characteristics................................................................52
6.3
Treatment exposure and compliance .....................................................................52
6.4
Efficacy..................................................................................................................53
6.4.1
Numerical rating scale spinal pain assessment .....................................53
6.4.2
Bath ankylosing spondylitis disease activity index (BASDAI) ............53
6.4.3
Ankylosing spondylitis disease activity score.......................................54
6.4.4
Functional assessment of chronic illness therapy-fatigue.....................55
6.4.5
Patient acceptable symptoms state........................................................55
6.4.6
ASAS Health Index...............................................................................55
6.4.7
Appropriateness of efficacy assessments..............................................56
6.5
Safety.....................................................................................................................56
6.5.1
Physical examination ............................................................................56
6.5.2
Vital signs..............................................................................................56
6.5.3
Height and body weight ........................................................................57
6.5.4
Laboratory evaluations..........................................................................57
6.5.5
Pregnancy and assessments of fertility .................................................58
6.5.6
Appropriateness of safety measurements..............................................58


Novartis
Confidential
Page 4
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
6.6
Other assessments..................................................................................................58
7
Safety monitoring..............................................................................................................58
7.1
Adverse events.......................................................................................................58
7.2
Serious adverse events...........................................................................................60
7.2.1
Definition of serious adverse event.......................................................60
7.2.2
Serious adverse event reporting ............................................................61
7.3
Liver safety monitoring .........................................................................................61
7.4
Renal safety monitoring.........................................................................................62
7.5
Reporting of study treatment errors including misuse/abuse ................................63
7.6
Pregnancy reporting...............................................................................................63
8
Data review and database management.............................................................................64
8.1
Site monitoring ......................................................................................................64
8.2
Data collection.......................................................................................................64
8.3
Database management and quality control............................................................64
8.4
Data monitoring committee...................................................................................65
8.5
Adjudication committee.........................................................................................65
9
Data analysis......................................................................................................................65
9.1
Analysis sets ..........................................................................................................65
9.2
Patient demographics and other baseline characteristics.......................................66
9.3
Treatments .............................................................................................................66
9.3.1
Study treatment .....................................................................................66
9.3.2
Prior and concomitant treatment...........................................................66
9.4
Analysis of the primary variable............................................................................67
9.4.1
Primary variable....................................................................................67
9.4.2
Statistical model, hypothesis, and method of analysis..........................67
9.4.3
Handling of missing values/censoring/discontinuations.......................67
9.4.4
Sensitivity analyses ...............................................................................67
9.5
Analysis of secondary variables ............................................................................68
9.5.1
Efficacy variables..................................................................................68
9.5.2
Safety variables .....................................................................................68
9.6
Analysis of exploratory variables ..........................................................................69
9.7
Interim analyses.....................................................................................................69
9.8
Sample size calculation..........................................................................................69
10 Ethical considerations........................................................................................................69
10.1
Regulatory and ethical compliance........................................................................69
10.2
Informed consent procedures.................................................................................69


Novartis
Confidential
Page 5
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
10.3
Responsibilities of the investigator and institutional review 
board/independent ethics committee .....................................................................70
10.4
Publication of study protocol and results...............................................................70
10.5
Quality control and quality assurance....................................................................70
11 Protocol adherence ............................................................................................................71
11.1
Protocol amendments.............................................................................................71
12 References .........................................................................................................................71
13 Appendices ........................................................................................................................75
13.1
Appendix 1: Clinically notable laboratory values .................................................75
13.2
Appendix 2: Liver event and laboratory trigger definitions and follow-up 
requirements ..........................................................................................................76
13.3
Appendix 3: Specific renal alert criteria and actions.............................................78
13.4
Appendix 4: Assessment of spondyloarthritis international society criteria for 
axial spondyloarthritis ...........................................................................................79
13.5
Appendix 5: Modified New York diagnostic criteria for ankylosing 
spondylitis..............................................................................................................80
13.6
Appendix 6: Definition of sacroiliitis on imaging.................................................81
13.7
Appendix 7: Spinal pain numerical rating scale....................................................82
13.8
Appendix 8: Bath ankylosing spondylitis disease activity index ..........................83
13.9
Appendix 9: Guidelines for administering the questionnaires for patient 
reported outcomes..................................................................................................84
13.10 Appendix 10: ASAS recommendations for collecting, analyzing and 
reporting NSAID intake.........................................................................................86
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 5-1
Corticosteroids conversion table for the equivalence of 1 mg of 
cortisone................................................................................................39
Table 5-2
Prohibited medication ...........................................................................40
Table 6-1
Assessment schedule.............................................................................45
Table 6-2
Overview of study drug administration for Treatment Period 2...........50
Table 6-3
Items of the ASAS health index............................................................55
Table 7-1
Treatment error types ............................................................................63
Table 13-1
Safety analyses: expanded limits and notable criteria...........................75
Table 13-2
Liver event and laboratory trigger definitions ......................................76
Table 13-3
Follow-up requirements for liver events and laboratory triggers..........76
Table 13-4
Specific renal alert criteria and actions.................................................78


Novartis
Confidential
Page 6
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Table 13-5
ASAD-NSAID equivalent score ...........................................................86
List of figures
Figure 3-1
Study design..........................................................................................24


Novartis
Confidential
Page 7
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
List of abbreviations
ACR
Albumin-Creatinine Ratio
AE
Adverse Event
ADR
Adverse Drug Reaction
ALP
Alkaline Phosphatase
ALT/SGPT
Alanine Aminotransferase/Serum Glutamic Pyruvic Transaminase
ANOVA
Analysis of Variance
anti-TNFα
anti-Tumor Necrosis Factor alpha
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST/SGOT
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
ATC
Anatomical Therapeutic Classification
axSpA
axial SpondyloArthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
CD
Cluster of Differentiation
CI
Confidence Interval
COX-1
CycloOXygenase-1
COX-2
CycloOXygenase-2
CPO
Country Pharma Organization
CRF
Case Report Form
CRO
Contract Research Organization
DS&E
Drug Safety and Epidemiology
DMARDs
Disease Modifying Antirheumatic Drugs
eCRF
electronic CRF
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA/EMEA
European Medicines Agency
EU
European Union
FACIT-Fatigue©
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS-TP1
Full Analysis Set for Treatment Period 1
FAS-TP2
Full Analysis Set for Treatment Period 2
FDA
Food and Drug Administration
GCP
Good Clinical Practice
γGT
Gamma Glutamyl Transferase
hCG
Human Chorionic Gonadotropin
HIV
Human Immunodeficiency Virus
HLA-B27
Human Leukocyte Antigen-B27
hsCRP
high sensitivity C-Reactive Protein
IB
Investigator’s Brochure
IBP
Inflammatory Back Pain
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 


Novartis
Confidential
Page 8
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFU
Instructions For Use
IL
Interleukin
IN
Investigator Notification
INR
International Normalized Ratio (for blood clotting times)
IRB
Institutional Review Board
IRT
Interactive Response Technology
i.v.
Intravenous
LFT
Liver Function Test (raised serum transaminase and/or bilirubin levels)
LLN
Lower Limit of Normal
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic Resonance Imaging
MTX
Methotrexate
nr-axSpA
non-radiographic axial SpondyloArthritis
NSAID(s)
Nonsteroidal Anti-Inflammatory Drug(s)
NRS
Numerical Rating Scale
PASS
Patient Accepted Symptoms State
PCR
Protein-Creatinine Ratio
PFS(s)
PreFilled Syringe(s)
PRN
Pro re nata (as needed)
PRO
Patient Reported Outcome
PsA
Psoriatic Arthritis
PT
Preferred Term
PT/INR
Prothrombin Time/ International Normalized Ratio
QoL
Quality of Life
SAE
Serious Adverse Event
SAF-TP1
Safety Set for Treatment Period 1
SAF-TP2
Safety Set for Treatment Period 2
s.c.
Subcutaneous
SIJ
Sacroiliac Joints
SmPC
Summary of Product Characteristics
SOC
System Organ Class
SpA
SpondyloArthritis
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TBL
Total Bilirubin
TNF
Tumor Necrosis Factor
TNFα-IR
Tumor Necrosis Factor α Inadequate Responder
ULN
Upper Limit of Normal
WBC
White Blood Cells
WHO
World Health Organization


Novartis
Confidential
Page 9
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Glossary of terms
Assessment
A procedure used to generate data required by the study
Dosage
Dose of the study treatment given to the patient in a time unit 
Enrollment
Point/time of patient entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol)
Inadequate response to TNFα
Active disease despite stable treatment with anti-tumor necrosis 
factor alpha (TNFα) for at least 3 months at an approved dose or 
for at least one dose in the case of lack of tolerance
Medication number
A unique identifier on the label of each study treatment package in 
studies that dispense study treatment
Patient number
A number assigned to each patient who enrolls in the study. When 
combined with the center number, a unique identifier is created for 
each patient in the study
Period
A portion of the study that serves a specific purpose. Typical 
periods are: Screening, treatment, and follow-up
Source data/document
Source data refers to the initial record, document, or primary 
location from where data comes. The data source can be a 
database, a dataset, a spreadsheet or even hard-coded data, such 
as paper or eSource
Study treatment
Any single drug or combination of drugs administered to the patient 
as part of the required study procedures; includes investigational 
drug (s), placebo/comparator active drug run-ins or background 
therapy
Study treatment discontinuation
When the patient 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 consent
Withdrawal of consent from the study is defined as when a patient 
does not want to participate in the study any longer, and does not 
want any further visits or assessments, and does not want any 
further study related contact, and does not allow analysis of already 
obtained biologic material


Novartis
Confidential
Page 10
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Protocol summary
Protocol number
CAIN457H3301
Full Title
A 24-week, randomized, double-blind, placebo-controlled, multicenter study 
to evaluate the efficacy and safety of secukinumab in controlling spinal pain 
in patients with axial spondyloarthritis
Brief title
SKIPPAIN – Speed of onset of SecuKinumab-Induced relief from Pain in 
Patients with AxIal SpoNdyloarthritis
Sponsor and clinical 
phase
Novartis, Phase IIIb
Investigation type
Drug; biological
Study type
Interventional 
Purpose and rationale
The majority of patients with axial spondyloarthritis (axSpA) experience 
inflammatory back pain (IBP) as the first symptom of disease and the 
burden of pain is comparable for patients with non-radiographic axSpA 
(nr-axSpA) and ankylosing spondylitis (AS). Most patients with axSpA also 
experience severe fatigue, which has been shown to be deeply influenced 
by pain. It has been reported how pain, disease activity, fatigue and 
disease flares affect the quality of life (QoL) of patients with axSpA. 
According 
to 
treat-to-target 
recommendations 
for 
patients 
with 
spondyloarthritis (SpA), the primary goal of the treatment is to maximize 
long-term health-related QoL and social participation through control of 
signs and symptoms, including pain. In addition, improvement of disease 
activity and fatigue, as well as the achievement of a stable disease status 
with control of disease flares, are considered key targets of the treatment 
strategy. Therefore, the fast onset in pain relief is one of the most relevant 
outcomes for patients with axSpA determining individual QoL.
In order to address these unmet patient needs, this double-blind, 
randomized, parallel-group, placebo-controlled study is primarily assessing 
the efficacy of secukinumab 150 mg compared to placebo in terms of 
significant relief from spinal pain, as measured by a numerical rating scale 
(NRS < 4), as early as Week 8. The cut-off value of NRS < 4 has been 
chosen in accordance with the cut-off points for mild, moderate, and severe 
pain on the visual analogue scale for pain in patients with chronic 
musculoskeletal pain. In addition, improvement in disease activity, fatigue 
and assessment of disease flares will be evaluated at Week 8 and/or 
Week 12 and at Week 24.
At Week 8, patients randomized to either secukinumab or placebo 
treatment at Baseline will be re-randomized to active treatment with 
secukinumab 150 mg or 300 mg. Re-randomization will provide patients 
with the maximal opportunity to respond to secukinumab treatment.
The potential benefit of dose escalation from secukinumab 150 mg to 
300 mg will be explored during Treatment Period 2 (Week 8 to Week 24) in 
a proportion of patients assigned to secukinumab 150 at Baseline who did 
not achieve a response (i.e. spinal pain < 4) at Week 8. Similarly, a 
proportion of patients in the placebo group will be assigned secukinumab 
300 mg during Treatment Period 2 so as to explore how those patients 
respond to a higher starting dose of secukinumab.


Novartis
Confidential
Page 11
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Primary objective 

To assess the superiority of secukinumab 150 mg compared to 
placebo in achieving a spinal pain score 4 on a 0-10 NRS at 
Week 8.
Secondary objective

To assess the superiority of secukinumab 150 mg compared to 
placebo in achieving a Bath Ankylosing Spondylitis Disease 
Activity Index (BASDAI) score 4 at Week 8.
Exploratory objectives

Proportion of patients achieving a spinal pain score 4 on a 0-10 
NRS at Week 1, 2, 3 and 4 with secukinumab 150 mg compared 
to placebo.

Proportion of patients in each treatment arm achieving a spinal 
pain score 4 on a 0-10 NRS at Week 24.

Proportion of patients in each treatment arm achieving a BASDAI 
score 4 at Week 24.

Proportion of patients in each treatment arm achieving Ankylosing 
Spondylitis Disease Activity Score (ASDAS) score 2.1 at Week 8 
and Week 24.

Proportion of patients in each of treatment arm achieving ASDAS 
score 1.3 at Week 8 and Week 24.

Mean change from Baseline in functional assessment of chronic 
illness therapy-fatigue (FACIT-Fatigue©) score in patients on 
secukinumab 150 mg compared to placebo at Week 8.

Mean change from Baseline in FACIT-Fatigue© score in each 
treatment arm at Week 24.

Proportion of patients in Arm A1 who have pain flares defined as 
NRS score 6 at Week 12 or Week 24.

Proportion of patients achieving a satisfactory Patient Acceptable 
Symptom State (PASS) at Week 1, 2, 3, 4 and 8 with 
secukinumab 150 mg compared to placebo.

Proportion of patients in each treatment arm achieving a 
satisfactory PASS at Week 12, Week 20 and Week 24.

Spinal pain NRS score according to previous exposure to tumor 
necrosis factor (TNF) blockers at Week 1, 2, 3, 4, 8, 12 and 24.

Proportion of patients achieving a spinal pain score 4 on a 0-10 
NRS for TNF-naïve patients compared to TNFα-inadequate 
responder (TNFα-IR) patients at Week 8 and Week 24.

Proportion of patients who responded to secukinumab 150 mg at 
Week 8 (i.e. spinal pain score 4 on a 0-10 NRS) maintaining a 
response at Week 24.

Proportion of patients achieving an improvement in Assessment of 
SpondyloArthritis International Society (ASAS) health index with 
secukinumab 150 mg compared to placebo at Week 8.

Proportion of patients achieving an improvement in ASAS health 
index in each treatment arm at Week 24.

ASAS health index at Week 8 and Week 24.

Change from baseline in total NRS score at all time points.

Change from baseline in total BASDAI score at all time points.

ASDAS-CRP at Week 8 and Week 24.


Safety and tolerability of secukinumab 150 mg and 300 mg over 


Novartis
Confidential
Page 12
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
the study period.
Study design
This 
is 
a 
24-week, 
randomized, 
double-blind, 
placebo-controlled, 
multicenter study to evaluate the efficacy and safety of secukinumab in 
controlling spinal pain in patients with axSpA. The study will consist of 
2 treatment periods; a double-blind, placebo-controlled period from 
Baseline to time of study drug administration at Week 8 during which 
patients will be randomized to secukinumab 150 mg or placebo; followed 
by a double-blind secukinumab treatment period from Week 8 to Week 24 
during which patients will be re-randomized to 1 of 5 treatment arms to 
receive either secukinumab 150 mg or secukinumab 300 mg. 
Patients assigned to secukinumab 150 mg (Group A) at Baseline who are 
responders (i.e. spinal pain score < 4) at Week 8 will continue on the same 
dose until Week 24 under 1 treatment arm (Arm A1). Patients assigned to 
secukinumab 150 mg at Baseline who are non-responders at Week 8 will 
be re-randomized to 1 of 2 treatment arms: secukinumab 150 mg (Arm A2)
or secukinumab 300 mg (Arm A3) from Week 8 to Week 24. Similarly, 
patients assigned to placebo (Group B) at Baseline will be re-randomized 
to 1 of 2 treatment arms: secukinumab 150 mg (Arm B1) or secukinumab 
300 mg (Arm B2) from Week 8 until Week 24.
Population
Male and female patients ≥18 years of age (at the time of consent) with 
axSpA diagnosis (either AS or nr-axSpA) fulfilling the ASAS criteria. 
Patients must have clinical signs of spinal involvement defined by presence 
of IBP with active disease defined by BASDAI score ≥4, spinal pain NRS 
score > 4 and inadequate response (including intolerance) to at least 2 
non-steroidal anti-inflammatory drugs (NSAIDs) over a 4-week period, 
unless contraindicated. Patients will be allowed to continue background 
medications (including NSAIDs, selected disease modifying anti-rheumatic 
drugs (DMARDs), i.e. methotrexate (MTX) and sulfasalazine, and 
corticosteroids) in this study in accordance with the protocol sections on 
concomitant and prohibited medications.
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 
provide written, signed and dated informed consent before any study 
assessment is performed.
2.
Male or non-pregnant, non-nursing female patients at least 18 years of 
age with diagnosis of axSpA (either AS or nr-axSpA) according to 
ASAS axSpA classification criteria to be applied in patients with back 
pain for at least 3 months and age of onset < 45 years:

Sacroiliitis on imaging with ≥ 1 SpA feature or

Human Leukocyte Antigen-B27 (HLA-B27) positive with ≥2 SpA 
features.
3.
Active axSpA as assessed by total BASDAI score ≥4 at Baseline.
4.
Spinal pain NRS score > 4 at Baseline.
5.
Patients should have been on at least 2 different NSAIDs at the highest 
recommended dose for at least 4 weeks in total prior to randomization 
with an inadequate response or failure to respond, or less if therapy 
had to be withdrawn due to intolerance, toxicity or contraindication.
6.
Patients who are regularly taking NSAIDs (including cyclooxygenase-1 
(COX-1) or cyclooxygenase-2 (COX-2) inhibitors) as part of their 


Novartis
Confidential
Page 13
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
axSpA therapy are required to be on a stable dose for at least 2 weeks 
before randomization.
7.
Patients who have previously on a TNFα inhibitor will be allowed entry 
into study after an appropriate what-out period prior to randomization:

4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 
30 hours (s.c. route)

8 weeks for Remicade® (infliximab) – with a terminal half-life of 
8.0-9.5 days (i.v. infusion)

10 weeks for Humira® (adalimumab) – with a terminal half-life of 
10-20 days (average 2 weeks) (s.c. route)

10 weeks for Simponi® (golimumab) – with a terminal half-life of 
11-14 days

10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 
14 days
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in 
this study. No additional exclusions may be applied by the investigator in 
order to ensure that the study population will be representative of all eligible 
patients.
1.
Chest X-ray or magnetic resonance imaging (MRI) with evidence of 
ongoing infectious or malignant process obtained within 3 months of 
Screening and evaluated by a qualified physician (otherwise chest 
X-ray or MRI is required to be performed at Screening).
2.
Previous treatment with prohibited medication as outlined in Section 
5.5.7 and Section 5.5.8 of the main protocol. Prohibited medication 
may be washed out before randomization in accordance with Section 
5.5.7 and Section 5.5.8 of the main protocol.
3.
Previous exposure to secukinumab or any other biologic drug directly 
targeting interleukin-17 (IL-17) or interleukin-23 (IL-23).
4.
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.
5.
History of hypersensitivity to the study drug or its excipients or to drugs 
of similar chemical classes.
6.
Patients previously treated with any biological immunomodulating 
agents, except those targeting TNFα.
7.
Patients who have been exposed to more than one anti-tumor necrosis 
factor alpha (anti-TNFα) agent
8.
Previous treatment with any cell-depleting therapies including but not 
limited to anti-cluster of differentiation (CD)20 or 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 childbearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods 
of contraception during entire study or longer if required by locally 
approved prescribing information (e.g. 20 weeks since last dose of 
secukinumab in the European Union (EU)). Effective contraception 
methods include:

Total abstinence, when this is in line with the preferred and usual 


Novartis
Confidential
Page 14
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
lifestyle of the patient. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy 
with or without hysterectomy) or tubal ligation at least 6 weeks 
before taking study treatment. In case of oophorectomy alone, 
only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment.

Male sterilization (at least 6 months prior to Screening). For 
female patients on the study, the vasectomized male partner 
should be the sole partner for that patient.

Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository.

Use of oral, injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device or intrauterine system.
In case of use of oral contraception, women should have been stable 
on the same pill for a minimum of 3 months before taking study 
treatment.
Women are considered post-menopausal or not of childbearing
potential if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 
6 weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up 
hormone level assessment is she considered not of childbearing 
potential.
11. Active ongoing inflammatory diseases other than axSpA that might 
confound the evaluation of the benefit of secukinumab therapy (such as 
inflammatory bowel disease and uveitis).
12. Other ongoing mechanical diseases affecting the spine (such as severe 
osteoarthritis of spine and diffuse idiopathic skeletal hyperostosis and 
fibromyalgia) that may confound evaluation of the benefit of 
secukinumab therapy.
13. 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.
14. Significant medical problems or diseases, including but not limited to 
the following: uncontrolled hypertension (≥ 160/95 mmHg), congestive 
heart failure (New York Heart Association status of class III or IV), 
uncontrolled diabetes, or very poor functional status (unable to perform 
self-care).
15. History of clinically significant liver disease or liver injury as indicated 
by abnormal liver function tests such as aspartate aminotransferase/ 
serum glutamic oxaloacetic transaminase (AST/SGOT), alanine 
aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT), 


Novartis
Confidential
Page 15
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
alkaline phosphatase, or serum bilirubin. The investigator should be 
guided by the following criteria:

Any single parameter may not exceed 2 × upper limit of normal 
(ULN). A single parameter elevated up to and including 2 × ULN 
should be re-checked once more as soon as possible, and in all 
cases, at least prior to enrollment/randomization, to rule out 
laboratory error.

If the total bilirubin concentration is increased above 2 × ULN, total 
bilirubin should be differentiated into the direct and indirect 
reacting bilirubin.
16. 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).
17. Screening total white blood cell (WBC) count < 3000/µL, or platelets 
< 100 000/µL or neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL 
(85 g/L).
18. Active systemic infections during the last 2 weeks prior to 
randomization (exception: common cold).
19. History of ongoing, chronic or recurrent infectious disease or evidence 
of tuberculosis (TB) infection as defined by a positive QuantiFERON 
TB-Gold test. 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 TB. If presence 
of latent TB is established, then treatment according to local country 
guidelines must have been initiated.
20. Known infection with human immunodeficiency virus (HIV), hepatitis B 
or hepatitis C at Screening or randomization.
21. 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 keratosis 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).
22. Any current severe progressive or uncontrolled disease, which in the 
judgment of the clinical investigator renders the patient unsuitable for 
the trial.
23. 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.
24. History or evidence of ongoing alcohol or drug abuse within the last 
6 months before randomization.
25. Administration of live vaccines 6 weeks prior to randomization or plans 
for administration of live vaccines during the study period; live vaccines 
should not be given until 12 weeks after last study treatment 
administration.
Study treatment
Secukinumab 150 mg will be provided in 1 mL prefilled syringes (PFSs) for 
s.c. injection. Secukinumab 300 mg will be provided as 2 PFSs each 
containing 150 mg secukinumab. Secukinumab placebo will be provided as 
1 mL PFS. 
Treatment Period 1 (Baseline to Week 8)
At Baseline, all patients whose eligibility is confirmed will be randomized in 
a 3:1 ratio to secukinumab 150 mg or placebo as shown below. Patients 


Novartis
Confidential
Page 16
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
will be stratified at randomization according to previous exposure to TNF 
blockers (i.e. according to whether they are naïve to TNFα inhibitors or are 
TNFα-IR patients. 
Group A: secukinumab 150 mg

Secukinumab 150 mg (1 × 1.0 mL PFS) at Baseline, Week 1, 2, 3
and 4
Group B: placebo

Placebo (1 × 1.0 mL PFS) at Baseline, Week 1, 2, 3 and 4
Treatment Period 2 (Week 8 to Week 24)
At Week 8, patients randomized to Group A (secukinumab 150 mg) at 
Baseline will be classified as responders (spinal pain NRS score < 4) or 
non-responders (spinal pain NRS score ≥ 4) based on their spinal pain 
scores and re-randomized to 1 of 3 treatment arms to receive either 
secukinumab 150 mg or 300 mg. Those patients randomized to Group B 
(placebo) at Baseline will be re-randomized to 1 of 2 treatment arms to 
receive either secukinumab 150 mg or 300 mg at Week 8.
Responders in Group A (spinal pain NRS score < 4):

Arm A1: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo
(1 × 1.0 mL PFS) administered every 4 weeks from Week 8 to
Week 20
Non-responders in Group A (spinal pain NRS score ≥4):

Arm A2: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo
(1 × 1.0 mL PFS) administered every 4 weeks from Week 8 to
Week 20

Arm A3: secukinumab 300 mg (2 × 1.0 mL PFS) administered
every 4 weeks from Week 8 to Week 20
Patients randomized to placebo (Group B) at Baseline will be 
re-randomized to secukinumab 150 mg or 300 mg at Week 8: 

Arm B1: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo
(1 × 1.0 mL PFS) administered every 4 weeks from Week 8 to
Week 20

Arm B2: secukinumab 300 mg (2 × 1.0 mL PFS) administered
every 4 weeks from Week 8 to Week 20
Patients will be allowed to continue background medications during the 
study in accordance with the protocol sections on concomitant and 
prohibited medications. 
Efficacy assessments

Spinal pain NRS assessment

BASDAI

ASDAS

FACIT-Fatigue©

PASS

ASAS Health Index
Safety assessments

Evaluation of adverse events (AEs) and serious adverse events
(SAEs) including injection site reactions

Physical examination

Vital signs

Laboratory evaluations (hematology, clinical chemistry and


Novartis
Confidential
Page 17
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
urinalysis)
Data analysis
The primary efficacy endpoint is the proportion of patients with a spinal pain 
NRS score < 4 at Week 8. The primary analysis will be performed 
comparing treatments with respect to the primary efficacy endpoint in a 
logistic regression model with the factors treatment, country and the 
stratification factor (naïve/ inadequate responders to TNFα inhibitors). The 
odds ratio and its 95% confidence interval (CI) and p-value will be given. 
For the primary endpoint, patients with missing assessments at Week 8 will 
be considered as non-responders.
The raw spinal pain NRS scores will be analyzed using a repeated 
measures analysis of variance (ANOVA) model. The model will include the 
same factors as the logistic model above plus the baseline score as a 
covariate.
The secondary efficacy endpoint, the proportion of patients with a BASDAI 
score < 4 at Week 8, will be analyzed similarly to the primary endpoint.
Key words
Axial spondyloarthritis, ankylosing spondylitis, non-radiographic axial 
spondyloarthritis, inflammatory back pain, spinal pain, secukinumab, 
AIN457


Novartis
Confidential
Page 18
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
1
Introduction
1.1
Background
Axial spondyloarthritis (axSpA) is a group of rheumatic disorders with spinal inflammation 
and inflammatory back pain (IBP) as typical hallmarks. The prevalence of axSpA is up to 
1-2% in the Caucasian population (Braun et al 2011). Patients with chronic back pain (onset 
before 45 years of age) are classified according to the Assessment of SpondyloArthritis 
International Society (ASAS) classification criteria for axSpA if they fulfill either the clinical 
arm or the imaging arm of the criteria (Rudwaleit et al 2009a).
Patients with axSpA are classified into ankylosing spondylitis (AS) and non-radiographic 
axSpA (nr-axSpA) based on the presence or absence of sacroiliitis on conventional X-ray 
radiographs according to the 1984 modified New York diagnostic criteria (van der Linden et 
al 1984). Patients with presence of sacroiliitis on X-ray are classified as having AS whereas 
patients with absence of sacroiliitis on X-ray but presence of inflammatory lesions in the 
sacroiliac joints (SIJ) on a magnetic resonance imaging (MRI) scan may be classified as 
having nr-axSpA.
Studies and registry data have shown that patients with nr-axSpA have a similar burden of 
disease to patients with AS in terms of pain, fatigue and impairment of health-related quality 
of life (QoL) (Wallis et al 2013). Disease parameters and response rates to treatment with 
tumor necrosis factor (TNF) antagonists are similar in patients with AS and nr-axSpA, 
supporting the concept that axSpA may represent a disease with distinct stages (Song et al 
2013). 
The majority of patients with axSpA experience IBP as the first symptom of the disease. 
According to ASAS criteria, IBP is defined as chronic back pain (lasting longer than 3 months) 
where 4 out of the following 5 parameters are present: 1) age at onset is below 40 years, 
2) insidious onset, 3) causes pain at night with improvement upon getting up, 4) improves 
with exercise but 5) does not improve at rest. As reported in one study (Rudwaleit et al 2006), 
IBP usually improves with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). 
Recent studies also demonstrated how spinal pain strongly correlates with QoL measured by 
the ASQoL questionnaire. Spinal pain also strongly correlates with disease duration and Short 
Form-36 questionnaire sub-scales (Bodur et al 2011). 
Fatigue is another major clinical feature of rheumatic diseases and is defined as a state of 
reduced muscle capacity and decreased work ability accompanied by feelings of tiredness, 
weariness, and lack of energy (Missaoui and Revel 2006). A recent study by 
Bedaiwi et al (2015) demonstrated that 67.3% of patients with axSpA had severe fatigue, and 
that patients with AS and nr-axSpA were equally affected. Brophy et al 2013 demonstrated 
how fatigue is deeply influenced by pain. In fact, according to the findings of this study, the 
measures to address fatigue in AS need to focus primarily on the pain rather than anxiety, 
physical activity, motivation, or sleep. Pain is the single factor examined that contributes to 
explaining the variation in fatigue. Treatment with anti-tumor necrosis factor  therapy may 
improve levels of pain and fatigue; however, the majority of patients with axSpA may still 


Novartis
Confidential
Page 19
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
experience significant residual pain (mean 54.4 on a scale of 0-100) and fatigue (mean 51.8 
on a scale of 0-100) while on treatment.
Secukinumab (AIN457) is a recombinant high-affinity fully human monoclonal anti-human 
Interleukin-17A (IL-17A) antibody of the IgG1-κ class. IL-17A is mainly produced by 
memory cluster of differentiation (CD)4+ and CD8+ T lymphocytes and is one of the
principal pro-inflammatory cytokines in AS as well as other immune mediated inflammatory
diseases such as psoriasis, and psoriatic arthritis (PsA). Secukinumab is selective for human 
IL-17A and potently neutralizes the bioactivity of this cytokine. Secukinumab is marketed as 
Cosentyx® in more than 60 countries worldwide (including Europe and the US) and is 
available as solution in different doses for subcutaneous (s.c.) injection. The product is 
indicated for the treatment of AS (the recommended dose is 150 mg), PsA (the recommended 
dose is 150 mg; however, for patients who are TNFα inadequate responders (TNFα-IR) or 
have concomitant moderate to severe psoriasis, the recommended dose is 300 mg) and 
moderate to severe plaque psoriasis (the recommended dose is 300 mg).
Secukinumab has demonstrated improvements in total spinal pain compared to placebo in 
Phase III studies in patients with AS at all time points from Baseline to Week 16, and 
improvements observed at Week 16 were sustained up to Week 52. Secukinumab also led to 
greater reductions than placebo with regard to the change from Baseline in functional 
assessment of chronic illness therapy-fatigue (FACIT-Fatigue©) scale total score at all time 
points assessed from Week 4 to Week 16. However, besides the insights for secukinumab 
efficacy generated so far, data derived from a controlled and blinded study with a dedicated 
primary objective assessing pain levels as a potential decision-maker for further treatment 
options after a relatively short exposure to secukinumab are currently not available.
1.2
Purpose
The purpose of the study is to evaluate the efficacy and safety of secukinumab 150 mg 
compared to placebo in the early management (Baseline to Week 8) of spinal pain, disease 
activity, fatigue and predictability of disease flares in patients with axSpA who have an 
inadequate response to prior NSAIDs. This study will also assess the efficacy and safety of 
secukinumab 300 mg compared to secukinumab 150 mg from Week 8 to Week 24 in order to 
assess the potential additional benefits of dose escalation in patients with axSpA.


Novartis
Confidential
Page 20
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
2
Study objectives and endpoints
2.1
Objectives and related endpoints
Objectives and related endpoints for the study are described in Table 2-1. Note: the treatment 
arms referred to in Table 2-1 are defined in Section 5.2. 
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective

To assess the superiority of secukinumab 
150 mg compared to placebo in achieving a 
spinal pain score 4 on a 0-10 numerical 
rating scale (NRS) at Week 8.
Primary endpoint 

Proportion of patients with a spinal pain NRS 
score < 4 at Week 8 in Group A compared to 
Group B.
Secondary objective

To assess the superiority of secukinumab 
150 mg compared to placebo in achieving a 
Bath Ankylosing Spondylitis Disease Activity 
Index (BASDAI) score 4 at Week 8.
Secondary endpoints

Proportion of patients with a BASDAI score 
< 4 at Week 8 in Group A compared to 
Group B.
Exploratory objectives
Exploratory endpoints

Proportion of patients achieving a spinal pain 
score 4 on a 0-10 NRS at Week 1, 2, 3 and 
4 with secukinumab 150 mg compared to 
placebo.

Proportion of patients with a spinal pain NRS 
score < 4 in Group A compared to Group B at 
Week 1, 2, 3 and 4.

Proportion of patients in each treatment arm 
achieving a spinal pain score 4 on a 0-10 
NRS at Week 24.

Proportion of patients with a spinal pain NRS 
score < 4 in Arm A1, Arm A2 vs Arm A3, and 
Arm B1 vs Arm B2 at Week 24.

Proportion of patients in each treatment arm 
achieving BASDAI score 4 at Week 24.

Proportion of patients achieving a BASDAI 
score < 4 in Arm A1, Arm A2 vs Arm A3, and 
Arm B1 vs Arm B2 at Week 24.

Proportion of patients in each of the treatment 
arms achieving Ankylosing Spondylitis 
Disease Activity Score (ASDAS) score 2.1 
at Week 8 and Week 24.

Proportion of patients with a ASDAS score 
< 2.1 in Group A compared to group B at 
Week 8 and in Arm A1, Arm A2 vs Arm A3, 
and Arm B1 vs Arm B2 at Week 8 and 
Week 24.

Proportion of patients in each treatment arm 
achieving ASDAS score 1.3 at Week 8 and 
Week 24.

Proportion of patients with a ASDAS score 
< 1.3 in Group A compared to Group B at 
Week 8 and in Arm A1, Arm A2 vs Arm A3, 
and Arm B1 vs Arm B2 at Week 8 and 
Week 24.

Mean change from Baseline in functional 
assessment of chronic illness therapy-fatigue 
(FACIT-Fatigue©) score in patients on 
secukinumab 150 mg compared to placebo at 
Week 8.

FACIT-Fatigue© score in Group A compared 
to Group B at Week 8.


Novartis
Confidential
Page 21
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Objectives
Endpoints

Mean change from Baseline in 
FACIT-Fatigue© score in each of treatment 
arm at Week 24.

FACIT-Fatigue© score in Arm A1, Arm A2 vs
Arm A3, and Arm B1 vs Arm B2 at Week 24.

Proportion of patients in Arm A1 who have 
pain flares defined as NRS score 6 at Week 
12 or Week 24.

Proportion of patients who have pain flares, 
defined as NRS score > 6, in Arm A1 at 
Week 12 or Week 24.

Proportion of patients achieving a satisfactory
Patient Acceptable Symptom State (PASS) at 
Week 1, 2, 3, 4 and 8 with secukinumab 
150 mg compared to placebo.

Proportion of patients achieving a satisfactory 
PASS at Week 1, 2, 3, 4 and 8 in Group A 
compared to Group B.

Proportion of patients in each of treatment 
arm achieving a satisfactory PASS at 
Week 12, Week 20 and Week 24.

Proportion of patients achieving a satisfactory
PASS at Week 12, Week 20 and Week 24 in 
Arm A1, Arm A2 vs Arm A3, and Arm B1 vs
Arm B2.

Spinal pain NRS score according to previous 
exposure to tumor necrosis factor (TNF) 
blockers at Week 1, 2, 3, 4, 8, 12 and 24.

Proportion of patients achieving a spinal pain 
score < 4 in TNF-naïve and TNF-exposed 
subgroups at Week 1, 2, 3, 4, 8, 12 and 24.

Proportion of patients achieving a spinal pain 
score 4 on a 0-10 NRS for TNF-naïve 
patients compared to TNFα-IR patients at 
Week 8 and Week 24.

Proportion of patients achieving a spinal pain 
score < 4 for TNF-naïve patients compared to 
TNFα-IR patients at Week 8 and Week 24

Proportion of patients who responded to 
secukinumab 150 mg at Week 8 (i.e. spinal 
pain score 4 on a 0-10 NRS) maintaining a 
response at Week 24.

Proportion of patients with spinal pain score 
< 4 on a 0-10 NRS at Week 8 maintaining a 
spinal pain score < 4 at Week 24.

Proportion of patients achieving an 
improvement in ASAS health index with 
secukinumab 150 mg compared to placebo at 
Week 8. 

Proportion of patients achieving an 
improvement in ASAS health index with 
secukinumab 150 mg compared to placebo at 
Week 8.

Proportion of patients achieving an 
improvement in ASAS health index in each 
treatment arm at Week 24.

Proportion of patients achieving an 
improvement in ASAS health index in each 
treatment arm at Week 24.

ASAS health index at Week 8 and Week 24.

Mean ASAS health index score in each 
treatment arm at Week 8 and Week 24

Change from baseline in total spinal pain 
NRS score at all time points.

Total spinal pain NRS score in each treatment 
arm at all time points.

Change from baseline in total BASDAI score 
at all time points.

Total BASDAI score in each treatment arm at 
all time points.

ASDAS-CRP at Week 8 and Week 24.

Mean ASDAS-CRP in each treatment arm at 
Week 8 and Week 24.



 

 
 

Safety and tolerability of secukinumab 
150 mg and 300 mg over the study period.

Adverse Events (AEs) and adverse drug 
reactions (ADRs) over the study period.


Novartis
Confidential
Page 22
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
3
Investigational plan
3.1
Study design
This is a 24-week, randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety of secukinumab in controlling spinal pain in patients with 
axSpA. The study will consist of 2 treatment periods: a double-blind, placebo-controlled 
period from Baseline to Week 8 (i.e. Treatment Period 1) and a double-blind secukinumab 
treatment period from Week 8 to Week 24 (i.e. Treatment Period 2). At Baseline, patients will
be randomized to either secukinumab 150 mg or placebo. At Week 8, patients will be 
re-randomized to 1 of 5 treatment arms to receive either secukinumab 150 mg or secukinumab 
300 mg. 
Patient eligibility criteria will be assessed during the Screening Period, which will occur for 
up to 10 weeks prior to randomization.
At Baseline, all patients whose eligibility is confirmed will be randomized in a 3:1 ratio to 
secukinumab 150 mg or placebo as described below. Patients will be stratified at 
randomization according to previous exposure to TNF blockers (i.e. according to whether they 
are naïve to TNFα inhibitors or are TNFα-IR patients) to ensure a comparable number of 
patients for each subgroup. It is assumed that approximately one third of the randomized 
patients will be TNFα-IR.
The primary endpoint of this study is spinal pain at Week 8. At Week 8, patients randomized 
to Group A (secukinumab 150 mg) at Baseline will be assessed as responders (spinal pain 
NRS score < 4) or non-responders (spinal pain NRS score ≥ 4) based on their spinal pain 
scores. Responders will be re-assigned to 1 treatment arm to continue secukinumab 150 mg 
(Arm A1) from Week 8 until Week 24. Non-responders will be separately re-randomized to 
1 of 2 treatment arms to receive either secukinumab 150 mg (Arm A2) or secukinumab 
300 mg (Arm A3) from Week 8 until Week 24. At Week 8, patients randomized to Group B 
(placebo) at Baseline will be separately re-randomized to 1 of 2 treatment arms to receive 
either secukinumab 150 mg (Arm B1) or secukinumab 300 mg (Arm B2) from Week 8 until 
Week 24. A schematic of the study design is presented in Figure 3-1.
3.1.1
Treatment Period 1
At Baseline, patients whose eligibility is confirmed will be randomized to receive 
double-blind treatment with either secukinumab 150 mg or placebo (3:1) in Treatment 
Period 1 (Baseline to time of study drug administration at Week 8):

Group A: secukinumab 150 mg (1 x 1.0 mL) s.c. administered at Baseline, Week 1, 2, 3 
and 4

Group B: placebo (1 x 1.0 mL) s.c. administered at Baseline and Week 1, 2, 3 and 4
Secukinumab 150 mg and matching placebo will be provided as 1.0 mL pre-filled syringes 
(PFSs).


Novartis
Confidential
Page 23
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
3.1.2
Treatment Period 2
At Week 8, patients will enter Treatment Period 2 (Week 8 to Week 24). Patients randomized 
to Group A (secukinumab 150 mg) at Baseline will be assessed for the achievement of spinal 
pain NRS score and will be classified as responders (spinal pain NRS score < 4) or 
non-responders (spinal pain NRS score ≥4). Responders will be re-assigned to 1 treatment 
arm (Arm A1) to continue double-blind treatment with secukinumab 150 mg every 4 weeks 
from Week 8 to Week 24 (last dose administered at Week 20). Non-responders will be 
separately re-randomized to 1 of 2 arms to receive double-blind treatment with either 
secukinumab 150 mg or secukinumab 300 mg every 4 weeks starting at Week 8 up to 
Week 24 (last dose administered at Week 20), as follows:

Patients on secukinumab 150 mg who achieve spinal pain NRS score < 4 at Week 8 will 
be re-assigned to continue secukinumab 150 mg every 4 weeks (Arm A1) 

Arm A1: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered 
at Week 8, 12, 16 and 20

Patients on secukinumab 150 mg who do not achieve spinal pain NRS score < 4  at 
Week 8 will be re-randomized to continue secukinumab 150 mg every 4 weeks (Arm A2) 
or to escalate to secukinumab 300 mg every 4 weeks (Arm A3):

Arm A2: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered 
at Week 8, 12, 16 and 20

Arm A3: secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20
At Week 8, patients randomized to Group B (placebo) at Baseline will be re-randomized to 
either secukinumab 150 mg every 4 weeks (Arm B1) or secukinumab 300 mg every 4 weeks 
(Arm B2):

Arm B1: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered 
at Week 8, 12, 16 and 20

Arm B2: secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20
During the study, patients will be required to self-administer secukinumab or placebo at all 
study visits and at home at Week 16 (see Table 6-1 and Table 6-2 for the timing of study 
treatment administration). 
On each treatment day during Treatment Period 1, one s.c. injection with either secukinumab 
150 mg or placebo will be administered via PFSs. 
On each treatment day during Treatment Period 2, two s.c. injections will be administered via 
PFSs either as 1 injection of secukinumab 150 mg and 1 injection of placebo, or 2 injections 
of secukinumab 150 mg. This is necessary to maintain the blind since secukinumab is 
supplied in 1.0 mL PFSs each containing 150 mg secukinumab, i.e. secukinumab 150 mg is 
supplied as 1 PFS and secukinumab 300 mg as 2 PFSs. Placebo to secukinumab will be 
supplied in 1.0 mL PFSs to match the active drug. 
Patients will be allowed to continue background medications in accordance with Section 5.5.7
(concomitant medications) and Section 5.5.8 (prohibited medications). For patients taking 
NSAIDs, intake will be recorded according to ASAS recommendations for collecting, 
analyzing and reporting NSAID intake (Appendix 10).


Novartis
Confidential
Page 24
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Figure 3-1
Study design
Patients will be stratified at baseline based on whether they are naïve to TNFα inhibitors or had an inadequate response (including intolerance) to 
TNFα inhibitors.
R+ = responder, i.e. patient with spinal pain NRS score < 4
R- = non-responder, i.e. patient with spinal pain NRS score ≥ 4
axSpA=axial spondyloarthritis, BSL=baseline, PE=primary endpoint, SE=secondary endpoint, TNFα=tumor necrosis factor alpha, 
TNFα-IR=tumor necrosis factor α inadequate responder, W=week 


Novartis
Confidential
Page 25
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
3.2
Rationale for study design
The majority of patients with axSpA experience IBP as the first symptom of the disease and 
the burden of pain is comparable for patients with nr-axSpA and AS. Most patients with 
axSpA also experience severe fatigue, which has been shown to be deeply influenced by pain. 
It has been reported how pain, disease activity, fatigue, and disease flares affect the QoL of 
patients with axSpA. According to treat-to-target recommendations for patients with 
spondyloarthritis (SpA), the primary goal of the treatment is to maximize long-term health-
related QoL and social participation through control of signs and symptoms, including pain 
(Smolen et al 2014). In addition, improvement of disease activity and fatigue, as well as the 
achievement of a stable disease status with control of disease flares are considered key targets 
of the treatment strategy (Wendling 2015).
However, besides the insights for secukinumab efficacy generated so far, data derived from a 
controlled and blinded study with a dedicated primary objective assessing pain levels as a 
potential decision-maker for further treatment options after a relatively short exposure to 
secukinumab are currently not available. 
In order to address these unmet medical needs, this double-blind, randomized, parallel-group,
placebo-controlled study will primarily assess the efficacy of secukinumab 150 mg compared 
to placebo in providing a significant relief from spinal pain, as measured by spinal pain 
NRS score < 4, as early as Week 8. The cut-off value of spinal pain NRS < 4 has been chosen 
in accordance with the accepted cut-off points for mild, moderate, and severe pain on the 
visual analogue scale for pain in patients with chronic musculoskeletal pain (Boonstra et al 
2014). In addition, improvement in disease activity, fatigue and assessment of disease flares 
will be evaluated at Week 8 and/or Week 12 and at Week 24 to monitor pain levels after the 
early drug response to secukinumab for all patients.
The treatment duration of the placebo group has been considered to have the appropriate 
length to ensure the reliable evaluation of the primary endpoint. At Week 8, patients 
randomized to either secukinumab or placebo treatment at Baseline will be re-randomized to 
active treatment with secukinumab 150 mg or 300 mg. Re-randomization will be performed to 
provide all patients with the maximal opportunity to respond to secukinumab treatment 
(Section 3.5).
In order to accomplish treat-to-target recommendations for the management of SpA 
(Smolen et al 2014), a proportion of non-responder patients (i.e. patients not responding to 8 
weeks of treatment with secukinumab 150 mg) will be assigned to an escalated dose of 
secukinumab (i.e. 300 mg) for 16 weeks (i.e. from Week 8 to Week 24) with the aim of 
exploring potential additional benefits in treatment adjustment and optimization. In addition, a 
proportion of patients from the placebo group will be assigned secukinumab 300 mg from 
Week 8 to Week 24 so as to explore the potential benefits of a higher dose of secukinumab
(Section 3.3).
The regular assessments of disease activity ensure that safety will be monitored closely and 
both the patient and the investigator will have the opportunity to assess if the patient’s 
continued participation in the study is to his/her benefit. If the patient’s participation is 


Novartis
Confidential
Page 26
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
deemed not to be of benefit to him/her, the patient can exit the study at any time (see 
Section 5.6.2). 
This study has been discussed by a Patient Associations’ Steering Committee to guarantee 
that the study endpoints and the study conduct are fully aligned with patients’ expectations 
and unmet clinical needs from a patient’s perspective. The stratification criterion was chosen 
because previous TNFα exposure can have an influence on secukinumab response (Baeten et 
al 2015), and therefore allows for a balanced distribution between the verum and the placebo 
group.
3.3
Rationale for dosing regimen, route of administration and 
duration of treatment 
Although nr-axSpA is often regarded as a milder disease compared to AS, it has been 
demonstrated that the burden of the 2 diseases is similar in terms of pain and activity
(Sieper et al 2013). As a consequence, the dose, dose regimen, formulation and route of 
administration of secukinumab are the same in these 2 populations. 
The dose (150 mg and 300 mg), dose regimen (weekly from Baseline to Week 4, monthly 
from Week 8 to Week 20), formulation (liquid in PFSs) and route of administration (s.c.) for 
secukinumab used in this study are supported by the comprehensive AS clinical trial program 
(including the pivotal Phase 3 studies CAIN457F2305 and CAIN457F2310 (Baeten et al 2015) 
and the CAIN457F2320 study) that demonstrated the efficacy, tolerability and safety of 
secukinumab.
The potential additional benefit of dose escalation from secukinumab 150 mg to 300 mg will 
be explored during Treatment Period 2 (Week 8 to Week 24) in a proportion of patients 
assigned to secukinumab 150 at Baseline who did not achieve a response at Week 8. Similarly, 
a proportion of patients in the placebo group will be assigned secukinumab 300 mg during 
Treatment Period 2 so as to explore how those patients respond to a higher starting dose of 
secukinumab.
3.4
Rationale for choice of comparator
A placebo arm up to Week 8 is included in this study. Due to the nature of the disease and the 
outcome measures used (e.g. spinal pain NRS score as primary endpoint, and BASDAI score 
as secondary endpoint), a placebo arm is necessary to obtain reliable efficacy measurements 
for comparison between the active treatment group and placebo in a controlled fashion up to 8 
weeks. The continuation of the placebo group up to Week 8 can be supported from an ethical 
standpoint, as patients continue their treatment with NSAIDs and other concomitant 
treatments including methotrexate (MTX) and sulfasalazine. In addition, regular and 
controlled assessment of pain and disease activity ensures that patients experiencing 
worsening of the disease in any treatment group can exit the study. Moreover, the inclusion of 
a placebo group is considered relevant for trials in nr-axSpA, in accordance with previously 
implemented methodology and in compliance with the European Medicines Agency 
(EMA/EMEA) guidelines for AS (CPMP/EWP/4891/03), and as recommended by the Food 
and Drug Administration (FDA).


Novartis
Confidential
Page 27
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
3.5
Rationale for re-randomization of patients 
Re-randomization will be performed to provide all patients with the maximal opportunity to 
respond to secukinumab treatment. Patients assigned to secukinumab 150 mg at Baseline who 
are responders (i.e. spinal pain score < 4) at Week 8 will be re-assigned to receive the same 
dose until Week 24 thereby providing the opportunity to confirm that patients sustain their 
treatment response until the end of the study. Patients assigned to secukinumab 150 mg at 
Baseline who are non-responders at Week 8, and all patients assigned to placebo at Baseline, 
will be re-randomized to secukinumab 150 mg or 300 mg from Week 8 until Week 24. 
Besides supporting the blinding strategy of the study, this provides patients who did not 
respond to active treatment during the first 8 weeks a further chance to respond to 
secukinumab over an additional 16 weeks and potential differences between the 2 treatment 
regimens can be explored. Patients on placebo until Week 8, whose bone structure may be 
impacted by the underlying chronic disease, will have the opportunity to have their chronic 
disease treated by active treatment with secukinumab for up to 16 weeks. The descriptive 
analysis of these data can help to understand the different combinations of response to explore 
further insights for the 2 treatment regimens.
3.6
Purpose and timing of interim analyses/design adaptations
Not applicable. No interim analysis or design adaptations are planned for this study.
3.7
Risks and benefits
As of June 2016, approximately 16,400 patients and healthy subjects have been enrolled in 
both completed and ongoing studies with secukinumab, with over 14000 having received 
secukinumab at doses ranging from single and multiple i.v. doses of 0.1 mg/kg up to 
30 mg/kg and s.c. doses of 25 mg up to 300 mg across various indications including AS, 
psoriasis, rheumatoid arthritis, PsA, multiple sclerosis, uveitis, dry eye, Crohn’s disease, 
asthma and polymyalgia rheumatica.
The risk profile of secukinumab in axSpA is informed by the safety data from the pivotal 
clinical trials in moderate to severe plaque psoriasis and the spondyloarthritides (e.g. PsA and 
AS). For these indications, secukinumab has shown a higher rate of total adverse events (AEs), 
mainly infections, when compared to placebo (placebo-controlled periods of 12 to 16 weeks 
depending on the protocol). The majority of infections were non-serious upper respiratory 
tract infections. However, no clinically meaningful difference was observed in infectious 
serious adverse events (SAEs). In addition, no dose dependency with secukinumab (300 mg 
and 150 mg) was observed in the overall rate of infections or upper respiratory tract infections.
Adverse drug reactions (ADRs) classified as very common (≥1/10 patients) or common 
(≥1/100 but 1/10 patients) included upper respiratory tract infections (nasopharyngitis, 
upper respiratory tract infection, rhinitis and pharyngitis), oral herpes, rhinorrhea, diarrhea 
and urticaria. Uncommon (≥1/1000 but 1/100 patients) ADRs included sinusitis, tonsillitis, 
oral candidiasis, tinea pedis, neutropenia and conjunctivitis.
Infections, neutropenia and hypersensitivity are important identified risks, while malignancies, 
major adverse cardiovascular events, immunogenicity, Crohn’s disease, and hepatitis B 


Novartis
Confidential
Page 28
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
reactivation (Europe only) are important potential risks. Interaction with live vaccines is an 
important potential risk.
Immunogenicity was low with secukinumab and did not correlate with loss of efficacy in all 
indications studied to date.
From the standpoint of the overall risk benefit assessment, the current trial with secukinumab 
is justified.
The risk to patients in this trial will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, and extensive guidance for the investigators provided in the 
Investigator’s Brochure (IB). Additional safety information can also be found in the IB.
4
Population
The study population will consist of male and female patients (≥18 years old at the time of 
consent) with axSpA diagnosis, either AS or nr-axSpA fulfilling the ASAS criteria 
(Rudwaleit et al 2009a). Patients must report clinical signs of spinal involvement defined by 
presence of IBP with active disease defined by BASDAI score ≥4, spinal pain NRS score > 4 
and an inadequate response to at least 2 NSAIDs (including intolerance) over at least a 
4-week period, unless contraindicated.
The study aims to screen approximately 423 patients in order to randomize approximately 
352 patients across the participating countries. 
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 provide written, signed and dated informed 
consent before any study assessment is performed.
2. Male or non-pregnant, non-nursing female patients at least 18 years of age with diagnosis 
of axSpA (either AS or nr-axSpA) according to ASAS axSpA classification criteria 
(Appendix 4) to be applied in patients with back pain for at least 3 months and age of 
onset < 45 years:

Sacroiliitis on imaging (see Appendix 6) with ≥ 1 SpA feature (see Appendix 4) 
or

Human Leukocyte Antigen-B27 (HLA-B27) positive with ≥2 SpA features (see 
Appendix 4).
3. Active axSpA as assessed by total BASDAI score ≥4 at Baseline.
4. Spinal pain NRS score > 4 at Baseline.
5. Patients should have been on at least 2 different NSAIDs at the highest recommended 
dose for at least 4 weeks in total prior to randomization with an inadequate response or 
failure to respond, or less if therapy had to be withdrawn due to intolerance, toxicity or 
contraindication.


Novartis
Confidential
Page 29
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
6. Patients who are regularly taking NSAIDs (including COX-1 or COX-2 inhibitors) as part 
of their axSpA therapy are required to be on a stable dose for at least 2 weeks before 
randomization.
7. Patients who have previously been on a TNFα inhibitor will be allowed entry into study 
after an appropriate wash-out period prior to randomization:

4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 hours (s.c. 
route)

8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. 
infusion)

10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days 
(average 2 weeks) (s.c. route)

10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days

10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Chest X-ray or MRI with evidence of ongoing infectious or malignant process obtained 
within 3 months of Screening and evaluated by a qualified physician (otherwise chest 
X-ray or MRI is required to be performed at Screening).
2. Previous treatment with prohibited medication as outlined in Section 5.5.7 and 
Section 5.5.8. Prohibited medication may be washed out before randomization in 
accordance with Section 5.5.7 and Section 5.5.8.
3. Previous exposure to secukinumab or any other biologic drug directly targeting 
interleukin-17 (IL-17) or interleukin-23 (IL-23).
4. 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.
5. History of hypersensitivity to the study drug or its excipients or to drugs of similar 
chemical classes.
6. Patients previously treated with any biological immunomodulating agents, except those 
targeting TNFα.
7. Patients who have been exposed to more than one anti-tumor necrosis factor alpha 
(anti-TNFα) agent.
8. Previous treatment with any cell-depleting therapies including but not limited to 
anti-CD20 or investigational agents (e.g. Campath®, anti-CD4, anti-CD5, anti-CD3, 
anti-CD19).
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 childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during entire 


Novartis
Confidential
Page 30
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
study or longer if required by locally approved prescribing information (e.g. 20 weeks 
since last dose of secukinumab in the European Union (EU)). Effective contraception 
methods include:

Total abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment.

Male sterilization (at least 6 months prior to Screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient.

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception.

Placement of an intrauterine device or intrauterine system.
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal or not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow-up hormone level assessment is she considered not of childbearing 
potential.
11. Active ongoing inflammatory diseases other than axSpA that might confound the 
evaluation of the benefit of secukinumab therapy (such as inflammatory bowel disease and 
uveitis).
12. Other ongoing mechanical diseases affecting the spine (such as severe osteoarthritis of 
spine and diffuse idiopathic skeletal hyperostosis and fibromyalgia) that may confound 
evaluation of the benefit of secukinumab therapy.
13. 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.
14. Significant medical problems or diseases, including but not limited to the following: 
uncontrolled hypertension (≥ 160/95 mmHg), congestive heart failure (New York Heart 
Association status of class III or IV), uncontrolled diabetes, or very poor functional status 
(unable to perform self-care).


Novartis
Confidential
Page 31
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
15. History of clinically significant liver disease or liver injury as indicated by abnormal liver 
function tests such as aspartate aminotransferase/serum glutamic oxaloacetic transaminase 
(AST/SGOT), alanine aminotransferase/serum glutamic pyruvic transaminase 
(ALT/SGPT), alkaline phosphatase, or serum bilirubin. The investigator should be guided 
by the following criteria:

Any single parameter may not exceed 2 × upper limit of normal (ULN). A single 
parameter elevated up to and including 2 × ULN should be re-checked once more as 
soon as possible, and in all cases, at least prior to enrollment/randomization, to rule 
out laboratory error.

If the total bilirubin concentration is increased above 2 × ULN, total bilirubin should 
be differentiated into the direct and indirect reacting bilirubin.
16. 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).
17. Screening total white blood cell (WBC) count < 3000/µL, or platelets < 100 000/µL or 
neutrophils < 1,500/µL or hemoglobin < 8.5 g/dL (85 g/L).
18. Active systemic infections during the last 2 weeks prior to randomization (exception: 
common cold).
19. History of ongoing, chronic or recurrent infectious disease or evidence of tuberculosis (TB) 
infection as defined by a positive QuantiFERON TB-Gold test. 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 TB. If presence of latent 
TB is established, then treatment according to local country guidelines must have been 
initiated.
20. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at 
Screening or randomization.
21. 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 
keratosis 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).
22. Any current severe progressive or uncontrolled disease, which in the judgment of the 
clinical investigator renders the patient unsuitable for the trial.
23. 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.
24. History or evidence of ongoing alcohol or drug abuse within the last 6 months before 
randomization.
25. Administration of live vaccines 6 weeks prior to randomization or plans for administration 
of live vaccines during the study period; live vaccines should not be given until 12 weeks 
after last study treatment administration.


Novartis
Confidential
Page 32
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5
Treatment
5.1
Study treatment
5.1.1
Investigational and control drugs
Novartis or a designated Contract Research Organization (CRO) will supply the following:

Investigational treatment

AIN457 (secukinumab) 150 mg provided in a 1.0 mL PFS

Matching placebo

AIN457 (secukinumab) placebo provided in a 1.0 mL PFS
The PFSs are packed in a double-blinded fashion. The study treatments will be labeled as 
follows:

AIN457 150mg/1.0 mL/Placebo.
5.1.2
Additional treatment
During this study, NSAIDs, selected analgesics, selected disease-modifying anti-rheumatic 
drugs (DMARDs), i.e. MTX and sulfasalazine, and systemic corticosteroids are permitted as 
part of patients’ routine medical care and will not be provided by Novartis. 
Concomitant medications are described in Section 5.5.7 and prohibited medications are 
described in Section 5.5.8.
5.2
Treatment arms
At Baseline, all patients whose eligibility is confirmed will be randomized in a 3:1 ratio to 
secukinumab 150 mg or placebo as shown below. Patients will be stratified at randomization 
according to whether they are naïve to TNFα inhibitors or are TNFα-IR patients. The primary 
endpoint of this study is reduction of spinal pain at Week 8. At Week 8, patients randomized 
to Group A (secukinumab 150 mg) at Baseline will be assessed as responders (spinal pain 
NRS score < 4) or non-responders (spinal pain NRS score ≥ 4) based on their spinal pain 
scores. Responders will be re-assigned to secukinumab 150 mg (Arm A1) from Week 8 until 
Week 24. Non-responders will be separately re-randomized to 1 of 2 treatment arms to 
receive either secukinumab 150 mg (Arm A2) or secukinumab 300 mg (Arm A3) from 
Week 8 to Week 24. At Week 8, patients randomized to Group B (placebo) at Baseline will be 
separately re-randomized to 1 of 2 treatment arms to receive either secukinumab 150 mg 
(Arm B1) or secukinumab 300 mg (Arm B2) from Week 8 to Week 24.
Group A: secukinumab 150 mg
Treatment Period 1

Secukinumab 150 mg (1 × 1.0 mL prefilled syringe (PFS)) at Baseline, Week 1, 2, 3 and 4
Treatment Period 2

Responders (spinal NRS score < 4):


Novartis
Confidential
Page 33
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301

Arm A1: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) 
administered every 4 weeks from Week 8 to Week 20

Non-responders (spinal pain NRS score ≥4):

Arm A2: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) 
administered every 4 weeks from Week 8 to Week 20

Arm A3: secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from 
Week 8 to Week 20
Group B: placebo
Treatment Period 1

Placebo (1 × 1.0 mL PFS) at Baseline, Week 1, 2, 3 and 4
Treatment Period 2
Patients randomized to placebo at Baseline will be re-randomized to secukinumab 150 mg or 
300 mg at Week 8: 

Arm B1: secukinumab 150 mg (1 × 1.0 mL PFS) + placebo (1 × 1.0 mL PFS) 
administered every 4 weeks from Week 8 to Week 20

Arm B2: secukinumab 300 mg (2 × 1.0 mL PFS) administered every 4 weeks from 
Week 8 to Week 20
Patients will be allowed to continue background medications in accordance with concomitant 
medication and prohibited medication (Section 5.5.7 and Section 5.5.8). 
5.3
Treatment assignment and randomization
At Baseline, all eligible patients will be randomized to one of the treatment groups (Group A 
and Group B) via an Interactive Response Technology (IRT) system or similar system. The 
investigator or his/her delegate will contact the IRT after confirming that the patient fulfills all 
the inclusion/exclusion criteria. The IRT will assign a randomization number to the patient, 
which will be used to link the patient to a treatment group and will specify a unique 
medication number for the first package of study drug to be dispensed to the patient. The 
randomization number will not be communicated to the caller.
Randomization at Baseline will be stratified based on prior TNFα inhibitor exposure (i.e. 
according to whether patients are TNFα inhibitor naïve or TNFα-IR). It is assumed that 
approximately one third of the randomized patients will be TNFα-IR.
At Week 8, patients randomized to Group A (secukinumab 150 mg) at Baseline will be 
assessed for the achievement of spinal pain NRS score and will be classified as responders 
(spinal pain NRS score < 4) or non-responders (spinal pain NRS score ≥4) and re-randomized 
or re-assigned via IRT to one of the treatment arms (Arm A1, Arm A2, Arm A3) as outlined 
in Section 5.2. At Week 8, patients randomized to Group B (placebo) at Baseline will be 
re-randomized via IRT to one of the 2 treatment arms (Arm B1 or Arm B2) as outlined in 
Section 5.2.
The IRT will be used to link the patient to a treatment group/arm and will specify unique 
medication numbers for the study drug to be dispensed to the patient. The randomization 


Novartis
Confidential
Page 34
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
numbers will not be communicated to the caller and will be generated using the following 
procedure to ensure that treatment assignment is unbiased and concealed from patients and 
investigator staff. A patient randomization list will be generated in collaboration with the IRT 
provider using a validated system that automates the random assignment of patient numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
groups/arms, which are in turn linked to medication numbers. A separate medication list will 
be produced in collaboration with Novartis Drug Supply Management using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drugs. 
The randomization scheme for patients will be reviewed and endorsed by a statistical expert.
5.4
Treatment blinding
Patients, investigator staff, persons performing the assessments, and data analysts will remain 
blind to the identity of the treatment from the time of randomization until database lock using 
the following methods: 

Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study. 

The identity of the treatments will be concealed by the use of study drug that are all 
identical in packaging, labeling, schedule of administration, appearance, taste and odor.
Unblinding will only occur in the case of patient emergencies (see Section 5.5.9) and at the 
conclusion of the study. 
5.5
Treating the patient
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
5.5.1
Patient numbering
Each patient is uniquely identified by a Patient Number which is composed of the site number 
assigned by Novartis and a sequential number assigned by the investigator. Once assigned to a 
patient, the Patient Number will not be re-used. 
Upon signing the informed consent form (ICF), the patient will be assigned the next 
sequential number by the investigator. The investigator or his/her staff will contact the IRT 
and provide the requested identifying information for the patient to register them into the IRT. 
The site must select the case report form (CRF) book with a matching Patient Number from 
the electronic data capture (EDC) system to enter data.
If the patient fails to be treated for any reason, the IRT must be notified within 2 days that the 
patient was not treated. The reason for not being treated will be entered on the Screening 
Period Study Disposition electronic CRF.
5.5.2
Dispensing the study drug
Each study site will be supplied with study drug in packaging of identical appearance.


Novartis
Confidential
Page 35
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
The study drug packaging has a 2-part label. A unique medication number is printed on each 
part of this label, which corresponds to placebo or active treatment. Investigator staff will 
identify the study drug packages to dispense to the patient by contacting the IRT and 
obtaining the medication numbers. Immediately before dispensing the packages to the patient, 
investigator staff will detach the outer parts of the labels from the packages and affix them to 
the source document (Drug Label Form) for that patient’s unique Patient Number.
At Week 12, the investigator will dispense to the patient, supported by IRT, 2 study drug 
packages for home administrations at Week 16 (see Table 6-1). The investigator will detach 
the outer parts of the labels and affix them to the source documentation (Drug Label Page). 
Detailed instructions on the self-administration of the study treatment will be described in the 
Instructions for Use (IFU) provided to each patient and made available to the site staff and 
investigator. These instructions should be reviewed in detail by the patient and the site 
personnel.
5.5.3
Handling of study and additional treatment
5.5.3.1
Handling of study treatment
The 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. The investigator should educate the patient on how to properly store the 
study treatment when the patient is self-administering at home. Technical complaints are to be 
reported to the respective Novartis Country Pharma Organization (CPO) Quality Assurance or 
trial assigned Quality Assurance function.
The PFSs, which are sealed in their outer box, must be stored in a locked refrigerator between 
2°C and 8°C (36°F and 46°F) and must be carefully controlled in accordance with regulations 
governing investigational medicinal products, local regulations and in accordance with 
instructions from the Novartis Drug Supply Management or Novartis Drug Supply Chain or 
corresponding service providers. The study drug should be protected from light and must not 
be frozen.
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 patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site.


Novartis
Confidential
Page 36
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5.5.3.2
Handling of other study treatment
Not applicable.
5.5.4
Instructions for prescribing and taking study treatment
Patients will self-administer the study treatment (secukinumab 150 mg, secukinumab 300 mg 
and placebo) by s.c. injection using 1 mL PFSs throughout the study. The dosing frequency 
will be either weekly or every 4 weeks in accordance with the administration schedule (Table 
6-1 and Table 6-2). 
Patients will receive instructions and training from study center staff on how to 
self-administer the study drug. Detailed instructions on the self-administration of the study 
treatment will be described in the IFU for secukinumab and provided to each patient. Patients 
will be asked to raise any questions and then to proceed with self-injection.
The injections scheduled to occur at the study center (i.e. Baseline, Week 1, Week 2, Week 3 
and Week 4 during Treatment Period 1, and Week 8, Week 12 and Week 20 during Treatment 
Period 2) will be done by the patient (or caregiver) at the study center, under the supervision 
of the investigator or study staff.
The injection not scheduled to occur during a study center visit (i.e. Week 16 injection) will 
be done by eligible patients (or caregiver) at their home. 
All doses prescribed and dispensed to the patient during the study must be recorded in the 
electronic CRF (eCRF). 
Patients will be asked to document all doses and dates of self-administration at home in a 
self-administration log and are required to return this log to the study center at the visit 
following home administration (i.e. Visit 9/Week 20). 
The investigator should promote compliance by instructing the patient to attend the study 
visits as scheduled and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient should be instructed to contact the investigator if he/she is 
unable for any reason to attend a study visit as scheduled or if he/she is unable for any reason 
to take the study treatment as prescribed.
At the beginning of the study, the investigator/qualified study center staff will determine if 
self-administration is appropriate for the patient, e.g. manual dexterity, ability to follow the 
secukinumab PFS-IFU. If a patient requires a caregiver to administer study drug, the caregiver 
should be trained by the investigator/qualified study center staff. If a caregiver is not available 
at a particular visit or the patient is having problems with self-administration, the 
investigator/qualified study center staff may administer the study drug to the patient. However, 
all patients should be trained sufficiently and be comfortable with the study drug 
self-administration before the first home administration visit. Patients will be instructed to 
contact the investigator site staff in case of any issue during home administration of the study 
treatment.
Records of study drug kits assigned to the patient during the study must be documented.
At each visit, all study assessments, including the completion of PROs, should be completed 
prior to self-injection of the study drug.


Novartis
Confidential
Page 37
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Prior to and following self-administration at home, patients should contact the 
investigator/site staff in case they are experiencing any AEs, SAEs, or have any concerns.
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 permitted if, in the opinion of the investigator, a patient is 
deemed to be at a significant safety risk unless dosing is temporarily interrupted. In such cases 
study treatment should be interrupted only during the time that this risk is present and ongoing. 
Study treatment can be re-started after resolution of the safety risk. For additional points, 
please refer to Section 5.5.6.
Any study treatment interruption must be recorded on the corresponding eCRF page.
5.5.6
Allowed treatment modifications and escape treatment
Treatment modifications as well as new therapeutic interventions or a significant change to 
ongoing therapy must not be made before completion of Week 8 assessments.
Although no patient will be restricted from receiving necessary medications for lack of benefit 
or worsening of disease, if treatment with prohibited biologics (as described in Section 5.5.8) 
occurs, patients may remain in the trial but must discontinue study treatment. Efficacy will be 
assessed in detail at every study visit, and patients who are deemed not to be benefiting from 
the study treatment based on safety and efficacy assessments or for any reason of their own 
accord will be free to discontinue participation in the study at any time (see Section 5.6.2). 
As per Section 5.5.7, changes in non-biologic DMARDs and corticosteroids are permitted as 
per the investigator’s clinical judgment after all Week 8 assessments are completed. However, 
it is recommended that these medications are continued at a stable dose from Week 8 through 
to Week 24. NSAIDs are to be administered in accordance with the posology and method of 
administration as described in the local Summary of Product Characteristics (SmPC).
Any treatment modifications or new therapeutic interventions must be recorded in the 
Concomitant medications eCRF page.
5.5.7
Concomitant medication
The investigator must instruct the patient to notify the study site about any new medications 
he/she takes after the patient was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled into the study must be recorded in the concomitant 
medications / significant non-drug therapies eCRF.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started.


Novartis
Confidential
Page 38
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5.5.7.1
Nonsteroidal anti-inflammatory drugs (including COX-1 or COX-2 
inhibitors)
Patients who are regularly taking NSAIDs (including cyclo-oxygenase-1 (COX-1) and 
cyclo-oxygenase 2 (COX-2) inhibitors) at Screening are allowed to continue the specific 
treatment in accordance to the posology and method of administration as described in the 
local SmPC.
Patients must refrain from any NSAID intake during at least 24 hours before a visit involving 
a disease activity assessment.
The dose of NSAID(s) taken during the study must be recorded on the corresponding eCRF 
page. More guidance on NSAIDs can be found in Appendix 10.
5.5.7.2
Analgesics other than NSAIDs
Patients may take paracetamol/acetaminophen at doses of ≤ 500 mg per day. Patients must 
refrain from any paracetamol/acetaminophen intake during at least 24 hours before a study 
visit involving a disease activity assessment. 
5.5.7.3
Methotrexate
Patients who are taking MTX (≤ 25 mg/week) at Screening should be on a stable dose for at 
least 4 weeks before randomization to be eligible for inclusion in the study and apply folic 
acid supplement to avoid toxic effects. 
Patients are required to remain on a stable dose of MTX (≤ 25 mg/week) along with a folic 
acid supplement from Baseline until Week 8. The dose may be decreased only due to toxicity. 
After Week 8, it is recommended that the patient continues on the same stable dose of MTX 
until Week 24. The folic acid supplement should be continued throughout the study 
irrespective of the dose of MTX.
Stable folic acid supplementation is required latest at randomization in order to minimize the 
likelihood of MTX-associated toxicity. 
The dose of MTX taken during the study must be recorded on the corresponding eCRF page.
5.5.7.4
Sulfasalazine
Patients taking sulfasalazine (≤ 3 g/day) at Screening should be on a stable dose for at least 
4 weeks before randomization to be eligible for inclusion in the study. 
Patients are required to remain on a stable dose of sulfasalazine (≤ 3 g/day) from Baseline 
until Week 8. After Week 8, it is recommended that the patient continues on the same stable 
dose of sulfasalazine until Week 24. 
The dose of sulfasalazine taken during the study must be recorded on the corresponding eCRF 
page.


Novartis
Confidential
Page 39
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5.5.7.5
Corticosteroids
Patients who received any intramuscular, intra-articular or intravenous corticosteroid within 
4 weeks prior to randomization are NOT eligible to enter this study. Patients who are taking 
systemic corticosteroids at Screening should be on a stable dose ≤ 10 mg/day of prednisone or 
equivalent (see Table 5-1) for at least 2 weeks before randomization to be eligible for 
inclusion in the study. 
Patients are required to remain on a stable dose of systemic corticosteroids up to a maximum 
daily dosage of 10 mg prednisone equivalent from Baseline until Week 8. After Week 8, it is 
recommended that the patient continues on the same stable dose of corticosteroids until 
Week 24.
The dose of systemic corticosteroids during the study must be recorded on the corresponding 
eCRF page.
Table 5-1
Corticosteroids conversion table for the equivalence of 1 mg of 
cortisone
Corticosteroid
Equivalence of 1 mg of cortisone
Cortisone
1 mg
Prednisone, prednisolone
0.2 mg
Methylprednisone, triamcinolone
0.16 mg
Dexamethasone
0.03 mg
Fludrocortisone
0.08 mg
Deflazacort
0.24 mg
Paramethasone
0.08 mg
Hydrocortisone, cortisol
0.8 mg
Sources: Asare 2007, Colburn 2012, Grover et al 2007, Liu et al 2013, Saviola et al 2007, 
Shaikh et al 2012.
5.5.8
Prohibited medication
Use of the treatments displayed in Table 5-2 is not allowed after the start of the wash-out 
period unless otherwise specified below. 
Patients who have previously been on a TNFα inhibitor will be allowed entry into the study 
after an appropriate wash-out period prior to randomization (see Table 5-2):

4 weeks for Enbrel® (etanercept) – with a terminal half-life of 102 ± 30 hours (s.c. route)

8 weeks for Remicade® (infliximab) – with a terminal half-life of 8.0-9.5 days (i.v. 
infusion)

10 weeks for Humira® (adalimumab) – with a terminal half-life of 10-20 days
(average 2 weeks) (s.c. route)

10 weeks for Simponi® (golimumab) – with a terminal half-life of 11-14 days (s.c. route)

10 weeks for Cimzia® (certolizumab) – with a terminal half-life of 14 days (s.c. route)
Live vaccines should not be given until 12 weeks after last study treatment administration.


Novartis
Confidential
Page 40
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Table 5-2
Prohibited medication
Medication
Washout period
(before randomization)
Etanercept*
4 weeks
Infliximab*
8 weeks
Adalimumab*
10 weeks
Golimumab*
10 weeks
Certolizumab*
10 weeks
Unstable dose of MTX or sulfasalazine
4 weeks
Conventional synthetic DMARDs other than MTX or sulfasalazine
4 weeks
Leflunomide
8 weeks
Leflunomide with cholestyramine wash-out
4 weeks
Targeted synthetic DMARDs (e.g. apremilast)
4 weeks
Systemic corticosteroids > 10 mg prednisone equivalent**
2 weeks
Intramuscular, intra-articular or intravenous corticosteroid treatment
4 weeks
Any biological immunomodulating agents, except those targeting
TNFα*
No prior exposure
Any cell-depleting therapies including but not limited to anti-CD20 or 
investigational agents (e.g. Campath®, anti-CD4, anti-CD5, anti-CD3, 
anti-CD19)
No prior exposure
Any investigational treatment or participation in any interventional trial
4 weeks or 5 half-lives
(whichever is longer)
Analgesics other than NSAIDs or low strength opioids PRN, tramadol 
(refer to Section 5.5.7.2 for allowed doses of analgesics other than 
NSAIDs)
4 weeks
High strength opioids
4 weeks
Live vaccinations
6 weeks
CD=cluster of differentiation, COX1=cyclo-oxygenase 1, COX2=cyclo-oxygenase 1, DMARDs=disease-
modifying anti-rheumatic drugs, MTX=methotrexate, NSAIDs=non-steroidal anti-inflammatory drugs, 
PRN=pro re nata (as needed), TNFα=tumor necrosis factor alpha
* These agents fall under the category of biologic immunomodulators and are prohibited medications; 
administration of these agents requires study treatment discontinuation (see Section 5.6.2)
** See details about corticosteroid management in Section 5.5.7.5
5.5.9
Emergency breaking of assigned treatment code
Emergency breaking of an assigned treatment code must only be undertaken when it is 
essential in order to treat a patient safely. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study patient who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the IRT. When the investigator contacts the system to break a treatment code for a patient, 
he/she must provide the requested patient identifying information and confirm the necessity to 
break the treatment code for the patient. The investigator will then receive details of the 
investigational drug treatment for the specified patient and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
Study Team that the code has been broken.


Novartis
Confidential
Page 41
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The investigator will inform the patient how to contact 
his/her backup in cases of emergency when he/she is unavailable. The investigator will 
provide the protocol number (CAIN457H3301), the study drug name (if available), the Patient 
Number, and instructions for contacting the local Novartis CPO (or any entity to which it has 
delegated responsibility for emergency code breaks) to the patient in case an emergency 
unblinding is required at a time when the investigator and backup are unavailable. 
Study drug must be discontinued after emergency unblinding.
5.6
Study completion and discontinuation 
5.6.1
Study completion and post-study treatment
A patient will be considered to have completed the study when the patient has completed the 
last visit planned in the protocol i.e. Visit 10/Week 24 (see Table 6-1). Information on the 
patient’s completion or discontinuation from the study and the reason for discontinuation from 
the study will be recorded on the appropriate Study Phase Completion page in the eCRF. In 
any case, the investigator or site staff must contact the IRT as soon as possible to record the 
patient’s study completion and/or discontinuation.
The investigator must provide follow-up medical care for all patients who are prematurely 
withdrawn from the study or must refer them for appropriate ongoing care. This care may 
include initiating another treatment outside of the study as deemed appropriate by the 
investigator. Based on the individual risk/benefit profile of a patient, treatment options may 
include DMARDs. In case of a biologic treatment, a waiting period of 3 months before 
initiating the treatment is recommended.
5.6.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the patient or the investigator. 
If discontinuation occurs for any reason in a treatment period (i.e. Treatment Period 1 or 2), 
the investigator/qualified site staff must make every effort to determine the primary reason for 
the patient’s discontinuation from the study. This information will then be recorded by the 
investigator/qualified site staff in the applicable eCRF section.
Study treatment must be discontinued if the investigator determines that continuation of study 
treatment would result in a significant safety risk for a patient. 
The following circumstances require study treatment discontinuation:

Withdrawal of informed consent

Emergence of the following AEs:
a. Any severe AE or SAE that is not compatible with administration of study medication, 
including AEs that require treatment with prohibited co-medication
b. Onset of lymphoproliferative disease or any malignancy except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or non-
-invasive malignant colon polyps, which are being or have been removed


Novartis
Confidential
Page 42
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
c. Life-threatening infection
d. Severe hypersensitivity reaction or anaphylactic reaction
e. Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the patient at a safety risk for continuation in the 
study (general guidance on clinically notable laboratory values is provided in 
Appendix 1)
f.
Pregnancy
g. Use of any biologic immunomodulating agent except secukinumab
For patients who discontinue study treatment the CRF should be completed, giving the date 
and primary reason for stopping study treatment.
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.
If study drug discontinuation occurs because the treatment code has been broken, please refer 
to Section 5.5.9.
Efficacy and safety will be assessed in detail at every study visit, and patients who are deemed 
not to be benefiting from the study treatment based upon safety and efficacy assessments by 
the investigator or for any reason on their own accord will be free to discontinue participation 
in the study at any time.
Patients who prematurely discontinue the study should return and complete assessments 
associated with the Week 24 visit (4 weeks after the last study treatment, see Table 6-1) and 
any AEs that are treatment emergent should be reported until 12 weeks after the last study 
treatment. The final visit should be performed before any new treatment is initiated.
Patients who prematurely withdraw from the study will not be replaced.
5.6.3
Withdrawal of informed consent
Withdrawal of consent occurs only when a patient does not want to participate in the study 
any longer and does not want any further visits or assessments, does not want any further 
study related contacts and does not allow analysis of already obtained biological material.
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information.
Study treatment must be discontinued and no further assessments conducted. All biological 
material that has not been analyzed at the time of withdrawal must not be used.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table (Table 6-1).


Novartis
Confidential
Page 43
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
5.6.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g. dates of 
telephone calls, registered letters, etc. A patient should not be formally considered lost to 
follow-up until his/her scheduled end of study visit 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 for participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
patient must be seen as soon as possible and treated as a prematurely withdrawn patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) of the early termination of the trial.
6
Visit schedule and assessments
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
During the study, the assessments must be performed as indicated in Table 6-1. 
Patients must be seen for all visits on the designated day, or as close to it as possible to the 
original planned visit.

For visits scheduled through Week 4, the study treatment should not be administered less 
than 3 days after the previous administration.

For visits scheduled after Week 4, the study treatment should not be administered less than 
14 days after the previous administration.
Note: Missed or rescheduled visits should not lead to automatic discontinuation of patients.
Patients who prematurely discontinue the study for any reason should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled and 
the AEs and concomitant medications reconciled on the CRF. If patients refuse to return for 
these assessments or are unable to do so, every effort should be made to contact them or a 
knowledgeable informant by telephone to determine the reason. Documentation of attempts to 
contact the patient should be recorded in the source documentation.
No study assessment will be performed unless patients sign the ICF. Once a patient signs the 
ICF, he/she will be screened for eligibility criteria. The Screening Period will be flexible in 
terms of the time required to washout prior anti-rheumatic and other medications and will 
have a recommended duration of up to 10 weeks. During the Screening Visit, assessments will 
be performed as outlined in Table 6-1. Patients who have screen-failed once may be 
re-screened once if, in the opinion of the investigator, the risk/benefit ratio for the patient is 
positive and it is likely that the patient can meet all eligibility criteria at the second screening 


Novartis
Confidential
Page 44
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
time point. In this case, the patient will receive a new Patient Number (new Informed Consent 
process, separate IRT entry and eCRF data set applies).
The duration of the washout period will be determined at the Screening Visit. Note: All 
patients evaluated at Screening (Visit 1) for eligibility should not be screen failed based on a 
medication requiring washout, unless the patient will be unable to complete the washout in the 
appropriate time frame before randomization. 
Patients should be seen for all visits to perform the scheduled assessments on the designated 
day, or as close to is as possible, i.e. not exceeding the recommended visit window outlined in 
Table 6-1 and Table 6-2. 


Novartis
Confidential
Page 45
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Table 6-1
Assessment schedule
Screening
Treatment Period 1
Double-blind 
placebo-controlled
(last dose at Week 4)
Treatment Period 2
Double-blind active
(last dose at Week 20)
USV**
Comments
Visit number
1
2
3
4
5
6
7
8
9
10
EOS/
PPD*
* EOS/PPD - Patients who prematurely 
discontinue during the treatment period 
should return for assessments associated 
with the Week 24 visit (i.e. 4 weeks after the 
last study treatment).
** Unscheduled visit – assessments at the 
discretion of the investigator.
Week
−10 
to -1
0
1
2
3
4
8
12
20
24
Recommended visit window (days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
Information and informed consent
X
Inclusion & exclusion criteria
X
X
axSpA history
X
Spinal pain responder assessment
X
Demographics
X
Relevant medical history/
current medical conditions
X
Prior medication/
concomitant medication
X
X
X
X
X
X
X
X
X
X
X
AEs/ SAEs (including injection site 
reactions)
X
X
X
X
X
X
X
X
X
X
X
AEs/SAEs occurring after the patient has 
signed the informed consent (including 
those that occur during home administration 
of study drug) must be captured on the 
appropriate eCRF page. Any AEs that are 
treatment-emergent should be reported until 
12 weeks after the last study treatment. 


Novartis
Confidential
Page 46
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Screening
Treatment Period 1
Double-blind 
placebo-controlled
(last dose at Week 4)
Treatment Period 2
Double-blind active
(last dose at Week 20)
USV**
Comments
Visit number
1
2
3
4
5
6
7
8
9
10
EOS/
PPD*
* EOS/PPD - Patients who prematurely 
discontinue during the treatment period 
should return for assessments associated 
with the Week 24 visit (i.e. 4 weeks after the 
last study treatment).
** Unscheduled visit – assessments at the 
discretion of the investigator.
Week
−10 
to -1
0
1
2
3
4
8
12
20
24
Recommended visit window (days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
Smoking history
X
Cardiovascular medical history
X
Physical examination
S
S
S
S
S
S
S
S
S
S
S
Height† and weight
X
X
X
† Height will be assessed at Visit 2 or 
unscheduled visit only. 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
QuantiFERON TB-Gold test 
X
X
Chest X-ray or MRI
(for study eligibility)
X
X
A chest X-ray or MRI is required if it 
was not performed and evaluated within 
3 months before Screening. The X-ray 
should be performed after it is certain 
the patient meets inclusion/exclusion 
criteria in order to minimize 
unnecessary exposure to radiation. In 
some sites selected, the X-ray may be 
replaced by a chest MRI assessment.
Electrocardiogram
X
X
Hematology
X
X
X
X
X
X
X


Novartis
Confidential
Page 47
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Screening
Treatment Period 1
Double-blind 
placebo-controlled
(last dose at Week 4)
Treatment Period 2
Double-blind active
(last dose at Week 20)
USV**
Comments
Visit number
1
2
3
4
5
6
7
8
9
10
EOS/
PPD*
* EOS/PPD - Patients who prematurely 
discontinue during the treatment period 
should return for assessments associated 
with the Week 24 visit (i.e. 4 weeks after the 
last study treatment).
** Unscheduled visit – assessments at the 
discretion of the investigator.
Week
−10 
to -1
0
1
2
3
4
8
12
20
24
Recommended visit window (days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
Blood chemistry 
X
X
X
X
X
X
X
Blood sample to be collected with 
patient in fasting state.
HLA-B27
 
X
High sensitivity C-reactive protein
X
X
X
X
X
Results should be blinded in the 
laboratory report after Visit 2.
Urinalysis
X
X
X
X
X
X
X
Urine dipstick test to be performed at 
site. Test supply will be provided by 
central laboratory.
Serum pregnancy test
X
X
Urine pregnancy test
X
X
X
X
X
X
Test to be performed at site. Test 
supply will be provided by central 
laboratory.
Hepatitis B, C or HIV serology (only in 
countries where required)
S
Hepatitis B and/or hepatitis C and/or 
HIV serology testing to be performed 
during Screening period only if required 
as per local medical practice or local 
regulations prior to initiation of therapy. 


Novartis
Confidential
Page 48
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Screening
Treatment Period 1
Double-blind 
placebo-controlled
(last dose at Week 4)
Treatment Period 2
Double-blind active
(last dose at Week 20)
USV**
Comments
Visit number
1
2
3
4
5
6
7
8
9
10
EOS/
PPD*
* EOS/PPD - Patients who prematurely 
discontinue during the treatment period 
should return for assessments associated 
with the Week 24 visit (i.e. 4 weeks after the 
last study treatment).
** Unscheduled visit – assessments at the 
discretion of the investigator.
Week
−10 
to -1
0
1
2
3
4
8
12
20
24
Recommended visit window (days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
These assessments will be 
documented in source records only and 
will not be entered into the eCRF.
Randomization via IRT
X
X†
† At Visit 8, non-responders and 
patients receiving placebo will be re-
randomized to secukinumab 150 mg or 
300 mg 
IRT contact such as for registration or 
drug supply including home
administration
X
X
X
X
X
X
X
X
X
X
Administration of study treatment
X
X
X
X
X
X
X
X
Patients will be required to self-
administer secukinumab at home at 
Week 16. Please refer to Table 6-2 for 
timing of home administration.
Check self-administration log for home 
administration
S
At Visit 9, patients must return the 
self-administration log along with all 
dispensed PFS and drug packaging 


Novartis
Confidential
Page 49
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Screening
Treatment Period 1
Double-blind 
placebo-controlled
(last dose at Week 4)
Treatment Period 2
Double-blind active
(last dose at Week 20)
USV**
Comments
Visit number
1
2
3
4
5
6
7
8
9
10
EOS/
PPD*
* EOS/PPD - Patients who prematurely 
discontinue during the treatment period 
should return for assessments associated 
with the Week 24 visit (i.e. 4 weeks after the 
last study treatment).
** Unscheduled visit – assessments at the 
discretion of the investigator.
Week
−10 
to -1
0
1
2
3
4
8
12
20
24
Recommended visit window (days)
± 2
± 2
± 2
± 2
± 2
± 5
± 5
± 5
Spinal pain assessment on NRS
X
X
X
X
X
X
X
X
X
X
X
BASDAI
X
X
X
X
X
X
X
X
X
X
X
PASS
X
X
X
X
X
X
X
X
X
X
Patient global assessment of disease 
activity
X
X
X
X
FACIT-Fatigue©
X
X
X
X
ASAS Health Index
X
X
X
X
Treatment completion form
X
AE=adverse event, ASAS=Assessment of Spondyloarthritis International Society, axSpA=axial spondyloarthritis, BASDAI=Bath ankylosing spondylitis disease 
activity index, BSL=baseline, eCRF=electronic case report form, EOS=end of study, 
FACIT-Fatigue©=functional assessment of chronic illness therapy-fatigue, HIV=human immunodeficiency virus, HLA-B27=Human Leukocyte Antigen-
B27, IRT=interactive response technology, MRI=magnetic resonance imaging, NRS=numerical rating scale, PASS=Patient Accepted Symptoms State,
PFS=prefilled syringe, PPD=Premature patient withdrawal, SAE=Serious adverse event, SCR=screening, TB=tuberculosis, USV=unscheduled visit
X=assessment to be recorded on clinical database, S=assessment to be recorded on source documentation only


Novartis
Confidential
Page 50
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
An overview of study drug administration for Treatment Period 2 is presented in Table 6-2. 
Table 6-2
Overview of study drug administration for Treatment Period 2
Study visit
7
8
9
Week
8
12
16
20
Recommended visit  windows (days)
± 2
± 5
± 5
± 5
Study drug administration (all groups)
S
S
H
S
H=home; S=study center
6.1
Information to be collected on screening failures
All patients who have signed informed consent but not entered into the next period will have 
the study completion page for the Screening period, demographics, inclusion/exclusion, and 
SAE data collected. Adverse events that are not SAEs will be followed by the investigator and 
collected only in the source data. Information on withdrawal of consent must be completed if 
consent has been withdrawn during the Screening period. The Death eCRF should be 
completed in the case of death during the Screening period.
All patients who provide signed informed consent but discontinue prior to first intake of study 
drug on Day 1 (Baseline Visit) are considered to be screen failures. If a patient discontinues 
prior to or at Day 1, the reason for screen failure will be entered on the appropriate eCRF page. 
For details on completing the eCRF please refer to the CRF completion guideline. 
For all patients who sign the informed consent and enter into the next period of the study, all 
AEs occurring after the informed consent is signed will be recorded on the AE eCRF page.
6.2
Patient demographics/other baseline characteristics
All Baseline assessments should be performed prior to first study drug administration. These 
may occur during the Screening period or at the Baseline visit depending on the assessment 
(Table 6-1). 
6.2.1
Demographic data
Patient demographic data to be collected for all patients include: date/year of birth (as allowed 
per local regulation), sex, race, ethnicity, height, weight, child-bearing potential (for females 
only), and source of patient referral.
6.2.2
Baseline characteristics
6.2.2.1
AxSpA history
Patient’s disease history will be collected at the Baseline Visit. The information to be 
collected and entered as “axSpA history” and “prior axSpA therapies” includes the following:

Date of first diagnosis of axSpA prior to the Baseline Visit (by a rheumatologist)

Date of first signs and symptoms of axSpA including date of onset of IBP

AS diagnosis  including X-ray with presence/absence of sacroiliitis


Novartis
Confidential
Page 51
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301

nr-axSpA diagnosis by MRI or by presence of HLA-B27

Positive SpA features (Appendix 4)

Previous treatments of axSpA and the reason for discontinuation of these treatments
Diagnosis of axSpA (either AS or nr-axSpA) should have been in accordance with ASAS 
axSpA criteria (Appendix 4 and Appendix 5) as defined in the inclusion criteria (Section 4.1).
6.2.2.2
Smoking history
The current and/or previous use of tobacco products including e-cigarettes will be recorded, as 
well as the approximate consumption per year. Non-smokers will be advised not to start 
smoking during the study.
6.2.2.3
Co-morbidities – cardiovascular medical history
Any information pertaining to cardiovascular medical history assessed prior to Screening 
should be reported as cardiovascular history in the eCRF. Cardiovascular risk factors should 
also be recorded.
6.2.2.4
Relevant medical history/current medical conditions
Relevant medical history and current medical conditions (not including axSpA) present prior 
to signing the ICF will be recorded in the medical history eCRF. Whenever possible, 
diagnoses and not symptoms will be recorded.
Significant findings that are observed after the patient has signed the ICF and that meet the 
definition of an AE must be recorded in the AE summary pages.
6.2.2.5
Prior medication/concomitant medication
Prior medications taken within the 6 months preceding the study Screening Visit (Visit 1), any 
other relevant medication taken before these 6 months at the discretion of the investigator, and 
any concomitant medication irrespective of the start date will be captured in the eCRF.
6.2.2.6
Chest X-ray
If patients do not have a chest X-ray obtained within 3 months preceding the Screening Visit, 
a chest X-ray should be performed. In order to minimize unnecessary exposure to radiation, 
the chest X-ray should only be performed after confirming that the patient meets all 
inclusion/exclusion criteria. In some sites selected by Novartis, the X-ray assessment may be 
replaced by a MRI assessment.
6.2.2.7
Tuberculosis status
A QuantiFERON TB-Gold test is to be performed at Screening and the results must be 
available prior to randomization to determine the patient’s eligibility. The test will be used to 
screen the patient population for latent TB infection. 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 TB, or if presence of latent TB is 
established then treatment according to local guidelines must have been initiated.


Novartis
Confidential
Page 52
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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.
6.2.2.8
HLA-B27
A blood sample will be obtained from all patients to analyze HLA-B27, 
 
.
Details on the collection, handling and shipment of the sample to the central laboratory will be
provided to investigators in the Laboratory Manual.
6.2.2.9
Hepatitis B, C and HIV serology
Hepatitis B, C and HIV serology can be performed at Screening if required as per local 
medical practice or local regulations prior to initiation of biological therapy in order to rule 
out the presence of Hepatitis B, C or HIV infection.
6.2.3
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed as indicated in Table 6-1. The 
investigator/qualified site staff must review and initial the tracing. The tracing must then be 
stored with the patient’s source documents. If the ECG findings are clinically relevant and 
would prevent the patient from participating in the study (taking into account the patient’s 
overall status as well as the medication profile), the patient should be recorded as a screen 
failure, should NOT be enrolled and should not receive treatment. Any clinically relevant 
finding should be reported as medical history.
6.2.4
Other baseline characteristics
Other baseline characteristic data to be collected for all patients (all laboratory tests are 
performed centrally except where indicated; see also Table 6-1) include the following:

Vital signs, hematology, clinical chemistry and urine laboratory tests, and physical 
examination. Height and weight will also be assessed. For women of childbearing 
potential, a serum pregnancy test will be performed at Screening and a urine pregnancy 
test will be performed at Baseline.

Baseline assessments of spinal pain (NRS), BASDAI, patient’s global assessment of 
disease activity, PASS, ASAS health index, FACIT-Fatigue©, and hsCRP assessment as 
described in Section 6.4. 
Whenever possible, diagnoses and not symptoms will be recorded. 
6.3
Treatment exposure and compliance
All doses and dates of study treatment administration will be recorded on the appropriate 
Dosage Administration Record eCRF page.
Compliance will also be assessed continuously during the conduct of the study by Novartis 
study personnel using medication kits and corresponding documentation. Study drug doses 
and corresponding dates of self-administration at home should be documented in a 


Novartis
Confidential
Page 53
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
self-administration log. Patients are required to return the self-administration log as well as all 
dispensed study drug for a compliance check at their subsequent visit back to the study center. 
6.4
Efficacy
Efficacy will be evaluated using the following assessments:

Spinal pain NRS

BASDAI

ASDAS

FACIT-Fatigue©

PASS

ASAS Health Index
All of the above listed efficacy assessments are PROs except for ASDAS. 
All questionnaires should be completed at the scheduled study visit prior to the patient seeing 
the investigator for any other clinical assessment or evaluation. The patient should be given 
sufficient instruction, space, time and privacy to complete the questionnaires. The study 
coordinator should check each questionnaire for completeness and encourage the patient to 
complete any missing responses. Investigators should not encourage the patients to change the 
responses reported in the completed questionnaires. Guidelines for administering the PRO 
questionnaires can be found in Appendix 9.
Completed questionnaires should be reviewed and examined by the investigator before the 
clinical examination, for responses that may indicate potential AEs or SAEs. The investigator 
should review not only the responses to the questions in the questionnaires but also for any 
unsolicited comments written by the patient. If AEs or SAEs are confirmed, then the 
physician must record the events as per instructions given in Section 7 of the protocol.
All questionnaires are available, where possible, in the local languages of the participating 
countries. PRO questionnaires will be administered as defined in the schedule of assessments 
(see Table 6-1).
6.4.1
Numerical rating scale spinal pain assessment
The spinal pain NRS assessment is an 11-point scale to assess pain intensity in patients who 
are able to self-report. The patient should answer 2 questions in order to make 2 pain ratings 
(point a number on NRS between 0 and 10), corresponding to the intensity of spinal pain 
experienced on an average during the previous week; the average of the 2 ratings is to be used 
to represent the patient’s level of pain (see Appendix 7).
6.4.2
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 NRS), which is used to answer 6 questions pertaining to the 5 major 
symptoms of AS:

Fatigue/tiredness

Spinal pain (neck, back or hip pain)


Novartis
Confidential
Page 54
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301

Pain/swelling in joints (other than neck, back, hips)

Enthesitis, or inflammation of tendons and ligaments (areas of localized tenderness)

Morning stiffness duration and severity
The purpose of BASDAI in this study is to assess pain, discomfort and fatigue in patients with 
axSpA. BASDAI was originally validated to measure disease status and symptoms in patients 
with AS; however, one study (Rudwaleit et al 2009b) demonstrated that the level of disease 
activity as measured by the BASDAI, morning stiffness, fatigue, and pain at night is highly 
comparable between patients with AS and those with nr-axSpA.
Please see Appendix 8 for more details.
6.4.3
Ankylosing spondylitis disease activity score
The ASDAS is a composite index to assess disease activity in AS (Sieper 2009, Lukas 2009). 
The ASDAS-CRP will be used to assess the disease activity status. Parameters used for the 
ASDAS include: 

Spinal pain (BASDAI question 2) (Section 6.4.2)

Patient’s global assessment of disease activity (Section 6.4.3.1)

Peripheral pain/swelling (BASDAI question 3) (Section 6.4.2)

Duration of morning stiffness (BASDAI question 6) (Section 6.4.2)

hsCRP in mg/L (Section 6.4.3.2)
Disease activity states are defined as follows: inactive disease, moderate disease activity, high 
disease activity, and very high disease activity. The 3 values selected to separate these states 
are < 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate 
disease activity and high disease activity, and > 3.5 between high disease activity and very 
high disease activity. Selected cut-offs for improvement scores are a change ≥ 1.1 unit for 
“minimal clinically important improvement” and a change ≥ 2.0 units for “major 
improvement” (Machado 2011).
6.4.3.1
Patient’s global assessment of disease activity
The patient’s global assessment of AS disease activity will be performed using a NRS ranging 
from 0 (not active) to 10 (very active) (Sieper et al 2009) based on the following question: 
How active was your disease on average during the last week?
6.4.3.2
High sensitivity C-reactive protein
A central laboratory will be used for analysis of hsCRP. Details on the collection, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the 
Laboratory Manual. Blood for this assessment will be obtained in order to identify the 
presence of inflammation, to determine its severity, and to monitor response to treatment. 
Since the results of this test may unblind study personnel, results from the central laboratory 
will be provided for Screening and Baseline only. The hsCRP results from samples collected 
during the treatment periods will be revealed following the database lock only.


Novartis
Confidential
Page 55
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
6.4.4
Functional assessment of chronic illness therapy-fatigue
The FACIT-Fatigue© is a 13-item questionnaire (Cella et al 1993, Yellen et al 1997) that 
assesses self-reported fatigue and its impact upon daily activities and function. The patient 
should complete all items.
The purpose of FACIT-Fatigue© in this study is to assess the impact of fatigue on patients 
with axSpA.
6.4.5
Patient acceptable symptoms state
The PASS has been defined as the highest level of symptoms beyond which patients consider 
themselves well. Measurement of patient well-being also enables evaluation of how soon and 
for how long the patient feels good (Maksymovych et al, 2010).
During the PASS assessment, the patient will answer the following question: 

Considering all the different ways your disease is affecting you, if you would stay in this 
state for the next months, do you consider that your current state is satisfactory?
The purpose of PASS in this study is to assess the well-being of patients with axSpA. 
Achievement of PASS indicates that the patient feels well.
6.4.6
ASAS Health Index
The ASAS health index is a disease-specific questionnaire that was developed based on the 
comprehensive international classification of functioning, disability and health (ICF) Core Set 
for AS (Kiltz et al 2014). The ASAS health index is a linear composite measure and contains 
17 items (dichotomous response option: “I agree” and “I do not agree”), which cover most of 
the ICF core set, as presented in Table 6-3. 
Table 6-3
Items of the ASAS health index
Item
Categories
ICF number
Pain sometimes disrupts my normal activities. 
Pain
b280 
I find it hard to stand for long.
Maintaining a body position
d415 
I have problems running.
Moving around
d455 
I have problems using toilet facilities. 
Toileting
d530 
I am often exhausted.
Energy and drive
b130 
I am less motivated to do anything that requires 
physical effort.
Motivation
b1301
I have lost interest in sex.
Sexual functions 
b640 
I have difficulty operating the pedals in my car.
Driving 
d475 
I am finding it hard to make contact with people.
Community life 
d910 
I am not able to walk outdoors on flat ground.
Moving around
d455 
I find it hard to concentrate.
Handling stress
d240 
I am restricted in traveling because of my mobility. 
Recreation and leisure
d920 
I often get frustrated.
Emotional functions 
b152 
I find it difficult to wash my hair.
Washing oneself 
d510 
I have experienced financial changes because of 
Economic self-sufficiency
d870


Novartis
Confidential
Page 56
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Item
Categories
ICF number
my rheumatic disease.
I sleep badly at night
Sleep
b134
I cannot overcome my difficulties.
Handling stress
d240
Source: Kiltz et al 2014
6.4.7
Appropriateness of efficacy assessments
The efficacy outcome measures used in this study are standard measures used across AS and 
nr-axSpA trials.
6.5
Safety

Physical examination

Vital signs

Laboratory evaluations

Pregnancy and assessment of fertility
6.5.1
Physical examination
Physical examinations, which will be performed as defined in Table 6-1, will include the 
examination of general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological system.
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present before signing the ICF must be included in the 
relevant medical history eCRF. Significant findings made after signing the ICF that meet the 
definition of an AE must be recorded in the AE eCRF and if SAE criteria are met, findings 
must also be reported as a SAE.
6.5.2
Vital signs
Vital signs (including blood pressure and pulse measurements) will be assessed after the 
patient has been sitting for 5 minutes, with back supported and both feet placed on the floor.   
Sites should use a validated device with an appropriately sized cuff and each blood pressure 
measurement will be recorded in the source (Mancia et al 2007). In case the cuff sizes 
available are not large enough for the patient’s arm circumference, a sphygmomanometer with 
an appropriately sized cuff may be used. If possible, assessments should be performed by the 
same study site staff member throughout the study. 
Systolic and diastolic blood pressure will be measured twice (measurements separated by 1 to 
2 minutes).
Normal blood pressure will be defined as a systolic pressure of 90 to < 120 mmHg, and a 
diastolic blood pressure of 60 to < 80 mmHg under the measurement conditions outlined 
above. Notable blood pressure will be hypertension (systolic blood pressure of ≥ 140 mmHg 
and/or diastolic blood pressure of ≥ 90 mmHg) or hypotension (systolic blood pressure of 
< 90 mmHg and/or a diastolic blood pressure of < 60 mmHg). A blood pressure indicative of 


Novartis
Confidential
Page 57
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
prehypertension (systolic blood pressure of 120 to < 140 mmHg and/or diastolic blood 
pressure of 80 to < 90 mmHg) will not be regarded as notable (Chobanian et al 2003).
A normal pulse rate will be defined as a rate of 60 to 100 beats per minute (bpm) under the 
measurement conditions outlined above. Notable pulse rates are a rate below 60 bpm 
(bradycardia) or above 100 bpm (tachycardia).
Whether action needs to be taken to address notable vital signs will be decided by the 
investigator, taking into account the overall status of the patient. No specific action is foreseen 
as part of the study protocol.
6.5.3
Height and body weight
Height in cm and body weight (to the nearest 0.1 kg in indoor clothing) (both without shoes) 
will be measured as indicated in Table 6-1. If possible, body weight assessments should be 
performed by the same study site staff member using the same scale throughout the study.
6.5.4
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected as listed below and 
outlined in the schedule of assessments (see Table 6-1). Urinalysis and urine pregnancy tests 
will be performed on site with supplies provided by the central laboratory. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. Clinically notable laboratory findings are defined in 
Appendix 1.
All patients with laboratory tests containing clinically significant abnormal values are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined.
6.5.4.1
Hematology
Hemoglobin, platelets, red blood cell count and WBC count with differential counts will be 
measured at scheduled visits.
6.5.4.2
Clinical chemistry
Serum chemistries will include glucose, urea, creatinine, total bilirubin, AST/SGOT, 
ALT/SGPT, gamma-glutamyl transferase (γGT), alkaline phosphatase, sodium, potassium, 
bicarbonate, calcium, phosphorus, total protein, albumin, and uric acid.
6.5.4.3
Urinalysis
Dipsticks will be provided by the central laboratory to the sites for local urinalysis 
assessments. The measurements for standard parameters such as protein, glucose, blood and 
WBCs will be performed and results recorded in the appropriate eCRF page.


Novartis
Confidential
Page 58
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
6.5.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have a serum β-hCG test 
(serum pregnancy test) performed at the Screening visit and local urine pregnancy tests as 
indicated in Table 6-1. A positive urine pregnancy test requires immediate interruption of 
study drug until serum β-hCG is performed and found to be negative.
In the case of oophorectomy alone, the woman is considered not of childbearing potential 
only when her reproductive status has been confirmed by follow-up hormone level assessment.
6.5.6
Appropriateness of safety measurements
The safety measures used in this study are reliable and relevant standard measures for a 
biologic in axSpA. A chest X-ray at Screening (or within 3 months prior to Screening) is 
performed to rule out the presence of a pulmonary malignancy of infectious process in 
particular TB. 
The radiation exposure that results from these safety measurements are estimated to be far 
below 1 mS. For effective radiation doses under 3 mS (300 mrem), the risk is considered to be 
minimal. Therefore, the radiation exposure in this study involves minimal risk and is 
necessary to ensure reliable safety measures before the treatment with a biologic. 
6.6
Other assessments
No additional tests will be performed on patients entered into this study.
7
Safety monitoring
7.1
Adverse events
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a patient 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 
AE irrespective if a clinical event has occurred.
The occurrence of AEs must be sought by non-directive questioning of the patient at each 
visit during the study. AEs also may be detected when they are volunteered by the patient 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Abnormal laboratory values or test results constitute AEs 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


Novartis
Confidential
Page 59
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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 patients 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual patient and identifying AEs. Alert ranges for laboratory and other test 
abnormalities are included in Appendix 1.
AEs must be recorded in the AE eCRF under the signs, symptoms or diagnosis associated 
with them. Medical conditions/diseases present before starting study treatment will only be 
considered AEs if they worsen after starting study treatment (any procedures specified in the 
protocol). 
As far as possible, each AE should be described by (but not limited to) the following 
information:

the severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities

its relationship to the study treatment (no/yes)

its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported

whether it constitutes an SAE (see Section 7.2 for definition of SAE) and which 
seriousness criteria have been met

action taken regarding study treatment

whether other medication or therapies have been taken (concomitant medication/non-drug 
therapy)

its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an AE 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 IB. This information will be included in the patient informed consent and should 
be discussed with the patient 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). New 
information might require an update to the informed consent and has then to be discussed with 
the patient.
The investigator must also instruct each patient to report any new AE (beyond the protocol 
observation period) that the patient, or the patient’s personal physician, believes might 
reasonably be related to study treatment. Any AEs that are treatment emergent should be 
reported until 12 weeks after last study treatment. This information must be recorded in the 


Novartis
Confidential
Page 60
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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 serious adverse event
An SAE is defined as any AE (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

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above e.g. 
may require 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
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if 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 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (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.


Novartis
Confidential
Page 61
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
7.2.2
Serious adverse event reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 12 weeks after last administered dose of study treatment
must be reported to Novartis safety within 24 hours of learning of its occurrence. Any SAEs 
experienced after this should only be reported to Novartis safety 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 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 (either initial or follow-up) is collected and recorded on the SAE 
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 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 after 
awareness of the SAE to the local Novartis Drug Safety and Epidemiology (DS&E) 
Department.. Detailed instructions regarding the submission process and requirements for 
signature are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. The follow-up 
information should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not, and whether the patient continued or withdrew 
from study participation. 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.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment a DS&E Department associate may urgently 
require further information from the investigator for health authority reporting. Novartis may 
need to issue an 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.
7.3
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following 2 categories of abnormalities / AEs have to be considered during the course of 
the study (irrespective of whether classified/reported as (S)AE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter


Novartis
Confidential
Page 62
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base Liver CRF pages
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personnel at the trial site as summarized below (please see Appendix 2 for detailed 
information).
For the liver laboratory trigger:

Repeating the liver function test (LFT) within the next week to confirm elevation.
These LFT repeats must be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory must then be performed at central laboratory as soon as possible. If 
a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event must be reported on the Liver CRF pages.

If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug if appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)

An investigation of the liver event, which needs to be followed until resolution
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist consultancies, based on the investigator’s discretion. All follow-up information, 
and the procedures performed must be recorded on appropriate CRF pages, including the liver 
event overview CRF pages.
7.4
Renal safety monitoring
The following 2 categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum event:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to Baseline 
during normal hydration status

Urine event

new onset (≥ 1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio or urinary protein-creatinine ratio (PCR) (if applicable)

new onset (≥ 1+), hematuria or glycosuria
Every renal laboratory trigger or renal event should be followed up by the investigator or 
designated personnel at the trial site as summarized in Appendix 3.


Novartis
Confidential
Page 63
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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, patient or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record eCRF 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.
See Table 7-1 for guidance on capturing the study treatment errors including misuse/abuse.
Table 7-1
Treatment error types
Treatment error 
type
Document in DAR 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes 
Yes, even if not associated 
with a SAE
AE=adverse event, eCRF=electronic case report form, DAR=dose administration record, SAE=serious 
adverse event
7.6
Pregnancy reporting
To ensure patient safety, each pregnancy in a patient on study drug must be reported to 
Novartis/CRO within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
The study drug must be discontinued, though the patient may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The patient may continue all other protocol assessments.
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis DS&E Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the 
Novartis study drug. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form.


Novartis
Confidential
Page 64
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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 capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (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 data capture / data entry, the adherence to the protocol and to GCP, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis Clinical Research Associate organization. Additionally, a central 
analytics organization may analyze data and identify risks and trends for site operational 
parameters, and provide reports to Novartis Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the patient's file. The 
investigator must also keep the original informed consent form signed by the patient (a signed 
copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
8.2
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRFs using 
fully validated software that conforms to US CFR 21 Part 11 requirements. Designated 
investigator site staff will not be given access to the EDC 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 eCRFs are complete and accurate. After database lock, the 
investigator will receive copies of the patient data for archiving at the investigational site. 
8.3
Database management and quality control
Novartis staff or the CRO working on behalf of Novartis reviews the data entered into the 
CRFs by investigational staff for completeness and accuracy and instructs the site personnel 
to make any required corrections or additions. Queries are sent to the investigational site using 


Novartis
Confidential
Page 65
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff or the CRO working on behalf of Novartis that will make the correction 
to the database. The signed copy of the Data Query Form is kept at the investigator site. 
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and AEs will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally (if indicated as centrally measured as per 
Table 6-1) and the results will be sent electronically to Novartis (or a designated CRO).
Electrocardiogram readings will be collected locally and the results will be reported in the 
CRF to Novartis (or a designated CRO) or, in case of site lacking equipment, may be 
collected and processed centrally and reported electronically to Novartis (or a designated 
CRO).
Randomization codes and data about all study drug(s) dispensed to the patient and all dosage 
changes will be tracked using an IRT.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. Any 
changes to the database after that time can only be made after written agreement by Novartis 
management.
8.4
Data monitoring committee
Not required.
8.5
Adjudication committee
Not required.
9
Data analysis
Data analysis will be conducted on all patient data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. For all details please refer to the Statistical Analysis Plan.
9.1
Analysis sets 
The following analysis sets will be used in this study:
The Enrolled Set will include all patients who provided informed consent.


Novartis
Confidential
Page 66
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
The Randomized Set will consist of all patients who were randomized into this study at 
Baseline.
The Safety Set for Treatment Period 1 (SAF-TP1) will consist of all patients who received 
at least 1 dose of study treatment during this treatment period. Data will be analyzed 
according to the treatment actually received.
The Safety Set for Treatment Period 2 (SAF-TP2) will consist of all patients who received 
at least 1 dose of study treatment during this treatment period. Data will be analyzed 
according to the treatment actually received.
The Full Analysis Set for Treatment Period 1 (FAS-TP1) will consist of all patients who 
were randomized into this study at Baseline and received at least 1 dose of study treatment 
during this treatment period. Data will be analyzed according to the treatment assigned at 
randomization.
The Full Analysis Set for Treatment Period 2 (FAS-TP2) will consist of all patients who 
were re-randomized at Visit 7 (Week 8) and received at least 1 dose of study treatment during 
this treatment period. Data will be analyzed according to the treatment assigned at 
randomization.
9.2
Patient demographics and other baseline characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics 
for each treatment group and for all patients in the randomized set. The number and 
percentage of patients in each category will be presented for categorical variables for each 
treatment group and for all patients.
9.3
Treatments
9.3.1
Study treatment
The analysis of study treatment data will be based on the Safety Set. 
The duration of exposure to study treatment will be summarized by treatment group. In 
addition, the number of patients with exposure of certain thresholds of study treatment will be 
displayed. Compliance will be calculated based on documented study drug administrations 
and syringe counts and displayed by treatment group.
9.3.2
Prior and concomitant treatment
Prior and concomitant treatments and non-drug therapies will be summarized by treatment 
group in separate tables.
Prior treatments are defined as treatments taken and stopped prior to the first dose of study 
treatment. Any treatment given at least once between the day of first dose of randomized 
study treatment and the last study visit day will be a concomitant treatment, including those 
that were started pre-baseline and continued into the treatment period.
Treatments will be presented in alphabetical order, by anatomical therapeutic classification 
(ATC) codes and grouped by anatomical main group. The overall number and percentage of 


Novartis
Confidential
Page 67
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
patients receiving at least 1 treatment in a particular ATC will also be presented in summary 
tables.
9.4
Analysis of the primary variable
9.4.1
Primary variable
The primary endpoint is the proportion of patients with a spinal pain NRS score < 4 at Week 8. 
This is referred to as ‘response’ below.
9.4.2
Statistical model, hypothesis, and method of analysis
The null hypothesis to be rejected is that the odds of response at Week 8 are equal in both 
treatment groups. The corresponding alternative hypothesis is that the odds of response at 
Week 24 are higher under secukinumab compared to placebo.
Let pj denote the proportion of responders at Week 8 for treatment group j, j=0, 1, where

0 corresponds to placebo

1 corresponds to secukinumab
The following hypotheses will be tested:
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus HA: (p1 / (1- p1)) / (p0 / (1- p0)) ≠1
In other words:
HA: The odds ratio of achieving a response at Week 8 for secukinumab vs. placebo is 
different from 1.
The primary analysis will be performed comparing treatments with respect to the primary 
efficacy variable in a logistic regression model with the factors treatment, country and the 
2 stratification factors (prior exposure to TNF inhibitors and naïve/ inadequate responders to 
TNFα inhibitors). The odds ratio and its 95% confidence interval (CI) and p-value will be 
given. The null hypothesis of equal odds will be rejected if the 2-sided p-value from the 
logistic regression model for the factor “treatment” is < 0.05; however, superiority of 
secukinumab will be claimed only if the direction is correct, i.e. if the odds of response are 
larger under secukinumab.
9.4.3
Handling of missing values/censoring/discontinuations
For the primary endpoint, patients with missing assessments at Week 8 will be considered as 
non-responders.
9.4.4
Sensitivity analyses
The raw spinal pain NRS scores will be analyzed using a repeated measures analysis of 
variance (ANOVA) model. The model will include the same factors as the logistic model 
above plus the baseline score as a covariate.


Novartis
Confidential
Page 68
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
9.5
Analysis of secondary variables
9.5.1
Efficacy variables
The secondary endpoint, the proportion of patients with a BASDAI score < 4 at Week 8, will 
be analyzed analogous to the primary endpoint. The secondary endpoint will be included in a 
confirmatory testing strategy, it will be tested hierarchically after the primary endpoint. 
Confirmatory evidence for the superiority of secukinumab with respect to the secondary 
endpoint will be claimed only if the 2-sided p-value from the logistic regression model for the 
factor “treatment” is < 0.05 and if the direction is correct, i.e. if the odds of response are larger 
under secukinumab and if the superiority of secukinumab with respect to the primary endpoint 
has already been demonstrated.
9.5.2
Safety variables
9.5.2.1
Adverse events
Treatment emergent AEs (events started after the first dose of study treatment or events 
present prior to the first dose of study treatment but increased in severity based on preferred 
term) will be summarized.
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any AE, having an AE in each primary system organ class (SOC) 
and having each individual AE (preferred term (PT)). Adverse events will also be summarized 
by severity and relationship to study treatment. If a patient reported more than 1 AE with the 
same PT, the AE with the greatest severity will be presented. If a patient reported more than 
1 AE within the same primary SOC, the patient will be counted only once with the greatest 
severity at the SOC level, where applicable. Serious adverse events will also be summarized.
These summaries may be presented separately by study periods, i.e. Treatment period 1 (from 
Baseline to time of study drug administration at Week 8) and Treatment Period 2 (from 
dosing at Week 8 to Week 24).
Separate summaries will be provided for any deaths, SAEs, other significant AEs such as AEs 
leading to discontinuation and AEs leading to dose adjustment (including study treatment 
discontinuation).
9.5.2.2
Laboratory data
Laboratory evaluations will be summarized for 3 groups of laboratory tests (hematology, 
serum chemistry and urinalysis). Descriptive summary statistics for the change from Baseline 
in laboratory data at each study visit will be presented. These descriptive summaries will be 
presented by test group, laboratory test and treatment group. Change from Baseline will only 
be summarized for patients with both Baseline and post-Baseline assessments. For each 
parameter, the maximum change from Baseline within each study period will also be analyzed.
9.5.2.3
Vital signs
Analysis of the vital sign measurements using summary statistics for the change from 
Baseline for each post-Baseline visit will be performed. These descriptive summaries will be 


Novartis
Confidential
Page 69
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
presented by vital sign and treatment group. Change from Baseline will only be summarized 
for patients with both a Baseline and post-Baseline value.
9.6
Analysis of exploratory variables
All endpoints relating to exploratory objectives will be summarized descriptively. Summary 
statistics will include relative and absolute frequencies for the categorical variables and the 
number of patients, minimum, mean, median and maximum for continuous variables. Time 
courses of response rates and mean NRS-scores will be displayed graphically. Inferential 
statistical test may be calculated as appropriate, they will use the same methodology as 
described for the primary endpoint. Details will be specified in the Statistical Analysis Plan.
9.7
Interim analyses
No interim analysis is planned for this study.
9.8
Sample size calculation
To assess the assumed effect size at Week 8, a 43.6% response rate (NRS < 4) is assumed for 
the secukinumab 150 mg group. This number is derived as an average of the response rates 
observed in the CAIN457F2320 and CAIN457F2310 studies (Baeten et al 2015). For the 
placebo group, a response rate at Week 8 of 23.5% (NRS < 4) was selected as assessed in the 
CAIN457F2320 study. This intermediate scenario takes into consideration a certain likelihood 
of a relatively high placebo response also in line with data from the TNFα reference studies 
and the CAIN457F2305 study in addition to the slightly milder course of the disease in the 
studied population (Baeten et al 2015).
Assuming conservatively a response rate of 23.5% in the placebo group and a response rate of 
43.6% under secukinumab 150 mg, 332 patients in total (i.e. 249 patients in secukinumab 150 
mg group and 83 patients in placebo group) would be needed under 3:1 (secukinumab: 
placebo) allocation to achieve 90% power on a (2-sided) 5% significance level. To 
compensate for drop-out patients or those with protocol deviations, a total of 352 patients 
(264 in secukinumab 150 mg group and 88 in the placebo group) should be recruited.
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 International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines 
for GCP, with applicable local regulations (including European Directive 2001/20/EC, US 
CFR 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
10.2
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if applicable after 


Novartis
Confidential
Page 70
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
such consent has been provided by a legally acceptable representative(s) of the patient. In 
cases where the patient’s representative gives consent, the patient must be informed about the 
study to the extent possible given his/her understanding. If the patient is capable of doing so, 
he/she must indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting 
any study-specific procedures (e.g. all of the procedures described in the protocol). The 
process of obtaining informed consent must be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval.
Women of childbearing 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. If there is any question that the patient will not reliably comply, they 
must not be entered in the study.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional IRB/IEC approval will be obtained.
10.3
Responsibilities of the investigator and institutional review 
board/independent ethics committee
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
patient recruitment procedures (e.g. advertisements) and any other written information to be 
provided to patients. Prior to study start, the investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to Novartis monitors, auditors, Novartis Quality Assurance 
representatives, designated agents of Novartis, IRBs/IECs, and regulatory authorities as 
required. If an inspection of the clinical site is requested by a regulatory authority, the 
investigator must inform Novartis immediately that this request has been made.
10.4
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
10.5
Quality control and quality assurance
Novartis maintains a robust Quality Management system that includes all activities involved 
in quality assurance and quality control, including the assignment of roles and responsibilities, 


Novartis
Confidential
Page 71
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
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, 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 processes, 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 should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. All significant protocol deviations will be recorded and reported in the Clinical 
Study Report.
11.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 (Safety monitoring) must be followed.
12
References
References are available upon request
Asare K (2007) Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient. 
Pharmacotherapy;25(11):1512-28
Bedaiwi M, Sari I, Thavaneswaran A, et al (2015) Fatigue in Ankylosing Spondylitis and 
Nonradiographic Axial Spondyloarthritis: Analysis from a Longitudinal Observation Cohort. 
J Rheumatol;42(12):2354-60 


Novartis
Confidential
Page 72
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Baeten D, Sieper J, Braun J et al; MEASURE 1 Study Group; MEASURE 2 Study Group 
(2015) Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Engl J Med; 
373(26):2534-48
Bennett P and Burch T (1968) Population studies of the rheumatic diseases. Amsterdam, 
Excerpta Medica Foundation;456-57
Bodur H, Ataman S, Rezvani A, et al (2011) Quality of life and related variables in patients 
with ankylosing spondylitis. Qual Life Res;20(4):543-9
Boonstra AM, Schiphorst Preuper HR, Balk GA et al (2014) Cut-off points for mild, moderate 
and severe pain on the visual analogue scale for pain in patients with chronic musculoskeletal 
pain. Pain;155(12):2545-50
Braun J, van den Berg R, Baraliakos X, et al (2011) 2010 update of the ASAS/EULAR 
recommendations for the management of ankylosing spondylitis. Ann Rheum Dis; 
70(6):896-904
Brophy S, Davies H, Dennis MS, et al (2013) Fatigue in ankylosing spondylitis: treatment 
should focus on pain management. Semin Arthritis Rheum;42(4):361-7
Cella DF, Wiklund I, Shumaker A, et al (1993) Integrating health-related quality of life into 
cross-national clinical trials. Qual Life Res;2:433-40
Chobanian AV, Bakris GL, Black HR, et al (2003) National Heart, Lung, and Blood Institute 
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure; National High Blood Pressure Education Program Coordinating Committee (2003) 
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure: the JNC 7 report. Hypertension;42:1206-52 
Colburn NT (2012) Review of Rheumatology. 1st ed; London:Springer.
Dougados M, Simon P, Braun J, et al (2011) ASAS recommendations for collecting, 
analysing, and reporting NSAID intake in clinical trials/Epidemologic studies in axial 
spondylarthritis. Ann Rheum Dis;70(2):249-51
European Medicines Agency (EMA) Committee for Medicinal Products for Human Use 
(CHMP) (2009) Guideline on clinical investigation of medicinal products for the treatment of 
ankylosing spondylitis (CPMP/EWP/4891/03)
Grover VK, Babu R, Bedi SPS (2007) Steroid Therapy – Current Indications in Practice. 
Indian J of Anaesth;51:389-93
ICH E2D Post-Approval Safety Data Management: Definitions and Standards for Expedited 
Reporting
Kiltz U, van der Heijde D, Boonen A, et al (2014) The ASAS Health Index (ASAS HI) - a 
new tool to assess the health status of patients with spondyloarthritis. Clin Exp Rheumatol; 
32(5 Suppl 85):S-105-8
van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for 
ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum; 
27(4):361-8
Lukas C, Landewé R, Sieper J, et al (2009) Development of an ASAS-endorsed disease 
activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis.; 68(1):18-24


Novartis
Confidential
Page 73
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Liu D, Ahmet A, Ward L, Krishnamoorthy P, et al (2013) A practical guide to the monitoring 
and management of the complications of systemic corticosteroid therapy. Allergy Asthma 
Clin Immunol;9(1):30-54
Machado P, Landewé R, Lie E, et al (2011) Ankylosing Spondylitis Disease Activity Score 
(ASDAS): defining cut-off values for disease activity states and improvement scores. Ann 
Rheum Dis; 70:47-53
Maksymovych WP, Gooch K, Dougados M, et al (2010) Thresholds of Patient-Reported 
Outcomes That Define the Patient Acceptable Symptom State in Ankylosing Spondylitis Vary 
Over Time and by Treatment and Patient  Characteristics. Arthritis Care Res; 62 (69: 826-34
Mancia G, De Backer G, Dominiczak A, et al (2007) Guidelines for the Management of 
Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the 
European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J 
Hypertens;25:1105-87
Missaoui B and Revel M (2006) Fatigue in ankylosing spondylitis. Ann Readapt Med Phys; 
49(6):305-8
Rudwaleit M, van der Heijde D, Landewe R, et al (2009a) The development of Assessment of 
SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part 
II): validation and final selection. Ann Rheum Dis;68(6):777-83
Rudwaleit M, Haibel H, Baraliakos X, et al (2009b) The early disease stage in axial 
spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Arthritis 
Rheum;60(3):717-27
Rudwaleit M, Metter A, Listing J, et al (2006) Inflammatory back pain in ankylosing 
spondylitis: a reassessment of the clinical history for application as classification and 
diagnostic criteria. Arthritis Rheum;54(2):569-78
Saviola G, Abdi Ali L, Shams Eddin S et al (2007) Compared clinical efficacy and bone 
metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory 
arthropathies: a 12-month open randomized pilot study. Rheumatology;46(6):994-8
Shaikh S, Verma H, Yadav N, et al (2012) Applications of Steroid in Clinical Practice: A 
Review. ISRN Anesthesiology;2012:1-11
Sieper J, van der Heijde D, Dougados M, et al (2013) Efficacy and safety of adalimumab in 
patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-
controlled trial (ABILITY-1). Ann Rheum Dis;72(6):815-22
Sieper J, Rudwaleit M, Baraliakos X, et al (2009) The Assessment of SpondyloArthritis 
international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis; 
68 Suppl 2:1-44
Smolen JS, Braun J, Dougados M, et al (2014) Treating spondyloarthritis, including 
ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international 
task force. Ann Rheum Dis;73(1):6-16
Song IH, Weiss A, Hermann KG, et al (2013) Similar response rates in patients with 
ankylosing spondylitis and non-radiographic axial spondyloarthritis after 1 year of treatment 
with etanercept: results from the ESTHER trial. Ann Rheum Dis;72(6):823-5


Novartis
Confidential
Page 74
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Wallis D, Haroon N, Ayearst R, et al (2013) Ankylosing spondylitis and nonradiographic 
axial spondyloarthritis: part of a common spectrum or distinct diseases? J Rheumatol; 
40(12):2038-41
Wendling (2015) Interleukin-17 targeted therapies in axial spondyloarthritis. Immunotherapy; 
7(11):1125-8
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with the functional assessment of cancer therapy (FACT) measurement system. 
J Pain Symptom Manage;13:63-74


Novartis
Confidential
Page 75
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13
Appendices
13.1
Appendix 1: Clinically notable laboratory values
The following criteria included in Table 13-1 will be used to define expanded limits and 
notable abnormalities of key laboratory tests.
Clinically notable values will be forwarded to Novartis at the same time that they are sent to 
investigators. Any action based on these laboratory values should be discussed with Novartis 
personnel.
Table 13-1
Safety analyses: expanded limits and notable criteria
Laboratory variable
Final harmonization
Notable criteria
Standard units
SI units
Liver function and related variables
AST/SGOT
3 x ULN
3 x ULN
ALT/SGPT
3 x ULN
3 x ULN
Bilirubin
2 x ULN
2 x ULN
Alkaline phosphatase
2.5 x ULN
2.5 x ULN
Renal function and related variables
Creatinine (serum)
2 x ULN
2 x ULN
Hematology variables
Hemoglobin
20 g/L decrease from Baseline
Platelet count
100 x 10E9/L
White blood cell count
0.8 x LLN
Neutrophils
0.9 x LLN
ALT/SGPT=alanine aminotransferase/serum glutamic pyruvic transaminase, AST/SGOT=aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase, LLN=lower limit of normal, ULN=upper 
limit of normal


Novartis
Confidential
Page 76
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.2
Appendix 2: Liver event and laboratory trigger definitions and 
follow-up requirements
Table 13-2
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers

3 x ULN < ALT / AST 5 x ULN

1.5 x ULN < TBL 2 x ULN
Liver events

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × ULN (in the absence of known Gilbert syndrome)

ALT or AST > 3 × ULN and INR > 1.5 

Potential Hy’s Law cases (defined as ALT or AST > 3 × 
ULN and TBL > 2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to > 2 × ULN)

Any clinical event of jaundice (or equivalent term)

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia

Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
ALT=alanine aminotransferase, ALP=alkaline phosphatase, AST=aspartate aminotransferase, 
INR=international normalized ratio, TBL=total bilirubin, UNL=upper normal limit
Table 13-3
Follow-up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and 
INR > 1.5

Discontinue the study treatment 
immediately

Hospitalize, if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue follow-
up monitoring
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)


Novartis
Confidential
Page 77
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
Criteria
Actions required
Follow-up monitoring

If elevation persists for more than 
2 weeks, discontinue the study drug

Establish causality

Complete liver CRF
> 3 × ULN 
accompanied by 
symptomsb

Discontinue the study treatment 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)

Repeat LFT within 48 hours

If elevation persists, establish 
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

If elevation persists, discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice

Discontinue the study treatment 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study treatment interruption 
or discontinuation 

Hospitalization if clinically appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
Alb=albumin, AESI=adverse event of special interest, ALP=alkaline phosphatase, CRF=case report 
form, INR=international normalized ratio, γGT=gamma glutamyl transferase, LFT=liver function test, 
PT=prothrombin time, TBL=total bilirubin, ULN= upper limit normal


Novartis
Confidential
Page 78
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.3
Appendix 3: Specific renal alert criteria and actions 
Table 13-4
Specific renal alert criteria and actions
Serum event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Acute Kidney Injury: serum creatinine increase 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption 
Consider patient hospitalization /specialized 
treatment
Urine event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase 
≥2-fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or 
≥3 mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation 
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed 
Monitor patient regularly (frequency at investigator’s discretion) until either: 
Event resolution: serum creatinine within 10% of baseline or protein-creatinine ratio within 50% of 
baseline, or
Event stabilization: serum creatinine level with ± 10% variability over last 6 months or protein-
creatinine ratio stabilization at a new level with ± 50% variability over last 6 months.


Novartis
Confidential
Page 79
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.4
Appendix 4: Assessment of spondyloarthritis international 
society criteria for axial spondyloarthritis
ASAS criteria for classification of axSpA will be applied as defined by Sieper et al (2009).
Diagnosis of axial spondyloarthritis according to the assessment of 
spondyloarthritis international society classification criteria
Diagnosis of axSpA (either AS or nr-axSpA) according to ASAS axSpA classification criteria 
to be applied in patients with back pain for at least 3 months and age of onset < 45 years:

Sacroiliitis on imaging with ≥ 1 SpA feature or

HLA-B27 positive with ≥2 SpA features
Sacroiliitis on imaging

Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA 
(see Appendix 6)

Definite radiographic sacroiliitis according to the modified New York diagnostic criteria 
(van der Linden et al 1984) (see Appendix 5)
Spondyloarthritis features

IBP

Arthritis

Enthesitis (heel)

Uveitis

Dactylitis

Psoriasis

Crohn’s disease or colitis

Good response to NSAIDs

Family history for SpA

HLA-B27

Elevated C-Reactive Protein


Novartis
Confidential
Page 80
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.5
Appendix 5: Modified New York diagnostic criteria for ankylosing 
spondylitis
Patients with axSpA are classified as having AS, based on the fulfillment of the 1984 
modified New York diagnostic criteria (van der Linden et al 1984).
Clinical criteria for ankylosing spondylitis

Low back pain and stiffness for more than 3 months that improves with exercise, but is not 
relieved by rest

Limitation of motion of the lumbar spine in the sagittal and frontal planes

Limitation of chest expansion relative to normal values correlated for age and sex
Radiological criterion for ankylosing spondylitis

Sacroiliitis grade ≥ 2 bilaterally or grade 3–4 unilaterally
Definite AS if the radiological criterion is associated with at least one clinical criterion.


Novartis
Confidential
Page 81
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.6
Appendix 6: Definition of sacroiliitis on imaging
Sacroiliitis on magnetic resonance imaging
An MRI will be considered positive for sacroiliitis (active inflammatory lesions, “positive 
MRI”, MRI+) if the following characteristics are evident (Sieper et al 2009):

The presence of definite subchondral bone marrow edema/osteitis highly suggestive of 
sacroiliitis is mandatory

The presence of synovitis, capsulitis, or enthesitis only without concomitant subchondral 
bone marrow edema/osteitis is compatible with sacroiliitis but not sufficient for making a 
diagnosis of active sacroiliitis

Amount of signal required: if there is one signal (lesion) only, this should be present on at 
least two slices. If there is more than one signal on a single slice, one slice may be enough
Sacroiliitis on X-ray
Grading of radiographic sacroiliitis according to the New York diagnostic criteria 
(Bennett and Burch 1968):

Grade 0: normal

Grade 1: suspicious changes

Grade 2: minimal abnormality (small localized areas with erosion or sclerosis, without 
alteration in the joint width)

Grade 3: unequivocal abnormality - (moderate or advanced sacroiliitis with erosions, 
evidence of sclerosis, widening, narrowing, or partial ankylosis

Grade 4: severe abnormality (total ankylosis)


Novartis
Confidential
Page 82
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.7
Appendix 7: Spinal pain numerical rating scale
The spinal pain NRS is an 11-point scale to assess pain intensity in patients who are able to 
self-report. The patient is asked to answer 2 questions in order to make 2 pain ratings (point a 
number on NRS between 0 and 10), corresponding to the intensity of spinal pain experienced 
on an average during the previous week; the average of the 2 ratings is to be used to represent 
the patient’s level of pain.
Nocturnal back pain
Based on your assessment, please indicate what is the amount of back pain at night that you 
experienced during the last week?
NRS scale 0 to 10, no pain to unbearable pain
Total back pain
Based on your assessment, please indicate what is the amount of back pain at any time that 
you experienced during the last week?
NRS scale 0 to 10, no pain to unbearable pain


Novartis
Confidential
Page 83
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.8
Appendix 8: Bath ankylosing spondylitis disease activity index 
The BASDAI consists of a 0 through 10 scale (0 being no problem and 10 being the worst 
problem, captured as a continuous numerical rating scale), which is used to answer 6 
questions (pertaining to the 5 major symptoms of AS):
1. How would you describe the overall level of fatigue/tiredness you have experienced?
2. How would you describe the overall level of AS neck, back or hip pain you have had?
3. How would you describe the overall level of pain/swelling in joints other than neck, back, 
hips you have had?
4. How would you describe the overall level of discomfort you have had from any areas 
tender to touch or pressure?
5. How would you describe the overall level of morning stiffness you have had from the time 
you wake up?
6. How long does your morning stiffness last from the time you wake up?
To give each symptom equal weighting, the mean (average) of the 2 scores relating to 
morning stiffness (questions 5 and 6) is taken. The mean of questions 5 and 6 is added to the 
scores from questions 1-4. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 
BASDAI score. Scores of 4 or greater suggest suboptimal control of disease, and patients with 
scores of 4 or greater are usually good candidates for either a change in their medical therapy 
or for enrollment in clinical trials evaluating new drug therapies directed at AS. BASDAI is a 
quick and simple index (taking between 30 seconds and 2 minutes to complete).


Novartis
Confidential
Page 84
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.9
Appendix 9: Guidelines for administering the questionnaires for 
patient reported outcomes
Before trial start
Study coordinators should familiarize themselves with the PRO questionnaires in the trial and 
identify any items where a patient’s response might highlight issues of potential concern.
Before completion
1. Patients should be provided with the correct questionnaire at the appropriate visits and in 
the appropriate language
2. Patients should have adequate space and time to complete the forms
3. Questionnaire should be administered before the clinical examination
During completion
1. Administrator may clarify the questions but should not influence the response
2. Only one response for each question
3. Also see “Addressing Problems and Concerns”
After completion
1. Check for completeness and not for content (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)
2. Check for multiple responses that were made in error
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. Any person other than the designated study coordinator should provide no help to 
the patient. The coordinator should not influence patient responses. The study coordinator 
cannot translate the question into simpler language and has to be read verbatim.


Novartis
Confidential
Page 85
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
The patient wants someone else to complete the questionnaire(s)
In no case should the coordinator or anyone other than the patient provide responses to the 
questions. Unless specified in the study protocol, proxy data are not an acceptable substitute 
for patient self-report. Patients should be discouraged from asking a family member or friend 
for help in completing a questionnaire.
The patient does not want to finish completing the questionnaire(s)
If non-completion is a result of the patient having trouble understanding particular items, ask 
the patient to explain the difficulty. Re-read the question for them verbatim but do not 
rephrase the question. If the respondent is still unable to complete the questionnaire, accept it 
as incomplete. Thank the patient.
The patient is concerned that someone will look at his/her responses
Emphasize that all responses are to be kept confidential. Point out that their names do not 
appear anywhere on the questionnaire, so that their results will be linked with an ID number 
and not their name. Tell the patient that his/her answers will be pooled with other patients’ 
answers and that they will be analyzed as a group rather than as individuals. Tell the patient 
that completed forms are not routinely shared with treating staff and that their responses will 
only be seen by you (to check for completeness) and by the investigator. Any response that 
may directly impact on or reflect their medical condition (e.g. noting of severe depression) 
will be communicated by the coordinator to the physician.
The patient asks the meaning of a question/item
While completing the questionnaire, some patients might ask the meaning of specific items so 
that they can better understand and respond. If this happens, assist the patient by rereading the 
question for them verbatim. If the patient asks to interpret the meaning of an item, do not try 
to explain it, but suggest that he/she use his/her own interpretation of the question. Patients 
should answer the questions based on what they think the questions mean.
General information about all questionnaire(s)
All questionnaires have to be completed by the patients in their local languages using an 
electronic device. The questionnaires should be completed by the patients in a quiet area free 
from disturbance, and before any visit assessments. Patients should receive no help from 
family members; if questions cannot be answered alone (due to problems with reading or 
understanding), then the doctor or nurse should read the questions and record the patient’s 
responses without influencing their answers. The information provided is strictly confidential 
and will be treated as such. If a patient has missed a question or given more than one response 
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.


Novartis
Confidential
Page 86
Clinical Trial Protocol (Version 00)
Protocol No. CAIN457H3301
13.10
Appendix 10: ASAS recommendations for collecting, analyzing 
and reporting NSAID intake
Table 13-5
ASAD-NSAID equivalent score
NSAID
Dose comparable to 
150 mg diclofenac
Maximum dose used in 
AS
Consensus
Diclofenac
/
n=60*
150 (150-200)
150
Naproxen
n=57
1000 (1000-1000)
n=59
1000 (1000-1500)
n=47/50†
1000
Aceclofenac
n=15
200 (200-200)
n=14
200 (200-200)
n=29/29
200
Celecoxib
n=61
400 (300-400)
n=60
400 (400-400)
n=47/50
400
Etodolac
n=15
600 (400-800)
n=13
600 (600-600)
n=17/20
600
Etoricoxib
n=36
90 (90-90)
n=37
120 (90-120)
n=42/46
90
Flurbiprofen
n=13
200 (200-300)
n=13
300 (200-300)
n=15/18
200
Ibuprofen
n=54
2400 (1600-2400)
n=54
2400 (2400-2400)
n=39/45
2400
Indometacin
n=57
150 (100-150)
n=58
150 (150-200)
n=42/47
150
Ketoprofen
n=26
200 (200-200)
n=25
200 (200-300)
n=21/23
200
Meloxicam
n=58
15 (15-15)
n=55
15 (15-22.5)
n=42/48
15
Nimesulide
n=8
200 (200-200)
n=9
200 (200-200)
n=16/16
200
Phenylbutazone
n=28
400 (200-500)
n=28
400 (250-600)
n=25/28
400
Piroxicam
n=51
20 (20-20)
n=50
20 (20-40)
n=46/46
20
Tenoxicam
n=17
20 (20-20)
n=16
25 (20-40)
n=18/18
20
Source: Dougados et al 2011
Results of the survey evaluating the opinion of ASAS members about the comparable efficacy of each NSAID with 
150 mg of diclofenac. 
Values given are:
*first row, n-number of ASAS members giving an answer to the question;
second row, median dose in mg (tertiles)
† first row, n=number of ASAS members who have voted in favour of such a dose/the total number of ASAS 
members who have voted; second row, agreed dose.
AS, ankylosing spondylitis; ASAS, Assessment of Spondyloarthritis International Society; NSAID, non-steroidal 
anti-inflammatory drug

SAP_000.pdf: 
Clinical Development
AIN457/Secukinumab
CAIN457H3301 / NCT03136861
SKIPPAIN (Speed of onset of SecuKinumab-Induced relief 
from Pain in Patients with AxIal SpoNdyloarthritis)
A 24-week, randomized, double-blind, placebo-controlled, 
multicenter study to evaluate the efficacy and safety of 
secukinumab in controlling spinal pain in patients with 
axial spon.dyloarthritis
Statistical Analysis Plan (SAP)
Author:
Trial statistician,
Document type:
SAP Documentation
Document status:
Amendment v2
Release date:
29-MAY-2019
Number of pages:
41
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP
CAIN457H3301
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted 
(Current)
18-
May-
2018
CTT decided to modify 
various 
sections 
and 
related analysis
Some analysis added to 
exploratory 
endpoint. 
Analyses 
related 
to 
primary and secondary 
endpoint are modified. 
Overall safety set is 
included.
Overall 
SAP 
document 
is 
modified 
and 
hence impacted.
16-
Apr-
2019
To impute partial dates for 
calculation of duration 
since the subject has been 
identified for disease 
history
Added Medical History 
date of diagnosis 
imputation
Added 
new 
section 5.1.4
16-
Apr-
2019
Clarified that subjects 
who are re-assigned the 
treatment in 2nd period
are included in FAS-TP2
Revised FAS-TP2 
analysis set definition
2.2
29-
May-
2019
Impute partial CM and AE 
end date
Added imputation rule 
for CM end date and AE 
end date
Added
text for 
the 
same 
in 
section 5.1.2 & 
5.1.3


Novartis
For business use only
Page 3
SAP
CAIN457H3301
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................12
2.1
Data analysis general information .........................................................................12
2.1.1
General definitions................................................................................12
2.1.2
Visits windows......................................................................................13
2.1.3
Multiple assessments within visit windows..........................................15
2.2
Analysis sets ..........................................................................................................15
2.2.1
Subgroup of interest ..............................................................................16
2.3
Patient disposition, demographics and other baseline characteristics ...................16
2.3.1
Patient disposition.................................................................................16
2.3.2
Patient demographic and other baseline characteristics........................17
2.3.3
Medical history......................................................................................17
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................18
2.4.1
Study treatment / compliance................................................................18
2.4.2
Prior, concomitant and post therapies...................................................19
2.5
Analysis of the primary objective..........................................................................19
2.5.1
Primary endpoint...................................................................................19
2.5.2
Statistical hypothesis, model, and method of analysis..........................20
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Sensitivity analyses ...............................................................................21
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
2.7.2
Statistical hypothesis, model, and method of analysis..........................21
2.7.3
Handling of missing values/censoring/discontinuations.......................22
2.8
Safety analyses.......................................................................................................22
2.8.1
Adverse events (AEs)............................................................................22
2.8.2
Deaths....................................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................27
2.9
Pharmacokinetic endpoints....................................................................................27


Novartis
For business use only
Page 4
SAP
CAIN457H3301
2.10
PD and PK/PD analyses.........................................................................................27
2.11
Patient-reported outcomes .....................................................................................28
2.12
Biomarkers.............................................................................................................29
2.13
Other Exploratory analyses....................................................................................29
2.14
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
4
Change to protocol specified analyses ..............................................................................31
5
Appendix ...........................................................................................................................31
5.1
Imputation rules.....................................................................................................31
5.1.1
Study drug.............................................................................................31
5.1.2
AE date imputation ...............................................................................31
5.1.3
Concomitant medication date imputation .............................................33
5.2
AEs coding/grading ...............................................................................................35
5.3
Laboratory parameters derivations ........................................................................35
5.4
Statistical models...................................................................................................36
5.4.1
Primary analysis....................................................................................36
5.4.2
Key secondary analysis.........................................................................37
5.5
Rule of exclusion criteria of analysis sets..............................................................37
6
Reference...........................................................................................................................41


Novartis
For business use only
Page 5
SAP
CAIN457H3301
List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
ADR
Adverse Drug Reaction
ALP
Alkaline Phosphatase
ALT/SGPT
Alanine Aminotransferase/Serum Glutamic Pyruvic Transaminase
ANOVA
Analysis of Variance
anti-TNFα
anti-Tumor Necrosis Factor alpha
AS
Ankylosing Spondylitis
ASAS
Assessment of SpondyloArthritis International Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST/SGOT
Aspartate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase
ATC
Anatomical Therapeutic Classification
axSpA
axial SpondyloArthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BMI
Body mass index
bpm
Beats per minute
CD
Cluster of Differentiation
CI
Confidence interval
CMD
Concomitant medication
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-reactive protein
CSR
Clinical Study report
DAR
Drug administration record
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
FACIT-Fatigue©
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS-TP1
Full Analysis Set for Treatment Period 1
FAS-TP2
Full Analysis Set for Treatment Period 2
hCG
Human Chorionic Gonadotropin
HLA-B27
Human Leukocyte Antigen-B27
HLT
High Level Term
HR-QoL
Health-related quality of life
ICF
Informed Consent Form
IEC
Independent Ethics Committee
i.v.
Intravenous
LFT
Liver Function Test (raised serum transaminase and/or bilirubin levels)
MCII
Minimal Clinically Important Improvement
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed Model Repeated Measures
MRI
Magnetic resonance imaging
NMQ
Novartis MedDRA Query


Novartis
For business use only
Page 6
SAP
CAIN457H3301
NSAID(s)
Nonsteroidal Anti-Inflammatory Drug(s)
NRS
Numerical Rating Scale
PASS
Patient Accepted Symptoms State
PD
Protocol deviation
PFS(s)
PreFilled Syringe(s)
PRO
Patient Reported Outcome
PT
Preferred Term
RAN
Randomized set
SAE
Serious Adverse Event
SAF-TP1
Safety Set for Treatment Period 1
SAF-TP2
Safety Set for Treatment Period 2
SAP
Statistical Analysis Plan
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
SpA
SpondyloArthritis
TB
Tuberculosis
TBL
Total Bilirubin
TNF
Tumor Necrosis Factor
TNFα-IR
Tumor Necrosis Factor α Inadequate Responder
ULN
Upper Limit of Normal


Novartis
For business use only
Page 7
SAP
CAIN457H3301
1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses,
which will be used in the phase IIIb clinical trial CAIN457H3301.
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical study 
report.
Data will be analyzed by Novartis using statistical software SAS version 9.4 according to the 
data analysis section 9 of the study protocol, which is available in Appendix 16.1.1 of the 
CSR (clinical study report). That statistical methodology is described below and any
deviations from the protocol are documented. Additional detailed information regarding the
analysis methodology is contained in the Appendix section 16.1.9 of CSR.
Please refer to the following document:
Clinical Protocol CAIN457H3301
1.1
Study design
This is a 24-week, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
the efficacy and safety of secukinumab in controlling spinal pain in patients with axSpA. The 
study will consist of 2 treatment periods: a double-blind, placebo-controlled period from 
Baseline to Week 8 (i.e. Treatment Period 1) and a double-blind secukinumab treatment period 
from Week 8 to Week 24 (i.e. Treatment Period 2). At Baseline, patients will be randomized to 
either secukinumab 150 mg or placebo. At Week 8, patients will be re-randomized and re-
assigned respectively to 1 of 5 treatment arms to receive either secukinumab 150 mg or 
secukinumab 300 mg.
The schematic of study design is given in Figure 1.1 below.
Planned number of patients and randomization
It is intended that a total of 352 patients (264 in secukinumab 150 mg group and 88 in the 
placebo group) will be recruited to compensate dropouts and protocol violators.
Patient eligibility criteria will be assessed during the Screening Period, which will occur for up 
to 10 weeks prior to randomization.
Treatment Period 1
At Baseline, patients whose eligibility is confirmed will be randomized to receive double-blind 
treatment with either secukinumab 150 mg or placebo (3:1) in Treatment Period 1 (Baseline to 
time of study drug administration at Week 8):

Group A: secukinumab 150 mg (1 x 1.0 mL) s.c. administered at Baseline, Week 1, 2, 
3 and 4

Group B: placebo (1 x 1.0 mL) s.c. administered at Baseline, Week 1, 2, 3 and 4


Novartis
For business use only
Page 8
SAP
CAIN457H3301
Secukinumab 150 mg and matching placebo will be provided as 1.0 mL pre-filled syringes 
(PFSs).
On each treatment day during Treatment Period 1, one s.c. injection with either secukinumab 
150 mg or placebo will be administered via PFSs.
Treatment Period 2
At Week 8, patients will enter Treatment Period 2 (Week 8 to Week 24). Patients randomized 
to Group A (secukinumab 150 mg) at Baseline will be assessed for the achievement of spinal 
pain NRS score and will be classified as responders (spinal pain NRS score < 4) or non-
responders (spinal pain NRS score ≥ 4). Responders will be re-assigned to 1 treatment arm 
(Arm A1) to continue double-blind treatment with secukinumab 150 mg every 4 weeks from 
Week 8 to Week 24 (last dose administered at Week 20). Non-responders will be separately re-
randomized to 1 of 2 arms to receive double-blind treatment with either secukinumab 150 mg 
or secukinumab 300 mg every 4 weeks starting at Week 8 up to Week 24 (last dose administered 
at Week 20).
Patients on secukinumab 150 mg who achieve spinal pain NRS score < 4 at Week 8 will be re-
assigned to continue secukinumab 150 mg every 4 weeks (Arm A1)

Arm A1: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered 
at Week 8, 12, 16 and 20
Patients on secukinumab 150 mg who do not achieve spinal pain NRS score < 4 at Week 8 will 
be re-randomized to continue secukinumab 150 mg every 4 weeks (Arm A2) or to escalate to 
secukinumab 300 mg every 4 weeks (Arm A3):

Arm A2: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered at 
Week 8, 12, 16 and 20

Arm A3: secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20
At Week 8, patients randomized to Group B (placebo) at Baseline will be re-randomized to 
either secukinumab 150 mg every 4 weeks (Arm B1) or secukinumab 300 mg every 4 weeks 
(Arm B2)

Arm B1: secukinumab 150 mg (1 x 1.0 mL) plus placebo (1 x 1.0 mL) administered at 
Week 8, 12, 16 and 20

Arm B2: secukinumab 300 mg (2 x 1.0 mL) administered at Week 8, 12, 16, and 20
During the study, patients will be required to self-administer secukinumab or placebo at all 
study visits and at home at Week 16.
On each treatment day during Treatment Period 2, two s.c. injections will be administered via 
PFSs either as 1 injection of secukinumab 150 mg and 1 injection of placebo, or 2 injections of 
secukinumab 150 mg. This is necessary to maintain the blind since secukinumab is supplied in 
1.0 mL PFSs each containing 150 mg secukinumab, i.e. secukinumab 150 mg is supplied as 1 
PFS and secukinumab 300 mg as 2 PFSs. Placebo to secukinumab will be supplied in 1.0 mL 
PFSs to match the active drug.


Novartis
For business use only
Page 9
SAP
CAIN457H3301
Figure 1-1  Study design
Patients will be stratified at baseline based on whether they are naïve to TNFα inhibitors or had an 
inadequate response (including intolerance) to TNFα inhibitors.
R+ = responder, i.e. patient with spinal pain NRS score < 4
R- = non-responder, i.e. patient with spinal pain NRS score ≥ 4
axSpA=axial spondyloarthritis, BSL=baseline, PE=primary endpoint, SE=secondary endpoint, 
TNFα=tumor necrosis factor alpha, TNFα-IR=tumor necrosis factor α inadequate responder, 
W=week
Primary analysis time point
The primary analysis will be performed based on Week 8 assessment data. Average spinal pain 
NRS score will be considered as primary endpoint and will be analyzed for all applicable 
variables.
Interim analyses
No interim analysis is planned for this study.
The statistical analysis will be performed after all the patients have completed the study. Once 
all the data are complete and clean, the database will be locked and analyzed.
1.2
Study objectives and endpoints
Table 1.2-1
Objectives and related endpoints
Objective
Endpoint
Primary objective
Superiority of secukinumab 150 mg compared 
to placebo in achieving a spinal pain score < 4 
on a 0-10 NRS at Week 8.
Proportion of patients with a spinal pain 
NRS score < 4 at Week 8 in Group A 
compared to Group B.


Novartis
For business use only
Page 10
SAP
CAIN457H3301
Secondary objectives
Superiority of secukinumab 150 mg compared 
to placebo in achieving a Bath Ankylosing 
Spondylitis Disease Activity Index (BASDAI) 
score < 4 at Week 8.
Proportion of patients with a BASDAI score 
< 4 at Week 8 in Group A compared to 
Group B.
Exploratory objectives
Proportion of patients achieving a spinal pain
score < 4 on a 0-10 NRS at Week 1, 2, 3 and
4 with secukinumab 150 mg compared to
placebo.
Proportion of patients with a spinal pain 
NRS score < 4 in Group A compared to 
Group B at Week 1, 2, 3 and 4.
Proportion of patients in each treatment arm
achieving a spinal pain score < 4 on a 0-10
NRS at Week 24.
Proportion of patients with a spinal pain 
NRS score < 4 in Arm A1, Arm A2 vs Arm 
A3, and Arm B1 vs Arm B2 at Week 24.
Proportion of patients in each treatment arm 
achieving BASDAI score < 4 at Week 24.
Proportion of patients achieving a BASDAI
score < 4 in Arm A1, Arm A2 vs Arm A3, 
and Arm B1 vs Arm B2 at Week 24.
Proportion of patients in each of the treatment 
arms 
achieving 
Ankylosing 
Spondylitis 
Disease Activity Score (ASDAS) score < 2.1
at Week 8 and Week 24.
Proportion of patients with a ASDAS score
< 2.1 in Group A compared to group B at 
Week 8 and in Arm A1, Arm A2 vs Arm  
A3,
and Arm B1 vs Arm B2 at Week 8 and 
Week 24.
Proportion of patients in each treatment arm
achieving ASDAS score < 1.3 at Week 8 and
Week 24.
Proportion of patients with a ASDAS score
< 1.3 in Group A compared to Group B at
Week 8 and in Arm A1, Arm A2 vs Arm 
A3, and Arm B1 vs Arm B2 at Week 8 and
Week 24.
Mean change from Baseline in functional 
assessment of chronic illness therapy-fatigue 
(FACIT-Fatigue©) score in patients on 
secukinumab 150 mg compared to placebo at 
Week 8.
FACIT-Fatigue©
score 
in 
Group 
A 
compared to Group B at Week 8.
Mean change from Baseline in FACIT-
Fatigue© score in each of treatment arm at 
Week 24.
FACIT-Fatigue© score in Arm A1, Arm A2 
vs Arm A3, and Arm B1 vs Arm B2 at 
Week 24.
Proportion of patients in Arm A1 who have 
pain flares defined as NRS score > 6 at Week 
12 or Week 24.
Proportion of patients who have pain flares,
defined as NRS score > 6, in Arm A1 at 
Week 12 or Week 24.
Proportion of patients achieving a satisfactory 
Patient Acceptable Symptom State (PASS) at 
Week 1, 2, 3, 4 and 8 with secukinumab 150 
mg compared to placebo.
Proportion 
of 
patients 
achieving 
a 
satisfactory PASS at Week 1, 2, 3, 4 and 8 
in Group A compared to Group B.


Novartis
For business use only
Page 11
SAP
CAIN457H3301
Proportion of patients in each of treatment arm 
achieving a satisfactory PASS at Week 12, 
Week 20 and Week 24.
Proportion 
of 
patients 
achieving 
a 
satisfactory PASS at Week 12, Week 20 and 
Week 24 in Arm A1, Arm A2 vs Arm A3, 
and Arm B1 vs Arm B2.
Spinal pain NRS score according to previous 
exposure to tumor necrosis factor (TNF) 
inhibitors at Week 1, 2, 3, 4, 8, 12 and 24
Proportion of patients achieving a spinal 
pain score < 4 for TNF-naïve patients 
compared to TNFα-IR patients at Week 1, 
2,3, 4, 8, 12 and Week 24
Proportion of patients who responded to 
secukinumab 150 mg at Week 8 (i.e. spinal 
pain score < 4 on a 0-10 NRS) maintaining a 
response at Week 24.
Proportion of patients with spinal pain score 
< 4 on a 0-10 NRS at Week 8 maintaining a 
spinal pain score < 4 at Week 24.
Proportion 
of 
patients 
achieving 
an 
improvement in ASAS health index with 
secukinumab 150 mg compared to placebo at 
Week 8.
Proportion 
of 
patients 
achieving 
an 
improvement in ASAS health index with 
secukinumab 150 mg compared to placebo 
at Week 8.
Proportion 
of 
patients 
achieving 
an 
improvement in ASAS health index in each 
treatment arm at Week 24.
Proportion 
of 
patients 
achieving 
an 
improvement in ASAS health index in each 
treatment arm at Week 24.
ASAS health index at Week 8 and Week 24.
Mean ASAS health index score in each
treatment arm at Week 8 and Week 24
Change from baseline in total spinal pain NRS 
score at all time points.
Total spinal pain NRS score in each 
treatment arm at all time points.
Change from baseline in total BASDAI score
at all time points.
Total BASDAI score in each treatment arm 
at all time points.
ASDAS-CRP at Week 8 and Week 24.
Mean ASDAS-CRP in each treatment arm 
at Week 8 and Week 24.
 
Safety and tolerability of secukinumab
150 mg and 300 mg over the study period.
Safety and tolerability, as measured by 
frequency and severity of adverse events 
and changes in laboratory values of interest 
for secukinumab 150 mg and placebo
(Baseline to Week 8) and for secukinumab 
150 mg and 300 mg (Week 8 to Week 24).


Novartis
For business use only
Page 12
SAP
CAIN457H3301
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis and/or by the designated CRO (clinical research 
organization). It is planned that the data from all centers that participate in this protocol will be 
used for analysis. Analysis datasets and statistical outputs will be produced using the most 
recent SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global 
programming & statistical environment (GPS).
Summary statistics for continuous variables will include number of patients (n), mean, standard 
deviation, minimum, lower quartile, median, upper quartile, maximum. Summary statistics for 
discrete variables will be presented in the number and percent of patients in each category. 
Summary statistics will also be presented graphically wherever applicable.
The two-sided p-values and confidence interval (CI) will be presented.
Data analyses will be presented by treatment group for both period I and period II separately. 
Efficacy and safety data for the placebo-controlled period I will be presented by the following 
2 treatment groups of A and B whereas for period II the data will be presented for 5 treatment 
groups A1, A2, A3, B1 and B2. 
The analysis will be conducted on all patients’ data at the time the trial ends (Week 24).
Comparative efficacy data
Comparative efficacy analyses (i.e. inferential efficacy comparisons with placebo) will focus 
on the Treatment Period 1, when active drug and the placebo are given in a manner suitable for 
making comparisons (i.e., first 8 weeks of treatment). Comparative efficacy will be performed 
based on the FAS-TP1 population using the randomized treatment for Treatment Period 1. After 
week 8 till week 24, the efficacy endpoints will be summarized descriptively or otherwise 
specified using inferential analysis, on the FAS population using the randomized/re-assigned
treatment for Treatment Period 2.
2.1.1
General definitions
Study treatment: Study treatment refers to:  
Secukinumab 150 mg provided in 1 ml PFS or secukinumab placebo provided in 1 ml PFS.
Study treatment start and end date: Study treatment start date is defined as the first date,
when a non-zero dose of study drug is administered and recorded on the Drug Administration 
Record (DAR) CRF page. Similarly, study drug end date is defined as the last date, when a non-
zero dose of study drug is administered and recorded on the DAR CRF page of the core study.
Study day: Study day will be calculated as (event date – study drug start date + 1 day) for 
events that occurred on or after study drug start date (e.g., visit, lab samples, AEs). For events 
prior to study drug start date (e.g., time of diagnosis), study day will be negative and calculated 
as (event date – study drug start date). Note that study drug start date is study day 1 and the day 
before study drug start date is study day -1 (i.e. no study day 0).


Novartis
For business use only
Page 13
SAP
CAIN457H3301
Due to the study drug dosing schedule, one month will be considered as 28 days. However, for 
“time since event” data (e.g., medical history), one month will be considered as 365.25/12 days 
for events that occurred prior to study Day 1. Time from events prior to the start of study drug, 
e.g., time since diagnosis, is calculated as the difference between the start date of study drug 
and the date of prior event.
Note that, the first dose day is Day 1, and the day before the first dose day is counted as Day -
1 (not Day 0).
Baseline and post baseline: In general, a baseline value refers to the last measurement made 
prior to administration of the first dose of study treatment. A post-baseline value refers to a 
measurement taken after the first dose of study treatment.
Treatment Period: There are 2 treatment periods for this study defined as:
Treatment Period 1 is defined as an 8-week placebo-controlled, double-blind treatment period 
starting from baseline till Week 8. Assessments of Week 8 are included in TP1 whereas 
administration of study drug at week 8 will be a part of TP2. Week 8 is the last visit of TP1 
for all assessments except drug intake.
Treatment Period 2 is a 16 week double-blinded, active treatment period starting from Week 8
till Week 24 for administration of study drug. Week 8 assessments are considered as the baseline 
values for assessments during TP2. 
Lost to follow up: The patients whose study completion status is unclear because they fail to 
appear for study visits without stating an intention to withdraw.
On-treatment period: The period where the patients are exposed to the study treatment. For 
this study, the treatment phase consists of 24 weeks. For this study, the treatment phase consists 
of 8 weeks of on-treatment for period I (for treatment group A or group B) for secukinumab or 
placebo respectively, and 16 weeks of on-treatment for period II (for treatment group A1, A2, 
A3, B1 and B2) for secukinumab with 150 mg or 300 mg.
2.1.2
Visits windows
Visit windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows are created in SAP 
to cover the complete range of days within the study.  The visit windows are shown in Table 2-
1. These apply to measurements taken at every visit. For assessments collected less often,
different visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 8. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below.
Of note, subjects are allowed to have gaps in visits.


Novartis
For business use only
Page 14
SAP
CAIN457H3301
Table 2-1
Assessment windows for scheduled visits 
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71**
Week 12
12
85
Day 72-113
Week 20
20
141
Day 114-151
Week 24
24
162
>=152 Days
* Baseline measurement before the first drug administration for safety assessments and before 
the randomization for efficacy assessments. For efficacy visit windows, refer to date of 
randomization.
** For primary endpoint analysis, data will be considered as Week 8 data, if Week 8 dose 
administration was done on or after the assessment date. 
For parameters, which are not collected at every visit (e.g., FACIT-Fatigue©, ASAS Health 
Index), visit windows defined in Table 2-1 will be combined. For example, if a parameter is 
measured at Week 12 and Week 24 only, Week 12 visit window will extend from Day 2 to Day 
113 (combining Week 1 to Week 12 visit windows), Week 24 will extend from Day 114
to >=152 days (combining Week 20 to Week 24). If more than one assessment falls into the 
interval, the rules defined in Section 2.1.3 below are applied.
Table 2-2a
Assessment windows for scheduled visits of Exposure Data
The administration of study drug at week 16 is not in relation to a study visit. For exposure data, 
a specific assessment window for week 16 is used in order to account for the home 
administration at week 16.
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1*
Week 1
1
8
Day 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8
8
57
Day 44-71
Week 12
12
85
Day 72-99
Week 16
16
113
Day 100-127
Week 20
20
141
>= 128 Days


Novartis
For business use only
Page 15
SAP
CAIN457H3301
2.1.3
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (see Table 
2-1).
For baseline assessment definition, see Section 2.1.1. For post-baseline visit windows, the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined.

in case qualitative variables are based on quantitative variables, e.g. spinal pain NRS
response, the visit will be assigned to the quantitative variable, and this visit will be used 
for the derived qualitative variable. 
Table 2-3
Rules for selecting values for analysis
Timing of measurement
Type of data
Rule
Baseline
All data
See  Section 2.1 Data analysis 
general information
Post-baseline efficacy
All data
Cases where the same 
parameter is recorded
more than once on the same 
date will be handled
as follows:
If time of completion exists the 
earliest
measurement will be used;
If time does not exist the 
measurement
from the lowest CRF visit 
number will be
used.
2.2
Analysis sets
The following analysis sets will be used in this study:
The Enrolled Set will include all patients, who provided informed consent.
The Randomized Set will consist of all patients, who were randomized into this study at 
Baseline. Mis-randomized patients will not be included in this analysis set.
The Safety Set for Treatment Period 1 (SAF-TP1) will consist of all patients, who received 
at least 1 dose of study treatment during this treatment period. Data will be analyzed according 
to the treatment actually received.


Novartis
For business use only
Page 16
SAP
CAIN457H3301
The Safety Set for Treatment Period 2 (SAF-TP2) will consist of all patients, who received 
at least 1 dose of study treatment during this treatment period. Data will be analyzed according 
to the treatment actually received.
The Safety set (SAF) will consists of all patients, who received at least one dose of study 
treatment. To analyze entire study period safety assessments, this dataset will be used.
The Full Analysis Set for Treatment Period 1 (FAS-TP1) will consist of all patients, who 
were randomized into this study at Baseline and received at least 1 dose of study treatment 
during this treatment period. Data will be analyzed according to the treatment assigned at 
randomization.
The Full Analysis Set for Treatment Period 2 (FAS-TP2) will consist of all patients, who 
were re-randomized or re-assigned at Visit 7 (Week 8) and received at least 1 dose of study 
treatment during this treatment period. Data will be analyzed according to the treatment 
assigned at randomization.
2.3
Patient disposition, demographics and other baseline 
characteristics
Summary statistics will be presented for continuous demographic and baseline characteristics 
for each treatment group and for all patients in the randomized set. The number and percentage 
of patients in each category will be presented for categorical variables for each treatment group 
and for all patients.
2.3.1
Patient disposition
The number and percentage of patients screened will be presented. In addition, the reasons for 
screen failures will be provided. 
The number and percentage of patients in the randomized set, who enrolled, and who 
completed the treatment period and who discontinued the study prematurely (including the 
primary reason for discontinuation), will be presented at the end of each treatment period 
(Week 8 and Week 24), if appropriate, for each treatment group and all patients. 


Novartis
For business use only
Page 17
SAP
CAIN457H3301
2.3.2
Patient demographic and other baseline characteristics
The following demographic and baseline variables, if collected, will be summarized:
Continuous variables:

Age (which is derived from date/year of birth and the screening assessment date)

Height

Weight

Body mass index (BMI) = (body weight in kilograms) / (height in meters)2

For BMI, height and body weight used is the last value prior to randomization. If there 
is no weight recorded prior to taking of study drug, BMI will be missing.
Categorical variables:

Age categories (<=30, >30-<55 and >=55)

Sex

Race

Ethnicity

Source of patient referral
Baseline disease characteristics will also be summarized for the following variables:

History of axSpA including time (months) since first diagnosis of axSpA, time since 
first signs and symptoms, previous treatments of axSpA and reasons for 
discontinuation of these treatments.

Smoking status at baseline

HLA-B27 status

Spinal pain assessment on NRS, BASDAI, PASS, ASDAS, Patient’s global 
assessment of disease activity, FACIT-Fatigue© and ASAS health index.
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all patients (total) in the randomized set. The number and 
percentage of patients in each category will be presented for categorical variables for each 
treatment group and all patients (total) in the randomized set.
Baseline disease characteristics QuantiFERON TB-Gold test and electrocardiogram related 
results will be listed only.
2.3.3
Medical history
Relevant medical history and current medical conditions will be summarized by system organ 
classes (SOC) and preferred terms (PT) of the latest version of MedDRA dictionary. Other 
relevant baseline information will be listed and summarized using descriptive statistics, as 
appropriate.  


Novartis
For business use only
Page 18
SAP
CAIN457H3301
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Study Treatment
The summaries by treatment will be performed by the actual treatment received (as follows) for 
each treatment period.
Treatment group for period I:

Group A: AIN457 150 mg

Group B: Placebo
Treatment group for period II:

Arm A1: AIN457 150 mg

Arm A2: AIN457 150 mg

Arm A3: AIN457 300 mg

Arm B1: AIN457 150 mg

Arm B2: AIN457 300 mg
The analysis of study treatment data will be based on the safety set for period I, period II and 
the entire treatment period separately. The number of active and placebo injections will be 
summarized by treatment group up to Week 8, the number of double blind injections will be 
summarized by treatment group from Week 8 to Week 24.
Rescue medication
Not applicable.
Duration of exposure
The duration of exposure to study treatment will be summarized by treatment group. In 
addition, the number and percentage of patients with cumulative exposure levels (e.g. any 
exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, ≥ 8 weeks, etc.) will be presented.
Duration of exposure for secukinumab groups will be defined as the time from first dose of 
study treatment to the time of treatment end for each treatment period. Duration of exposure 
for the placebo group will be defined as the time from first dose of placebo treatment to the 
time of treatment end in treatment period 1 and the time from first dose of active treatment to 
the time of treatment end in treatment period 2.
For patients who discontinue, this will be the patient’s last visit in the corresponding treatment 
period.
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100


Novartis
For business use only
Page 19
SAP
CAIN457H3301
The analyses of duration of exposure described above will be done for both the study treatment 
periods.
Compliance
Compliance will be calculated based on documented study drug administrations and syringe 
counts and displayed by treatment group. 
Compliance is expected to be 100%, unless temporary interruption is needed for safety reasons. 
Compliance will also be assessed by a Novartis monitor using information provided by the 
authorized site personnel.
Compliance (%) = 100*(total no of injections administered)/ (no. of injections prescribed).
Compliance for entire treatment period will  be based on active treatment exposure.
2.4.2
Prior, concomitant and post therapies
Prior and concomitant therapies
Prior and concomitant medications will be summarized in separate tables by treatment group. 
Prior medications are defined as treatments taken and stopped prior to first dose of study
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment and the date of the last study visit will be a concomitant medication, including those, 
which were started pre-baseline and continued into the period where study treatment is 
administered.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number 
and percentage of patients receiving at least one treatment of a particular ATC code and at 
least one treatment in a particular anatomical main group.
Significant prior and concomitant surgeries and procedures will be summarized by primary 
system organ class and MedDRA preferred term.
The number and percentage of patients receiving prior and concomitant spondyloarthritis 
therapy will be presented by randomized treatment group as well as the reasons for stopping 
their therapies (primary lack of efficacy, secondary lack of efficacy, lack of tolerability, 
other).
Prior or concomitant medication will be identified by comparing recorded or imputed start 
and end dates of medication taken to the reference start date. 
2.5
Analysis of the primary objective
The primary objective is to assess the superiority of secukinumab 150 mg compared to placebo 
in achieving a spinal pain score < 4 on a 0-10 NRS at Week 8.
2.5.1
Primary endpoint
The primary efficacy endpoint is the proportion of patients with a response of spinal pain 
NRS score < 4 in secukinumab 150 mg s.c. and placebo at Week 8. 


Novartis
For business use only
Page 20
SAP
CAIN457H3301
The analysis of the primary variable will be based on the FAS-TP1 patients.
2.5.2
Statistical hypothesis, model, and method of analysis
The null hypothesis to be rejected is that the odds of response at Week 8 are equal in both 
treatment groups. The corresponding alternative hypothesis is that the odds of response at Week 
8 are higher under secukinumab compared to placebo.
Let pj denote the proportion of responders at Week 8 for treatment group j, j=0, 1, where

0 corresponds to placebo

1 corresponds to secukinumab
In statistical terms, the following hypothesis will be tested:
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus HA: (p1 / (1- p1)) / (p0 / (1- p0)) ≠1
In other words,
HA: The odds ratio of achieving a response at Week 8 for secukinumab vs. placebo is different 
from 1.
The primary analyses will be conducted via logistic regression model with treatment, country 
and the stratification factor of prior exposure to TNF inhibitors (naïve/ inadequate responders 
to TNFα inhibitors) as factor. The Odds ratio, 95% confidence interval (CI) and p-value will be 
presented comparing secukinumab 150 mg treatment group to placebo group at Week 8.
The null hypothesis of equal odds will be rejected if the 2-sided p-value from the logistic 
regression model for the factor “treatment” is < 0.05; however, superiority of secukinumab will 
be claimed only if the direction is correct, i.e. if the odds of response are larger under 
secukinumab.
Summary statistics will also be reported for each treatment group and by visit. Graphical 
representation will also be performed.
Grouping of countries: Due to the small number of subjects in some of the countries, the below
mentioned countries will be grouped together to perform inferential analysis. The basis of 
grouping is a similar medical practice and geographical proximity in these countries:
1) Ireland & Great Britain
2) Italy, Spain & Croatia
3) Switzerland & Belgium 
4) Finland & Sweden 
5) Lithuania, Latvia & Estonia
If the grouping of countries does not allow proper analysis and if there are any challenges in 
model convergence, covariate “country” will be excluded from model.
2.5.3
Handling of missing values/censoring/discontinuations
If a patient has no value at Week 8, the missing value will be imputed as non-responders.
Average NRS spinal pain score will be calculated only if total and nocturnal pain score are non-
missing.


Novartis
For business use only
Page 21
SAP
CAIN457H3301
2.5.4
Sensitivity analyses
The average spinal pain and raw (total and nocturnal spinal pain separately) NRS scores will be 
analyzed using a repeated measures analysis of variance (ANOVA) model. The model will 
include the same factors as the logistic model of primary analysis plus the respective baseline 
score as a covariate. Analysis visit will be used as repeat factor.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary efficacy objective(s)
The secondary objective is to assess the proportion of patients with a BASDAI score < 4 at 
Week 8 of secukinumab 150 mg compared to placebo. The secondary endpoint will be analyzed 
analogous to the primary endpoint. The secondary endpoint will be included in a confirmatory 
testing strategy, it will be tested hierarchically after the primary endpoint.
2.7.1
Secondary endpoints
The secondary efficacy endpoint is the proportion of patients with a response of BASDAI score 
< 4 in secukinumab 150 mg and placebo at Week 8. 
The analysis of the secondary variable will be based on the FAS-TP1 patients.
2.7.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis for BASDAI score < 4 being tested is that the odds of response at 
Week 8 are equal in the secukinumab 150 mg treatment group versus placebo group.
Let pj denote the proportion of responders at Week 8 for treatment group j, j=0, 1, where

0 corresponds to placebo

corresponds to secukinumab
In statistical terms, the following hypothesis will be tested:
H0: (p1 / (1- p1)) / (p0 / (1- p0)) = 1 versus HA: (p1 / (1- p1)) / (p0 / (1- p0)) ≠1
In other words,
HA: The odds ratio of achieving a response at Week 8 for secukinumab vs. placebo is different 
from 1.
The secondary analyses will be conducted analogous to the primary analyses, i.e., via logistic 
regression model with treatment, country and the stratification factor of prior exposure to TNF 
inhibitors (naïve/ inadequate responders to TNFα inhibitors) as factor. The Odds ratio, 95% 
confidence interval (CI) and p-value will be presented comparing secukinumab 150 mg 
treatment group to placebo group at Week 8. Confirmatory evidence for the superiority of 
secukinumab with respect to the secondary endpoint will be claimed only if the 2-sided p-value 
from the logistic regression model for the factor “treatment” is < 0.05 and if the direction is 
correct, i.e. if the odds of response are larger under secukinumab and if the superiority of 
secukinumab with respect to the primary endpoint has already been demonstrated.


Novartis
For business use only
Page 22
SAP
CAIN457H3301
Summary statistics will also be reported for each treatment group and by visit. Graphical 
representation will also be performed.
2.7.3
Handling of missing values/censoring/discontinuations
If a patient has no value at Week 8, the missing value will be imputed as non-responders.
       BASDAI score will be calculated based on the average of the non-missing answers available.  
2.8
Safety analyses
All the safety analysis will be performed on the Safety Sets for period I and period II 
separately and also for entire treatment period, where applicable. Summaries will be 
performed separately for period I (from baseline to Week 8) and period II (from dosing at 
Week 8 to Week 24).
The safety follow-up will be carried forward until 12 weeks after the last study treatment. The
analyses of the follow-up period will be consolidated to summaries for treatment-emergent
adverse events, and serious adverse events to Treatment Period 2.
Safety analyses will be performed on treatment received or actual treatment as described
below:
The actual treatment or treatment received for summaries of safety data will differ to the
treatment assigned at randomization only, if a subject received the wrong treatment during the
entire study.
For those patients who received erroneously at least once, the wrong treatment (not the correct 
one at randomization) an additional AE listing will be prepared displaying which events 
occurred after the treatment errors and the relationship with study drug.
2.8.1
Adverse events (AEs)
Summary tables for adverse events (AEs) will include only the treatment-emergent AEs i.e. 
events that started after the first dose of study treatment or events present prior to the first 
dose of study treatment but increased in severity based on preferred term until 12 weeks after 
last dose of study treatment.
The treatment-emergent adverse events will be summarized by system organ class and 
preferred term, severity (mild, moderate, severe), type of adverse event, relation to study 
treatment. If a patient reported more than one AE with the same preferred term, the AE with 
the greatest severity will be presented. If a patient reported more than one AE within the same 
primary system organ class, the patient will be counted only once with the greatest severity at 
the system organ class level, where applicable.
For the reporting requirements of ClinicalTrials.gov and EudraCT, two required tables on 
<on-treatment/treatment emergent> adverse events which are not serious adverse events with 
an incidence greater than 2% and on <on-treatment/treatment emergent> SAEs and SAEs 
suspected to be related to study treatment will be provided by SOC system organ class and PT 
preferred term on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:


Novartis
For business use only
Page 23
SAP
CAIN457H3301
•         a single occurrence will be counted if there is ≤1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•         more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For calculating the frequencies, the presence of at least one SAE / SAE suspected to be related 
to study treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap 
block, if at least one SAE is occurring, then one occurrence is calculated for that SAE.
The following adverse event summaries will be produced by treatment for Safety Set:

Adverse events (overall and severe), regardless of study drug relationship by primary 
system organ class and preferred term

Adverse events, regardless of study drug relationship by primary system organ class and 
preferred term and severity 

Adverse events (overall and severe), with suspected study drug relationship by primary 
system organ class and by preferred term 

Serious adverse events (overall and severe), regardless of study drug relationship, by 
primary system organ class and preferred term

Serious adverse events (overall and severe), with suspected study drug relationship, by 
primary system organ class and preferred term 

Adverse events leading to study drug discontinuation (overall and severe), regardless of 
study drug relationship, by primary system organ class and preferred term
Adverse events requiring dose adjustment or study-drug interruption (overall and severe), 
regardless of study drug relationship, by primary system organ class and preferred term
Adverse events requiring additional therapy (overall and severe), regardless of study drug 
relationship, by primary system organ class and preferred term

Deaths by primary system organ class and preferred term. 

Non-serious adverse events with a frequency greater than 2% regardless of study drug 
relationship, by primary system organ class and preferred term (for the legal requirements 
of ClinicalTrials.gov and EudraCT)
The crude rates of treatment-emergent adverse events will be summarized by primary system 
organ class and preferred term. 
In addition, exposure time-adjusted incidence rates including 95% confidence intervals will be 
provided for the entire treatment period at the preferred term level for all SAEs and the 
common AEs (defined as with a frequency greater than 2%). A graphical display of the crude 
rates and exposure-adjusted incidence rates will be presented for all AEs and SAEs by SOC.
Exposure-adjusted AE incidence is defined as:
(Number of patients with new or worsened treatment emergent AEs) / (Total number of days a 
patient is on treatment summed over all patient/365.25)
The logic for calculation of the duration on treatment for a patient for exposure- adjusted AE at 
week x is as follows.


Novartis
For business use only
Page 24
SAP
CAIN457H3301
1) For treatment period 1 related reports:
If event occurred till week x: Duration=AE start date- date of first dose on study treatment +1
If event did not occur till week x: Duration= date of week x- date of first dose on study treatment 
+1
2) For entire treatment period related reports:
Please do not consider the duration when the subject is on placebo.
If event occurred till week x: Duration=AE start date- date of first dose on active study treatment 
+1
If event did not occur till week x: Duration= date of week x- date of first dose on active study 
treatment +1. 
2.8.1.1
Adverse events of special interest / grouping of AEs
The following Safety Topic of Interest will be used to define adverse events of special interest
(AESI):

Major adverse cardiovascular events (MACE): identified per Novartis MedDRA 
Query (NMQ) “MACE (MI, Stroke, Cardiovascular death)”

Inflammatory bowel disease: identified per NMQ “Inflammatory bowel disease”

Infections and Infestations: identified per SOC “Infections and infestations”

Malignancy: identified per NMQ “Malignant or unspecified tumors“

Hypersensitivity and injection site reaction: identified per SMQ (Standardized 
MedDRA Query) “Hypersensitivity”
For “Infections and infestations”, please follow below table:
Safety Topic Of Interest
(AESI)
SOC
Data 
Domain
MedDRA 
Code
MedDRA Term
MedDR
A Level
MedDRA 
Qualifier
Tinea pedis
Infections 
and 
infestations
MEDDRA
10043873
Tinea pedis
PT
Oral herpes
Infections 
and 
infestations
MEDDRA
10067152
Oral herpes
PT
Oral candidiasis
Infections 
and 
infestations
MEDDRA
10030963
Oral candidiasis
PT
Infections 
(Staphylococcal) 
Infections 
and 
infestations
MEDDRA
10041925
Staphylococcal 
infections
HLT
Infections (Skin 
structure)
Infections 
and 
infestations
MEDDRA
90000542
Infections of 
skin structures 
[STANDARD] 
(NMQ)
NMQ1
Infections (Oesophageal 
candidiasis) (narrow)
Infections 
and 
infestations
MEDDRA
90000882
Oesophageal 
candidiasis 
NMQ1
NARROW


Novartis
For business use only
Page 25
SAP
CAIN457H3301
[STANDARD] 
(NMQ)
Infections 
(Mycobacterial)
Infections 
and
infestations
MEDDRA
10028440
Mycobacterial 
infectious 
disorders
HLGT
Infections (Herpes viral) 
Infections 
and 
infestations
MEDDRA
10019972
Herpes viral 
infections
HLT
Infections (Fungal)
Infections 
and 
infestations
MEDDRA
10017528
Fungal 
infectious
disorders
HLGT
Infections (Central 
nervous system infections 
and inflammations)
Infections 
and 
infestations
MEDDRA
10007951
Central nervous 
system 
infections and 
inflammations
HLGT
Infections (Opportunistic
) 
Infections 
and 
infestations
MEDDRA
90000701
Opportunistic 
infections 
[FINGOLIMOD
] (CMQ)
NMQ1
Infections (Oesophageal 
candidiasis) (broad)
Infections 
and 
infestations
MEDDRA
90000882
Oesophageal 
candidiasis 
[STANDARD] 
(NMQ)
NMQ1
BROAD
Infections (Infectious 
pneumonia)
Infections 
and 
infestations
MEDDRA
90000161
Infectious 
pneumonia 
[STANDARD] 
(NMQ)
NMQ1
BROAD
Infections
Infections 
and 
infestations
MEDDRA
10021881
Infections and 
infestations
SOC
Candida infections
Infections 
and 
infestations
MEDDRA
10007134
Candida 
infections
HLT
Above AESI will be considered and the number of patients with at least one event in each 
AESI grouping will be reported. Such AESI grouping consist of adverse events, for which 
there is a specific clinical interest in connection with secukinumab, or adverse events, which 
are similar in nature (although not identical). 
All AESI groupings are defined through the use of PT, high level terms (HLT), SOC, SMQ, 
NMQ or through a combination of these components.
The AESI search table will be used to map reported adverse events to the notable adverse 
events groupings. The list of adverse events of special interest may be updated during the 
course of the trial based on accumulating safety data. Therefore, the clinical study report will 
list the AE groupings used and provide a listing of the corresponding AESI search table. 
The crude rates of adverse events of special interest will be summarized by primary system 
organ class and preferred term. 


Novartis
For business use only
Page 26
SAP
CAIN457H3301
In addition, exposure time-adjusted incidence rates including 95% confidence intervals will be 
provided for the entire treatment period at the preferred term level to adjust for differences in 
exposure. A graphical display of the crude rates and exposure-adjusted incidence rates will be 
presented for all AESIs by SOC.
Note that certain adverse events may be reported within multiple groupings.
2.8.2
Deaths
Separate summaries and listings will be provided for deaths for each treatment period. The 
number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for three groups of laboratory tests
(hematology, chemistry and urinalysis). 
For urinalysis, only data listing will be presented.
Descriptive summary statistics for the change from baseline to each study visit will be
presented. These descriptive summaries will be presented by laboratory test and treatment
group. Change from baseline will only be summarized for patients with both baseline and
post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
For each parameter, the maximum change from baseline within each study period will be
analyzed analogously.
Table 2.8-1
Liver-related events
Parameter
Criterion
ALT
AST
ALT or AST
TBL
ALP
ALT or AST & 
TBL
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>3xULN; >5xULN; >8xULN >10xULN; >20xULN
>1.5xULN, >2xULN, >3xULN,
>2xULN, >3xULN. >5xULN
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST &
TBL & ALP
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Hy’s Law)
Note: elevated ALP may suggest obstruction as a consequence of gall 
bladder or bile duct disease; ALP may also be increased in 
malignancy. FDA therefore terms Hy’s Law cases as indicators of 
pure hepatocellular injury. This does not mean that cases of ALT or 
AST >3xULN & TBL >2xULN & ALP ≥2xULN may not result
in severe DILI.
Notes:
In studies which enroll patients with pre-existing liver disease, baseline LFT may be increased above


Novartis
For business use only
Page 27
SAP
CAIN457H3301
ULN; in such a case it is meaningful to add the condition “and worse than baseline” to the abnormality 
Criteria
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit.
The criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for
ALT >3xULN and ALT>5x ULN.
Individual subject data listings will be provided for patients with abnormal laboratory data.
Data of patients with newly occurring or worsening liver enzyme abnormalities will be listed 
in an additional listing.
Separate summaries and listings will be provided for urine pregnancy results by visit for each 
treatment period.
Listing will be provided for all renal events captured in the study.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable. 
2.8.4.2
Vital signs
Analysis in vital signs measurement using descriptive summary statistics for the change from
baseline for each post-baseline visit will be performed. These descriptive summaries will be
presented by vital sign and treatment group. Change from baseline will only be summarized
for patients with both baseline and post-baseline values and will be calculated as:
change from baseline = post-baseline value – baseline value
The number and percentage of patients with newly occurring notable vital signs will be
presented. Criteria for notable vital sign abnormalities are provided in Table 2.8-2 below.
Table 2.8-2 
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities (for hypertension)
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.


Novartis
For business use only
Page 28
SAP
CAIN457H3301
2.11
Patient-reported outcomes
Variables related to health-related quality of life (HR-QoL) are described below. All HR-QoL
variables will be evaluated based on the FAS-TP1 and FAS-TP2 population at (Baseline to 
Week 8) and (Week 8 to Week 24) respectively.
FACIT-Fatigue© score

Change from baseline in FACIT-Fatigue© score for each treatment group at Week 8.

Change from baseline in FACIT-Fatigue© score for each treatment group at Week 24.

Change from Week 8 in FACIT-Fatigue© score for each treatment group at Week 24.
All FACIT scales are scored so that a high score is good. 
To achieve this, we reverse response scores on negatively-phrased questions. The total score 
is then calculated as the sum of the un-weighted subscale scores.  
Calculate the score only if at least 11 questions are answered.
Calculate the total score as mentioned in below table:
Patient Accepted Symptoms State

Proportion of patients in each treatment group with satisfactory PASS at Week 1, 2, 3, 4 
and 8.

Proportion of patients in each treatment group with satisfactory PASS at Week 12, 20 and 
24.
ASAS Health Index

Proportion of patients in each treatment group of achieving a minimal improvement 
(MCII) in ASAS health index at Week 8. 

Proportion of patients in each treatment group of achieving a minimal improvement 
(MCII) in ASAS health index at Week 24.


Novartis
For business use only
Page 29
SAP
CAIN457H3301

Proportion of patients in each treatment group of achieving a significant improvement 
(SCI) in ASAS health index at Week 8. 

Proportion of patients in each treatment group of achieving a significant improvement 
(SCI) in ASAS health index at Week 24.

Change from baseline in ASAS health index for each treatment group at Week 8 and 
Week 24.
Total Score calculation:
Total Score will be analyzed, if no more than 20% of data is missing. The total score is 
calculated as follows for respondents with one to a maximum of three missing responses
Sumscore={x/(N-m)}*N
Where 
x= Item summation score
N=Total no of items applicable (Items “I have lost interest in sex.” and “I have difficulty  
operating the pedals in my car” can be not applicable for few patients).
m=Number of missing Items
The definition of improvement is as follows:

MCII (minimal clinically important improvement) ≥ 1 point of decrease from previous 
ASAS HI measurement

SCI (Significant clinically improvement) ≥ 4 points of decrease from previous ASAS 
HI measurement
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
All the exploratory efficacy evaluation will be performed on FAS-TP1 and FAS-TP2 population 
based on the corresponding treatment periods. Refer to Table 1.2-1 of Section 1 for the list of 
exploratory endpoints.
The following exploratory efficacy variables will be analyzed on the FAS-TP1 and FAS-TP2 
population at (Baseline to Week 8) and (Week 8 to Week 24) respectively for all applicable 
analysis visits unless otherwise specified.

Spinal pain score: Average NRS spinal pain score will be calculated only if total and 
nocturnal pain score are non-missing.

BASDAI score: It will be calculated based on the average of the non-missing answers 
available.  

ASDAS CRP

Patient reported outcomes: FACIT-Fatigue©, PASS, ASAS health index


Novartis
For business use only
Page 30
SAP
CAIN457H3301

The average and raw (total and nocturnal) spinal pain NRS scores will be analyzed using a 
repeated measures analysis of variance (ANOVA) model with treatment, country and the 
stratification factor of prior exposure to TNF inhibitors (naïve/ inadequate responders to 
TNFα inhibitors) as factors and respective baseline NRS score as covariate. The least 
squares means of the two treatment groups, least squares mean difference and 95% 
confidence interval for the difference in the two treatment groups will be presented along 
with the p-value based on the fitted linear model.

Formula for ASDAS-CRP calculation: ASDAS (CRP) = 0.121 x total back pain + 0,110 x 
patient global + 0.073 x peripheral pain/swelling + 0.058 x duration of morning stiffness + 
0.579 x LN (CRP+1)
The parameters, which are taken from patient reported outcomes, are expected to have 
values 0-10. CRP needs to be in the unit mg/L.
All endpoints relating to exploratory objectives will be summarized descriptively. Summary 
statistics will include relative and absolute frequencies for the categorical variables and the 
number of patients (n), minimum, mean, median and maximum for continuous variables will 
be separately provided for both period I and period II. Time courses of response rates and mean 
NRS-scores will be displayed graphically.
The following categorical exploratory endpoints will also be summarized categorically as 
absolute and relative frequencies (proportions, %). Any improvement or reduction is referred 
to as ‘response’ for all the below mentioned endpoints.

Proportion of patients in each treatment group with response in spinal pain score < 4 at 
Week 1, 2, 3 and 4.

Proportion of patients in each treatment group with response in spinal pain score < 4 at 
Week 24.

Proportion of patients in each treatment group with response in BASDAI score < 4 at 
Week 24. 

Proportion of patients in each treatment group with response in ASDAS score < 2.1 at 
Week 8 and Week 24.

Proportion of patients in each treatment group with response in ASDAS score < 1.3 at 
Week 8 and Week 24.

Proportion of patients in Arm 1 with spinal pain score > 6 at Week 12 or Week 24.

Proportion of patients achieving a spinal pain score < 4 for TNF-naïve patients compared 
to TNFα-inadequate responder (TNFα-IR) patients at Week 8 and Week 24. 

Proportion of patients with response in spinal pain score < 4 to secukinumab 150 mg at 
Week 8 maintaining a response at Week 24. Only descriptive statistics will be presented 
for this endpoint.
The statistical significance of the above endpoints between groups will be analyzed by 95% 
CI of proportion. P-value will be added if there are enough number of patients available. 
The following continuous exploratory endpoints will also be summarized descriptively with 
number of patients (n), minimum, mean, standard deviation, median and maximum.


Novartis
For business use only
Page 31
SAP
CAIN457H3301

Change from baseline in spinal pain score according to previous exposure to tumor 
necrosis factor (TNF) blockers at Week 1, 2, 3, 4, 8, 12 and 24.

Change from baseline in total spinal pain score at all time points by each treatment group 
for each treatment period.

Change from baseline in total BASDAI score at all time points by each treatment group 
for each treatment period.

Change from baseline in ASDAS-CRP at Week 8 and Week 24.
If for a significant number of patients, the assignment to responder and / or non-responder 
status is incorrect, then a risk analysis may be performed.
2.14
Interim analysis
No interim analysis is planned for this study.
3
Sample size calculation
To assess the assumed effect size at Week 8, a 43.6% response rate (spinal pain NRS < 4) is 
assumed for the secukinumab 150 mg group. This number is derived as an average of the 
response rates observed in the CAIN457F2320 and CAIN457F2310 studies (Baeten et al 2015). 
For the placebo group, a response rate at Week 8 of 23.5% (NRS < 4) was selected as assessed 
in the CAIN457F2320 study. This intermediate scenario takes into consideration a certain 
likelihood of a relatively high placebo response also in line with data from the TNFα reference 
studies and the CAIN457F2305 study in addition to the slightly milder course of the disease in 
the studied population (Baeten et al 2015).
Assuming conservatively a response rate of 23.5% in the placebo group and a response rate of 
43.6% under secukinumab 150 mg, 332 patients in total (i.e. 249 patients in secukinumab 150 
mg group and 83 patients in placebo group) would be needed under 3:1 (secukinumab: placebo) 
allocation to achieve 90% power on a (2-sided) 5% significance level. To compensate for drop-
out patients or those with protocol deviations, a total of 352 patients (264 in secukinumab 150 
mg group and 88 in the placebo group) should be recruited.
4
Change to protocol specified analyses
None.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Not Applicable
5.1.2
AE date imputation
AE date imputation is based only on a comparison of the partial AE start date to the treatment 
start date as mentioned in the Table 1-2 below.  


Novartis
For business use only
Page 32
SAP
CAIN457H3301
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore:
a.
If the AE year is less than the treatment year and the AE month is missing, the 
imputed AE start date is set to the mid-year point (01JulYYYY).
b. Else if the AE year is less than the treatment year and the AE month is not missing, 
the imputed AE start date is set to the mid-month point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE year is greater than the treatment year and the AE month is missing, the 
imputed AE start date is set to the year start point (01JanYYYY).
b. Else if the AE year is greater than the treatment year and the AE month is not 
missing, the imputed AE start date is set to the month start point (01MONYYYY).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing or the AE month is equal to the treatment start 
month, the imputed AE start date is set to one day after treatment start.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
c.
Else if the AE month is greater than the treatment start month, the imputed AE 
start date is set to the start month point (01MONYYYY).
Table 5.1-2: AE start date imputation
MON
MON < CFM
MON = CFM
MON > CFM
MISSING
YYYY 
MISSING
NULL
NULL
NULL
NULL
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
( D ) = 01JULYYYY
( C )= 15MONYYYY
( C )= 15MONYYYY
( C )= 15MONYYYY
Before Treatment Start Before Treatment Start Before Treatment Start Before Treatment Start
YYYY = 
CFY
(B)= TRTSTD+1
( C )= 15MONYYYY
(A)= TRTSTD+1
(A)= 01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
(A)= 01MONYYYY
After Treatment Start 
After Treatment Start 
After Treatment Start 
After Treatment Start 
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
LEGEND:


Novartis
For business use only
Page 33
SAP
CAIN457H3301
(A)
         MAX(01MONYYYY,TRTSTD+1)
(B)
         TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
AE end date imputation
For the purpose of date imputation, the study treatment follow-up period date is defined as the 
last available visit date, i.e. including unscheduled visits after the end of study visit.
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (study treatment follow-up period date, 31DECYYYY, date of death).
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(study treatment follow-up period date, last day of the month, date of death).
3. If AE year is missing or AE is ongoing, the end date will not be imputed.
If the imputed AE end date is less than the existing AE start date then use AE start date as AE 
end date.
5.1.3
Concomitant medication date imputation
Concomitant medication (CMD) date imputation uses both a comparison of the partial CMD 
start date to the treatment start date, and the value of the CMDTYP1C flag (1, 2, or 3).  Event 
date comparisons to treatment start date are made based on the year and month values only 
(any day values are ignored) in Table 1-3 below.
1. If the CMD start date year value is missing, the date will be imputed based on the 
CMDTYP1C flag value.  If the flag value is 1 or 3, the imputed CMD start date is set to 
one day before the treatment start date.  Else, if the flag value is missing or 2, the imputed 
CMD start date is set to one day after the treatment start date. (Note that for some legacy 
data, the CMDTYP1C variable may not exist in the data. When this happens and the CMD 
start date year value is missing, the imputed date value will be NULL.)
2. If the CMD start date year value is less than the treatment start date year value, the CMD 
started before treatment.  Therefore:
a.
if the CMD year is less than the treatment year and the CMD month is missing, the 
imputed CMD start date is set to the mid-year point (01JulYYYY).
b. Else if the CMD year is less than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the mid-month point 
(15MONYYYY).
3. If the CMD start date year value is greater than the treatment start date year value, the 
CMD started after treatment. Therefore:
a.
If the CMD year is greater than the treatment year and the CMD month is missing, 
the imputed CMD start date is set to the year start point (01JanYYYY).


Novartis
For business use only
Page 34
SAP
CAIN457H3301
b. Else if the CMD year is greater than the treatment year and the CMD month is not 
missing, the imputed CMD start date is set to the month start point 
(01MONYYYY).
4. If the CMD start date year value is equal to the treatment start date year value:
a.
and the CMD month is missing or the CMD month is equal to the treatment start 
month,
i.
If the flag value is 1 or 3, the imputed CMD start date is set to one day 
before the treatment start date.
ii.
Else, if the flag value is missing or 2, the imputed CMD start date is set to 
one day after the treatment start date.
b. Else if the CMD month is less than the treatment start month, the imputed CMD 
start date is set to the mid-month point (15MONYYYY).
c.
Else if the CMD month is greater than the treatment start month, the imputed 
CMD start date is set to the start month point (01MONYYYY).
Table 5.1-3:  CMD date imputation
MON MISSING
MON < CFM
MON = CFM
MON > CFM
YYYY 
MISSING (F)
(F)
(F)
(F)
Uncertain
Uncertain
Uncertain
Uncertain
YYYY < 
CFY
(D)=01JULYYYY
(C)=15MONYY
(C)=15MONYY
(C)=15MONYY
Before Treatment Start
Before Treatment Start Before Treatment Start
Before Treatment Start
YYYY = 
CFY
(B)
(C)=15MONYY
(B)
(A)=01MONYYYY
Uncertain
Before Treatment Start Uncertain
After Treatment Start
YYYY > 
CFY
(E)= 01JANYYYY
(A)=01MONYYYY
(A)=01MONYYYY
(A)=01MONYYYY
After Treatment Start
After Treatment Start
After Treatment Start
After Treatment Start
Before Treatment Start 
Partial indicates date prior to Treatment Start Date
After Treatment Start 
Partial indicates date after Treatment Start Date
Uncertain
Partial insufficient to determine relationship to Treatment Start Date
         LEGEND:
(A)
MAX (01MONYYYY,TRTSTD+1)
(B)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
     ELSE IF CMDTYP1C in (. , 2) THEN TRTSTD+1
(C)
15MONYYYY
(D)
01JULYYYY
(E)
01JANYYYY
(F)
IF CMDTYP1C IN (1,3) THEN TRTSTD-1
    ELSE IF CMDTYP1C in (. , 2) THEN TRTSTD+1


Novartis
For business use only
Page 35
SAP
CAIN457H3301
CM end date imputation
1. If the CM end date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end 
date will be set to NULL.
2. Else, if the CM end date month is missing, the imputed end date will be set to the earliest of 
the (Last contact date of subject in study, 31DECYYYY, date of death).
3. If the CM end date day is missing, the imputed end date will be set to the earliest of the
(Last contact date of subject in study, last day of the month, date of death).
4. If the imputed CM end date is less than the existing CM start date, the CM start date will be 
used as the imputed CM end date.
5.1.3.1
Prior therapies date imputation
Not applicable
5.1.3.2
Post therapies date imputation
Not applicable
5.1.4
Medical History date of diagnosis imputation
Completely missing dates will not be imputed. Partial dates of diagnosis will be compared 
to the treatment start date.

If DIAG year < study treatment start date year and DIAG month is missing, the imputed 
DIAG date is set to the mid-year point (01JULYYYY)

Else if DIAG month is not missing, the imputed DIAG date is set to the mid-month point 
(15MONYYYY)
If DIAG year = study treatment start date year and (DIAG month is missing OR DIAG month 
is equal to study treatment start month), the imputed DIAG date is set to one day before study 
treatment start date
5.2
AEs coding/grading
The verbatim term recorded on CRF will be identified as adverse event and will be coded by 
primary system organ class and preferred term using Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1 and above.
5.3
Laboratory parameters derivations
Refer to main section of SAP.


Novartis
For business use only
Page 36
SAP
CAIN457H3301
5.4
Statistical models
5.4.1
Primary analysis
The null hypothesis to be rejected is that the odds of response at Week 8 are equal in both 
treatment groups. The corresponding alternative hypothesis is that the odds of response at 
Week 8 are higher under secukinumab compared to placebo.
The primary analyses will be conducted via logistic regression model with treatment, country 
and the stratification factor of prior exposure to TNF inhibitors (naïve/ inadequate responders 
to TNFα inhibitors) as factors. The Odds ratio, 95% confidence interval (CI) and p-value will 
be presented comparing secukinumab 150 mg treatment group to placebo group at Week 8.
SAS Code for logistic model
Proc logistic data=aaa;
Class TRT STRATA / param=glm;
Model AVAL = TRT COUNTRY STRATA;
Lsmeans TRT / diff cl exp;
Ods output diffs=lsm_diff;
Run;
In cases where separation is a concern for the primary endpoint at Week 8, e.g. 0% or 100%
response in one treatment (sub)group, an exact logistic regression model will be applied to all
visits. To ensure convergence, this model will not include any continuous covariates.
Proc logistic data=aaa exactonly;
Class TRT STRATA / param=glm;
Model AVAL = TRT COUNTRY STRATA;
Exact TRT / estimate=both;
Ods output exactoddsratio=exactoddsratio;
Run;
In addition to that the above analysis will also be performed a sensitivity analysis for raw 
spinal pain NRS score.
Mixed Model Repeated Measures (MMRM)
The following MMRM (or repeated measures ANOVA) model will be used for analysis of
raw (total & nocturnal) and average spinal pain NRS score:
proc mixed data=.... order=internal;
where vis_1n in (2, 3, 4, 5, 6, 7);
class trt country strata;
model val_1n = trt bsval_1n country strata/ddfm=kr;
repeated vis_1n / subject=sid1a type=un;
lsmeans trt/ cl diff;


Novartis
For business use only
Page 37
SAP
CAIN457H3301
run;
If type=Unstructured (un) fails, we will use Compound Symmetry (cs)
5.4.2
Key secondary analysis
Not applicable
5.5
Rule of exclusion criteria of analysis sets 
Table 1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
INCL01A
ICF is not signed or missing date of 
signing ICF
EXCLUDE FROM FAS 
and SAF
3
INCL01B
ICF date is after visit or assessment 
date
EXCLUDE FROM FAS 
1
INCL01C
Patient unable to understand and 
communicate with the investigator
EXCLUDE FROM FAS
1
INCL02A
Pregnant or lactating female patients
INCLUDE IN 
EVERYTHING
0
INCL02B
Age is less than 18 years
EXCLUDE FROM FAS
1
INCL02C
Subject is not diagnosed with axSpA 
(either AS or nr-axSpA) according to 
ASAS axSpA classification criteria
INCLUDE IN 
EVERYTHING
0
INCL02D
Subject with back pain for less than 3 
months and/or age on onset at or 
greater than 45 years.
INCLUDE IN 
EVERYTHING
0
INCL03
Active axSpA as assessed by BASDAI, 
BASDAI score is less than 4 or missing 
at baseline
INCLUDE IN 
EVERYTHING
0
INCL04
Spinal pain NRS score equal or less 
than 4 at Baseline
INCLUDE IN 
EVERYTHING
0
INCL05
Patients do not have at least 2 different 
NSAIDs at the highest recommended
dose for at least 4 weeks in total prior to 
randomization
INCLUDE IN
EVERYTHING
0
INCL06
Patients who are regularly taking 
NSAIDs as part of their axSpA therapy 
are not on stable dose for at least 2 
weeks before randomization
INCLUDE IN 
EVERYTHING
0
INCL07
Patients who have previously been on a 
TNFalpha inhibitor with no appropriate 
wash-out period prior to randomization
INCLUDE IN 
EVERYTHING
0
EXCL01
Chest X-ray or chest MRI with evidence 
of ongoing infectious or malignant 
process
INCLUDE IN 
EVERYTHING
0


Novartis
For business use only
Page 38
SAP
CAIN457H3301
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
EXCL02
Previous treatment with prohibited 
medication not washed out 
appropriately before randomization
INCLUDE IN 
EVERYTHING
0
EXCL03
Previous exposure to secukinumab or 
other biologic drug directly targeting IL-
17 or IL-17 receptor
INCLUDE IN 
EVERYTHING
0
EXCL04
Patient used investigational drug or 
devices within 4 weeks before 
randomization or a period of 5 half-lives 
of the investigational drug
INCLUDE IN 
EVERYTHING
0
EXCL05
Subject with history of hypersensitivity 
to the study drug or its excipients or to 
drugs of similar chemical classes
INCLUDE IN 
EVERYTHING
0
EXCL06
Patients previously treated with any 
biological immunomodulating agents, 
except those targeting TNFalpha
INCLUDE IN 
EVERYTHING
0
EXCL07
Patients who have been exposed to 
more than one anti-tumor necrosis 
factor alpha (anti- TNFalpha) agent
INCLUDE IN 
EVERYTHING
0
EXCL08
Patients with previous treatment with 
any cell depleting therapies including 
but not limited to anti-CD20 or 
investigational agents
INCLUDE IN 
EVERYTHING
0
EXCL09
Pregnant or nursing (lactating) women, 
confirmed by a positive human 
chorionic gonadotropin (hCG) 
laboratory test
INCLUDE IN 
EVERYTHING
0
EXCL10
Women of childbearing potential, not 
using effective methods of 
contraception during the entire study 
INCLUDE IN 
EVERYTHING
0
EXCL11
Patients with active ongoing 
inflammatory diseases other than 
axSpA that might confound the 
evaluation of the benefit of 
secukinumab therapy
INCLUDE IN 
EVERYTHING
0
EXCL12
Patients with other ongoing mechanical 
diseases affecting the spine that may 
confound evaluation of the benefit of 
secukinumab therapy
INCLUDE IN 
EVERYTHING
0
EXCL13
Patients with underlying metabolic, 
hematologic, renal, hepatic, pulmonary, 
neurologic, endocrine, cardiac, 
infectious or gastrointestinal conditions,
which immunocompromise the patient.
INCLUDE IN
EVERYTHING
0
EXCL14
Patients with significant medical 
problems or diseases
INCLUDE IN
EVERYTHING
0


Novartis
For business use only
Page 39
SAP
CAIN457H3301
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
EXCL15
Patients with history of clinically 
significant liver disease or liver injury as 
indicated by abnormal liver function 
tests
INCLUDE IN 
EVERYTHING
0
EXCL16
Patients with history of renal trauma, 
glomerulonephritis, or patients with one 
kidney only, or an exceeding serum 
creatinine level
INCLUDE IN 
EVERYTHING
0
EXCL17
Patients with abnormal total white blood 
cell count or platelets or neutrophils or 
hemoglobin at screening
INCLUDE IN 
EVERYTHING
0
EXCL18
Active systemic infections during the 
last 2 weeks prior to randomization 
(exception: common cold)
INCLUDE IN 
EVERYTHING
0
EXCL19
Patients with history of ongoing, chronic 
or recurrent infectious disease or 
evidence of active tuberculosis 
infection.
INCLUDE IN 
EVERYTHING
0
EXCL20
Patients with known infection with 
human immunodeficiency virus,
hepatitis B or hepatitis C at screening
or randomization
INCLUDE IN 
EVERYTHING
0
EXCL21
Patients with history of 
lymphoproliferative disease or any 
known malignancy or history of 
malignancy of any organ system within 
the past 5 years
INCLUDE IN 
EVERYTHING
0
EXCL22
Patients with any current severe 
progressive or uncontrolled disease
INCLUDE IN 
EVERYTHING
0
EXCL23
Patients with any medical or psychiatric 
condition, which would preclude the 
participant from adhering to the study 
protocol.
INCLUDE IN 
EVERYTHING
0
EXCL24
Patients with history or evidence of 
ongoing alcohol or drug abuse within 
the last 6 months before randomization
INCLUDE IN 
EVERYTHING
0
EXCL25
Patients with administration of live 
vaccines 6 weeks prior to 
randomization or plans for 
administration of live vaccines during 
the study period
INCLUDE IN 
EVERYTHING
0
OTH01
Pregnancy test not performed as 
required per protocol
INCLUDE IN 
EVERYTHING
0
OTH02
Spinal pain NRS score at week 8 is 
missing. 
INCLUDE IN 
EVERYTHING
0
OTH03
Spinal pain NRS score at baseline is 
missing
INCLUDE IN 
EVERYTHING
0


Novartis
For business use only
Page 40
SAP
CAIN457H3301
Deviation 
ID
Description of Deviation
Exclusion in Analyses
Severity 
code
OTH04
Patient PRO data was not collected 
according to the protocol
INCLUDE IN 
EVERYTHING
0
WITH01
Pregnant patient not withdrawn from 
study
INCLUDE IN 
EVERYTHING
0
WITH02
ICF withdrawn but patient continuing in 
the study
INCLUDE IN 
EVERYTHING
0
TRT01
Dosing error in comparative dosing 
phase (too many injections in treatment 
phase 1 and 2)
INCLUDE IN 
EVERYTHING
0
TRT02
Dosing error in comparative dosing 
phase (less than 2 injections in 
treatment phase 2)
INCLUDE IN 
EVERYTHING
0
TRT03
No study medication administered.
INCLUDE IN 
EVERYTHING
0
TRT04
Patient randomized mistakenly in the 
study and did not receive study drug.
EXCLUDE FROM FAS
and SAF
3
TRT05
The patient was re-randomized to the 
wrong treatment arm.
INCLUDE IN 
EVERYTHING
0
TRT06
Patient was randomized to the wrong 
stratum at baseline.
INCLUDE IN 
EVERYTHING
0
TRT07
Study medication was administered, 
which could have been damaged.
INCLUDE IN 
EVERYTHING
0
COMD01
Prohibited medication consumed during 
study.
INCLUDE IN 
EVERYTHING
0
COMD02
Painkillers intake during 24h before a 
visit involving a disease activity 
assessment.
INCLUDE IN 
EVERYTHING
0
Table 2
Analysis set exclusions based on population codes
Analysis set 
Population codes that cause a subject to be 
excluded
RAN 
NA
SAF 
2, 3
FAS 
1, 3
Table 3
Population code text
Population Code
Population code text
0
INCLUDE IN EVERYTHING
1
EXCLUDE FROM FULL ANALYSIS SET 
(FAS)
2
EXCLUDE FROM SAFETY SET (SAF)


Novartis
For business use only
Page 41
SAP
CAIN457H3301
3
EXCLUDE FROM FAS AND SAF
6
Reference
Baeten D, Sieper J, Braun J et al; MEASURE 1 Study Group; MEASURE 2 Study Group 
(2015) Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis. N Eng J Med; 
376(26):2534-48