Clinical trial NCT04737330
Conditions: Thyroid Eye Disease Graves Orbitopathy
Keywords: TED Bulging eyes Exophthalmos
Sponsor: Novartis Pharmaceuticals
Start date: 2021-11-29; Completion date: 2023-05-16
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Thyroid eye disease (TED) is a rare autoimmune, inflammatory disorder of the orbit and represents the most common extra-thyroidal manifestation of Graves' disease (GD). Several lines of evidence suggest an important role of interleukin-17A (IL-17A) in the pathogenesis of TED; increased levels of IL-17A have been detected in the serum and tears of patients with TED and IL-17A levels correlate with clinical activity of the disease. T-helper 17 cells (Th17 cells) (as well as other cellular sources of IL-17A, e.g., Tc17 cells) have been shown to infiltrate the orbital tissue of affected patients, producing IL-17A. IL-17A stimulates fibroblast activation, leading to retrobulbar tissue expansion and orbital fibrosis, which causes significant functional impairment. Secukinumab is a recombinant high-affinity fully human monoclonal anti-IL-17A antibody currently approved for the treatment of 3 inflammatory/ autoimmune diseases: moderate to severe plaque psoriasis (PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) (ankylosing spondylitis (AS) and non-radiographic axSpA). The purpose of this study was to demonstrate the efficacy and safety of secukinumab 300 mg subcutaneous (s.c.) in adults with active, moderate to severe TED.

Detailed description:
This study consisted of the following 3 periods:

1. Screening period (Week -6 to Baseline):

   Participants' eligibility was assessed during the Screening period, which occurred for a maximum of 6 weeks.
2. Treatment period (Baseline to Week 16):

   Eligible participants were randomized in a 1:1 ratio to one of the following double-blinded treatment arms:
   * Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12
   * Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12

   Participants were stratified according to current smoking status (up to 20% smokers per arm) since smoking has a well-known impact on treatment efficacy in TED.
3. Follow-up/open-label retreatment period (Week 16 up to Week 108):

   * Proptosis responders (see definition below) at Week 16 were followed for relapse up to Week 68. If these participants relapsed, they were offered a course of open-label secukinumab at the time of relapse (see "proptosis relapsers" definition below).
   * Proptosis non-responders (see definition below) at Week 16 were offered the option of open-label secukinumab treatment (with maintenance of blind to initial randomized treatment) for a duration of 16 weeks, i.e., up to Week 32 with last dose at Week 28, as follows:

     * Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 28. Thereafter (i.e., from Week 32), participants were followed up for a further 24 weeks to assess the relapse rate.
     * For participants who were proptosis non-responders and who did not receive open-label secukinumab treatment, a follow-up visit 8 weeks after the Week 16 visit needed to be scheduled per protocol. At this follow-up visit, the assessments associated with the Week 24 visit (for responders) were to be performed.
   * Proptosis relapsers (see definition below) during the follow-up period (from Week 16 onward to Week 68) were offered the option of retreatment with open-label secukinumab for a duration of 16 weeks (with maintenance of blind to initial randomized treatment) at the time of relapse as follows:

     * Open-label secukinumab 300 mg s.c. at time of relapse, then at 1, 2, 3, 4, 8 and 12 weeks since time of relapse. Thereafter, participants were followed up for a further 24 weeks (i.e., 40 weeks after start of retreatment) to assess rate of relapse and safety.
     * For participants not receiving open-label secukinumab treatment a follow-up visit 8 weeks after the Week 16 visit were to be scheduled per protocol, if not yet completed. At this follow-up visit, the assessments associated with the Week 24 visit (for responders) were to be performed.

Definitions of proptosis responder, non-responder and relapser:

* Proptosis responders: Participants achieving response in reduction of proptosis at Week 16 defined as follows: reduction of \>= 2 mm from Baseline in the study eye without deterioration (\>= 2 mm increase) of proptosis in the fellow eye.
* Proptosis non-responders: Participants not achieving response in reduction of proptosis at Week 16 with "response" defined as follows: reduction of \>= 2 mm from Baseline in the study eye without deterioration (\>= 2 mm increase) of proptosis in the fellow eye.
* Proptosis relapsers: Participants who were "proptosis responders" as defined above, and then relapsed based on proptosis at any time during the 52-week follow-up period with relapse defined as follows: increase in proptosis of \>= 2 mm compared to Week 16 in the study eye or deterioration of proptosis (\>= 2 mm increase) in the fellow eye at any time during 52-week follow-up period.

In case of worsening of the disease, participants were allowed to receive alternative treatment for TED at the discretion of the investigator and were discontinued from the study treatment.

The primary endpoint analysis was planned to be performed once all participants had reached Week 40, which included the primary efficacy endpoint (Week 16), efficacy of retreatment for initial non-responders and relapse rates during 24 weeks of follow-up.

The final analysis was planned to be performed when the last participant had reached the end of trial.

The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) expressed different preferences regarding the primary and secondary objectives and endpoints and their ordering. Therefore, this study intended to have 2 different analysis strategies and corresponding primary, secondary objective and endpoint definitions; Plan A was intended for submission in Europe (EU) and other applicable countries and Plan B was intended for submission in the United States (US) and other applicable countries. As the study was early terminated, only Plan A analysis was conducted.

Arms: arm 1: Secukinumab 300 mg subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12 arm 2: Placebo subcutaneous (s.c.) injection at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12
Interventions: intervention 1: Secukinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12 intervention 2: Placebo s.c. at Baseline, Weeks 1, Week 2, Week 3, Week 4, Week 8, Week 12

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
AIN457/Secukinumab 
Protocol CAIN457ADE16 / NCT04737330
A two-year multi-center Phase 3 study to investigate the 
efficacy and safety of secukinumab in adult patients with 
active, moderate to severe thyroid eye disease (ORBIT), 
with a randomized, parallel-group, double-blind, placebo-
controlled, 16-week treatment period, and a follow-
up/retreatment period  
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-001611-24 
Version number: 
02 (Track Changes) 
Clinical Trial Phase: 
Phase 3 
Release date: 
15-Mar-2022 (Final)
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 (August 2021) ............................................................................................ 12 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 24 
1.1 
Background ............................................................................................................ 24 
1.2 
Purpose .................................................................................................................. 26 
2 
Objectives and endpoints ................................................................................................... 26 
2.1 
Primary estimands ................................................................................................. 31 
2.2 
Secondary estimands ............................................................................................. 32 
3 
Study design ...................................................................................................................... 33 
4 
Rationale ............................................................................................................................ 36 
4.1 
Rationale for study design ..................................................................................... 36 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 36 
4.3 
Rationale for choice of control drug (placebo) ...................................................... 38 
4.4 
Purpose and timing of primary analysis ................................................................ 38 
4.5 
Risks and benefits .................................................................................................. 39 
5 
Study population ................................................................................................................ 40 
5.1 
Inclusion criteria .................................................................................................... 40 
5.2 
Exclusion criteria ................................................................................................... 41 
6 
Treatment ........................................................................................................................... 44 
6.1 
Study treatment ...................................................................................................... 44 
6.1.1 
Investigational and control drugs .......................................................... 44 
6.1.2 
Additional study treatments .................................................................. 44 
6.1.3 
Treatment arms...................................................................................... 44 
6.1.4 
Treatment duration ................................................................................ 45 
6.2 
Other treatments..................................................................................................... 45 
6.2.1 
Concomitant therapy ............................................................................. 45 
6.2.2 
Prohibited medication and procedures .................................................. 46 
6.2.3 
Rescue medication ................................................................................ 47 
6.3 
Patient numbering .................................................................................................. 48 
6.3.1 
Patient numbering ................................................................................. 48 
6.3.2 
Treatment assignment, randomization .................................................. 48 


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6.4 
Treatment blinding ................................................................................................ 48 
6.5 
Dose escalation and dose modification.................................................................. 49 
6.5.1 
Follow-up for toxicities ......................................................................... 49 
6.6 
Additional treatment guidance ............................................................................... 49 
6.6.1 
Treatment compliance ........................................................................... 49 
6.6.2 
Emergency breaking of assigned treatment code .................................. 49 
6.7 
Preparation and dispensation ................................................................................. 50 
6.7.1 
Handling of study treatment and additional treatment .......................... 51 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 51 
7 
Informed consent procedures ............................................................................................ 52 
8 
Visit schedule and assessments ......................................................................................... 53 
8.1 
Screening ............................................................................................................... 59 
8.1.1 
Information to be collected on screening failures ................................. 59 
8.2 
Patient demographics/other baseline characteristics ............................................. 59 
8.2.1 
Smoking history .................................................................................... 59 
8.2.2 
Tuberculosis screening .......................................................................... 60 
8.2.3 
Relevant medical history/ current medical history ................................ 60 
8.2.4 
Prior and concomitant medications ....................................................... 60 
8.2.5 
TED and thyroid medical and treatment history ................................... 60 
8.2.6 
Serum pregnancy test ............................................................................ 60 
8.2.7 
Other baseline characteristics ................................................................ 60 
8.3 
Efficacy .................................................................................................................. 61 
8.3.1 
Clinical activity score according to EUGOGO ..................................... 61 
8.3.2 
Proptosis ................................................................................................ 61 
8.3.3 
Diplopia grading.................................................................................... 62 
8.3.4 
Ophthalmological assessments.............................................................. 62 
8.3.5 
Disease severity assessments ................................................................ 62 
8.3.6 
Thyroid eye disease quality of life ........................................................ 63 
8.3.7 
Appropriateness of efficacy assessments .............................................. 63 
8.4 
Safety ..................................................................................................................... 63 
8.4.1 
Laboratory evaluations .......................................................................... 65 
8.4.2 
Pregnancy and assessments of fertility ................................................. 66 
8.4.3 
Other safety evaluations ........................................................................ 66 
8.4.4 
Appropriateness of safety measurements .............................................. 66 
8.5 
Additional assessments .......................................................................................... 66 
8.5.1 
Thyroid eye disease quality of life ........................................................ 66 
 
 67 


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 68 
 
. 68 
8.5.5 
Magnetic resonance imaging................................................................. 68 
 
 69 
9 
Study discontinuation and completion .............................................................................. 70 
9.1 
Discontinuation and completion ............................................................................ 70 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 70 
9.1.2 
Withdrawal of informed consent ........................................................... 72 
9.1.3 
Lost to follow-up ................................................................................... 73 
9.1.4 
Early study termination by the sponsor ................................................. 73 
9.2 
Study completion and post-study treatment .......................................................... 73 
10 Safety monitoring and reporting ........................................................................................ 74 
10.1 
Definition of adverse events and reporting requirements ...................................... 74 
10.1.1 
Adverse events ...................................................................................... 74 
10.1.2 
Serious adverse events .......................................................................... 75 
10.1.3 
SAE reporting........................................................................................ 76 
10.1.4 
Pregnancy reporting .............................................................................. 77 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 77 
10.2 
Additional Safety Monitoring ................................................................................ 78 
10.2.1 
Liver safety monitoring ......................................................................... 78 
10.2.2 
Renal safety monitoring ........................................................................ 79 
10.2.3 
Data monitoring committee ................................................................... 79 
10.2.4 
Adjudication committee ........................................................................ 79 
11 Data collection and database management ........................................................................ 79 
11.1 
Data collection ....................................................................................................... 79 
11.2 
Database management and quality control ............................................................ 79 
11.3 
Site monitoring ...................................................................................................... 80 
12 Data analysis and statistical methods ................................................................................ 81 
12.1 
Analysis sets .......................................................................................................... 81 
12.2 
Patient demographics and other baseline characteristics ....................................... 81 
12.3 
Treatments ............................................................................................................. 81 
12.4 
Analysis of the primary endpoints/estimands ........................................................ 82 
12.4.1 
Definition of primary endpoints/estimands ........................................... 82 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 82 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 84 
12.4.4 
Handling of missing values not related to intercurrent event ............... 84 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 84 


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12.4.6 
Supplementary analysis ......................................................................... 84 
12.4.7 
Supportive analyses ............................................................................... 84 
12.5 
Analysis of secondary endpoints/estimands .......................................................... 84 
12.5.1 
Efficacy endpoints ................................................................................. 84 
12.5.2 
Safety endpoints .................................................................................... 85 
 
 85 
 
 86 
 
 86 
 
 86 
12.7 
Interim analyses ..................................................................................................... 86 
12.8 
Sample size calculation.......................................................................................... 87 
12.8.1 
Primary endpoint ................................................................................... 87 
12.8.2 
Secondary endpoints ............................................................................. 88 
13 Ethical considerations and administrative procedures ...................................................... 88 
13.1 
Regulatory and ethical compliance ........................................................................ 88 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 88 
13.3 
Publication of study protocol and results............................................................... 88 
13.4 
Quality control and quality assurance.................................................................... 88 
14 Protocol adherence ............................................................................................................ 89 
14.1 
Protocol amendments............................................................................................. 89 
15 References ......................................................................................................................... 90 
16 Appendices ........................................................................................................................ 93 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 93 
 
 93 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 96 
16.3 
Appendix 3: GO-QoL assessment ......................................................................... 99 
 


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List of tables 
Table 2-1 
Plan A - Objectives and related endpoints ............................................ 26 
Table 2-2 
Plan B - Objectives and related endpoints ............................................ 29 
Table 6-1 
Investigational and control drug ............................................................ 44 
Table 6-2 
Prohibited medication / treatments/ procedures .................................... 46 
Table 8-1 
Assessment schedule (double-blind treatment period and follow-up 
for responders at Week 16) ................................................................... 54 
Table 8-2 
Assessment schedule (re-treatment for non-responders and 
relapsers) ............................................................................................... 57 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 77 
 
 
 93 
 
 94 
Table 16-3 
Liver event and laboratory trigger definitions ...................................... 96 
Table 16-4 
Follow-up requirements for liver events and laboratory triggers .......... 96 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 35 
Figure 4-1 
PK modeling of second treatment course including initial loading ...... 38 
 


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List of abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AS 
Ankylosing Spondylitis 
AST 
axSpA 
Aspartate Aminotransferase 
Axial Spondyloarthritis 
BCVA 
Best Corrected Visual Acuity 
BUN 
Blood Urea Nitrogen 
CAS 
Clinical Activity Score 
CD 
CI 
Cluster of Differentiation 
Confidence Interval 
ClinRO 
Cmax 
Clinician Reported Outcomes 
Maximum Concentration 
CMO&PS  
Chief Medical Office and Patient Safety 
CRF 
Case Report/Record Form (paper or electronic) 
CO 
Country Organization 
CRO 
Contract Research Organization 
DBP 
Diastolic Blood Pressure 
 
 
DON 
Dysthyroid Optic Neuropathy 
ECG 
ECM 
Electrocardiogram 
Extracellular Matrix Components 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EUGOGO 
European Group on Graves’ Orbitopathy 
EOS 
End of Study 
EOT 
End of Treatment 
eSource 
Electronic Source 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
fT3 
free T3 (tri-iodothyronine) 
fT4 
free T4 (thyroxine) 
GBCA 
Gadolinium-based contrast agent 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GD 
Graves’ Disease 
GGT 
Gamma-Glutamyl Transferase 
GO 
Graves’ orbitopathy 
GO-QoL 
Grave’s orbitopathy quality of life 
h 
Hour 


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HA 
Health Authority/Authorities 
HbA1c 
Hemoglobin A1c 
hCG 
Human chorionic gonadotropin 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC 
Independent Ethics Committee 
IL-17A 
IMP 
Interleukin 17A 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
i.v. 
Intravenous 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test  
LLN 
Lower Limit of Normal 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
MMRM 
milliliter(s) 
Mixed Model for Repeated Measures 
MRI 
Magnetic Resonance Imaging 
MTD 
nr-axSpA 
Maximum Tolerated Dose 
Non-radiographic Axial Spondyloarthritis 
NSF 
Nephrogenic systemic fibrosis 
PA 
posteroanterior 
PD 
Pharmacodynamic(s) 
PFS 
Prefilled Syringe 
PK 
Pharmacokinetic(s) 
PsA 
Psoriatic Arthritis 
PsO 
Psoriasis 
pt 
PT 
prothrombin time 
Preferred Term 
QFT 
QuantiFERON TB-PLUS test 
QMS 
Quality Management System 
QoL 
Quality of Life 
RBC 
Red Blood Cell(s) 
SAE(s) 
Serious Adverse Event(s) 


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SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
s.c. 
Subcutaneous 
sCR 
Serum Creatinine 
SD 
Standard Deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
SOC 
Serum Glutamic Pyruvic Transaminase 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
TEAE 
TED 
Thyroxine 
Treatment-emergent adverse event(s) 
Thyroid Eye Disease 
Th17 
TNFα 
T-helper 17 cell 
Tumor Necrosis Factor Alpha 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell(s) 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g., any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study patient  
Cohort 
A specific group of patients fulfilling certain criteria and generally treated at the 
same time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment 
bias, preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
Electronic data 
capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the use 
of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care 
End of the 
clinical trial 
The end of the clinical trial is defined as the last visit of the last patient. 
Enrollment 
Point/time of patient entry into the study at which informed consent must be 
obtained  
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Medication 
number 
A unique identifier on the label of medication kits 
Mis-randomized 
patients 
Mis-randomized patients are those who were not qualified for randomization 
and who did not take study treatment, but have been inadvertently randomized 
into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e., 
concomitant or rescue therapy) 
Patient number 
A unique number assigned to each patient upon signing the informed consent. 
This number is the definitive, unique identifier for the patient and should be used 
to identify the patient throughout the study for all data collected, sample labels, 
etc. 
Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will be 
used in clinical trial database setup and eventually in analysis 
Personal data 
Patient information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes patient identifier 
information, study information and biological samples. 
 
 


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Premature patient 
withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time 
all study drug administration is discontinued and no further assessments are 
planned 
Randomization 
number 
A unique identifier assigned to each randomized patient 
Screen failure 
A patient who did not meet one or more criteria that were required for 
participation in the study 
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 electronic source 
(eSource) 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first patient. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
patients as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the patient permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each patient that is required to 
address the clinical question. The specification of the variable might include 
whether the patient experiences an intercurrent event. 
Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer and does not allow any further 
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Amendment 2 (February 2022) 
Amendment rationale 
The main purpose of this amendment is to provide clarification of wording for inclusion criterion 6 and 
for the requirement of patients to be fasting prior to laboratory assessments. 
 
 
 Furthermore, information was added that live 
vaccinations should not be given until 12 weeks after last study treatment administration to comply with 
current Novartis standards. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the protocol using 
strike through red font for deletions and red underlined font for insertions. 
• 
Section 5.1 (Inclusion criteria): Wording of inclusion criterion 6 was amended to clarify that 
central lab retests are allowed for the fT3 and fT4 values during the Screening Period.    
• 
Section 6.2.2 (Prohibited medication and procedures): Addition of the information that live 
vaccinations should not be given until 12 weeks after last study treatment administration. 
• 
Section 8 (Visit schedule and assessments): Clarification added that patients should be 
reminded to be fasting before visits with laboratory assessments.  
• 
Tables 8-1 and 8-2 (Assessment schedule):  
o 
Clarification of laboratory assessments that require fasting of the patients prior to the 
visit. 
o 
Clarification that the thyroid laboratory test can be performed at an unscheduled visit 
during the study, inclusive also of the screening period, at investigator´s discretion. 
• 
Section 8.4.1 (Laboratory evaluations): Information was added for the test categories 
“Chemistry” and “Thyroid” that the listed parameters need to be assessed from fasting blood 
samples.  
 
 
 
  
 
IRBs/IECs 
The changes described in this amendment provide clarification of wording for certain aspects of the 
protocol. The amendment does not require IRB/IEC and HA approval prior to implementation. 
 
 


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Amendment 1 (August 2021) 
Amendment rationale 
The main purpose of this amendment is to add additional ophthalmological assessments to the study 
protocol 
 
 
 
. Exclusion criterion #13 was specified by the 
addition of a wash-out period for the prior use of oral corticosteroids. For patients who prematurely 
discontinue the study or study treatment, the follow-up assessment 12 weeks after last administration of 
study treatment was amended to an End of Study (EOS) visit which includes safety and efficacy 
assessments and will be recorded in the eCRF in order to increase data consistency and to comply with 
current Novartis standards. 
Furthermore, minor clarifications and corrections of certain aspects and procedures as well as changes 
to correct formatting errors and administrative inconsistencies were made where applicable. 
At the time of the amendment, no patients had been screened for inclusion. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red/blue font for deletions and red/blue underlined font for insertions. 
 
• 
List of abbreviations was updated.  
 
 
 
• 
Sections 2.1 (Primary estimands) and 2.2 (Secondary estimands): Wording was amended for 
more clarity. 
• 
Figure 3.1 (Study design):  
o 
Addition of visits without Investigational Medicinal Product (IMP) and relapse visits to 
the figure. 
o 
Addition of a short description for Week 108 on the timeline. 
• 
Section 4.2 (Rationale for dose/regimen and duration of treatment): Wording on PK modeling 
was specified.   
• 
Section 5.1 (Inclusion criteria):  
o 
“in the study eye” was added for inclusion criterion 3.  
o 
“for race and gender” was removed from inclusion criterion 3.  
o 
Timepoint for blood withdrawal was added for inclusion criterion 6.   
• 
Section 5.1 (Exclusion criteria): 
o 
Addition of a wash-out period of 4 weeks for the prior use of oral corticosteroids for 
exclusion criterion 13.  
• 
Table 6-2 (Prohibited medications/treatments/procedures): 
o 
Addition of a wash-out period of 4 weeks for the prior use of oral corticosteroids. 
• 
Section 6.4 (Treatment blinding): Wording was amended for more clarity. 
• 
Sections 6.7, 8 and 8.4: Timepoint for visits in the event of a major healthcare disruption was 
amended. 
• 
Sections 8 (Visit schedule and assessments) and 9.1.1 (Study treatment discontinuation and 
study discontinuation): Renaming of “final visit” to “study discontinuation visit” for participants 
who prematurely discontinue the study.  
• 
Tables 8-1 and 8-2 (Assessment schedule):  
o 
Renaming of unscheduled visit. 
o 
Clarification of assessments that can be performed at the unscheduled visit at 
investigator´s discretion. 


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o 
Specification of visit day for Week 24 visit. 
o 
Removal of patient history. 
o 
Renaming of “Routine laboratory tests” to “Hematology and blood chemistry”. 
 
 
 
o 
CAS, proptosis measurement, diplopia grading and Graves’ Orbitopathy quality of life 
(GO-QoL) were changed from “optional” to “mandatory” assessments for Week 24 
Visit.  
o 
Addition of “Contact Interactive Response Technology (IRT)”.  
o 
Clarification which assessments are documented in source data instead of the eCRF. 
• 
Section 8.2 (Patient demographics/other baseline characteristics): Addition of patient race and 
ethnicity data to patient demographics that will be collected and analyzed in the study. 
• 
Section 8.3 (Efficacy): Additional ophthalmological assessments were added. 
 
 
 
 
  
• 
Section 9.1 (Study treatment discontinuation and study discontinuation) and 9.2 (Study 
completion and post-study treatment): The visit to assess safety 12 weeks after last 
administration of study treatment for patients who prematurely discontinue the study or study 
treatment was replaced by an EOS visit that should be recorded in the eCRF.  
• 
Section 12 (Data analysis and statistical methods): Specification of data analysis and 
methods. Addition of a definition for the Randomized Set.  
 
 
 
• 
The reference format in the text was updated.  
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and Health Authorities (HA). The changes described in this amendment require 
IRB/IEC and HA approval prior to implementation. In addition, a revised informed consent that takes into 
account the changes to the protocol described herein will be submitted to the IRB/IEC for approval. 
 
Summary of previous amendments 
None 
 


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Protocol summary 
Protocol number 
CAIN457ADE16 
Full Title 
A two-year multi-center Phase 3 study to investigate the efficacy and 
safety of secukinumab in adult patients with active, moderate to severe 
thyroid eye disease (ORBIT), with a randomized, parallel-group, double-
blind, placebo-controlled, 16-week treatment period, and a follow-
up/retreatment period 
Brief title 
A study of the efficacy and safety of secukinumab 300 mg in patients with 
thyroid eye disease (TED) 
Sponsor and 
Clinical Phase 
Novartis, Phase 3 
Investigation type 
Drug  
Study type 
Interventional 
Purpose and 
rationale 
Thyroid eye disease (TED) is a rare autoimmune, inflammatory disorder of 
the orbit and represents the most common extra-thyroidal manifestation of 
Graves’ disease (GD). Several lines of evidence suggest an important role 
of interleukin-17A (IL-17A) in the pathogenesis of TED; increased levels of 
IL-17A have been detected in the serum and tears of patients with TED and 
IL-17A levels correlate with clinical activity of the disease. T-helper 17 cells 
(Th17 cells) (as well as other cellular sources of IL-17A, e.g., Tc17 cells) 
have been shown to infiltrate the orbital tissue of affected patients, producing 
IL-17A. IL-17A stimulates fibroblast activation, leading to retrobulbar tissue 
expansion and orbital fibrosis, which causes significant functional 
impairment. Secukinumab is a recombinant high-affinity fully human 
monoclonal anti-IL-17A antibody currently approved for the treatment of 
3 inflammatory/ autoimmune diseases: moderate to severe plaque psoriasis 
(PsO), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) 
(ankylosing spondylitis (AS) and non-radiographic axSpA). The purpose of 
this study is to demonstrate the efficacy and safety of secukinumab 300 mg 
subcutaneous (s.c.) in adults with active, moderate to severe TED.  
Primary objective  
 
 
The Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) expressed different preferences regarding the primary and 
secondary objectives and endpoints and their ordering. Therefore, this study 
will have 2 different analysis strategies and corresponding primary, 
secondary 
 objective and endpoint definitions; Plan A is 
intended for submission in Europe (EU) and other applicable countries and 
Plan B is intended for submission in the United States (US) and other 
applicable countries. 
Plan A  
• 
To demonstrate that secukinumab is superior to placebo with regard to 
the overall responder rate after 16 weeks of treatment, where the overall 
responder rate is defined as a ≥ 2-point reduction in clinical activity score 
(CAS) AND ≥ 2 mm reduction in proptosis from Baseline in the study 
eye, provided there is no corresponding deterioration in CAS or 
proptosis (≥ 2 point or 2 mm increase, respectively) in the fellow eye 
after 16 weeks of treatment. 
 
 


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Plan B  
• 
To demonstrate that secukinumab is superior to placebo with regard to 
proptosis responder rate after 16 weeks of treatment, where the 
proptosis responder rate is defined as a reduction of ≥ 2 mm from 
Baseline in the study eye without deterioration (≥ 2 mm increase) of 
proptosis in the fellow eye.  
Secondary 
objectives  
 
Plan A  
• 
To demonstrate that secukinumab is superior to placebo with regard to 
the CAS responder rate after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
the proptosis responder rate after 16 weeks of treatment. 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in diplopia after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in CAS after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in proptosis after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
improvement in disease severity after 16 weeks of treatment. 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
improvement in Graves’ Orbitopathy-quality of life (GO-QoL) after 
16 weeks of treatment. §   
• 
To evaluate the safety of secukinumab compared to placebo.§ 
§ Secondary objectives common to Plan A and Plan B. 
 
Plan B  
• 
To demonstrate that secukinumab is superior to placebo with regard to 
CAS responder rate after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
overall responder rate after 16 weeks of treatment. 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in diplopia after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in CAS after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
reduction in proptosis after 16 weeks of treatment. § 
• 
To demonstrate that secukinumab is superior to placebo with regard to 
improvement in GO-QoL after 16 weeks of treatment. § 
• 
To evaluate the safety of secukinumab 300 mg compared to placebo. § 
§ Secondary objectives common to Plan A and Plan B. 


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Study design 
This is a randomized, placebo-controlled, double-blind, parallel-group, 
interventional, multicenter study in adult patients with moderate to severe 
TED. This study consists of the following 3 periods: 
Screening period (Week -6 to Baseline) 
Participants’ eligibility will be assessed during the Screening period, which 
will occur for a maximum of 6 weeks. 
Treatment period (Baseline to Week 16) 
Eligible patients will be randomized in a 1:1 ratio to one of the following 
double-blinded treatment arms: 
1. Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 
(n = 35) 
2. Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 (n = 35) 
Patients will be stratified according to current smoking status (up to 20% 
smokers per arm) since smoking has a well-known impact on treatment 
efficacy in TED. 
Follow-up/open-label retreatment period (Week 16 up to Week 108) 
• 
Proptosis responders (see definition below) at Week 16 will be followed 
for relapse up to Week 68. If these patients relapse they will be offered 
a course of open label secukinumab at the time of relapse (see 
“proptosis relapsers” definition below). 
• 
Proptosis non-responders (see definition below) at Week 16 will be 
offered the option of open-label secukinumab treatment (with 


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maintenance of blind of initial randomized treatment) for a duration of 
16 weeks, i.e., up to Week 32 with last dose at Week 28, as follows: 
Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 
28. Thereafter (i.e., from Week 32), patients will be followed up for a 
further 24 weeks
  
For patients who are proptosis non-responders and who do not receive 
open-label secukinumab treatment, a follow-up visit 8 weeks after the 
Week 16 visit should be scheduled. At this follow-up Visit, the 
assessments associated with the Week 24 visit (for responders) should 
be performed. 
• 
Proptosis relapsers (see definition below) during the follow-up period 
(from Week 16 onward to Week 68) will be offered the option of 
retreatment with open-label secukinumab for a duration of 16 weeks 
(with maintenance of blind to initial randomized treatment) at the time of 
relapse as follows:   
Open-label secukinumab 300 mg s.c. at time of relapse, then at 1, 2, 3, 
4, 8 and 12 weeks since time of relapse. Thereafter, patients will be 
followed up for a further 24 weeks (i.e., 40 weeks after start of 
retreatment) to assess 
 safety.  
For patients not receiving open-label secukinumab treatment a follow-up 
visit 8 weeks after Week 16 visit should be scheduled, if not yet 
completed. At this follow-up Visit, the assessments associated with visit 
Week 24 (for responder) should be performed. 
Definitions of proptosis responder, non-responder and relapser 
Proptosis responder: Patients achieving response in reduction of proptosis 
at Week 16 defined as follows: reduction of ≥ 2 mm from Baseline in the 
study eye without deterioration (≥ 2 mm increase) of proptosis in the fellow 
eye. 
Proptosis non-responder: Patients not achieving response in reduction of 
proptosis at Week 16 with “response” defined as follows: reduction of 
≥ 2 mm from Baseline in the study eye without deterioration (≥ 2 mm 
increase) of proptosis in the fellow eye. 
Proptosis relapser: Patients who are “proptosis responders” as defined 
above, and then relapse based on proptosis 
 
 with relapse defined as follows: increase in proptosis of 
≥ 2 mm compared to Week 16 in the study eye or deterioration of proptosis 
(≥ 2 mm increase) in the fellow eye at any time during 52-week follow-up 
period. 
In case of worsening of the disease, patients may receive alternative 
treatment for TED at the discretion of the investigator and will be 
discontinued from the study treatment.  
The primary endpoint analysis will be performed as an interim analysis once 
all patients have reached Week 40, which will include the primary efficacy 
endpoint (Week 16), efficacy of retreatment for initial non-responders and 
 during 24 weeks of follow-up. The final analysis will be 
performed when the last patient has reached the end of trial. Other interim 
analyses may be performed in accordance with HA requirements. 
Population 
Male or female patients with active, moderate to severe TED.  


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Key inclusion 
criteria 
• 
Patient must be able to understand and communicate with the 
investigator and comply with the requirements of the study and must 
give a written, signed and dated informed consent before any study 
assessment is performed.   
• 
Male or non-pregnant, non-lactating female patients ≥ 18 years of age.  
• 
Clinical diagnosis of active, moderate to severe TED (not 
sight-threatening) in the study eye at Baseline associated with 2 or more 
of the following: 
• 
Lid retraction ≥ 2 mm 
• 
Moderate or severe soft tissue involvement 
• 
Exophthalmos ≥ 3 mm above normal  
• 
Inconstant or constant diplopia 
• 
Onset of TED symptoms fewer than 12 months prior to Baseline.  
• 
CAS ≥ 4 (on a 7-point scale, with a score of ≥ 3 indicating active TED) 
in the more severely affected (study) eye at Screening and Baseline. 
Note: Proptosis is the primary qualifier for selection of the study eye. In 
case both eyes show a similar degree of proptosis, other inflammatory 
signs and symptoms (CAS) should be taken into account by the 
investigator for the selection of the study eye. 
• 
Peripheral euthyroidism or mild hypo-/hyperthyroidism defined as free 
T3 (fT3) and free T4 (fT4) < 30% above/below normal limits at 
Screening. Every effort should be made to correct the mild hypo-
/hyperthyroidism promptly and to maintain the euthyroid state until the 
end of this study. 
Note: Central lab retests will be allowed during the Screening Period if 
fT3 and fT4 values are outside the above-mentioned cut-off criteria.  
• 
Orbital MRI assessment available confirming the diagnosis of TED for 
patients initially presenting with hypo- or euthyroidism (without treatment 
for hyperthyroidism) before or at the time of TED diagnosis (to rule out 
other potential causes of orbital signs and symptoms. 
Key exclusion 
criteria 
• 
Improvement in CAS of ≥ 2 points and/or improvement in proptosis of 
≥ 2 mm in the study eye between Screening and Baseline. 
• 
Signs of sight-threatening TED defined by optic neuropathy or severe 
corneal injury. 
• 
Patients, in the opinion of the investigator, requiring immediate or urgent 
medical treatment with glucocorticoids for TED. 
• 
Patients requiring immediate surgical ophthalmological intervention or 
planning corrective surgery/irradiation during the course of the study. 
• 
Decreased best corrected visual acuity (BCVA) as defined by a 
decrease in vision of 2 lines on the Snellen chart, new visual field defect 
or color defect within the last 6 months.  
• 
Any other ophthalmic and/or orbital disease or condition that might 
interfere with the assessment of TED. 
• 
Previous orbital radiotherapy. 
• 
Previous ophthalmological/orbital surgery for TED (e.g., orbital 
decompression). 


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• 
Previous use of biological agents for the treatment of TED. 
• 
Previous use of systemic, non-biologic, immunomodulatory agents for 
the treatment of TED (e.g., mycophenolate or cyclosporine). 
• 
Previous exposure to secukinumab or other biologic drugs directly 
targeting IL-17A or the IL-17 receptor (e.g., ixekizumab, brodalumab).  
• 
Previous treatment with rituximab, tocilizumab or teprotumumab. 
• 
Previous use of systemic corticosteroids for the treatment of TED, 
except for oral corticosteroids with a cumulative dose equivalent to < 1 
g oral prednisone/prednisolone if the corticosteroid was discontinued at 
least 4 weeks prior to Baseline. 
• 
Previous treatment with any cell-depleting therapies including but not 
limited to anti-cluster of differentiation 20 (CD20) or investigational 
agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19). 
• 
Use of other investigational drugs within 5 half-lives of enrollment or 
within 30 days, whichever is longer. 
• 
Previous or ongoing use of prohibited treatments (see Section 6.2.2 of 
main protocol). Respective washout periods detailed in this section have 
to be adhered to. 
• 
History of hypersensitivity to any of the study drug constituents. 
Refer to Section 5.2. for full exclusion criteria list. 


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Study treatment 
The investigational treatment is secukinumab 300 mg that will be supplied 
as 2 x 150 mg prefilled syringes (PFS). The control will be placebo to 
secukinumab, which will also be supplied as 2 x PFS.  
Study treatment 
Dose form 
Route and frequency of 
administration 
Baseline to Week 16 
(Double-blind) 
 
 
Secukinumab 300 mg  
 
2 × 150 mg 
PFS  
s.c. at Baseline, Week 1, 
Week 2, Week 3, Week 4, 
Week 8 and Week 12. 
Placebo 
 
2 x 0 mg 
PFS  
s.c. at Baseline, Week 1, 
Week 2, Week 3, Week 4, 
Week 8 and Week 12. 
Week 16 to end of 
study (EOS)  
(open-label) 
 
 
Secukinumab 300 mg 
2 x 150 mg 
PFS 
Non-responders at 
Week 16:  
s.c. at Week 16, 
Week 17, Week 18, 
Week 19, Week 20, 
Week 24 and Week 28.  
 
Responders at Week 16 
who relapse thereafter:  
s.c. at time of relapse, 
then 1, 2, 3, 4, 8 and 
12 weeks from time of 
relapse. 
PFS = prefilled syringe, q4w = every 4 weeks, s.c. = subcutaneous 
Efficacy 
assessments 
• 
CAS 
• 
Proptosis 
• 
Diplopia grading 
• 
Ophthalmological assessments including subjective symptoms (e.g., 
epiphora, photophobia), Worth test, ocular motility, best corrected 
visual acuity (BCVA), visual field tests, pupil examination, swinging 
flashlight test, color vision assessment (Ishihara color plates), lid 
retraction, intraocular pressure (Goldman), fluorescein staining of the 
cornea, slit lamp examination, spectral domain-optical coherence 
tomography (SD-OCT) assessment of the macula and papilla and optic 
nerve assessment (only nonmydriatic) 
 
 
• 
Disease severity assessment 
Key safety 
assessments 
• 
Physical examination 
• 
Vital signs (systolic blood pressure, diastolic blood pressure (DBP), 
pulse) 
• 
Adverse event (AE) assessments 


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• 
Laboratory (hematology, clinical chemistry, urinalysis and Thyroid-
related parameters) assessments 
Other assessments 
• 
GO-QoL assessment 
 
 
 
 
 
 
 
  
 
 
Data analysis 
Plan A 
The primary endpoint is the proportion of patients achieving overall 
response at Week 16 defined as follows: ≥ 2 point reduction in CAS AND 
≥ 2 mm reduction in proptosis from Baseline in the study eye, provided 
there is no corresponding deterioration in CAS or proptosis (≥ 2 point or 2 
mm increase, respectively) in the fellow eye after 16 weeks of treatment. 
Plan B 
The primary endpoint is the proportion of patients achieving response in 
reduction of proptosis at Week 16 defined as follows: reduction of ≥ 2 mm 
from Baseline in the study eye without deterioration (≥ 2 mm increase) of 
proptosis in the fellow eye after 16 weeks of treatment. 
The null hypothesis to be rejected is that the difference in marginal response 
rates for patients with secukinumab vs. patients with placebo = 0 after 
16 weeks. 
Let pj denote the probability of a response at 16 weeks for treatment group 
j, j=0, 1 where 
• 
0 corresponds to placebo 
• 
1 corresponds to secukinumab 
The following hypotheses will be tested: 
H0: p1 = p0 versus HA: p1 ≠ p0 
 
The primary analysis will be performed comparing treatments with respect 
to the primary endpoint in a logistic regression model with treatment group 
and stratum (= smoking status) as factors and Baseline proptosis as 
covariate. Difference in marginal response proportions between treatments 
and its 95% confidence interval (CI) will be imputed using the marginal 
standardization method, details will be provided in the Statistical Analysis 
Plan (SAP). The primary analysis will be based on the Full Analysis Set 
(FAS) and will be performed when all patients 
have completed the Week 16 assessment. 
Key words 
CAS, diplopia, Graves’ disease, TED, Graves’ orbitopathy, proptosis, 
secukinumab 


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1 
Introduction 
1.1 
Background  
Thyroid eye disease (TED) also known as Graves’ orbitopathy (GO) or Graves’ 
ophthalmopathy, is a rare, autoimmune, inflammatory disorder of the orbit (Kahaly et al 2018). 
It represents the most common extra-thyroidal manifestation of Graves’ disease (GD), which is 
characterized by autoimmune-induced hyperthyroidism. TED also occurs in hypothyroid 
(Hashimoto’s) or euthyroid patients. Its prevalence is 2.9 to 4.5 cases per 10 000 people with a 
strong predominance for female patients (Perros et al 2017). Thyroid eye disease is 
characterized by exophthalmos, eyelid retraction, periorbital edema, swelling/redness of the 
eyelids, impaired ocular motility with consecutive strabismus or diplopia and impaired visual 
function. In very severe cases, TED can cause serious ophthalmologic complications such as 
corneal breakdown or dysthyroid optic neuropathy (DON), which can be sight-threatening. 
TED may severely affect patients’ quality of life (QoL) from the highly visible and stigmatizing 
impact of symptoms on patients’ facial expressions to highly bothersome symptoms such as 
retrobulbar pain, impaired visual function and diplopia (Kahaly et al 2005, Ponto et al 2013).  
The severity of the disease is typically graded into mild, moderate to severe or sight-threatening 
(i.e., ‘very severe’) (Bartalena et al 2016), and is defined based on the degree of lid retraction, 
soft tissue involvement, proptosis, diplopia, corneal exposure and optic nerve involvement. 
Most patients have mild TED (~66%), approximately 29 to 33% have moderate to severe TED, 
and ~2% have very severe TED (Perros et al 2017). The natural course of TED consists of 2 
phases: an active, inflammatory stage, followed by a post-inflammatory so-called inactive phase 
of the disease with in many cases remaining functional impairment (Bartley 2011, Barrio-Barrio 
et al 2015). TED activity is defined by the Clinical Activity Score (CAS), a validated scoring 
system that quantitatively measures the degree of active inflammation of the orbit (Mourits et 
al 1997).  
Regarding the pathogenesis of TED, various immune cells (such as T cell subsets, B cells, 
monocytes, natural killer cells and macrophages) infiltrate the orbital space during the active 
phase of the disease. B and T cells become autoreactive and recognize orbital fibroblasts, the 
main target cell of the autoimmune attack, expressing the relevant antigens, the thyroid 
stimulating hormone (TSH) receptor and insulin-like growth factor 1 receptors. B cells produce 
autoantibodies and T cells secrete various cytokines/chemokines (e.g., IL-4, IL-13, IL-17A, 
tumor necrosis factor alpha [TNFα]) attracting further immune cells and reinforcing 
inflammatory 
processes. 
These 
processes 
jointly 
promote 
activation 
and 
proliferation/differentiation of orbital fibroblasts, with consecutive synthesis and deposition of 
large amounts of extracellular matrix components like glycosaminoglycans or collagens in the 
orbital space. Expansion of the orbital tissue leads to retrobulbar pressure increase with 
impaired venous drainage and consecutive proptosis. Inflammatory signs and symptoms include 
chemosis, eyelid swelling and periorbital edema. Swelling of the extraocular muscles leads to 
impairment in ocular motility. Furthermore, fibrosis of the orbital space results in long-term 
functional impairment such as restricted eye motility and strabismus (Wiersinga 2017, 
Huang et al 2019, Taylor et al 2020). In very severe cases the pressure increase in combination 
with the inflammatory processes can result in DON, which is potentially sight-threatening 
(Gorman 1998). 


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The current treatment of moderate to severe cases is mainly based on high-dose intravenous 
(i.v.) corticosteroids, as well as second line options, such as orbital radiation or cyclosporine 
each in combination with corticosteroids or rituximab (both off-label). All these treatment 
options show limited efficacy with very little impact on the key clinical feature, proptosis, and 
with well-known side effects. In many patients the condition does not improve and in some 
patients even progresses. A significant portion of patients require rehabilitative eye surgery after 
the active phase of the disease to treat remaining functional impairments, such as strabismus, 
eyelid retraction or exophthalmos. Approximately 25-30% of patients with TED do not respond 
adequately or relapse after completion of corticosteroid treatment. Furthermore, corticosteroids 
often only marginally improve long-term outcome of TED (Ing et al 2019). Given the associated 
risks, the guidelines recommend that this treatment be administered in experienced centers that 
can carefully monitor for toxicity and safely manage serious adverse events (SAEs), including 
monitoring of liver enzymes, glucose levels and blood pressure (Bartalena et al 2016). In 
addition, psychiatric side effects such as insomnia or dysphoria can occur, often at the beginning 
of high-dose corticosteroid therapy, for which patients should also be monitored. Proton pump 
inhibitors are recommended to prevent gastric ulcer, and contraindications such as inadequately 
controlled diabetes, significant hepatic dysfunction or relevant cardiovascular or psychiatric 
morbidity have to be taken into consideration.  
Thus, there is a high need to identify new therapeutic strategies for TED. Teprotumumab, a 
fully human monoclonal antibody that acts by inhibiting the insulin-like growth factor 1 
receptor has been approved in January 2020 for the treatment of TED in the United States by 
the FDA (Smith et al 2017, Douglas et al 2020). 
There is an increasing amount of evidence showing the significant role of IL-17A in the 
immunopathogenesis of TED. IL-17A levels have been shown to be highly increased in the 
serum and lacrimal fluid (i.e., tears) of patients with TED, correlating with disease activity 
(Huang et al 2012, Kim et al 2012, Ujhelyi et al 2012, Wei et al 2014, Fang et al 2016a, ). Th17 
cells producing IL-17A, as well as other sources of IL-17A (such as Tc17 cells, γδ T cells or 
natural killer cells) have been shown to infiltrate the orbital space of active TED patients 
(Fang et al 2016b, Fang et al 2017, Hai et al 2019). IL-17A promotes orbital inflammation and 
has been shown to induce the proliferation and differentiation of orbital fibroblasts into 
(myo)fibrocytes and to stimulate their production of extracellular matrix components (ECM) 
(Fang et al 2016a, Fang et al 2016b, Fang et al 2017, Fang et al 2019, Huang et al 2019, 
Taylor et al 2020). Fibroblast activation and ECM production are key processes in the 
pathogenesis of TED, causing retrobulbar tissue expansion as well as orbital fibrosis and 
consecutive functional impairment. Thus, IL-17A is an attractive target for therapeutic 
intervention in patients with active TED.  
Secukinumab is a recombinant high-affinity fully human monoclonal anti-human IL-17A 
antibody of the immunoglobulin G1/kappa isotype. It is approved for the treatment of moderate 
to severe plaque psoriasis (PsO), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and non-
radiographic axial spondyloarthritis (nr-axSpA) with robust and clinically meaningful efficacy 
demonstrated. The safety profile of secukinumab has been established not only in a large 
clinical trial program across various indications (including long-term extension trials of up to 5 
years), but also in 5 years of real world experience in clinical practice outside clinical trials 
(Deodhar et al 2019). Based on the role of IL-17A and Th17 cells in TED, secukinumab could 
offer a new therapeutic approach for patients with TED. 


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1.2 
Purpose 
As mentioned above, IL-17A plays a significant role in the immunopathogenesis of TED, an 
autoimmune, inflammatory disorder of the orbit. Secukinumab is a recombinant high-affinity 
fully human monoclonal anti-IL-17A antibody currently approved for the treatment of three 
autoimmune/inflammatory diseases with IL-17A central in their etiology. The purpose of this 
study is to demonstrate the efficacy and safety of secukinumab 300 mg s.c. in adults with active, 
moderate to severe TED.   
2 
Objectives and endpoints 
This study has 2 analysis strategies in accordance with FDA and European Medicines Agency 
(EMA) advice. Plan A is intended for submission in Europe and other applicable countries and 
Plan B is intended for submission in the United States and other applicable countries. The main 
difference between Plan A and Plan B is the definition of the primary objective, whereby the 
primary objective of Plan A is included as secondary objective in Plan B and vice versa. 
Furthermore, the assessment of the EUGOGO disease severity is included as a secondary 
objective in Plan A 
 
The objectives and related endpoints are presented for Plan A (EU submission) in Table 2-1, 
and for Plan B (FDA submission) in Table 2-2.  
Table 2-1 
Plan A - Objectives and related endpoints 
Objectives 
Endpoints 
Primary objective 
Endpoint for primary objective 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to the 
overall responder rate after 16 weeks 
of treatment. 
• 
Proportion of patients achieving overall response 
defined as follows:  
≥ 2 point reduction in CAS AND ≥ 2 mm reduction 
in proptosis from Baseline in the study eye, 
provided there is no corresponding deterioration in 
CAS or proptosis (≥ 2 point or 2 mm increase, 
respectively) in the fellow eye after 16 weeks of 
treatment.  
 
See Section 2.1 for primary estimand.  
Secondary objectives 
Endpoints for secondary objectives 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to the 
CAS responder rate after 16 weeks of 
treatment. § 
• 
Proportion of patients achieving response in 
reduction of CAS at Week 16 defined as follows: 
reduction of ≥ 2 points from Baseline in the study 
eye without deterioration (≥ 2 point increase) of 
CAS in the fellow eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to the 
proptosis responder rate after 
16 weeks of treatment. 
• 
Proportion of patients achieving response in 
reduction of proptosis at Week 16 defined as 
follows:  
reduction of ≥ 2 mm from Baseline in the study eye 
without deterioration (≥ 2 mm increase) of 
proptosis in the fellow eye.  
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
• 
Proportion of patients achieving response in 
diplopia at Week 16 defined as follows:  


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Objectives 
Endpoints 
reduction in diplopia after 16 weeks of 
treatment. § 
Baseline diplopia > 0 and a reduction of ≥ 1 grade 
with no corresponding deterioration (≥ 1 grade 
worsening) in the fellow eye at Week 16. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
reduction in CAS after 16 weeks of 
treatment. § 
• 
Mean change from Baseline to Week 16 in CAS in 
the study eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
reduction in proptosis after 16 weeks 
of treatment. § 
• 
Mean change from Baseline to Week 16 in 
proptosis in the study eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
improvement in disease severity after 
16 weeks of treatment. 
• 
Proportion of patients with improvement in 
EUGOGO disease severity (see Section 8.3.5) 
between Baseline and Week 16.  
 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
improvement in GO-QoL after 
16 weeks of treatment. §   
• 
Mean change from Baseline to Week 16 in 
GO-QoL score. § 
• 
To evaluate the safety of 
secukinumab compared to placebo.§ 
• 
Frequency of AEs, TEAEs, AEs resulting in 
treatment discontinuation, SAEs. § 


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§ Secondary 
 objectives common to Plan A and Plan B. 
AE(s)=adverse events, CAS=clinical activity score, fT3= free T3 (tri-iodothyronine), fT4= free T4 
(thyroxine), GO-QoL = Graves’ Orbitopathy quality of life, 
, 
TEAE(s)=treatment-emergent AE(s), TSH=thyroid stimulating hormone 


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Table 2-2 
Plan B - Objectives and related endpoints 
Objectives 
Endpoints 
Primary objective 
Endpoint for primary objective 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
proptosis responder rate after 
16 weeks of treatment. 
• 
Proportion of patients achieving response in 
reduction of proptosis at Week 16 defined as 
follows:  
reduction of ≥ 2 mm from Baseline in the study eye 
without deterioration (≥ 2 mm increase) of 
proptosis in the fellow eye.  
See Section 2.1 for primary estimand.  
Secondary objectives 
Endpoints for secondary objectives 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
CAS responder rate after 16 weeks of 
treatment. § 
• 
Proportion of patients achieving response in 
reduction of CAS at Week 16 defined as follows: 
reduction of ≥ 2 points from Baseline in the study 
eye without deterioration (≥ 2 point increase) of 
CAS in the fellow eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
overall responder rate after 16 weeks 
of treatment. 
• 
Proportion of patients achieving overall response 
at Week 16 defined as follows:  
≥ 2 point reduction in CAS AND ≥ 2 mm reduction 
in proptosis from Baseline in the study eye, 
provided there is no corresponding deterioration in 
CAS or proptosis (≥ 2 point or 2 mm increase, 
respectively) in the fellow eye. 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
reduction in diplopia after 16 weeks of 
treatment. § 
• 
Proportion of patients achieving response in 
diplopia at Week 16 defined as follows:  
• 
Baseline diplopia > 0 and a reduction of ≥ 1 grade 
with no corresponding deterioration (≥ 1 grade 
worsening) in the fellow eye at Week 16. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
reduction in CAS after 16 weeks of 
treatment. § 
• 
Mean change from Baseline to Week 16 in CAS in 
the study eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
reduction in proptosis after 16 weeks 
of treatment. § 
• 
Mean change from Baseline to Week 16 in 
proptosis in the study eye. § 
• 
To demonstrate that secukinumab is 
superior to placebo with regard to 
improvement in GO-QoL after 
16 weeks of treatment. § 
• 
Mean change from Baseline to Week 16 in 
GO-QoL score. § 
• 
To evaluate the safety of 
secukinumab 300 mg compared to 
placebo. § 
• 
Frequency of AEs, TEAEs, AEs resulting in 
treatment discontinuation, SAEs. §  


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§ Secondary 
 objectives common to Plan A and Plan B. 
AE(s)=adverse events, CAS=clinical activity score, fT3= free T3 (tri-iodothyronine), fT4= free T4 
(thyroxine), GO-QoL = Thyroid eye disease quality of life, 
, 
TEAE(s)=treatment-emergent AE(s), TSH=thyroid stimulating hormone 
2.1 
Primary estimands 
Plan A 
The clinical question of interest is:  
What is the effect of secukinumab 300 mg s.c. versus placebo on proportion of participants 
achieving overall response in reduction of CAS and proptosis at Week 16 in participants with 
active, moderate to severe TED, irrespective of adherence to treatment but without another 
treatment or procedure for TED in case of worsening of the disease?  
The primary estimand is described by the following attributes: 
1. Population of interest: defined through appropriate inclusion/exclusion criteria to 
reflect the targeted TED population 
2. Variable of interest: overall response in reduction of CAS and proptosis at Week 16  
3. Treatment of interest: the randomized treatment (secukinumab 300 mg s.c. and 
placebo s.c.). Further details about the investigational treatment and control treatment 
are provided in Section 6. 
Handling of intercurrent events: 
• Treatment discontinuations/disruptions for any reason will be ignored (treatment 
policy strategy). The retrieved response status after treatment discontinuation will be 
used for the analysis. 
• Other treatment given for TED, or procedure performed for TED in case of worsening 
of the disease: participants will be counted as non-responders (composite strategy) 
The summary measure: difference in marginal response proportions between the treatments. 
 
 
 


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Plan B 
The clinical question of interest is:  
What is the effect of secukinumab 300 mg s.c. versus placebo on proportion of participants 
achieving response in reduction of proptosis at Week 16 in participants with active, moderate 
to severe TED, irrespective of adherence to treatment but without another treatment or 
procedure for TED in case of worsening of the disease? The primary estimand is described by 
the following attributes: 
• Population of interest: defined through appropriate inclusion/exclusion criteria to 
reflect the targeted TED population 
• Variable of interest: proportion of participants demonstrating response in reduction of 
proptosis at Week 16 
• Treatment of interest: the randomized treatment (secukinumab 300 mg s.c. and 
placebo s.c.). Further details about the investigational treatment and control treatment 
are provided in Section 6. 
Handling of intercurrent events: 
• Treatment discontinuations/disruptions for any reason: will be ignored (treatment 
policy strategy) The retrieved response status after treatment discontinuation will be 
used for the analysis. 
• Other treatment given for TED, or procedure performed for TED in case of worsening 
of the disease: participants will be counted as non-responders (composite strategy) 
The summary measure: difference in marginal response proportions between the treatments. 
 
2.2 
Secondary estimands 
The clinical questions of interest for dichotomous secondary objectives are: 
• What is the effect of secukinumab 300 mg s.c. versus placebo on proportion of 
participants achieving response (i.e., reduction of CAS, reduction of proptosis, 
reduction of CAS and proptosis, reduction of diplopia or improvement in EUGOGO 
disease severity) at Week 16 in participants with active, moderate to severe TED, 
irrespective of adherence to treatment but without another treatment or procedure for 
TED in case of worsening of the disease? 
The clinical questions of interest for continuous secondary objectives are: 
• What is the effect of secukinumab 300 mg s.c. versus placebo on change from baseline 
(i.e., in CAS, proptosis or GO-QoL score) at Week 16 in participants with active, 
moderate to severe TED, regardless of study treatment discontinuation and other 
treatment or procedure for TED in case of worsening of the disease? 
The secondary estimands relating to dichotomous endpoints (response rates) are defined 
analogous to the primary estimand, but for the variable of interest. 
The secondary estimand relating to continuous endpoints (mean change from Baseline to Week 
16) is described by the following attributes: 
1. Population of interest: defined through appropriate inclusion/exclusion criteria to 
reflect the targeted TED population 
2. Variable of interest: change from baseline to Week 16 in the variable of interest 


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3. Treatment of interest: the randomized treatment (secukinumab 300 mg s.c. and 
placebo s.c.). Further details about the investigational treatment and control treatment 
are provided in Section 6. 
Handling of intercurrent events: 
• Treatment discontinuations/disruptions for any reason: ignore (treatment policy 
strategy) 
• Other treatment given for TED, or procedure performed for TED in case of worsening 
of the disease: ignore (treatment policy strategy) 
The summary measure: difference in means between treatments. 
3 
Study design 
This is a randomized, placebo-controlled, double-blind, parallel-group, interventional, 
multicenter study in patients with moderate to severe TED. This study consists of the following 
3 periods (see Figure 3-1): 
Screening period (Week -6 to Baseline) 
Patients’ eligibility will be assessed during the Screening Period, which will occur for a 
maximum of 6 weeks. In the event of a major healthcare disruption (e.g., a pandemic, or 
epidemic) that limits or prevents on-site visits to the study sites the Screening Period may be 
extended to a maximum of 8 weeks before Baseline. 
Double-blind treatment period (Baseline to Week 16) 
Eligible patients will be randomized in a 1:1 ratio to one of the following double-blinded 
treatment arms: 
• Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 (n=35) 
• Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 (n=35) 
Patients will be stratified according to current smoking status (up to 20% smokers per arm), 
since smoking has a well-known impact on treatment efficacy in TED. 
Follow-up/open-label retreatment period (Week 16 up to Week 108) 
• Proptosis responders (see definition below) at Week 16 will be followed for relapse up to 
Week 68. If these patients relapse they will be offered a course of open label secukinumab 
at the time of relapse (see “proptosis relapsers” definition below). 
• Proptosis non-responders (see definition below) at Week 16 will be offered the option of 
open-label secukinumab treatment (with maintenance of blind of initial randomized 
treatment) for a duration of 16 weeks, i.e., up to Week 32 with last dose at Week 28, as 
follows: 
Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 28. 
 
 
  
For patients who are proptosis non-responders and who do not receive open-label 
secukinumab treatment, a follow-up visit (End of Study [EOS]) 8 weeks after the Week 16 
Visit should be scheduled. At this EOS Visit, the assessments associated with the Week 24 
visit (for responder) should be performed. 


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• Proptosis relapsers (see definition below) during the follow-up period (from Week 16 
onward to Week 68) will be offered the option of retreatment with open-label 
secukinumab for a duration of 16 weeks (with maintenance of blind to initial randomized 
treatment) at the time of relapse as follows:   
Open-label secukinumab 300 mg s.c., at time of relapse, then at 1, 2, 3, 4, 8 and 12 weeks. 
 
  
For patients not receiving open-label secukinumab treatment, a follow-up visit (EOS) 
8 weeks after the Week 16 Visit should be scheduled, if not yet completed. At this EOS 
Visit, the assessments associated with the Week 24 visit (for responder) should be 
performed. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visits, special efforts should be made to conduct the Week 16, R16 and NR16 
visits on-site, if feasible. If it is not feasible to conduct these visits on-site, visits to the patient´s 
home, or a virtual visit if a home visit is not feasible, should be attempted. 
Definitions of proptosis responder, non-responder and relapser 
Proptosis responder: Patients achieving response in reduction of proptosis at Week 16 defined 
as follows: reduction of ≥ 2 mm from Baseline in the study eye without deterioration (≥ 2 mm 
increase) of proptosis in the fellow eye. 
Proptosis non-responder: Patients not achieving response in reduction of proptosis at 
Week 16 with “response” defined as follows: reduction of ≥ 2 mm from Baseline in the study 
eye without deterioration (≥ 2 mm increase) of proptosis in the fellow eye. 
Proptosis relapser: Patient who are “proptosis responders” as defined above, and then relapse 
based on proptosis 
 with relapse defined as 
follows: increase in proptosis of ≥ 2 mm compared to Week 16 in the study eye or deterioration 
of proptosis (≥ 2 mm increase) in the fellow eye at any time during 52-week follow-up period. 
In case of worsening of the disease during study treatment, patients may receive alternative 
treatment for TED at the discretion of the investigator and will be discontinued from the study 
treatment (please refer to Sections 6.2.3 and 9.1.1).  
The maximum duration of the study is 108 weeks: 16 weeks (initial treatment phase) + 52 weeks 
(follow-up) + 16 weeks (second treatment cycle) + 24 weeks (second follow-up period).  
 


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Figure 3-1 
Study design 
 


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4 
Rationale 
4.1 
Rationale for study design 
This study consists of a 16-week double-blind treatment period during which the efficacy and 
safety of secukinumab 300 mg s.c. for the treatment of patients with moderate to severe TED 
will be evaluated in a placebo-controlled manner, and a 52-week follow-up period. In addition, 
it offers a course of open-label secukinumab for participants who fail to respond to treatment at 
Week 16 (second course for those who received secukinumab initially and first course for those 
who received placebo initially), and a course of secukinumab for patients who respond at 
Week 16 but subsequently relapse. Following the course of open-label secukinumab there is a 
subsequent 24-week follow-up period.    
The randomized design (including stratification for smoking, a key modifier of TED disease 
severity and response to immunosuppressive treatment of TED [Eckstein et al 2003]) ensures 
a comparable and balanced patient profile across treatment arms. The placebo-controlled, 
double-blind design allows the assessment of the efficacy and safety of secukinumab 300 mg 
in comparison to placebo in an adequate setting. 
 
 
 
 In case of relapse during the follow-up period, patients will be 
offered the option for re-treatment with open-label secukinumab 300 mg for 16 weeks 
(including 5 secukinumab injections during the first 5 weeks). This enables collection of data 
on the efficacy and safety of re-treatment in case of relapse.  
Furthermore, the trial offers proptosis non-responders at Week 16 the option of a course of 
open-label secukinumab 300 mg s.c. (administered as above for relapsers). This will allow 
exploration of whether an extended treatment period could be beneficial for patients who have 
not achieved a sufficient response after 16 weeks of treatment. This continued treatment option 
will be offered to patients from both treatment arms, active as well as placebo. Since a very low 
rate of response under placebo treatment can be expected, this study design enables placebo 
treated patients to also receive a course of active treatment within this clinical trial (in case they 
have not achieved response at Week 16). In addition, if placebo-treated patients achieve a 
response and relapse (unlikely scenario), they will be offered a course of open label 
secukinumab. 
4.2 
Rationale for dose/regimen and duration of treatment 
The secukinumab dosing regimen used in this study is in line with the approved dose in PsO, 
PsA with concomitant PsO or anti-TNF inadequate responders or in radiographic axSpA 
(AS depending on the clinical response). With a dose level of 300 mg, all available data in PsO 
and PsA strongly suggest that secukinumab operates at the plateau of the dose-exposure-
response curve in these autoimmune diseases, which is one of the reasons to also select this 
dose level in TED.  


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Initial loading, i.e., weekly dosing during the first 4 weeks (5 doses) ensures a rapid onset of 
action which is favorable in the setting of an acute disease such as active TED. Due to its 
approval in other indications (PsO, PsA, AS and nr-axSpA), an extensive safety database exists 
for secukinumab 300 mg given every 4 weeks; this 300 mg dosing regimen for secukinumab is 
associated with a reassuring safety profile as confirmed in multiple clinical trials (up to 5 years) 
and in the post-marketing setting. A 16-week duration of treatment falls within the range of 
other immunomodulatory treatment durations in TED (12-24 weeks) including corticosteroids 
and teprotumumab. European Group on Graves’ Orbitopathy (EUGOGO) guidelines include a 
12-week duration for corticosteroids (Bartalena et al 2012) and teprotumumab was approved 
based on a 24-week treatment duration. Notably, there was no further differentiation between 
teprotumumab and placebo regarding proptosis response between Week 18 and Week 24 
(Douglas et al 2020). 
Regarding pharmacokinetic (PK) considerations, IL-17A concentrations in lacrimal fluid (tears) 
of active TED patients have been reported from 30 pg/mL (Chen 2019) to 386 pg/mL (Ujhelyi 
et al 2012). The IL-17A concentration in the lesional skin of PsO patients is approximately 10 
pg/mL (Bruin et al 2017). The secukinumab trough serum levels using the every 4-week dosing 
regimen were 38 μg/mL at steady state; 30% of serum levels reach the skin (13 μg/mL). There 
is no evidence to suggest that secukinumab concentrations in the orbital tissue would differ 
from that significantly; good penetration of secukinumab into the inflamed and well-
vascularized orbital space is anticipated. There will potentially be higher local IL-17A 
concentrations in TED than in PsO. Even when higher local IL-17A concentrations can be 
expected in TED than in PsO, secukinumab will still be in highly sufficient molar excess to 
fully neutralize IL-17A bioactivity using the proposed dosing regimen. 
Patients who did not respond to the initial treatment course (secukinumab and placebo treated) 
at Week 16 will be offered a 16-week course of secukinumab (open-label) at that time with 
maintenance of the blind to the initial randomized treatment. Patients who are initial responders 
(secukinumab and placebo treated) at Week 16, and then relapse during follow-up will also be 
offered a 16-week course of secukinumab (open-label) at that time, while also maintaining the 
blind to the initial randomized treatment. 
The course of open-label secukinumab will be a second course of active treatment for patients 
initially randomized to secukinumab. It will include a loading similar to the initial treatment 
course (i.e., weekly dosing during the first 4 weeks, 5 doses). PK modeling was performed to 
simulate the maximum concentration (Cmax) for patients who have received secukinumab 
300 mg during the double-blind treatment phase, considering different starting time points with 
Week 16 as the earliest possible time point (for proptosis non-responders) (Figure 4-1). This 
modeling predicts a Cmax of about 120 μg/mL, when loading is initiated at Week 16, and a 
somewhat lower Cmax if the loading is initiated at a later time point (e.g., Week 20 or Week 
24). In case loading starts at Week 16, the predicted Cmax at approximately Week 21 is 
approximately 20% higher than after loading during initial treatment. No significant impact on 
patient safety is anticipated as short-term loading doses of higher exposure have been performed 
with no significant impact on safety (see Investigator’s Brochure (IB)). 
Patients initially randomized to placebo who receive open-label secukinumab during follow-up 
will follow the predicted time-concentration profile shown in Figure 4-1 without retreatment.     
 


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Figure 4-1 
PK modeling of second treatment course including initial loading 
 
4.3 
Rationale for choice of control drug (placebo) 
Placebo has been selected for the control arm, as it enables the best measure of efficacy of 
secukinumab in the treatment of moderate to severe TED. Furthermore, placebo will be given 
for a limited duration of 16 weeks.   
Except for teprotumumab (approved by FDA in Jan 2020), which is only available in the United 
States, there is no approved therapy for patients with active, moderate to severe TED as 
described in Section 1. Systemic corticosteroids are used in some patients, but they are 
characterized by sub-optimal efficacy with very limited impact on proptosis, a high relapse rate, 
marginal impact on long-term outcomes, as well as toxicity concerns. 
Other immunomodulatory compounds tested in TED, e.g., teprotumumab, rituximab or 
tocilizumab, were also tested in comparison to placebo for up to 24 weeks (Stan et al 2015, 
Perez-Moreiras et al 2018, Douglas et al 2020).  
Risks will be minimized by very frequent, careful ophthalmologic monitoring of signs of 
disease progression. In case of worsening of TED the patient should be discontinued from study 
drug at the discretion of the investigator (also refer to Section 9.1.1). Furthermore, the risk is 
minimized by the in- and exclusion criteria of the trial, which ensure that high-risk patients with 
high disease activity, need for surgery or signs of optic neuropathy are excluded from this study.   
4.4 
Purpose and timing of primary analysis 
The primary analysis will be performed after all patients have completed Week 40 assessments 
and it will include the primary endpoint (Week 16) and relapse rate data up to 24 weeks 
following the end of treatment. This will support potential regulatory filing. A final analysis is 
planned at the EOS once all patients have completed their EOS visit. There may be other 
analyses between Week 40 and Week 108 to support other regulatory filings. 


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4.5 
Risks and benefits 
Secukinumab has demonstrated a positive benefit-risk ratio in the treatment of several chronic 
inflammatory conditions for which IL17A plays a central role, including plaque-PsO, PsA, AS 
and nr-axSpA. As IL-17A has been recognized as an important mediator in the immuno-
pathogenesis of TED, secukinumab will potentially have beneficial effects for patients with 
TED by inhibiting IL-17A-driven inflammation which may reduce disease activity, tissue 
expansion, and fibrosis. As placebo patients who are non-responders at Week 16 have the option 
to receive secukinumab, they will also have this potential benefit.   
The safety data from the completed and ongoing studies across various indications including 
AE and SAE data, laboratory parameters and immunogenicity data demonstrate a consistent 
and favorable safety profile. No dose dependency with secukinumab (300 mg vs. 150 mg) has 
been observed with respect to overall rates of AEs/SAEs in the clinical development program. 
Details of the risks and benefits are outlined in the current version of the IB. 
Furthermore, extensive post-approval real-world evidence has been generated in clinical 
practice, confirming the favorable safety profile observed in the development program. 
Observed risks include infections, in particular, upper respiratory tract infections, neutropenia 
and hypersensitivity reactions that can be seen with administration of foreign proteins. Most of 
the infections were non-serious, mild to moderate in severity, clinically easily manageable and 
did not lead to treatment discontinuation. Cases of neutropenia were uncommon, generally mild 
to moderate, and transient and did not lead to treatment discontinuation.  
Patients randomized to the placebo arm will not receive active treatment with secukinumab 
during the first 16 weeks of the trial. However, they will be monitored very closely in order to 
identify any progression or need for other treatment. If they have not achieved a proptosis 
response at Week 16, they have the opportunity to receive a course of active secukinumab 
treatment starting at Week 16. 
In case of worsening of the disease and need for other treatment or therapeutic interventions, 
e.g., orbital decompression, investigators and patients can stop study treatment at any time and 
apply other treatments as needed. 
The risk to patients in this trial will be further minimized by compliance with the eligibility 
criteria, close clinical monitoring and extensive guidance to the investigators, provided in the 
current version of the IB. 
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 strictly adhere to the contraception requirements outlined 
in the exclusion criteria. If there is any question that the patient will not reliably comply, they 
should not be entered or continue in the study. 
Taking into account the individual risks, the expected risk profile of secukinumab from a 
mechanism of action perspective in patients with TED is anticipated to be similar to that of the 
approved indications. Novartis is not aware of any scientific evidence that would indicate 
potential differences in the safety profile of secukinumab between patients with TED and 
patients with PsO, PsA, AS or nr-axSpA. Patients with TED are usually on treatment with 


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anti-thyroid medication and therefore at a potentially higher risk for developing neutropenia, 
which will be carefully monitored by regular blood tests throughout the study.  
The bothersome symptoms of active, moderate to severe TED, the significant impact on 
patient’s quality of life, the potential long-term functional impairment and the very limited 
availability of effective and safe treatment options for these patients lead to a very high degree 
of unmet medical need in the treatment of this indication. The well-established, consistent and 
favorable safety profile of secukinumab and the potential of secukinumab to reduce disease 
activity, improve symptom severity and improve long-term functional outcome in patients with 
TED, suggest that participation in this trial offers a well justifiable benefit-risk profile. 
5 
Study population 
The study population comprises male or female patients with active, moderate to severe TED 
with a CAS of ≥ 4 in the more severely affected (study) eye. The “study eye” will be defined as 
the more severely affected eye at the Baseline Visit. Both “study eye” and “fellow eye” will be 
assessed for efficacy. Approximately 70 patients are planned to be randomized. No replacement 
patients are planned. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria: 
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must give a written, signed and dated informed 
consent before any study assessment is performed. 
2. Male or non-pregnant, non-lactating female patients ≥ 18 years of age.  
3. Clinical diagnosis of active, moderate to severe TED (not sight-threatening) in the study 
eye at Baseline associated with two or more of the following: 
• Lid retraction ≥ 2 mm. 
• Moderate or severe soft tissue involvement. 
• Exophthalmos ≥ 3 mm above normal  
• Inconstant or constant diplopia. 
4. Onset of TED symptoms fewer than 12 months prior to Baseline. 
5. Clinical activity score (CAS) ≥ 4 (on a 7-point scale, with a score of ≥ 3 indicating active 
TED) in the more severely affected (study) eye at Screening and Baseline. (Proptosis is 
the primary qualifier for selection of the study eye. In case both eyes show a similar 
degree of proptosis, other inflammatory signs and symptoms (CAS) should be taken into 
account by the investigator for the selection of the study eye). 
6. Peripheral euthyroidism or mild hypo-/hyperthyroidism defined as fT3 and fT4 < 30% 
above/below normal limits at Screening. Every effort should be made to correct the mild 
hypo-/hyperthyroidism promptly and to strictly maintain the euthyroid state until the end 
of this study. 
Note: Central lab retests will be allowed during the Screening Period (day -42 to -1) if fT3 
and fT4 values are outside the above-mentioned cut-off criteria.  


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7. Orbital MRI assessment available confirming the diagnosis of TED for patients initially 
presenting with hypo- or euthyroidism (without treatment for hyperthyroidism) before or 
at the time of TED diagnosis (to rule-out other potential causes of the orbital signs and 
symptoms). 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study: 
1. Improvement in CAS of ≥ 2 points and/or improvement in proptosis of ≥ 2 mm in the 
study eye between Screening and Baseline. 
2. Signs of sight-threatening TED defined by optic neuropathy or severe corneal injury. 
3. Patients, in the opinion of the investigator, requiring immediate or urgent medical 
treatment with glucocorticoids for TED. 
4. Patients requiring immediate surgical ophthalmological intervention or planning 
corrective surgery/irradiation during the course of the study. 
5. Decreased best corrected visual acuity (BCVA) as defined by a decrease in vision of 
2 lines on the Snellen chart, new visual field defect or color defect within the last 6 
months.  
6. Any other ophthalmic and/or orbital disease or other condition that might interfere with 
the assessment of TED. 
7. Previous orbital radiotherapy. 
8. Previous ophthalmological/orbital surgery for TED (e.g., orbital decompression). 
9. Previous use of biological agents for the treatment of TED. 
10. Previous use of systemic, non-biological, immunomodulatory agents for the treatment of 
TED (e.g., mycophenolate or cyclosporine).  
11. Previous exposure to secukinumab or other biologic drugs directly targeting IL-17A or the 
IL-17 receptor (e.g., ixekizumab, brodalumab).  
12. Previous treatment with rituximab, tocilizumab or teprotumumab. 
13. Previous use of systemic corticosteroids for the treatment of TED, except for oral 
corticosteroids with a cumulative dose equivalent to < 1 g oral prednisone/prednisolone if 
the corticosteroid was discontinued at least 4 weeks prior to Baseline. 
14. 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). 
15. Use of other investigational drugs within 5 half-lives of enrollment or within 30 days, 
whichever is longer. 
16. Previous or ongoing use of prohibited treatments (see Section 6.2.2). Respective washout 
periods detailed in this section must be adhered to. 
17. History of hypersensitivity to any of the study drug constituents. 
18. Pregnant or nursing (lactating) women. 
19. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during the 
study or longer if required by locally-approved prescribing information (e.g., 20 weeks in 
the European Union). Effective contraception methods include: 


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• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least 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). For countries where applicable, the use of spermicidal 
foam/gel/film/cream/vaginal suppository will be allowed. 
• Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device or intrauterine system or other 
forms of hormonal contraception that have comparable efficacy (failure rate < 1%); 
for example, hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 12 weeks before taking study treatment. 
Women are considered post-menopausal and 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), total 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. 
20. Past medical history record of infection with human immunodeficiency virus (HIV), 
hepatitis B or hepatitis C prior to Screening except for hepatitis C successfully treated and 
cured.  
21. Active systemic infections during the last 2 weeks (exception: common cold) prior to 
randomization or any infection that reoccurs on a regular basis. 
22. History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis 
infection as defined by a positive QuantiFERON TB-PLUS test (QFT) at Screening. 
Patients with a positive or indeterminate QFT test may participate in the study if full 
tuberculosis work up (according to local practice/guidelines) was completed within 
12 weeks prior to randomization and establishes conclusively that the patient has no 
evidence of active tuberculosis. If presence of latent tuberculosis is established, then 
treatment must have been initiated and maintained according to local guidelines prior to 
randomization. 
23. Significant medical problems, including but not limited to:  
• Congestive heart failure (New York Heart Association status of class III or IV).  
• Severely reduced kidney function (estimated glomerular filtration rate (eGFR) 
≤ 29 mL/min/1.73 m2). 
• Uncontrolled diabetes (Type I or Type II) defined as HbAlc ≥ 10% at Screening. 


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24. Total white blood cell (WBC) count < 3000/μL, or platelets < 100 000/μL or neutrophils 
< 1500/μl or hemoglobin < 8.5 g/dl at Screening. 
25.  History of clinically significant liver disease or liver injury indicated by abnormal liver 
function tests, such as serum glutamic oxaloacetic transaminase (SGOT) (aspartate 
aminotransferase (AST)), serum glutamic pyruvic transaminase (SGPT) (alanine 
aminotransferase (ALT)), alkaline phosphatase and serum bilirubin. The investigator 
should be guided by the following criteria: 
• SGOT (AST) and SGPT (ALT) may not exceed 3 × the upper limit of normal (ULN). 
A single parameter elevated up to and including 3 × ULN should be re-checked once 
more as soon as possible, and in all cases, at least prior to randomization, to rule-out 
laboratory error. 
• Alkaline phosphatase may not exceed 2 × ULN. An elevation up to and including 
2 × ULN should be re-checked once more as soon as possible, and in all cases, at least 
prior to randomization, to rule-out laboratory error. 
• Total bilirubin may not exceed 2 × ULN. If the total bilirubin concentration is 
increased above 2 × ULN, total bilirubin should be differentiated into the direct and 
indirect reacting bilirubin.  
26. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system treated or untreated within the past 5 years, regardless of whether 
there is evidence of local recurrence or metastases (except for skin Bowen’s disease, or 
basal cell carcinoma or actinic keratosis that have been treated with no evidence of 
recurrence in the past 12 weeks; carcinoma in situ of the cervix; or non-invasive malignant 
colon polyps that have been removed). 
27. Underlying conditions (including, but not limited to metabolic, hematologic, renal, 
hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal), which 
in the opinion of the Investigator significantly immunocompromise the patient and/or 
places the patient at unacceptable risk for receiving an immunomodulatory therapy. 
28. Diagnosis of inflammatory bowel disease (past or present). 
29.  Current severe progressive or uncontrolled disease, which in the judgment of the clinical 
investigator renders the patient unsuitable for the trial or puts the patient at increased risk. 
30. Any medical or psychiatric condition, which in the investigator’s opinion would preclude 
the patient from adhering to the protocol or completing the study per protocol.  
31. History or evidence of ongoing alcohol or drug abuse, within the last six months before 
randomization. 
32. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins). 
33. Ongoing participation (including safety follow-up period) in other interventional studies. 
No additional exclusions may be applied by the Investigator in order to ensure that the study 
population will be representative of all eligible patients. 
 


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6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug  
 
Study treatment 
Pharmaceutical 
dose form 
Route and frequency of 
administration 
Supply 
type 
Sponsor 
(global or 
local) 
Baseline to Week 16 
(Double-blind) 
 
 
 
 
Secukinumab 300 mg  
 
2 × 150 mg PFS  s.c. at Baseline, Week 1, 
Week 2, Week 3, 
Week 4, Week 8 and 
Week 12. 
Double-
blind 
supply; 
PFS 
Sponsor 
(local) 
Placebo 
 
2 x 0 mg PFS  
s.c. at Baseline, Week 1, 
Week 2, Week 3, 
Week 4, Week 8 and 
Week 12. 
Double-
blind 
supply; 
PFS 
Sponsor 
(local) 
Week 16 to end of 
study (EOS) 
(Open-label) 
 
 
 
 
Secukinumab 300 mg 
 
2 x 150 mg PFS 
Non-responders at 
Week 16:  
s.c. at Week 16, 
Week 17, Week 18, 
Week 19, Week 20, 
Week 24 and Week 28.   
 
Responders at Week 16 
who relapse thereafter:  
s.c. at time of relapse, 
then 1, 2, 3, 4, 8 and 12 
weeks from time of 
relapse. 
Open-label 
supply; 
PFS 
Sponsor 
(local) 
PFS = prefilled syringe, q4w = every 4 weeks, s.c. = subcutaneous 
 
 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms 
The maximum duration of the study is 108 weeks: 16 weeks (initial treatment phase) + 52 weeks 
(follow-up) + 16 weeks (second treatment phase) + 24 weeks (second follow-up period) as 
indicated in Figure 3-1.  


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Double-blind treatment period (Baseline to Week 16) 
Eligible patients will be randomized in a 1:1 ratio to one of the following double-blinded 
treatment arms: 
• Arm 1: secukinumab 300 mg s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, 
Week 12  
• Arm 2: placebo s.c. at Baseline, Week 1, Week 2, Week 3, Week 4, Week 8, Week 12 
Patients will be stratified according to smoking status (up to 20% per arm), since smoking has 
a well-known impact on treatment efficacy in TED. 
Follow-up/open-label retreatment period (Week 16 up to Week 108) 
• Proptosis non-responders at Week 16 (as defined in Section 3) will be offered the option 
of open-label secukinumab treatment (with maintenance of blind of initial randomized 
treatment) for a duration of 16 weeks, i.e., up to Week 32 with last dose at Week 28, as 
follows: 
Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 28. Thereafter 
(i.e., from Week 32), patients will be followed up for a further 24 weeks to 
 
 safety.  
• Proptosis relapsers (as defined in Section 3) from Week 16 to Week 68 will be offered the 
option of retreatment with open-label secukinumab for a duration of 16 weeks (with 
maintenance of blind to initial randomized treatment) at the time of relapse as follows:   
Open-label secukinumab 300 mg s.c. at time of relapse, then at 1, 2, 3, 4, 8 and 12 weeks 
since time of relapse. Thereafter, patients will be followed up for a further 24 weeks 
(i.e., 40 weeks after start of retreatment) to assess 
 safety.  
Definitions of responder, non-responder and relapser 
Please refer to Section 3 (Study design). 
6.1.4 
Treatment duration 
Patients will be treated with double-blind secukinumab or placebo for the first 16 weeks of the 
study (last administration at Week 12). Patients who are proptosis non-responders at Week 16 
or those who are proptosis responders at Week 16 but who relapse thereafter (relapsers) will be 
given the option of retreatment with open-label secukinumab for a further 16 weeks.  
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the patient was enrolled into the study must be recorded 
on the appropriate case report forms (CRFs). 
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. If the patient is already 


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enrolled, Novartis should be contacted to determine if the patient should continue participation 
in the study. 
6.2.2 
Prohibited medication and procedures 
Use of any treatments (medication and procedures) displayed in Table 6-2 that could confound 
the efficacy and safety of the study treatment are NOT allowed during the study, starting at 
Baseline (Day 1) and after, for any indication; wash-out periods for these treatments are 
indicated in the table. If the use of these treatments is required, then the patient should NOT be 
randomized into the study. 
The Investigator should instruct the patient to notify the study site about any new treatments 
he/she takes after the start of study treatment. All prohibited medications and significant non-
drug therapies administered after the patient starts study treatment must be listed on the CRF.  
If a prohibited treatment listed in Table 6-2 is used during the study, the patient should 
discontinue use of the prohibited treatment if he/she wishes to continue study treatment.  
If during study treatment a patient uses a treatment for TED or a procedure is performed for 
TED, other than secukinumab, in case of worsening of the disease, the investigator should 
discontinue the patient from study treatment and the patient will be classified as a non-
responder. 
At the discretion of the Investigator, if the patient’s use during the study of a prohibited 
treatment listed in Table 6-2 presents undue safety risk for the patient, the patient should be 
discontinued from study treatment as per Section 9.1.1.  
In case of use of prohibited medication that cannot be stopped during any follow-up period, the 
patient’s study discontinuation should be considered after discussion with the sponsor. 
Live vaccinations should not be given until 12 weeks after last study treatment administration. 
If the patient receives a live virus vaccination during a course of study treatment, the patient 
must discontinue study treatment.  
Table 6-2 
Prohibited medication / treatments/ procedures 
Prohibited treatments 
Wash-out period (before first 
study drug administration)  
Orbital radiotherapy 
No prior use allowed 
 
Surgery for the treatment of TED 
No prior use allowed 
 
Biological agents targeting IL-17 or the IL-17 receptor (e.g., 
secukinumab ixekizumab, brodalumab)  
No prior use allowed 
Biological agents targeting IL-23/p19 (e.g., guselkumab, 
risankizumab, tildrakizumab)  
No prior use allowed 
Ustekinumab 
No prior use allowed 
Rituximab, tocilizumab, teprotumumab 
No prior use allowed 


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Prohibited treatments 
Wash-out period (before first 
study drug administration)  
Biological and other systemic immunomodulating agents 
targeting TNF-alpha (e.g., adalimumab, infliximab, 
etanercept)  
12 weeks 
Systemic, biological agents for the treatment of TED 
No prior use allowed 
Any cell-depleting therapies including but not limited to 
anti-CD20 or other investigational agents (e.g., CAMPATH, 
anti-CD4, anti-CD5, anti-CD3, anti-CD19) 
No prior use allowed 
Biological immunomodulating agents other than above  
24 weeks 
Live virus vaccinations (including nasal-spray flu vaccine) 
6 weeks 
Non-biological, systemic immunomodulating agents (e.g., 
methotrexate, cyclosporine, azathioprine, mycophenolate 
mofetil, hydroxychloroquine) 
12 weeks  
Selenium and biotin 
3 weeks prior to Screening visit 
Systemic corticosteroids for treatment of TED 
No prior use allowed except for the 
following: oral corticosteroids with a 
cumulative dose equivalent < 1 g oral 
prednisone/prednisolone if the 
corticosteroid was discontinued at 
least 4 weeks prior to Baseline 
Systemic corticosteroids for treatment of other conditions 
than TED 
6 weeks prior to Screening visit 
(topical steroids for dermatological 
conditions and inhaled 
corticosteroids are allowed) 
Corticosteroid eye drops 
4 weeks 
Treatment for latent tuberculosis 
Must be initiated prior to 
randomization (see exclusion 
criterion No. 21 [Section 5.1]) 
Any other investigational treatment  
30 days or 5 half-lives (whichever is 
longer)  
6.2.3 
Rescue medication 
No rescue medication will be provided within this trial. 
Patients may receive other treatment or procedures for TED at the discretion of the investigator 
in case of worsening of the disease. Investigators should confirm that the new treatment is for 
TED due to worsening of the disease, and they must immediately discontinue patients from 
study treatment in this case. For follow-up after study treatment discontinuation, please refer to 
Section 3 (Study design).  


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6.3 
Patient numbering  
6.3.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is enrolled for Screening and is retained for the patient throughout his/her 
participation in the trial. A new Patient No. will be assigned at every subsequent enrollment if 
the patient is re-screened. The Patient No. consists of the Center Number (Center No.) (as 
assigned by Novartis to the investigative site) with a sequential patient number suffixed to it, 
so that each patient’s participation is numbered uniquely across the entire database. Upon 
signing the informed consent form (ICF), the patient is assigned to the next sequential Patient 
No. available. 
6.3.2 
Treatment assignment, randomization 
At Baseline (Randomization Visit/Day 1) all eligible patients will be randomized via Interactive 
Response Technology (IRT) to one of the treatment arms. The investigator or his/her delegate 
will contact the IRT after confirming that the patient fulfills all the inclusion/exclusion criteria. 
The IRT will assign a randomization number to the patient, which will be used to link the patient 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the patient. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by 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 arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment. 
Randomization will be stratified according to smoking status since smoking has a well-known 
impact on treatment efficacy in TED. 
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
Patients, investigator staff and persons performing the assessments will remain blind to the 
identity of the treatment assigned at Baseline from the time of randomization until final database 
lock, using the following methods:  
(1) Randomization data are kept strictly confidential until the time of unblinding and will not 
be accessible by anyone else involved in the study.  
(2) The identity of the treatments will be concealed by the use of study treatment that are all 
identical in packaging, labeling, schedule of administration, appearance, taste, and odor. 
 
 


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Unblinding of the original assigned treatment will occur in the case of patient emergencies and 
at the conclusion of the study.  
The clinical trial team will be blinded to the identity of the treatment assigned at Baseline from 
the time of randomization until certain members conducting the analysis will be unblinded after 
the Week 40 database lock (DBL). However, designated clinical trial team members including 
all members who are in contact with the clinical sites will remain blinded to the original 
treatment assignment until the final DBL and analysis. Details will be specified in the Blinding 
Charter.  Investigators, site personnel and participants will remain blinded until the end of the 
study.  
6.5 
Dose escalation and dose modification 
Study treatment dose adjustments are not permitted. Study treatment interruption should be 
avoided with the following exception: 
Study treatment interruption is only permitted if, in the opinion of the investigator, a patient is 
deemed to be placed at a significant safety risk unless dosing is temporarily interrupted. In such 
cases study treatment should be interrupted only during the time that this risk is present and 
ongoing. Study treatment can be restarted at the next scheduled visit after resolution of the 
safety risk.  
6.5.1 
Follow-up for toxicities 
Not applicable. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record CRF. Compliance to the planned administration schedule is expected to 
be high since the administration of study treatment will be done in the presence of the 
Investigator or study personnel. Compliance will also be assessed by means of site and patient-
specific drug accountability by Novartis study personnel during the site monitoring visits using 
medication pack numbers and Drug Label Form information. 
 
  
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
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 


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automatically inform the Novartis monitor for the site and the study team that the code has been 
broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• Protocol number 
• Name (if available) 
• Patient number 
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
For the double-blind period, investigator staff will select the study treatment to dispense to the 
patient as per the treatment assigned to the patient by contacting the IRT and obtaining the 
medication numbers.  
For the open-label period, investigator staff will identify the study medication kits to dispense 
to the patient by contacting the IRT and obtaining the medication numbers.  
The study medication has a 2-part label (base label plus tear-off label). Immediately before 
dispensing the medication kit to the patient, site personnel will detach the outer part of the label 
(tear-off label) from the packaging and affix it to the source document. 
In the event of a major healthcare disruption (e.g., a pandemic  or epidemic) that limits or 
prevents on-site visits to the study site, study drug may be shipped or provided directly to 
patients for home administration if needed. When site visits are not possible, regular phone 
calls/virtual contacts or visits of site staff to the patient´s home, depending on local regulations 
and capabilities (according to visit schedule or more frequently if needed, and weekly when 
patient is receiving weekly dosing) will occur between the site and the patient for instructional 
purposes, for safety monitoring and review of the patient´s ophthalmological and general health 
status until the patient can again visit the site. This is necessary to ensure that there are no safety 
concerns to the patient requiring treatment interruption or discontinuation. If in the opinion of 
the investigator the patient requires an in-person assessment, arrangements will be made for the 
patient to be evaluated at the site, or if this is not feasible, by a local ophthalmologist or in an 
emergency healthcare setting. In consultation with the investigator, selected ophthalmological 
assessments (e.g., visual acuity, intraocular pressure, color vision) can also be done by a local 
optometrist to enable continuous monitoring of the patient´s ophthalmological status if on-site 
visits or visits to a local ophthalmologist are not feasible. Assessment results must  be reported 
to and discussed with the investigator as soon as possible in this case. 


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Delivery of the Investigational Medicinal Product (IMP) directly to a patient’s home is at the 
discretion of the investigator and would be permitted only during the duration of the healthcare 
disruption. The patients will be supplied with material to document the home administration 
and to allow accountability of the study medication. At the site level, the agreement 
with/approval of the investigator should be obtained to implement home delivery. 
 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secure location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the IB. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the 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 (in case home administration became necessary, i.e., in case 
of a major healthcare disruption). 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.1.2 
Handling of additional treatment 
6.7.2 
Instruction for prescribing and taking study treatment 
Secukinumab solution for s.c. injection or placebo solution will be provided in PFS as described 
in Section 6.1.1. 
Each patient will require 1 box (containing 2 × PFS) for each treatment visit throughout the 
study, i.e., 
• Two secukinumab 150 mg PFS OR two secukinumab placebo 150 mg PFS during the 
double-blind period.  
• Two secukinumab 150 mg PFS during the open-label period.  
Patients will be assigned to treatment as described in Section 6.1.3.  


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All study treatment kits assigned by the IRT will be recorded in the IRT system. 
Administration 
Administration of all doses of study treatment at the study site should be performed after the 
study assessments for the specific visit, including blood sampling and QoL questionnaire, have 
been completed.  
The first study treatment administration will occur at the Baseline Visit, after all study 
scheduled assessments for this visit have been performed (and inclusion/exclusion criteria 
confirmed) and only after the scheduled blood samples have been drawn.  
Prior to administration, the boxes containing the PFS with study treatment solution should be 
allowed to come to room temperature unopened. Used PFS should be disposed immediately 
after use in a sharps container OR according to local regulations.  
The study treatment solution must be injected s.c. in intact areas of the skin. If possible 
throughout the trial, the study treatment should be administered to one of the following body 
regions, rotating the injection site from visit to visit: right thigh, left thigh, right stomach, left 
stomach, upper outer arm (when assisted by site personnel).  
All dates and times of injections during the study must be recorded on the appropriate CRF. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visits to the study site, home administration of the study drug is permitted as 
described above (Section 6.7). Home administration can be performed by the patient, a trained 
caregiver, or study personnel. Study participants or caregivers will be trained adequately on 
how to perform administration of the study treatment, if not already trained. If the patient or 
caregiver is not trained for drug administration and cannot visit the site to undergo training, the 
site can consider providing suitable virtual training and oversight. A joint decision together with 
the patient or caregiver should be made as to whether this constitutes sufficient training and 
oversight. 
7 
Informed consent procedures 
Eligible patients may only be included in the study after providing IRB/IEC-approved informed 
consent. 
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. 
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 investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification (IN) or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the patient. 


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Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1 and Table 8-2) lists all of the assessments and when they 
are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. 
Patients should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1 and Table 8-2) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation.  
Participants 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 study discontinuation 
visit will be performed. This study discontinuation visit should include all assessments of the 
Week 16 (if discontinued during double-blind treatment), NR32 (for non-responders), R16 (for 
relapsers) or Week 68 (for patients who discontinued during the follow-up period) visit. See 
also Section 9.1.1. 
At this study discontinuation visit, dispensed investigational product should be reconciled, and 
the AEs and concomitant medications recorded on the CRF. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visitsto the study site, regular phone calls/virtual contacts or visits of site staff 
to the patient´s home, depending on local regulations and capabilities, will occur (according to 
the visit schedule or weekly if during the weekly dosing period) for instructional purposes, for 
safety monitoring and review of the patient´s ophthalmological and general health status until 
the patient can again visit the site. This is necessary to ensure that there are no safety concerns 
to the patient requiring treatment interruption or discontinuation. If in the opinion of the 
investigator the patient requires an in-person assessment, arrangements will be made for the 
patient to be evaluated at the site, or if this is not feasible, by a local ophthalmologist or in an 
emergency healthcare setting. In consultation with the investigator, selected ophthalmological 
assessments (e.g., visual acuity, intraocular pressure, color vision) can also be done by a local 
optometrist to enable continuous monitoring of the patient´s ophthalmological status if on-site 
visits or visits to a local ophthalmologist are not feasible. Assessment results have to be reported 
to and discussed with the investigator as soon as possible in this case. 
Events qualifying for being reported in the case report form (e.g., AEs, etc.) should be entered 
as appropriate.  
Special efforts should be made to conduct the Week 16, R16 and NR16 visits on-site, if feasible. 
If it is not feasible to conduct these visits on-site, visits to the patient´s home or a virtual visit if 
a home visit not feasible, should be attempted. Patients should be reminded to be fasting prior 
to visits with laboratory assessments. 


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Table 8-1 
Assessment schedule (double-blind treatment period and follow-up for responders at Week 16) 
Period 
Screening 
Period 
Treatment Period 
Post-Treatment Follow-Up2 
Visit Name 
Screening 
(Week -6 to 
Baseline) 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 56 
Week 68 
USV3 
Days 
-42 to -1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
225 
281 
393 
477 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Washout evaluation/instruction 
S 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history  
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history/status 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TED medical history  
X 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
S 
S 
 
 
 
 
S 
 
S 
 
S 
 
S 
  
S 
(S) 
Ophthalmologic assessment1 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
12-Lead ECG 
S 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and blood 
chemistry (fasting) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
(X) 
Urinalysis (local analysis)4 
S 
S 
 
 
 
 
 
 
S 
 
S 
 
 
 
 
(S) 


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Period 
Screening 
Period 
Treatment Period 
Post-Treatment Follow-Up2 
Visit Name 
Screening 
(Week -6 to 
Baseline) 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 56 
Week 68 
USV3 
Days 
-42 to -1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
225 
281 
393 
477 
 
Thyroid laboratory test 
(fasting) 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
QuantiFERON TB-PLUS test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (local 
analysis) 
 
S 
 
 
 
S 
S 
S 
S 
S 
S 
S 
S 
 
S 
(S) 
Adverse events (including 
injections site reactions) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Responder/NR-assessment 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications/non-drug therapy 
Update as necessary 
CAS 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Proptosis measurement 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Diplopia grading6 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
GO-QoL 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Contact Interactive Response 
Technology (IRT) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 


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Period 
Screening 
Period 
Treatment Period 
Post-Treatment Follow-Up2 
Visit Name 
Screening 
(Week -6 to 
Baseline) 
Baseline 
Week 1 
Week 2 
Week 3 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 40 
Week 56 
Week 68 
USV3 
Days 
-42 to -1 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
225 
281 
393 
477 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
X = assessment to be recorded in the clinical database or received electronically from a vendor. 
S = source data. 
1 = Ophthalmic examination (please refer to Section 8.3.4).  
2 = For responders only. Non-responders and patients who relapse during follow-up, will receive a second treatment course (see next table). 
3 = Unscheduled visits (USV) might be required e.g., if patients observe symptoms between scheduled visits or for safety reasons. The safety assessments listed herein 
may be performed at the discretion of the investigator as needed to resolve the reason for the unscheduled visit. (S)AE assessment and concomitant medications are 
mandatory for all unscheduled visits. 
4 = Kits for urinalysis will be provided by central lab and test is performed locally. 
 
6 = Gorman score/subjective diplopia score (Bahn et al 1987).  
 
 
 
 
 
( ) = Parentheses denote assessments that are on a per need basis at investigator´s discretion. 


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Table 8-2 
Assessment schedule (re-treatment for non-responders and relapsers) 
Period 
Second Course Treatment Period 
Post-Treatment Follow-Up 
Visit name non-responder 
Week 
NR164 
Week 
NR17 
Week 
NR18 
Week 
NR19 
Week 
NR20 
Week 
NR24 
Week 
NR28 
Week 
NR32 
Week 
NR40 
Week 
NR56 
USV2 
Days 
113 
120 
127 
134 
141 
169 
197 
225 
281 
393 
 
Visit name relapsers§ 
Week R05 
Week R1 
Week R2 
Week R3 
Week R4 
Week R8 
Week R12 
Week R16 
Week R24 
Week R40 
USV2 
Days since relapse 
1 
8 
15 
22 
29 
57 
85 
113 
169 
281 
 
Physical examination 
S 
 
 
 
 
S 
 
S 
S 
 
(S) 
Ophthalmologic assessment1 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
(X) 
Weight 
X 
 
 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
Hematology and blood chemistry 
(fasting)  
X 
 
 
 
X 
X 
X 
X 
X 
 
(X) 
Urinalysis (local analysis)3 
S 
 
 
 
 
 
 
S 
S 
 
(S) 
Thyroid laboratory assessments 
(fasting) 
X 
 
 
 
X 
X 
X 
X 
X 
X 
(X) 
Urine pregnancy test (local 
analysis) 
S 
  
  
  
S 
S 
S 
S 
S 
S 
(S) 
Adverse events (including 
injections site reactions) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Responder/NR-assessment 
 
 
 
 
 
 
 
X 
 
 
 
Prior/concomitant 
medications/non-drug therapy 
Update as necessary 
CAS 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
(X) 


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Period 
Second Course Treatment Period 
Post-Treatment Follow-Up 
Visit name non-responder 
Week 
NR164 
Week 
NR17 
Week 
NR18 
Week 
NR19 
Week 
NR20 
Week 
NR24 
Week 
NR28 
Week 
NR32 
Week 
NR40 
Week 
NR56 
USV2 
Days 
113 
120 
127 
134 
141 
169 
197 
225 
281 
393 
 
Visit name relapsers§ 
Week R05 
Week R1 
Week R2 
Week R3 
Week R4 
Week R8 
Week R12 
Week R16 
Week R24 
Week R40 
USV2 
Days since relapse 
1 
8 
15 
22 
29 
57 
85 
113 
169 
281 
 
Proptosis measurement 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
(X) 
Diplopia grading6 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
(X) 
GO-QoL 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Contact Interactive Response 
Technology (IRT) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug administration* 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
* = Patients who are non-responders at Week 16 or patients who relapse during follow-up receive 16 weeks of treatment with open-label secukinumab.  
§ = Relapse can occur at any time during the 52-week follow-up period (i.e., from Week 16 onward to Week 68).  
X = assessment to be recorded in the clinical database or received electronically from a vendor. S = source data. 
1 = Ophthalmic examination (please refer to Section 8.3.4).  
2 = Unscheduled visits (USV) might be required e.g., if patients observe symptoms between scheduled visits or for safety reasons. The safety assessments listed 
herein may be performed at the discretion of the investigator as needed to resolve the reason for the unscheduled visit. (S)AE assessment and concomitant 
medications are mandatory for all unscheduled visits.  
3 = Kits for urinalysis will be provided by central lab and test is performed locally. 
4 = Only applicable for assessments that have not been performed at the W16 Visit in non-responders. 
5 = Only applicable for assessments that have not been performed at the Visit at which relapse was diagnosed. 
6 = Gorman score/subjective diplopia score (Bahn et al 1987).  
( ) = Parentheses denote assessments that are on a per need basis at investigator´s discretion. 
 
 


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8.1 
Screening 
Patient’s eligibility for the study will be assessed during the Screening period (Day -42 to -1) 
and at the Baseline Visit (see Table 8-1). 
Patients who fail Screening for any reason may be re-screened once. Patients who are 
re-screened must sign a new ICF and be issued a new Patient No. before any study-related 
assessment is performed or any data for the Screening Period are collected for the patient under 
the new Patient No.  
The Investigator or qualified site staff will record all re-screenings on the Re-screening eCRF 
page and any applicable Screening numbers the patient was issued prior to the current Screening 
number. The date of the new informed consent signature must be entered on the Informed 
Consent eCRF page to correspond with the new Screening Patient No. 
The Withdrawal of Consent eCRF page must be completed if consent was withdrawn during 
the Screening Period before the patient was randomized. 
8.1.1 
Information to be collected on screening failures 
Patients who sign an ICF and subsequently found to be ineligible prior to randomization will 
be considered a Screen Failure. All reasons for a Screen Failure should be recorded on the 
appropriate CRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for Screen Failure patients. No other data will be entered into the 
clinical database for patients who are Screen Failures, unless the patient experienced a SAE 
during the Screening Phase (see Section 10.1.3 for SAE reporting details). If the patient fails to 
be randomized, the IRT must be notified within 2 days of the Screen Fail that the patient was 
not randomized. 
Patients who are randomized and fail to start treatment will be considered an early terminator. 
The reason for early termination should be recorded on the appropriate CRF. 
Patients randomized in error (= mis-randomized subjects) are defined as those subjects who 
were mistakenly randomized into the IRT prior to the site confirming all eligibility criteria had 
been met and to whom no study medication was given. Mis-randomized subjects will be treated 
as Screen Failures. 
8.2 
Patient demographics/other baseline characteristics 
Baseline assessments will occur during the Screening Visit or the Baseline Visit depending on 
the assessment as indicated in Table 8-1.  
Patient demographics and Baseline characteristics to be collected for all patients include: year 
of birth, age, sex, race, ethnicity, height (cm), weight (kg). Patient race and ethnicity data are 
collected and analyzed to identify any variations in safety or efficacy due to these factors as 
well as to assess the diversity of the study population as required by Health Authorities.   
8.2.1 
Smoking history 
The current and/or previous use of tobacco products will be recorded, as well as the estimated 
number of pack-years based on the approximate consumption per year. Non-smokers will be 


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advised not to start smoking during the study. Patients will be stratified according to current 
smoking status (up to 20% smokers per arm) since smoking has a well-known impact on 
treatment efficacy in TED. 
8.2.2 
Tuberculosis screening 
A central laboratory immunological test (QuantiFERON TB-Plus) must be performed at 
Screening to screen the patient population for latent tuberculosis infection. The results must be 
known prior to randomization to determine the patient’s eligibility for the study. 
Patients with a positive test may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that: 
• The patient has no evidence of active tuberculosis. 
• If presence of latent tuberculosis is established then treatment must have been initiated and 
maintained according to local guidelines prior to randomization. 
The QuantiFERON TB-Plus 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. 
8.2.3 
Relevant medical history/ current medical history 
Relevant medical history and current medical conditions, not including TED, prior to signing 
the ICF will be recorded in the Medical History eCRF page. Whenever possible, diagnoses and 
not symptoms will be recorded. 
8.2.4 
Prior and concomitant medications 
Concomitant medications and prior medications taken over the 6 months preceding study 
enrollment for reasons other than thyroid disease and TED will be captured at the Screening 
Visit, and updated as necessary in the relevant eCRF.  
8.2.5 
TED and thyroid medical and treatment history 
Disease history will be collected at Screening. The information to be collected and entered in 
the TED History eCRF page and Prior TED Therapies eCRF page will include the following: 
• Date of onset of TED symptoms. 
• Date of first diagnosis of TED. 
• Underlying thyroid condition (Graves’ disease, Hashimoto’s thyroiditis, other). 
• Previous treatments for TED (including but not limited to previous use of biologic 
therapies) and the reason for discontinuation of each therapy. 
8.2.6 
Serum pregnancy test 
A serum pregnancy test will be performed for females of childbearing potential at Screening. 
8.2.7 
Other baseline characteristics 
Other Baseline characteristics will be collected as described in Section 8.3, Section 8.4 and 
Section 8.5.  


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8.3 
Efficacy 
Efficacy assessments will be performed for both eyes at each assessment time point. The most 
severely affected eye will be defined as the “study eye” at the Baseline Visit. If there is a 
discrepancy between CAS and proptosis in determining the study eye, this will be adjudicated 
always to the eye with the most significant proptosis. In case both eyes show a similar degree 
of proptosis, other inflammatory signs and symptoms (CAS) should be taken into account by 
the investigator for the selection of the study eye. If both eyes are affected equally, the 
Investigator will choose the “study eye”. Both eyes will be assessed for efficacy but the study 
eye will be used to assess the primary, secondary 
 outcome measures.  
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site study visits, selected efficacy assessments (if feasible for the individual 
assessments) can alternatively be done via phone calls/virtual contacts or visits of site staff to 
the patient´s home, depending on local regulations and capabilities. Special efforts should be 
made to conduct the Week 16, R16 and NR16 visits on site, if feasible. If it is not feasible to 
conduct these visits on-site, visits to the patient´s home or a virtual visit if a home visit not 
feasible, should be attempted. 
8.3.1 
Clinical activity score according to EUGOGO 
TED activity will be assessed using the CAS at the frequency indicated in the study schedule 
(Table 8-1 and Table 8-2) based on the following signs and symptoms in accordance with the 
European Group on Graves’ Orbitopathy (EUGOGO) guideline (Mourits et al 1997, Bartalena 
et al 2016):  
• Symptoms 
• Spontaneous retrobulbar pain 
• Pain on attempted upward or downward gaze 
• Signs 
• Redness of eyelids 
• Redness of conjunctiva 
• Swelling of caruncle or plica 
• Swelling of eyelids 
• Swelling of conjunctiva (chemosis) 
For each item present, 1 point is given. The sum of these points is the CAS score (Mourits et al 
1997), i.e., minimum score of 0 and maximum score of 7.  
• Inactive TED = CAS < 3. 
• Active TED = CAS ≥ 3. 
8.3.2 
Proptosis 
Proptosis measurements will be performed (ideally by the same observer) at the frequency 
indicated in the study schedule (Table 8-1 and Table 8-2). The same Hertel instrument, and the 
same outer intercanthal distance, should be used for each measurement. Instructions for the 
measurement 
of 
proptosis 
are 
included 
in 
ophthalmological 
manual 
(proptosis 
[exophthalmometry] assessment).   


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8.3.3 
Diplopia grading 
Diplopia will be graded according to the Gorman score/subjective diplopia score (Bahn et al 
1987). This assessment, which is also called “Bahn-Gorman Score” comprises 4 different 
grades:  
• 0 = No diplopia 
• 1 = Intermittent diplopia (i.e., diplopia in primary position of gaze when tired or when first 
awakening) 
• 2 = Inconstant diplopia  
• 3 = Constant diplopia 
A change of one grade will be considered to be clinically relevant. 
8.3.4 
Ophthalmological assessments 
Ophthalmological assessments will be performed as indicated in a separate ophthalmological 
manual. These examinations should include subjective symptoms (e.g., epiphora, photophobia), 
Worth test, ocular motility (measured in degrees, by means of the Light Reflex Method [Dolman 
et al 2012]), best corrected visual acuity (Snellen), visual field tests, pupil examination, 
swinging flashlight test, color vision assessment (Ishihara color plates), lid retraction, 
intraocular pressure (Goldman), fluorescein staining of the cornea, slit lamp examination, 
spectral domain-optical coherence tomography (SD-OCT) assessment of the macula and papilla 
and optic nerve assessment (only nonmydriatic). If significant abnormalities are noted 
compared to previous visits, including a loss of two lines or more of vision, development of 
pupil abnormalities including afference pupillary defect, rise in intraocular pressure, 
development of corneal infiltrates, or other abnormalities not here specified but of concern to 
the ophthalmologist, further investigations of visual function will be conducted according to the 
ophthalmologist decision.  
8.3.5 
Disease severity assessments 
Disease severity will be assess according to EUGOGO guidelines (Bartalena et al 2016).  
Severity 
Parameters 
Mild TED 
Patients whose features of GO have only a minor impact on daily life insufficient 
to justify immunosuppressive or surgical treatment. They usually have one or 
more of the following: minor lid retraction (< 2 mm), mild soft-tissue involvement, 
exophthalmos < 3 mm above normal, no or intermittent diplopia and corneal 
exposure responsive to lubricants.  
Moderate to 
severe TED 
Patients without sight-threatening GO whose eye disease has sufficient impact 
on daily life to justify the risks of immunosuppression (if active) or surgical 
intervention (if inactive). They usually have 2 or more of the following: 
lid retraction ≥ 2 mm, moderate or severe soft-tissue involvement, or 
exophthalmos ≥ 3 mm above normal, inconstant or constant diplopia. 
Sight-
threatening TED 
Patients with DON and/or corneal breakdown 


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To assess disease severity, the following parameters will be examined (refer to 
ophthalmological manual): 
Parameter 
Assessments 
Lid retraction 
Distance between the lid margins in mm with the patient looking in 
the primary position, sitting relaxed and with distant fixation 
Soft-tissue involvement 
Eyelid swelling, redness of eyelids (erythema), conjunctival redness 
or conjunctival edema/swelling (chemosis) 
Exophthalmos 
Measured in mm using the same Hertel exophthalmometer and same 
outer intercanthal distance for an individual patient.  
Diplopia 
Subjective diplopia score 
Corneal exposure 
 Normal/staining/erosion/ulceration 
Optic nerve involvement 
• Best corrected visual acuity 
• Color vision 
• Visual fields  
• Optic disc (OCT assessment) 
• Relative afferent pupillary defect (absent/present, assessed by 
swinging flashlight test) 
8.3.6 
Thyroid eye disease quality of life 
Please refer to Section 8.5.1. 
8.3.7 
Appropriateness of efficacy assessments 
The efficacy assessments selected are considered appropriate for this study in patients with 
moderate to severe TED.  
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. For details on AE collection and reporting, refer to AE section 
(Section 10). 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic examinations will be 
performed. 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an AE must 
be recorded as an AE. 
Vital signs 
Vital signs include systolic blood pressure (SBP), diastolic blood pressure 
(DBP), and pulse measurements. After the patient has been sitting for 5 


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Assessment 
Specification 
minutes, with back supported and both feet placed on the floor, SBP and 
DBP will be measured 3 times using an automated validated device with 
an appropriately sized cuff. The repeat sitting measurements will be made 
at 1 to 2 minute intervals and the mean of the 3 measurements will be 
used. The results of all measurements, including the mean measurement, 
should be recorded in the source data.  
If possible, assessments should be performed by the same study site staff 
member and at the same arm throughout the study. 
Normal blood pressure will be defined as SBP of 90 to < 120 mmHg, and 
diastolic blood pressure of 60 to < 80 mmHg under the measurement 
conditions outlined above. Notable blood pressure findings will be 
hypertension (SBP of ≥ 140 mmHg and/or DBP of ≥ 90 mmHg) or 
hypotension (SBP of < 90 mmHg and/or a DBP of < 60 mmHg). A blood 
pressure indicative of prehypertension (SBP of 120 to < 140 mmHg and/or 
DBP of 80 to < 90 mmHg) will not be regarded as notable (Whelton et al 
2017).  
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 
rate will be 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. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visits to the study site, regular phone calls, virtual contacts or visits of site staff 
to the patient´s home, depending on local regulations and capabilities, will occur (according to 
the visit schedule or weekly if during the weekly induction phase) for safety monitoring and 
review of the patient´s ophthalmological and general health status until the patient can again 
visit the site. This is necessary to ensure that there are no safety concerns to the patient requiring 
treatment interruption or discontinuation. If in the opinion of the investigator the patient requires 
an in-person assessment, arrangements will be made for the patient to be evaluated at the site, 
or if this is not feasible, by a local ophthalmologist or in an emergency healthcare setting. In 
consultation with the investigator, selected ophthalmological assessments (e.g., visual acuity, 
intraocular pressure, color vision) can also be done by a local optometrist to enable continuous 
monitoring of the patient´s ophthalmological status if on-site visits or visits to a local 
ophthalmologist are not feasible. Assessment results have to be reported to and discussed with 
the investigator as soon as possible in this case. 
Events qualifying for being reported in the case report form (e.g., AEs) should be entered as 
appropriate.  
If patients cannot visit the site to have urine pregnancy tests done, urine pregnancy test kits may 
be shipped or provided directly to the patient (e.g., together with the study drug). After 
appropriate instruction, patients can perform the urine pregnancy test at home and report the 
result to the site. It is important that patients do the pregnancy test first and only if the test result 
is negative proceed with the administration of the study drug. 


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Depending on local regulations and capabilities, study site staff may visit the patient at home 
to draw blood/urine samples if needed.   
8.4.1 
Laboratory evaluations 
Clinically notable laboratory findings are defined in Appendix 1. Please refer to Table 8-1 and 
Table 8-2 for the timing of laboratory evaluations.  
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or AEs as appropriate. 
 
Test category 
Test name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red Blood Cells (RBCs), White Blood 
Cells (WBCs), Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Bands) 
Chemistry 
Albumin, Alkaline Phosphatase, Alanine Amino Transferase (ALT), 
Aspartate Amino Transferase (AST), Gamma-glutamyl Transferase (GGT), 
Lactate Dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatinine, Direct Bilirubin, 
Indirect Bilirubin, Total Bilirubin, Total Cholesterol, Low Density Lipoprotein 
(LDL), High Density Lipoprotein (HDL), Total Protein, Triglycerides, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Glycated Hemoglobin (HbA1c) will 
be assessed from fasting blood samples.  
Urinalysis 
The central laboratory will provide dipsticks to the sites for local analysis of 
urine. Dipstick analysis will measure specific gravity, protein, glucose and 
blood. Microscopy and white blood cell count and red blood cell count 
sediments will be assessed in case of an abnormal dipstick test. Only 
samples with abnormal dipstick will be assessed by the central laboratory. 
Study sites should record the results in the source documentation. 
Pregnancy test 
Please refer to Section 8.4.2. 
Fertility test 
A follicle stimulating hormone (FSH) test will be performed if required for 
fertility testing in the absence of other records of fertility (see Section 8.4.2) 


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8.4.2 
Pregnancy and assessments of fertility 
Pregnancy testing 
Secukinumab must not be given to pregnant women; therefore, effective methods of birth 
control must be used for women of childbearing potential (see Exclusion Criteria definitions, 
Section 5.2). 
A serum β-human chorionic gonadotropin (hCG) test will be performed in all women of 
childbearing potential at Screening. All pre-menopausal women who are not surgically sterile 
at Screening will have local urine pregnancy tests performed as indicated in Table 8-1 and Table 
8-2. A positive urine pregnancy test requires immediate interruption of study treatment until 
serum β-hCG is performed and found to be negative. If positive, the patient must be 
discontinued from the trial. Additional pregnancy testing might be performed if requested per 
local requirements. Refer to Section 10.1.4 for details on reporting of pregnancy.  
Assessments of fertility 
Refer to Section 5.2 for criteria to determine women that are not of childbearing potential. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
childbearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy. 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
patient who states that they are of non-childbearing potential regardless of reported 
reproductive/menopausal status at Screening/Baseline. 
8.4.3 
Other safety evaluations 
A standard 12-lead electrocardiogram (ECG) will be performed as indicated in Table 8-1 and 
will be reviewed locally. Clinically relevant abnormalities should be recorded on the relevant 
medical history/current medical conditions/AE eCRF page for the Screening ECG.  
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population as well as for 
secukinumab clinical studies. 
8.5 
Additional assessments 
8.5.1 
Thyroid eye disease quality of life  
Quality of life will be evaluated with the use of the GO-QoL questionnaire, comprising 
2 subscales assessed separately or in combination (Terwee et al 1998). These 2 subscales are as 
follows:  
1. The consequences of double vision (diplopia) and decreased visual acuity on visual 
functioning, and  


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2. The psychological consequences of a changed appearance.  
Scores on each sub-scale as well as the score on the overall GO-QoL scale have a range of 0 to 
100 points. A change of 8 points is considered to be clinically relevant.  
Guidelines for administering GO-QoL questionnaire 
The patient must be given the GO-QoL questionnaire at the scheduled visit before any clinical 
assessments are conducted. A patient’s refusal to complete all or any part of a questionnaire 
should be documented in the study data capture system and should not be captured as a protocol 
deviation. Handling of protocol deviations can be modified if needed per study protocol. 
The GO-QoL questionnaire should be completed in the language most familiar to the patient. 
If self-administered, the patient should be given sufficient space and time to complete the 
questionnaire. 
The site personnel should check the GO-QoL for completeness and ask the patient to complete 
any missing responses. The questionnaire will be completed on paper. This will be considered 
the source file. 
Completed measure(s) (including when using paper questionnaire measures and any unsolicited 
comments written by the patient) must be reviewed and assessed by the investigator for 
responses, which may indicate potential AEs or SAEs before any clinical study examinations. 
This assessment should be documented in study source records. If AEs or SAEs are confirmed, 
study investigators should not encourage the patient to change responses reported in the 
completed questionnaires. Study investigators must follow reporting instructions outlined in 
Section 10 of the study protocol. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visits to the study site the GO-QoL might alternatively be done remotely from 
the patient´s home (e.g., online), depending on local regulations and technical capabilities. 
 
 


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9 
Study discontinuation and completion 
9.1 
Discontinuation and completion 
9.1.1 
Study treatment discontinuation and study discontinuation 
The investigator closely monitors the disease activity of a patient throughout the entire study 
and must discontinue study treatment or study participation for a given patient if he/she believes 
that continuation would negatively impact the patient's well-being. 
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. 
Study treatment must be discontinued under the following circumstances: 
• Subject decision. 
• If any of the following (evidence of disease progression) occurs in the study eye or fellow 
(contralateral) eye: 
• Compressive optic neuropathy that in the opinion of the investigator requires urgent 
surgical intervention or medical treatment with glucocorticoids 
• Severe corneal injury that requires surgical treatment 
• Severe/major loss of vision defined as a decrease of best-corrected visual acuity to below 
0.1 (Snellen equivalent of 20/200) 
• Other abnormalities not here specified but that the investigator determines would require 
study treatment discontinuation 
• Emergence of the following AEs: 
• Any severe or SAE that is not compatible with administration of study medication, 
including AEs that require treatment with an unacceptable concomitant medication. 


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• Onset of lymphoproliferative disease or any malignancy, except for treated basal cell 
carcinoma, treated actinic keratoses, treated in situ carcinoma of the cervix or 
non--invasive malignant colon polyps which are being or have been removed. 
• Life-threatening infection. 
• Severe hypersensitivity reaction or anaphylactic reaction. 
• Any laboratory abnormalities that in the judgment of the investigator are clinically 
significant and are deemed to place the patient at a safety risk for continuation in the 
study (a general guidance on clinically notable laboratory values is provided in 
Appendix 1). 
• Pregnancy. 
• Use of any biologic immunomodulating agent except secukinumab. 
• Other treatment or procedure for TED in case of worsening of the disease. 
• Any protocol deviation that results in a significant risk to the patient’s safety. 
• Use of prohibited treatment as per recommendations in the prohibited treatment section if 
the treatment with prohibited medication increases the patient's safety risk and if it cannot 
be discontinued. 
• Emergency unblinding 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the patient’s premature discontinuation of study treatment 
and record this information. 
In addition to the study treatment discontinuation criteria above, which apply throughout the 
entire study, the following criterion applies from week 16 onwards for discontinuation of study 
participation of a patient: 
 
Any deterioration compared to baseline values that the investigator considers to be clinically 
relevant in this individual case will result in study discontinuation of  the patient. The evaluation 
should take into account the overall course of the disease of the individual case (e.g., individual 
fluctuations of ocular parameters).    
Patients may decide to discontinue their participation in the study for any reason at any time. 
Premature discontinuation of study treatment 
Patients who prematurely discontinue study treatment during the double-blind treatment period 
(Weeks 0 - 16) or during a course of open-label secukinumab administered during the follow-
up period (at or after Week 16), for any reason other than withdrawal of informed consent 
should not be considered as discontinued from the study. Where possible, they should return 
for the study visits indicated in the Assessment Schedule during treatment. These include up 
to Week 16 (if discontinued during double-blind treatment), up to NR32 (for non-responders), 
and up to R16 (for relapsers). In case patients are not willing to continue attending further study 
visits, they should attend an End of Treatment (EOT) visit 4 weeks after the last dose of study 
drug. This EOT visit includes all assessments of the Week 16 (if discontinued during double-
blind treatment), NR32 (for non-responders) or R16 (for relapsers) visit.  


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Additionally, a follow-up visit (EOS) should be done 12 weeks after last study drug 
administration, including all assessments done at: Week 24 (if discontinued during double-blind 
treatment), Week NR40 (for non-responders) or Week R24 (for relapsers). 
Premature discontinuation of study 
Participants 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 study discontinuation 
visit will be performed. This study discontinuation visit should include all assessments of the 
Week 16 (if discontinued during double-blind treatment), NR32 (for non-responders), R16 (for 
relapsers) or Week 68 (for patients who discontinued during the follow-up period) visit.  
Additionally, all randomized and/or treated patients should have a follow-up (EOS) visit 
conducted 12 weeks after last administration of study treatment, if not yet completed (or at least 
a safety follow-up call or contact, if a visit cannot be performed). This EOS visit includes all 
assessments of the Week 24 (if discontinued during the double-blind treatment period or the 
follow-up for responders), Week NR40 (for non-responders) or Week R24 (for relapsers) visit. 
The information collected is recorded in the eCRF. Documentation of attempts to contact the 
patient should be recorded in the source documentation. 
For all premature discontinuations noted above, if the patient fails to return for these 
assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) should be made 
to contact the participant/pre-designated contact as specified in the lost to follow-up section. 
This contact should preferably be done according to the study visit schedule. 
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation or study discontinuation, at a minimum, in abbreviated 
visits, the following data should be collected at clinic visits or via telephone/email contact: 
• New/concomitant treatments 
• AEs/SAEs 
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 
9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 


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In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, patient therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the patient’s study discontinuation should be made as detailed in the 
assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
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 considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination may include:  
• Unexpected, significant, or unacceptable safety risk to patients enrolled in the study 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, patients 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 or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last patient finishes their study completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision (e.g., each patient will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them). 


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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation patient after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade: 
• Mild: usually transient in nature and generally not interfering with normal activities. 
• Moderate: sufficiently discomforting to interfere with normal activities. 
• Severe: prevents normal activities. 
2. Its relationship to the study treatment (suspected: yes or no). If the event is due to lack of 
efficacy or progression of underlying illness (i.e., progression of the study indication) the 
assessment of causality will usually be ‘not suspected.’ The rationale for this guidance is 
that the symptoms of a lack of efficacy or progression of underlying illness are not caused 
by the trial drug, they happen in spite of its administration and/or both lack of efficacy and 
progression of underlying disease can only be evaluated meaningfully by an analysis of 
cohorts, not on a single patient. 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding with study treatment. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose reduced/increased 
• Drug interrupted/withdrawn 


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6. Its outcome (i.e., recovery status or whether it was fatal). 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient. 
Adverse events (including laboratory abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment in case of early study discontinuation, preferably a follow-up visit or contact 
12 weeks after last study treatment should be performed. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g., continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
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 
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 patient with 
the underlying disease. Alert ranges for laboratory and other test abnormalities are included in 
Appendix 1. 
10.1.2 
Serious adverse events 
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: 
• Fatal 
• Life-threatening 
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 the ICH-E2D Guidelines). 
• Results in persistent or significant disability/incapacity. 
• Constitutes a congenital anomaly/birth defect. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission. 
• Is medically significant, e.g., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 


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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. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective 
if a clinical event has occurred (see Section 10.1.5).  
10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety within 24 hours of learning of its occurrence. Detailed instructions regarding 
the submission process and requirements are to be found in the Investigator folder provided to 
each site. 
Serious adverse events occurring after the patient has provided informed consent until the time 
the patient is deemed a Screen Failure must be reported to Novartis. 
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 
immediately, without undue delay, and under no circumstances later than 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. 
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 Chief Medical Office and Patient Safety 
(CMO&PS) Department associate may urgently require further information from the 
Investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all Investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected unexpected serious adverse reactions (SUSARs) will be collected and reported to the 
Competent Authorities and relevant Ethics Committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
SAE reporting will be done according to the assessment schedule throughout treatment and 
follow-up periods. 


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In case of early study discontinuation, any SAEs experienced after the 30-day period following 
the last administration of study treatment should only be reported to Novartis Safety if the 
Investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
If a female trial patient becomes pregnant, the study treatment should be stopped, and the trial 
patient must be asked to read and sign pregnancy consent form to allow the Study Doctor ask 
about her pregnancy.  
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, 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 recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness (Table 10-1). 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 


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For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring  
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug and/or concomitant medication (e.g., thyrostatic treatment) and/or 
hyperthyroidism related liver enzyme elevation, 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 
• 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. 


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10.2.2 
Renal safety monitoring 
To date, there has been no safety signal for nephrotoxicity with secukinumab in over 27,000 
patients and healthy subjects exposed, and from a mechanism of action standpoint there is no 
known effect of blocking IL-17A on the kidney. All subjects with laboratory tests resulting in 
clinically significant abnormal values (see Appendix 1 for notable laboratory values) are to be 
followed until the values return to normal ranges or until a valid reason, other than treatment 
related AE, is defined. Standard renal function tests (blood urea nitrogen or urea, serum 
creatinine) will be obtained at regular intervals, but special measures for renal safety monitoring 
are not planned. 
10.2.3 
Data monitoring committee 
Not applicable.  
10.2.4 
Adjudication committee 
Not applicable.  
11 
Data collection and database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1 and Table 8-2) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated contract research organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 


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site staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, Screen Failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the patient and all 
dosage changes will be tracked using an IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO 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/delegated CRO. 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, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 


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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. 
12 
Data analysis and statistical methods 
The data will be analyzed by Novartis and/or a designated CRO. 
The primary endpoint analysis will include the primary endpoint (Week 16) and results of 
retreatment for proptosis non-responders, after all patients have completed the Week 40 visit 
assessment. This will support potential regulatory filing as described in Section 4.4. A final 
analysis is planned at the EOS once all patients have completed their EOS visit. There may be 
analyses in addition to Week 40 and Week 108 timepoints to support regulatory filings.   
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Randomized Set consists of all randomized participants. Unless otherwise specified, mis-
randomized participants (mis-randomized in IRT) will be excluded from the randomized set. 
Mis-randomized participants are defined as those participants who were mistakenly randomized 
into the IRT prior to the site confirming all eligibility criteria had been met and to whom no 
study medication was given. Mis-randomized participants are treated as screen failures.  
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned. 
Patients will be analyzed according to the treatment they have been assigned to. 
The Safety Set includes all patients who received at least one dose of study treatment/reference 
treatment. Patients will be analyzed according to the study treatment received. 
12.2 
Patient demographics and other baseline characteristics  
Demographic and other Baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group and in total for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.  
Relevant medical histories and current medical conditions at Baseline will be summarized by 
system organ class (SOC) and preferred term (PT), and by treatment group. 
12.3 
Treatments 
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the anatomical therapeutic chemical 
(ATC) classification system, by treatment group. 


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12.4 
Analysis of the primary endpoints/estimands 
During scientific advice sessions, the FDA and the EMA expressed different preferences 
regarding the primary and secondary endpoints and their ordering. Therefore, this study will 
have 2 different analysis strategies and corresponding endpoint definitions, Plan A is intended 
for the EMA submission and Plan B is intended for the submission to FDA. The plan used for 
other health authorities will be based on local decisions. 
Plan A (EU) 
The primary objective of this study is to demonstrate the effect of secukinumab 300 mg 
compared to placebo on the overall responder rate at Week 16. 
The primary endpoint is the proportion of patients achieving overall response at Week 16 
defined as follows: ≥ 2 point reduction in CAS AND ≥ 2 mm reduction in proptosis from 
Baseline in the study eye, provided there is no corresponding deterioration in CAS or proptosis 
(≥ 2 point or 2 mm increase, respectively) in the fellow (contralateral) eye. 
Plan B (FDA) 
The primary objective is to demonstrate the effect of secukinumab 300 mg compared to placebo 
on the responder rate in ≥ 2 mm reduction of proptosis at Week 16. 
The primary endpoint is the proportion of patients achieving response in reduction of proptosis 
at Week 16 defined as follows: reduction of ≥ 2 mm from Baseline in the study eye without 
deterioration (≥ 2 mm increase) of proptosis in the fellow eye. 
12.4.1 
Definition of primary endpoints/estimands 
For the definition of primary and secondary estimands, see Section 2.1 and Section 2.2.   
12.4.2 
Statistical model, hypothesis, and method of analysis 
The null hypothesis to be rejected is that there is no difference in marginal response rates for 
patients with secukinumab vs. patients with placebo after 16 weeks.  
Let pj denote the probability of a response at 16 weeks for treatment group j, j=0, 1 where 
• 0 corresponds to placebo 
• 1 corresponds to secukinumab 
The following hypotheses will be tested: 
H0: p1 = p0 versus HA: p1 ≠ p0 
The primary analysis will be performed comparing treatments with respect to the primary 
endpoint in a logistic regression model with treatment group and stratum (i.e., smoking status) 
as factors and Baseline proptosis as covariate. Difference in marginal response proportions 
between treatments and its 95% confidence interval (CI) will be imputed using the marginal 
standardization method, details will be provided in the SAP. The primary analysis will be based 
on the FAS and will be performed when all patients have completed the Week 16 assessment.  


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Testing strategy 
The following hypotheses will be included in the testing strategy, and type-I-errors will be set 
such that a family-wise-type-I-error of α = 0.05 is kept. 
Plan A 
Primary objective: 
H1 Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving overall response (as defined above) at Week 16. 
Key secondary objectives: 
H2 Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving a CAS response defined as a ≥ 2-point reduction at Week 16 
without corresponding deterioration in CAS (≥ 2-point increase) in the fellow eye. 
H3 Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving a proptosis response defined as a ≥ 2 mm reduction in proptosis at 
Week 16 without corresponding deterioration in proptosis (≥ 2 mm increase) in the 
fellow eye. 
H4 Secukinumab 300 mg is not different to placebo regimen with respect to the mean 
change from baseline in CAS at Week 16. 
The family-wise error will be set to α = 0.05 (2-sided), which will be controlled via the proposed 
fixed testing sequence. The hypothesis for the composite primary objective will be tested first 
and in case of rejection, H2 and H3 will be tested simultaneously. This can be done without any 
multiplicity adjustment, as H2 and H3 are the hypotheses for the single components  
contained in the primary composite and rejection of H1 would necessitate the rejection of at 
least one of the component hypotheses H2 or H3. Then, based on the rejection of H2 and H3, the 
final test will be performed for H4. Further secondary endpoints will be tested outside of the 
confirmatory framework without adjustments for multiple testing.  
Plan B 
Primary objective: 
H1 
Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving a proptosis response defined as a ≥ 2 mm reduction in proptosis at 
Week 16 without corresponding deterioration in proptosis (≥ 2 mm increase) in the 
fellow eye. 
Key secondary objectives: 
H2 
Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving a CAS response defined as a ≥ 2-point reduction at Week 16 
without corresponding deterioration in CAS (≥ 2 points increase) in the fellow eye. 
H3 
Secukinumab 300 mg is not different to placebo regimen with respect to the proportion 
of patients achieving overall response (as defined above) at Week 16. 


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H4 
Secukinumab 300 mg is not different to placebo regimen with respect to the mean 
change from baseline in CAS at Week 16. 
The family-wise error will be set to α = 0.05 (2-sided), which will be controlled via the proposed 
fixed testing sequence. Further secondary endpoints will be tested outside of the confirmatory 
framework without adjustments for multiple testing. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Not applicable, all intercurrent events and their handling are defined above. 
12.4.4 
Handling of missing values not related to intercurrent event 
The primary endpoint should in principle be available for all patients who do not discontinue 
the trial. However, if for any reason the response status is unknown for such a patient, he/she 
will be counted as a non-responder. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
Treatment groups will be compared using a Mantel-Haenszel-Test. 
12.4.6 
Supplementary analysis 
12.4.7 
The primary analysis will be conducted separately within the two 
strata.Supportive analyses 
An additional Bayesian analysis may be conducted. Posterior distributions of the treatment 
effect will be derived as a guidance for internal decision making on further development in this 
indication. Details will be specified in a separate analysis plan.  
12.5 
Analysis of secondary endpoints/estimands 
12.5.1 
Efficacy endpoints 
Plan A 
The 2 components of the primary endpoint, the CAS response and the proptosis response will 
be analyzed separately using the same methodology as for the primary endpoint. 
Plan B 
The CAS response and the overall response will be analyzed using the same methodology as 
for the primary endpoint. 
The mean change from baseline in CAS, the mean change from baseline in proptosis and 
the mean change from baseline in GO-QoL score will be analyzed using a mixed model for 
repeated measures (MMRM) with factors treatment group and stratum and with baseline as a 
covariate. Least-square mean differences with corresponding confidence intervals and p-values 
will be calculated for each visit time point as estimates for the treatment effect. 


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The proportion of patients achieving response in diplopia and the proportion of patients 
with an improvement in disease severity at Week 16 will be analyzed analogous to the 
primary endpoint. 
12.5.2 
Safety endpoints 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group.  
Safety summaries (tables, figures) include only data from the on-treatment period and follow-
up period with the exception of Baseline data that will also be summarized where appropriate 
(e.g., change from Baseline summaries). In addition, a separate summary for death including 
on treatment and post treatment deaths will be provided. In particular, summary tables for AEs 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
Adverse events 
All information obtained on AEs will be displayed by treatment group and patient. 
The number and percentage of patients with treatment emergent AEs (events started after the 
first dose of study medication or events present prior to start of double-blind treatment but 
increased in severity based on PT) will be summarized in the following ways: 
• By treatment, primary SOC and PT. 
• By treatment, primary SOC, PT and maximum severity. 
Separate summaries will be provided for study treatment related AEs, death, SAEs, other 
significant AEs leading to discontinuation. 
The number (and proportion) of patients with adverse events of special interest (AESIs) will be 
summarized by treatment. 
A patient with multiple AEs within a primary SOC is only counted once towards the total of the 
primary SOC. 
Vital signs 
All vital signs data will be listed by treatment group, patient, and visit/time and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, patient, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.  
 
 
 
 


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12.7 
Interim analyses 
Please refer to Section 4.4. 


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12.8 
Sample size calculation 
For Plan A (EMA submission), the primary endpoint is the proportion of patients achieving 
overall response at Week 16 defined as follows: ≥ 2 point reduction in CAS AND ≥ 2 mm 
reduction in proptosis from Baseline in the study eye, provided there is no corresponding 
deterioration in CAS or proptosis (≥ 2 point or 2 mm increase, respectively) in the fellow eye.  
For Plan B (FDA submission), the primary endpoint is the proportion of patients achieving 
response in reduction of proptosis at Week 16 defined as follows: reduction of ≥ 2 mm from 
Baseline in the study eye without deterioration (≥ 2 mm increase) of proptosis in the fellow eye. 
The sample size calculation is given for the primary endpoint of the EMA strategy Plan A that 
takes into account both CAS and proptosis response rates. For the FDA strategy Plan B, the 
deliberations given for the secondary endpoint below apply, which in effect follow the same 
principles as the primary endpoint. 
12.8.1 
Primary endpoint 
In the Phase 3 teprotumumab study (Douglas et al 2020) for which data are available on active 
and placebo arms, the percentage of patients achieving a reduction of 2 mm or more in proptosis 
and a reduction of 2 points or more in CAS in the study eye at Week 24 was 78% for patients 
receiving teprotumumab and 7.1% for patients receiving placebo (p ˂ 0.001). In the Phase 2 
clinical trial of teprotumumab (Smith et al 2017), the corresponding responder rates at Week 24 
were 69% (teprotumumab) vs. 20% (placebo) (p ˂ 0.001). 
For the current study, we are hypothesizing response rates of 60% for secukinumab vs. 20% for 
placebo. A response rate of 60% is considered clinically meaningful given the medical need for 
effective treatment with a therapy of active, moderate to severe TED that does not carry the 
toxicity risks of current treatment alternatives, e.g., high dose i.v. corticosteroids. With this 
response rate and the expected safety profile of secukinumab to be similar to that already 
established, the response will fall in line with a favorable benefit-risk assessment. 
Under these assumptions, 35 patients per treatment arm (70 patients in total) are required to 
achieve a power of 90% to demonstrate superiority at a significance level of 0.05 using the 
2-group continuity corrected Chi-squared test of equal proportions. 
In case of deviations in the group proportions/percentages for the primary endpoint and keeping 
the number of patients per group at 35 and the significance level constant, the following table 
includes the differing power scenarios for the planned study. They show a robust statistical basis 
for this trial in terms of power. 
Placebo response 
Secukinumab response 
Power 
0.175 
0.60 
0.94 
0.20 
0.60 
0.90 
0.225 
0.60 
0.85 


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12.8.2 
Secondary endpoints 
For the key secondary endpoints included in the fixed testing sequence described above, 
treatment effects in about the same order of magnitude as for the primary endpoint are expected; 
therefore, the power for these endpoints should also be similar and should be adequate.  
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the 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. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g., Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality control and quality assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 


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Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study patients. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study patients. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Bahn RS, Gorman CA (1987) Choice of therapy and criteria for assessing treatment outcome 
in thyroid‐associated ophthalmology. Endocrinol Metab Clin North Am;16(2)391–407. 
Barrio-Barrio J, Sabater AL, Bonet-Farriol E, et al (2015) Graves’ Ophthalmopathy: VISA 
versus EUGOGO Classification, Assessment, and Management. J Ophthalmol 2015: 249125. 
Bartalena L, Krassas GE, Wiersinga W, et al (2012) Efficacy and Safety of Three Different 
Cumulative Doses of Intravenous Methylprednisolone for Moderate to Severe and Active 
Graves’ Orbitopathy. J Clin Endocrinol Metab; 97(12):4454-4463.  
Bartalena L, Baldeschi L, Boboridis K, et al (2016) The 2016 European Thyroid Association/ 
European Group on Graves’ Orbitopathy Guidelines for the Management of Graves’ 
Orbitopathy. Eur Thyroid J.;5(1):9–26. 
Bartley GB (2011) Rundle and His Curve. Arch Ophthamol; 129(3): 356.  
Bruin G, Loesche C, Hyirady J, et al (2017) Population Pharmacokinetic Modeling of 
Secukinumab in Patients with Moderate to Severe Psoriasis. J Clin Pharmacol; 57(7):876-885. 
Chen Q (2019) The expression of interleukin-15 and interleukin-17 in tears and orbital tissues 
of Graves ophthalmopathy patients. J Cell Biochem; 120(4):6299-6303.  
Deodhar A, Mease PJ, Mc Innes IB, et al (2019) Long-term safety of secukinumab in patients 
with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: 
integrated pooled clinical trial and post-marketing surveillance data. Arthritis Res 
Ther;21(1):111. 
Dolman PJ, Cahill K, Czyz CN, et al (2012) Reliability of estimating ductions in thyroid eye 
disease: an International Thyroid Eye Disease Society multicenter study. Ophthalmology; 
119(2):382-9. doi: 10.1016/j.ophtha.2011.07.011. 
Douglas R, Kahaly G, Patel A, et al (2020) Teprotumumab for the Treatment of Active 
Thyroid Eye Disease. N Engl J Med;382:341-52. 
Eckstein A, Quadbeck B, Mueller G (2003) Impact of smoking on the response to treatment 
of thyroid associated ophthalmopathy. Br J Ophthalmol; 87(6): 773-776.  
Fang S, Huang Y, Wang S, et al (2016a) IL-17A Exacerbates Fibrosis by Promoting the 
Proinflammatory and Profibrotic Function of Orbital Fibroblasts in TAO. J Clin Endocrinol 
Metab; 101(8):2955-2965.  
Fang S, Huang Y, Zhong S et al (2016b) IL-17A Promotes RANTES Expression, But Not 
IL-16, in Orbital Fibroblasts Via CD40-CD40L Combination in Thyroid-Associated 
Ophthalmopathy. Invest Ophthalmol Vis Sci.; 57:6123–6133. 
Fang S, Huang Y, Zhong S, et al (2017) Regulation of orbital fibrosis and adipogenesis by 
pathogenic Th17cells in graves orbitopathy. J Clin Endocrinol Metab; 102:4273-83. 


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Fang S, Huang Y, Wang N, et al (2019) Insights into local orbital immunity: Evidence for the 
involvement of the Th17 cell pathway in Thyroid associated opthalmopahty. J Clin 
Endocrinol Metab; 104:1697-1711. 
Gorman C (1998) The measurement of change in Graves' ophthalmopathy. Thyroid. 
Volume 8, Number 6. 
Hai Y, Lee A, Frommer L, et al (2019) Immunohistochemical analysis of human orbital tissue 
in Graves' orbitopathy. J Endocrinol Invest. Doi: 10.1007/s40618-019-01116-4 [Epub ahead 
of print] 
Huang D, Xu N, Song Y et al (2012) Inflammatory cytokine profiles in the tears of thyroid-
associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol; 250(4):619-625. 
Huang Y, Fang S, Li D et al (2019) The involvement of T cell pathogenesis in thyroid-
associated ophthalmopathy. Eye;33:176-82. 
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for expedited 
reporting. Accessed from: 
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002807.p
df Accessed on: 02Dec2016. 
Ing E (2019) Thyroid associated orbitopathy. Medscape; 1-23. Available at 
[https://emedicine.medscape.com/article/1218444] 
Kahaly GJ, Petrak F, Hardt J, et al (2005) Psychosocial morbidity of Graves’ orbitopathy. 
Clin Endocrinol (Oxf);63(4):395-402. 
Kahaly G, Riedl M, König J, et al (2018) Mycophenolate plus methylprednisolone vs 
methylprednisolone alone in active, moderate-to-severe Graves’ orbitopathy (MINGO): a 
randomized, observer-masked, multicenter trial. Lancet;6:287-98. 
Kim S, Yoon J, Kim K, et al (2012) Increased serum interleukin-17 in Graves’ 
ophthalmopathy. Graefes Arch Clin Exp Ophthalmol;250(10):1521-6. 
Mourits M, Prummel M, Wiersinga W, et al (1997) Clinical activity score as a guide in the 
management of patients with Graves’ ophthalmopathy. Clinical Endocrinology; 47(1):9-14. 
Perez-Moreiras J, Gomez-Reino J, Maneiro J, et al (2018) Efficacy of tocilizumab in patients 
with moderate to severe corticosteroid resistant Graves orbitopathy: a randomized clinical 
trial. Am J Ophthalmol;195:181–90. 
Perros P, Hegedus L, Bartalena L, et al (2017) Graves’ orbitopathy as a rare disease in 
Europe: a European Group on Graves’ Orbitopathy (EUGOGO) position statement. Orphanet 
Journal of Rare Diseases;12:72. 
Ponto KA, Merkesdal S, Hommel G, et al (2013) Public health relevance of Graves’ 
orbitopathy. J Clin Endocrinol Metab;98(1):145–52. 
Smith T, Kahaly G, Ezra D, et al (2017) Teprotumumab for Thyroid-Associated 
Opthalmopathy. NEJM; 376:1748-61. 


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Stan MN, Garrity JA, Carranza Leon BG, et al (2015) Randomized controlled trial of 
rituximab in patients with Graves’ orbitopathy. Journal of Clinical Endocrinology and 
Metabolism; 100:432–441.  
Stan MN, Salvi M (2017) Management of endocrine disease: rituximab therapy for Graves’ 
orbitopathy—lessons from randomized controlled trials. Eur J Endocrinol;176(2):R101–9. 
Taylor P, Zhang L, Lee R, et al (2020) New insights into the pathogenesis and nonsurgical 
management of Graves orbitopathy. Nat Rev Endocrinol;16(2):104-116. 
Terwee CB, Gerding MN, Dekker FW, et al (1998) Develop- ment of a disease specific 
quality of life questionnaire for patients with Graves’ ophthalmopathy: the GO-QOL. Br J 
Ophthalmol;82:773-9. 
Ujhelyi B, Gogolak P, Erdei A et al (2012) Graves’ orbitopathy results in profound changes in 
tear composition: a study of plasminogen activator inhibitor-1 and seven cytokines. Thyroid; 
22(4):407-414. 
Wei H, Guan M, Qin Y et al (2014) Circulating levels of miR146a and Il17 are significantly 
correlated with the clinical activity of Graves ophthalmopathy. Endocr J;61(11):1087-92. 
Wiersinga W (2017) Advances in treatment of active, moderate-to-severe GO. Lancet 
Diabetes Endocrinol; 5:134-42. 
Whelton PK, Carey RM, Aronow WS et al (2017) 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the 
prevention, detection, evaluation, and management of high blood pressure in adults: a report 
of the American College of Cardiology/American Heart Association Task Force on clinical 
practice guidelines. J Am Coll Cardiol; S0735-1097(17): 41519-1. 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs  
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. Notable values for blood pressure and pulse are presented in Section 8.4.  
No specific action is pre-defined within this protocol to respond to specific abnormal laboratory 
values, as it will be decided by the Investigator/qualified site staff whether and which specific 
action needs to be taken to respond to any abnormal values, taking into account the overall 
status of the patient. For additional information please refer to the laboratory manual.  
Liver function and related variables  
ALT (SGPT):  
 
 
 
> 3 x upper limit of normal (ULN) 
AST (SGOT):  
 
 
 
> 3 x ULN 
Total bilirubin: 
 
 
 
> 2 x ULN 
Alkaline phosphatase:  
 
 
> 2 x ULN 
Renal function and electrolyte variables 
Creatinine (serum): 
 
 
 
> 1.5 x ULN 
Hematology variables 
Hemoglobin:  
 
 
 
≥ 20 g/dL decrease from Baseline 
Platelet count:  
 
 
 
< lower limit of normal (LLN) 
White blood cell count: 
 
 
< 0.8 x LLN 
Neutrophils:  
 
 
 
< 0.9 x LLN 
Eosinophils:  
 
 
 
> 1.1 x ULN 
Lymphocytes:  
 
 
 
> 1.1 x ULN 
Urinalysis variable 
Protein urine dipstick:  
 
 
++* (* ++ is ≥ 100 mg/dL) 
 
 
 
  


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-3 
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 16-4 
Follow-up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s 
Law casea 
• 
Discontinue the study 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) 


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Criteria 
Actions required 
Follow-up monitoring 
> 5 to ≤ 8 × ULN 
• 
Repeat LFT within 48 hours 
• 
If elevation persists, continue follow-
up monitoring 
• 
If elevation persists for more than 
2 weeks, discontinue the study drug 
• 
Establish causality 
• 
Complete liver CRF 
ALT, AST, TBL, Alb, pt/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
• 
Discontinue the study 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  


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Criteria 
Actions required 
Follow-up monitoring 
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 of normal 


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16.3 
Appendix 3: GO-QoL assessment 
 

SAP_001.pdf: 
Clinical Development 
AIN457 (Secukinumab) 
CAIN457ADE16 / NCT04737330
A two-year multi-center Phase 3 study to investigate the 
efficacy and safety of secukinumab in adult patients with 
active, moderate to severe thyroid eye disease (ORBIT), 
with a randomized, parallel-group, double-blind, placebo-
controlled, 16-week treatment period, and a follow-
up/retreatment period 
Statistical Analysis Plan (SAP) 
Author: 
CRO Biometrician, 
 
Document type: 
SAP Documentation 
Document status: Final, Amendment 2 
Release date: 
25-Apr-2023
Number of pages: 27 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
27-Apr-2022 
Prior to 
DB lock 
Initial SAP, 
version 1.0 
N/A – First version 
N/A 
15-Nov-2022 
Prior to 
DB lock 
Review of TFL 
shells 
Analysis sets and definition of 
treatment groups changed; 
treatment sequence added; 
Study treatment related 
(S)AEs will not be analyzed 
separately 
2.1.1; 2.2; 2.5.2; 
2.8.1 
25-Apr-2023 
Prior to 
DB lock 
Update due to 
discontinuation 
of the study 
Due to feasibility reasons, 
purely descriptive analyses 
will be performed for primary 
and secondary endpoints. 
Adverse events of special 
interest (AESI) renamed to 
RMP risks. 
1.2, 2.1.1, 2.5 to 
2.14, 3, 4 
 


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Table of contents 
 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design............................................................................................................. 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
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 
Demographic variables and other baseline characteristics .................... 17 
2.3.3 
Medical history ...................................................................................... 17 
2.3.4 
TED and thyroid medical history .......................................................... 17 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary objective .......................................................................... 18 
2.5.1 
Primary endpoint ................................................................................... 18 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 18 
2.5.4 
Sensitivity analyses ............................................................................... 18 
2.5.5 
Subgroup analyses ................................................................................. 18 
2.6 
Analysis of the secondary objective ...................................................................... 18 
2.6.1 
Secondary endpoint ............................................................................... 18 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.6.4 
Subgroup analyses ................................................................................. 19 
2.7 
Analysis of exploratory objectives ........................................................................ 19 
2.8 
Safety analyses ....................................................................................................... 19 
2.8.1 
Adverse events (AEs) ............................................................................ 19 
2.8.2 
Deaths .................................................................................................... 21 


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2.8.3 
Laboratory data ..................................................................................... 21 
2.8.4 
Other safety data ................................................................................... 21 
2.9 
Pharmacokinetic endpoints .................................................................................... 22 
2.10 
PD and PK/PD analyses......................................................................................... 22 
2.11 
Patient-reported outcomes ..................................................................................... 22 
2.12 
Biomarkers ............................................................................................................. 22 
2.13 
Other Exploratory analyses .................................................................................... 22 
2.14 
Interim analysis ...................................................................................................... 22 
3 
Sample size calculation ..................................................................................................... 22 
4 
Change to protocol specified analyses .............................................................................. 22 
5 
Appendix ........................................................................................................................... 23 
5.1 
Imputation rules ..................................................................................................... 23 
5.1.1 
Concomitant medication date imputation ............................................. 23 
5.1.2 
Prior medications/ therapies date imputation ........................................ 23 
5.1.3 
Post therapies date imputation .............................................................. 24 
5.1.4 
Other imputations .................................................................................. 24 
5.2 
AEs coding/grading ............................................................................................... 24 
5.3 
Laboratory parameters derivations ........................................................................ 24 
5.4 
Statistical models ................................................................................................... 24 
5.4.1 
Primary analysis .................................................................................... 24 
5.4.2 
Key secondary analysis ......................................................................... 24 
5.4.3 
Safety analysis ....................................................................................... 24 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 25 
5.6 
Appendix A: Calculation rules .............................................................................. 25 
5.7 
Appendix C: Patient-reported Outcome Scoring rules/Forms/Instruments ........... 26 
5.8 
Disclosure reporting ............................................................................................... 27 
6 
References ......................................................................................................................... 27 


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List of abbreviations 
 
AE(s) 
Adverse Event(s) 
ALT 
Alanine Aminotransferase  
AST 
Asparate Aminotransferase 
ATC 
Anatomic Therapeutic Chemical classification  
CAS 
Clinical Activity Score 
COVID-19 
Coronavirus Disease 2019 
CREDI 
Clinical Regulatory Documentation and Information System 
CRO 
Contract Research Organization 
CRS 
Case Retrieval Sheet 
DBP 
Diastolic Blood Pressure 
DBTP 
Double-Blind Treatment Period 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
EUGOGO 
European Group on Graves’ Orbitopathy 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
fT3 
free T3 
fT4 
free T4 
FUP 
Follow-Up 
GO-QoL  
Grave’s Orbitopathy Quality of Life 
IP 
Investigational Product 
IRT 
Interactive Response Technology  
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NR 
Non-responder 
PD(s) 
Protocol Deviation(s) 
PFS 
Prefilled Syringe 
PRO(s) 
Patient Reported Outcome(s) 
PT 
Preferred Term  
RMP 
Risk Management Plan 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan  
SBP 
Systolic Blood Pressure 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 


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SOC 
System Organ Class  
TEAE(s) 
Treatment-Emergent Adverse Event(s)  
TED 
Thyroid Eye Disease 
TFLs 
Tables, Figures, Listings 


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1 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analysis 
according to Section 12 of the study protocol v02 for AIN457 (secukinumab) Study 
CAIN457ADE16 dated 15-Mar-2022. The scope of this plan includes the primary and 
secondary analyses.  The purpose of this amendment is to modify the analysis plan to reflect 
the early termination status of the study. At the time of termination, 28 patients had been 
randomized, 25 patients had completed the double-blind treatment period, and 23 patients had 
entered the follow-up period. 
1.1 
Study design 
This is a randomized, placebo-controlled, double-blind, parallel-group, interventional, 
multicenter study in patients with moderate to severe thyroid eye disease (TED). This study 
consists of the following 3 periods (see Figure 1-1): 
Screening period (Week -6 to Baseline) 
Patients’ eligibility will be assessed during the Screening Period, which will occur for a 
maximum of 6 weeks. In the event of a major healthcare disruption (e.g., a pandemic or 
epidemic) that limits or prevents on-site visits to the study sites, the Screening Period may be 
extended to a maximum of 8 weeks before Baseline. 
Double-blind treatment period (DBTP) (Baseline to Week 16) 
Eligible patients will be randomized in a 1:1 ratio to one of the following double-blinded 
treatment arms: 
• Arm 1: Secukinumab 300 mg s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 (n=35) 
• Arm 2: Placebo s.c. at Baseline, Week 1, 2, 3, 4, 8, 12 (n=35) 
Patients will be stratified according to current smoking status (up to 20% smokers per arm), 
since smoking has a well-known impact on treatment efficacy in TED. 
Follow-up/open-label retreatment period (Week 16 up to Week 108) 
• Proptosis responders (see definition below) at Week 16 will be followed for relapse up to 
Week 68. If these patients relapse, they will be offered a course of open-label 
secukinumab at the time of relapse (see “proptosis relapsers” definition below). 
• Proptosis non-responders (see definition below) at Week 16 will be offered the option of 
open-label secukinumab treatment (with maintenance of blind of initial randomized 
treatment) for a duration of 16 weeks, i.e., up to Week 32 with last dose at Week 28, as 
follows: 
Open-label secukinumab 300 mg s.c. at Week 16, 17, 18, 19, 20, 24 and 28. Thereafter (i.e., 
from Week 32), patients will be followed up for a further 24 weeks 
.  
For patients who are proptosis non-responders and who do not receive open-label 
secukinumab treatment, a follow-up visit (End of Study [EOS]) 8 weeks after the Week 16 
visit should be scheduled. At this EOS visit, the assessments associated with the Week 24 
visit (for responder) should be performed. 


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• Proptosis relapsers (see definition below) during the follow-up period (from Week 16 
onward to Week 68) will be offered the option of retreatment with open-label 
secukinumab for a duration of 16 weeks (with maintenance of blind to initial randomized 
treatment) at the time of relapse as follows:   
Open-label secukinumab 300 mg s.c., at time of relapse, then at 1, 2, 3, 4, 8 and 12 weeks.  
 
  
For patients not receiving open-label secukinumab treatment, a follow-up visit (EOS) 
8 weeks after the Week 16 visit should be scheduled, if not yet completed. At this EOS visit, 
the assessments associated with the Week 24 visit (for responder) should be performed. 
In the event of a major healthcare disruption (e.g., a pandemic or epidemic) that limits or 
prevents on-site visits, special efforts should be made to conduct the Week 16, R16 and NR16 
visits on-site, if feasible. If it is not feasible to conduct these visits on-site, visits to the patient´s 
home, or a virtual visit if a home visit is not feasible, should be attempted. 
Definitions of proptosis responder, non-responder and relapser 
• Proptosis responder: Patients achieving response in reduction of proptosis at Week 16 
defined as follows: reduction of ≥ 2 mm from Baseline in the study eye without 
deterioration (≥ 2 mm increase from Baseline) of proptosis in the fellow eye. 
• Proptosis non-responder: Patients not achieving response in reduction of proptosis at 
Week 16 with “response” defined as follows: reduction of ≥ 2 mm from Baseline in the 
study eye without deterioration (≥ 2 mm increase from Baseline) of proptosis in the fellow 
eye. 
• Proptosis relapser: Patients who are “proptosis responders” as defined above, and then 
relapse based on proptosis
 with relapse 
defined as follows: increase in proptosis of ≥ 2 mm compared to Week 16 in the study eye 
or deterioration of proptosis (≥ 2 mm increase compared to Week 16) in the fellow eye at 
any time during 52-week follow-up period. 
In case of worsening of the disease during study treatment, patients may receive alternative 
treatment for TED at the discretion of the investigator and will be discontinued from the study 
treatment.  


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Figure 1-1 
Study design 
 
 
1.2 
Study objectives and endpoints 
The purpose of this study is to demonstrate the efficacy and safety of secukinumab 300 mg s.c. 
in adults with active, moderate to severe TED. 
Due to non-efficacy (no responders at the time of premature study discontinuation), purely 
descriptive analyses will be performed for primary and secondary endpoints. Exploratory 
endpoints will not be analyzed. 
The objectives and related endpoints are presented in the table below.  
Table 1-1 
Objectives and related endpoints 
 
Objective 
Endpoint 
Primary objective 
Primary endpoint 
1) To demonstrate that secukinumab is 
superior to placebo with regard to the 
overall responder rate after 16 weeks 
of treatment. 
1) Proportion of patients achieving overall response 
defined as:  
≥ 2 point reduction in clinical activity score (CAS) AND ≥ 2 
mm reduction in proptosis from Baseline in the study eye, 
provided there is no corresponding deterioration in CAS or 
proptosis (≥ 2 point or 2 mm increase, respectively) in the 
fellow eye after 16 weeks of treatment. 
Secondary objectives 
Secondary endpoints 
2.1) To demonstrate that secukinumab 
is superior to placebo with regard to the 
CAS responder rate after 16 weeks of 
treatment. 
2.1) Proportion of patients achieving response in 
reduction of CAS at Week 16 defined as follows: 
reduction of ≥ 2 points from Baseline in the study eye 


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Objective 
Endpoint 
without deterioration (≥ 2 point increase) of CAS in the 
fellow eye. 
2.2) To demonstrate that secukinumab 
is superior to placebo with regard to the 
proptosis responder rate after 16 
weeks of treatment. 
2.2) Proportion of patients achieving response in 
reduction of proptosis at Week 16 defined as follows: 
reduction of ≥ 2 mm from Baseline in the study eye 
without deterioration (≥ 2 mm increase) of proptosis in 
the fellow eye. 
2.3) To demonstrate that secukinumab 
is superior to placebo with regard to 
reduction in diplopia after 16 weeks of 
treatment. 
2.3) Proportion of patients achieving response in diplopia 
at Week 16 defined as follows:  
Baseline diplopia > 0 and a reduction of ≥ 1 grade with no 
corresponding deterioration (≥ 1 grade worsening) in the 
fellow eye at Week 16. 
2.4) To demonstrate that secukinumab 
is superior to placebo with regard to 
reduction in CAS after 16 weeks of 
treatment. 
2.4) Mean change from Baseline to Week 16 in CAS in 
the study eye. 
2.5) To demonstrate that secukinumab 
is superior to placebo with regard to 
reduction in proptosis after 16 weeks of 
treatment. 
2.5) Mean change from Baseline to Week 16 in proptosis 
in the study eye. 
2.6) To demonstrate that secukinumab 
is superior to placebo with regard to 
improvement in disease severity after 
16 weeks of treatment. 
2.6) Mean change in EUGOGO disease severity from 
Baseline to Week 16. 
2.7) To demonstrate that secukinumab 
is superior to placebo with regard to 
improvement in GO-QoL after 16 weeks 
of treatment. 
2.7) Mean change from Baseline to Week 16 in GO-QoL 
score. 
Safety (secondary) endpoint 
Safety (secondary) endpoint 
2.8) To evaluate the safety of 
secukinumab 300 mg s.c. compared to 
placebo. 
2.8) Frequency of AEs, TEAEs, AEs resulting in 
treatment discontinuation, SAEs. 
2 
Statistical methods 
2.1 
Data analysis general information 
The data will be analyzed by Novartis and/or a designated clinical research organization (CRO). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Statistical analysis of all data will be performed using SAS® statistical software (SAS Institute, 
Cary, NC, USA) version 9.4 or higher.  


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General descriptive statistical rules 
Categorical data will be presented as frequencies and percentages. In general, missing values 
are not considered for calculation of percentages (i.e., adjusted percentages are calculated) if 
not otherwise specified. 
For continuous data, the number of non-missing observations, mean, standard deviation, median, 
minimum, and maximum will be presented. 
Unless otherwise stated, summary tables/figures/listings (TFLs) will be presented for each 
treatment arm in the respective analysis set. 
General information on treatment arm handling, decimal places and other output-related 
information will be specified in TFL shells accompanying this analysis plan. 
2.1.1 
General definitions  
Study treatment 
Novartis will supply the investigational medication listed below:  
• 2 × secukinumab 150 mg PFS, s.c. 
• 2 × matching placebo 0 mg PFS, s.c. 
Eligible patients will be randomized in a 1:1 ratio to one of the double-blinded treatment arms. 
Treatment groups  
• Randomized treatment: 
o AIN457 300 mg: All patients randomized to secukinumab. 
o Placebo: Patients randomized to placebo. 
• Treatment sequence: 
o AIN457 – AIN457: Patients randomized to secukinumab and switched to open-
label secukinumab treatment in follow-up period (“AIN457 non-responder”). 
o Placebo – AIN457: Patients randomized to placebo and switched to open-label 
secukinumab treatment in follow-up period (“placebo non-responder”). 
 
Frequency of administration 
Baseline to Week 16 (Double-blind): 
• Secukinumab (300 mg): Baseline, Week 1, Week 2, Week 3, Week 4, Week 8 and 
Week 12 
• Placebo: Baseline, Week 1, Week 2, Week 3, Week 4, Week 8 and Week 12 
Week 16 to end of study (EOS) (Open-label): 
• Non-responders at Week 16: Secukinumab (300 mg) at Week 16, Week 17, Week 18, 
Week 19, Week 20, Week 24 and Week 28; 
• Responders at Week 16 who relapse thereafter: Secukinumab (300 mg) at time of relapse, 
then 1, 2, 3, 4, 8 and 12 weeks from time of relapse. 


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Stratification factor 
Patients will be stratified according to current smoking status (up to 20% smokers per arm), 
since smoking has a well-known impact on treatment efficacy in TED. 
2.1.1.1 
Study dates 
Screening/ Baseline 
Screening period will occur for a maximum of 6 weeks (Day -42 to -1). Baseline is defined as 
the day with the last assessment on or before first dose. At Baseline all eligible patients will be 
randomized via Interactive Response Technology (IRT) to one of the treatment arms. 
Randomization (enrollment) date in DBTP  
Randomization (enrollment) date in double-blind treatment period (DBTP) is the date on which 
a subject is assigned to one of the treatments through IRT in DBTP.  
First IP dose date 
The first investigational product (IP) dose date is the date on which a subject is administered 
the first dose of IP following randomization. 
Last IP dose date 
The last IP dose date for each subject is defined as the latest date IP is administered (including 
study medication in the open-label retreatment phase). 
Subject-level end of treatment (EOT) date 
The EOT date (including the open-label retreatment phase) for each subject is defined as the 
minimum of (last dose date + 84 days) and EOS date.  
Subject-level end of study (EOS) date 
The EOS date for each subject is defined as the last date on which the subject participated in 
the study. The date will be recorded on the Disposition electronic case report form (eCRF) page. 
2.1.1.2 
Visit and analysis window 
Since the actual visit for a subject may not exactly coincide with their targeted visit date, the 
actual visit date is mapped to a study visit. 
The nearest study day window will be utilized to define study visit for laboratory, vital signs, 
number of doses received, ophthalmological assessments and GO-QoL collected during office 
visits before dose is administered. 
In case of multiple assessments within an analysis window, the day the closest to the scheduled 
visit day will be used. 
Unscheduled visits will only be used when there is no measurement from the scheduled visit in 
the defined window. In case of multiple assessment values among the same type of visit (i.e., 
scheduled vs. unscheduled) within the same analysis window, the closest to the scheduled visit 


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day will be used. In case of equal distances (e.g., same day), the latest assessment value will be 
used. 
For assessments that are not scheduled at all visits (e.g. hematology assessments) the derivation 
formula is: 
• Lower limit = upper limit of previous visit +1. 
• Upper limit = integer value of (target day + target day of next visit)/2. 
Table 2-1 
Study visit windows during DBTP  
Study visit 
Target day  
Study day 
DBTP 
Baseline 
1 
≤1 
Week 1 
8 
2 – 11 
Week 2 
15 
12 – 18 
Week 3 
22 
19 – 25 
Week 4 
29 
26 – 43 
Week 8 
57 
44 – 71 
Week 12 
85 
72 – 99 
Week 16 
113 
100 – 127 
Table 2-2 
Study visit windows during open-label treatment and follow-up for 
non-responders 
Study visit 
Target day  
Study day 
Week NR 16* 
113 
100 – 116  
Week NR 17 
120 
117 – 123 
Week NR 18 
127 
124 – 130 
Week NR 19 
134 
131 – 137 
Week NR 20 
141 
138 – 155  
Week NR 24 
169 
156 – 183  
Week NR 28 
197 
184 – 211 
Week NR 32 
225 
212 – 253 
Week NR 40 
281 
254 – 337 
Week NR 56 
393 
338 – 448 
*Only applicable for assessments that have not been performed at Week 16 visit in non-responders. 
2.1.1.3 
Demographics and other baseline characteristics 
Smoking status 
• “Smoker”: a subject is defined as smoker if “Has the subject ever smoked”= “Yes” and 
“Usage” = “Current”. 
• “Non-Smoker”: a subject is defined as non-smoker if “Has the subject ever smoked”= 
“No” OR “Has the subject ever smoked”= “Yes” and “Usage” = “Former”. 


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TED history 
• “Time (years) between onset of TED symptoms and Baseline” will be calculated as the 
difference between date of Baseline visit and date of onset of TED symptoms.  
• “Time (years) between first diagnosis of TED and Baseline” will be calculated as the 
difference between date of Baseline visit and date of first diagnosis of TED.  
Prior or concomitant medications (including previous TED treatments) 
• Prior or concomitant medications will be grouped into categories “ophthalmic 
medications” and “non-ophthalmic medications”. Non-ophthalmic medications are those 
with “laterality” = “not applicable”.  
2.1.1.4 
Efficacy endpoints 
Graves’orbitopathy – Quality of life questionnaire (GO-QoL) 
The GO-Quality of life questionnaire (GO-QoL) comprises 2 subscales assessed separately. 
These 2 subscales are as follows: 
• The consequences of double vision (diplopia) and decreased visual acuity on visual 
functioning and 
• The psychological consequences of a changed appearance. 
Total scores on each subscale will be calculated in the eCRF. Scoring rules used in the eCRF 
are defined in Appendix C (Section 5.7). 
For other efficacy endpoints no specific definition is needed. 
2.1.1.5 
Safety endpoints 
Discontinuation of treatment due to AE  
Discontinuation of treatment due to AE is determined by the information given on the Adverse 
events eCRF page (action taken=”Drug withdrawn”). “Death” as a reason for treatment 
discontinuation will be summarized separately.  
Treatment-emergent adverse events (TEAEs) 
Treatment-emergent adverse events (TEAEs) are defined as adverse events (AEs) that occurred 
on or after the first dose of study treatment up to 84 days following the last dose of study 
treatment. In addition, AEs registered prior to start of double-blind treatment are considered as 
treatment-emergent if they have increased severity based on preferred term any time after the 
first dose of study treatment. 
Serious adverse events (SAEs) 
SAEs are determined by the flag on the Adverse Events eCRF page.  


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Treatment-related adverse event 
Treatment-emergent adverse event is defined as treatment-related, if the investigator considered 
it as having a reasonable possibility to be related to study treatment, which is reflected in the 
eCRF with a corresponding flag. 
Duration of exposure to AIN457 or Placebo (DBTP) 
For calculations of exposure duration, last/ first dose date refers to receiving dose (prefilled 
syringe) > 0. 
The duration of exposure to study treatment or placebo is computed as: 
For patients completing the DBTP: 
• Week 16 visit date – first dose date + 1. 
For patients who discontinue treatment during DBTP: 
• min (last dose date +84 days, Week 16 visit date) – first dose date + 1. 
Duration of exposure to AIN457 (during entire study period) 
For calculations of exposure duration, last/ first dose date refers to receiving dose (prefilled 
syringe) > 0. Duration of exposure will be defined as the time from first dose of study treatment 
to the time of treatment switch (for subjects who switch treatment) or minimum of (last dose of 
the treatment + 84 days) and (last visit date). Patients who switch treatment during the study 
(e.g., from placebo to active treatment) will have exposure to both medications using the 
appropriate start and stop dates (full details are described in Section 3.1 of the protocol [i.e. 
study protocol v01 dated 24-Aug-2021]). 
2.2 
Analysis sets 
Mis-randomized patients who never received any study drug are considered as screen failures 
and are not included in the analysis sets. 
Efficacy analysis 
• The Full analysis set (FAS) will consist of all patients to whom study treatment (AIN457 
or placebo) has been assigned. Following the intent-to-treat principle, patients will be 
analyzed according to the treatment they have been assigned to.  
Safety analysis 
The Safety analysis set (SAF) will consist of all patients who received at least one dose of 
study treatment during the treatment period. Patients will be analyzed according to the study 
treatment received. 
 
 


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Table 2-3 
Treatment groups for safety analysis 
Analysis period 
Treatment group label 
DBTP (up to Week 16) 
AIN457 
Placebo 
Entire study period  
AIN4571 
Placebo2 
Any AIN4573  
1 All patients randomized to secukinumab: This includes responders who receive no treatment after 
Week 16 and secukinumab non-responders or relapsers who go on open-label secukinumab.  
2 Patients randomized to placebo with no open-label treatment in follow-up period. Any AEs reported 
in placebo patients prior to switching to AIN457 are also counted in this group. 
3 Any AIN457 does not refer solely to just patients randomized to AIN457. It includes all patients who 
received at least one dose of secukinumab in DBTP or open-label follow-up. AEs occurring in placebo 
patients after switching to AIN457 are counted in this group.  
2.2.1 
Subgroup of interest 
No subgroup analyses are planned.  
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
Randomized 
Subjects are considered randomized if they have been assigned a randomization number. 
Mis-randomized 
Subjects are considered as randomized in error (=mis-randomized) if they were mistakenly 
randomized into the IRT prior to the site confirming all eligibility criteria had been met and to 
whom no study medication was given. Mis-randomized subjects will be treated as Screen 
Failures.   
Screen failures 
Subjects are considered as screen failure if they do not meet one or more criteria that where 
required for participation in the study. 
Completing the DBTP 
Subjects are defined as completing the DBTP if they complete all visits including Week 16 
assessments. Subjects are defined as DBTP discontinuers if the Subject Status is not ticked as 
“Completed” for the blinded treatment disposition or if they missed any visit. 


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Completing the study 
Subjects are defined as completing the study if they complete all visits including the follow-up 
visit (EOS). It will be derived from Study Disposition Form. 
Patient disposition for the DBTP and follow-up period will be presented based on the FAS.  
A corresponding summary will include number and percentage of patients (treatment group 
specific and overall). The primary reason for premature study discontinuation will be displayed 
by randomized treatment and overall. 
The total number of patients screened and the number of screen failures will be summarized. 
The number of patients within each of the analysis sets used in the study will be given.  
Protocol deviations (PDs) will be summarized separately for PDs not related to coronavirus 
2019 (COVID-19) and for PDs related to COVID-19. For PDs not related to COVID-19, the 
number of patients with at least one PD will be presented (based on FAS) and the results of the 
PDs will be grouped using the broad categories (Selection criteria not met (Study eligibility); 
Withdrawal criteria met, but subject not withdrawn; Treatment deviation; Prohibited 
Concomitant Medication; Other). For PDs related to COVID-19, the number of patients with at 
least one PD will be presented (based on FAS) and the results of the PDs will be grouped by 
category of COVID-19 PD and type of relationship to COVID-19. 
A complete list of the PDs can be found in the Edit Check Specifications document in the 
Clinical Regulatory Documentation and Information System (CREDI). 
2.3.2 
Demographic variables and other baseline characteristics 
Demographic and other Baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group and in total for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, N, mean, 
standard deviation, median, minimum, and maximum will be presented. 
2.3.3 
Medical history 
Relevant medical history and current medical conditions at Baseline will be summarized by 
system organ class (SOC) and preferred term (PT), and by treatment group for the SAF. 
2.3.4 
TED and thyroid medical history 
Disease history collected at Screening contains information on the TED and thyroid medical 
history. Descriptive analyses will be done for time since onset of TED symptoms, time since 
first diagnosis of TED and underlying thyroid condition based on the FAS. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Descriptive statistics for exposure to study treatment will be provided based on the SAF. 
The duration of exposure to study treatment will be summarized by treatment group.  


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In addition, the number of treatment syringes will be presented by treatment group in frequency 
tables by visit and cumulatively. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the anatomical therapeutic chemical (ATC) 
classification system (ATC level 1 and preferred name), by treatment group for the SAF. 
Separate presentations will be provided for ophthalmic and non-ophthalmic medications.  
Concomitant medications and significant non-drug therapies during the double-blind treatment 
period and during the follow-up period will be displayed separately.  
TED and thyroid treatment history (previous and ongoing treatments for TED) will be included 
in the tables for prior/ concomitant ophthalmic medications. 
2.5 
Analysis of the primary objective 
Due to premature study discontinuation, purely descriptive analyses will be performed for the 
primary endpoint. Analysis on primary endpoints will be done based on FAS. 
2.5.1 
Primary endpoint 
The primary endpoint is the proportion of patients achieving overall response. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary endpoint will be presented by treatment group using a frequency table.  Superiority 
testing will be omitted. 
2.5.3 
Handling of missing values/censoring/discontinuations 
The primary endpoint should in principle be available for all patients who do not discontinue 
the trial prior to the discontinuation by the sponsor. Missing values will not be replaced. 
2.5.4 
Sensitivity analyses  
No sensitivity analyses are planned. 
2.5.5 
Subgroup analyses 
No subgroup analyses are planned.  
2.6 
Analysis of the secondary objective 
2.6.1 
Secondary endpoint 
The secondary objectives and endpoints are given in Table 1-1.  
Analysis of secondary endpoints will be done based on the FAS. 


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2.6.2 
Statistical hypothesis, model, and method of analysis 
The secondary objectives will be analyzed in a purely descriptive manner: summary statistics 
by visit and change to baseline. No testing strategy will be applied. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing values of secondary endpoints will not be replaced. 
2.6.4 
Subgroup analyses 
Not applicable. 
2.7 
Analysis of exploratory objectives 
Due to premature study discontinuation, exploratory objectives and endpoints will not be 
analyzed. 
2.8 
Safety analyses 
Summaries may be performed separately for initial (Baseline to Week 16) period and entire 
study period (including follow-up). Week 16 is chosen due to the fact that patients may be 
switched to another treatment at this time. Use of data up to and including the last visit before 
first switch opportunity provides an unbiased comparison between AIN and placebo; data 
collected beyond Week 16 are included in analyses which summarize the entire study period.   
All listings and tables will be presented by treatment group. Safety summaries include only data 
from the on-treatment period and follow-up period with the exception of Baseline data that will 
also be summarized where appropriate (e.g., change from Baseline summaries). The on-
treatment period is defined as date of first treatment to (date of last treatment + 84 days).  
In addition, a separate summary for death including on-treatment and post-treatment deaths will 
be provided. 
In particular, summary tables for AEs will summarize only on-treatment events, with a start 
date during the on-treatment period (treatment-emergent AEs) for the DBTP and the entire 
study period.  
Missing data will not be imputed for safety endpoints. 
2.8.1 
Adverse events (AEs) 
In the frame of safety analysis the following treatment-emergent AE types will be considered: 
• Any AE  
• Study treatment related AE 
• AE leading to study treatment discontinuation  
• Serious AE (SAE) 
• Study treatment related SAE 
• SAE leading to study treatment discontinuation 
• Death 


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• RMP risks 
All AE tables will be summarized by treatment group. 
 
The Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 or later will be used 
to code all AEs to a system organ class (SOC) and a preferred term (PT).  
An overview table of the number and percentage of patients having each type of AE will be 
given. Crude incidence and exposure adjusted incidence rates will be provided (see 
Section 5.4.3 [safety analysis]).  
Tables with number and percentage of patients having particular AE summarized by treatment 
group, SOC and PT will be provided for all AEs listed above except for death. Summaries will 
be provided for each AE type separately. 
For AE type ‘any AE’ tables with number and percentage of patients having particular AE 
summarized by treatment group, SOC, PT and maximum severity will be provided. 
The SOCs will be presented in the alphabetic order and PTs will be ordered within the SOCs 
by decreasing order of frequency in the secukinumab treatment group. 
If a patient reported more than one AE with the same PT, 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. 
All AEs, deaths, SAEs and AEs leading to permanent treatment discontinuation and leading to 
study discontinuation and AEs related to COVID-19 will be listed separately. In addition an 
ocular AE listing with laterality will be provided. 
Table 2-4 
Overview of analyses on some safety endpoints 
Analysis period 
AEs & SAEs 
AEs by maximum 
severity 
Study treatment 
related AEs 
Notables for  
vitals, lab 
criteria 
Day 1 – 
Week 16 
•Crude incidence 
•Crude incidence 
•Crude incidence 
•Crude incidence 
Entire study phase  
•Crude incidence 
Exposure time 
adjusted incidence 
•Crude incidence 
•Crude incidence 
•Crude incidence 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Safety topics of interest, such as risks defined in the Risk Management Plan (RMP), are defined 
in the Case Retrieval Sheet (CRS) that is stored in CREDI. For the evaluation of RMP risks, 
primary and secondary MedDRA SOCs will be considered.  
 


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2.8.2 
Deaths 
Deaths – including on treatment and post treatment deaths – will be listed by treatment group 
including the start date of the study treatment, the last date on study treatment, the death date 
and the reason for death. Deaths from the on-treatment period will be flagged. 
2.8.3 
Laboratory data 
All laboratory data (hematology, clinical chemistry, urinalysis and thyroid-related parameters) 
from the on-treatment period will be listed by treatment group, patient, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics for clinical 
notable laboratory values will be provided by treatment and visit. 
The following clinical notable laboratory values are defined: 
Liver function and related variables 
 
ALT (SGPT) 
> 3 × ULN 
AST (SGOT) 
> 3 × ULN 
Total bilirubin 
> 2 × ULN 
Alkaline phosphatase 
> 2 × ULN 
Renal function and electrolyte variables 
 
Creatinine (serum): 
> 1.5 × ULN 
Hematology variables 
 
Hemoglobin 
≥ 20 g/dL decrease from Baseline 
Platelet count 
< LLN 
White blood cell count: 
< 0.8 × LLN 
Neutrophils 
< 0.9 × LLN 
Eosinophils 
> 1.1 × ULN 
Lymphocytes 
> 1.1 × ULN 
Urinalysis variables 
 
Protein urine dipstick 
++* (* ++ is ≥ 100 mg/dL) 
2.8.4 
Other safety data 
2.8.4.1 
ECG  
A standard 12-lead electrocardiogram (ECG) will be performed at Screening (source data) and 
will be reviewed locally. ECG data will not be analyzed. 
2.8.4.2 
Vital signs 
Notable vital signs abnormalities will be analyzed by treatment group for the DBTP and the 
entire study period. A frequency table will be provided. 
Normal blood pressure will be defined as systolic blood pressure (SBP) of 90 to < 120 mmHg, 
and diastolic blood pressure of 60 to < 80 mmHg under the measurement conditions outlined in 
the protocol. Notable blood pressure findings will be hypertension (SBP of ≥ 140 mmHg and/or 
diastolic blood pressure [DBP] of ≥ 90 mmHg) or hypotension (SBP of < 90 mmHg and/or a 
DBP of < 60 mmHg).  


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A normal pulse rate will be defined as a rate of 60 to 100 beats per minute (bpm). Notable pulse 
rate abnormality will be a rate below 60 bpm (bradycardia) or above 100 bpm (tachycardia).  
2.8.4.3 
Pregnancy 
Serum pregnancy test results will be listed for women of childbearing potential. 
2.9 
Pharmacokinetic endpoints  
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable.  
2.11 
Patient-reported outcomes 
The only patient reported outcome (PRO) assessed in the study is the GO-QoL. Summary 
statistics will be provided by treatment and visit. 
2.12 
Biomarkers 
Not applicable, 
2.13 
Other Exploratory analyses 
Not applicable.  
2.14 
Interim analysis 
Due to premature study discontinuation, no interim analysis is planned. 
3 
Sample size calculation 
A final number of 28 patients is expected to be randomized by the time of study discontinuation. 
Therefore, all analyses will be performed and interpreted in a purely descriptive manner. 
4 
Change to protocol specified analyses 
Due to premature study discontinuation, purely descriptive analyses will be performed for 
primary and secondary endpoints. Exploratory endpoints will not be analyzed. 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Concomitant medication date imputation 
Incomplete day 
Incomplete start day will be imputed as MAX(date of study day 1, earliest possible start date). 
Incomplete end day will be imputed as MIN(EoS, latest possible end date). 
Earliest possible start/end date is calculated on the eCRF page and refers to the first day of the 
corresponding month. Latest possible start/end date is calculated on the eCRF page and refers 
to the last day of the corresponding month. 
Incomplete day/month 
Incomplete start day/month will be imputed as MAX(date of study day 1, 01-Jan of the year 
entered). 
Incomplete end day/month will be imputed as MIN(EoS, 31-Dec of the year entered). 
Incomplete day/month/year 
Incomplete day/months/year will not be imputed. 
If the imputed end date is less than the existing start date, use the start date as the imputed end 
date. 
5.1.2 
Prior medications/ therapies date imputation 
Prior medications/ therapies are those with an end date prior to the treatment phase (first drug 
administration). 
Incomplete day 
Incomplete start day will be imputed as earliest possible start date. 
Incomplete end day will be imputed as MIN (date of the day prior to study day 1, latest possible 
end date). 
Incomplete day/month 
Incomplete start day/month will be imputed as01-Jan of the year entered. 
Incomplete end day/month will be imputed as MIN(31-Dec of the year entered, date of the day 
prior to study day 1). 
Incomplete day/month/year 
Incomplete start date will be imputed as very early date, e.g., 01JAN1900. 
Incomplete end date will be imputed as a date of the day prior to study Day 1. 


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For “Date of onset of TED symptoms” and “date of first diagnosis of TED”, the date will be 
imputed in the same way as prior medication/ therapies start date. 
5.1.3 
Post therapies date imputation 
Not applicable. 
5.1.4 
Other imputations 
Not applicable. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Severity of adverse events is graded by investigator (mild, moderate, severe) and documented 
in the eCRF. 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
Not applicable. 
5.4.2 
Key secondary analysis 
Not applicable. 
5.4.3 
Safety analysis 
Crude incidence and 100*(1-α)% confidence interval 
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event. 
Absolute and relative frequencies will be displayed as well as 95% CI for the relative frequency 
based on the score method including continuity correction (Newcombe 1998).  
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-α/2), n as 
total number of subjects (i.e., number of subjects in the denominator), and p as estimated crude 
incidence (number of subjects with event / n) it is q=1-p. 
Then the lower limit is: 
𝐿= max⁡(0,
2𝑛𝑝+ 𝑧2 −1 −𝑧√𝑧2 −2 −1 𝑛
⁄ + 4𝑝(𝑛𝑞+ 1)
2(𝑛+ 𝑧2)
 


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And the upper limit is: 
𝑈= min⁡(1,
2𝑛𝑝+ 𝑧2 + 1 + 𝑧√𝑧2 + 2 −1 𝑛
⁄ + 4𝑝(𝑛𝑞+ 1)
2(𝑛+ 𝑧2)
 
 
Note: if p < L then L = p and if p > U then U = p. 
 
Exposure adjusted incidence rate and 100*(1-α)% confidence interval 
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,…,n) to the first 
occurrence of a certain treatment emergent event is observed, or if the event was not 
experienced, the (censored) time to the end of the observation period or last dose plus 84 days 
whichever occur earlier. The sequence of first occurrence of an event will be modelled to follow 
approximately a Poisson process with constant intensity Ɵ. The parameter Ɵ will be estimated 
as λ= D/T, where T is the sum of t1 to tn and D is the number of subjects with at least one event. 
Conditionally on T, an exact 100* (1-α)% CI for a Poisson variable with parameter ƟT and 
observed value D can be obtained based on Garwood 1936 from which an exact 100*(1-α)% 
CI for D/T will be derived as follows (Sahai 1993; Ulm 1990): 
Lower confidence limit 𝐿=
0.5𝑐𝛼/2,2𝐷
𝑇
 for D > 0, 0 otherwise, 
Upper confidence limit 𝑈=
0.5𝑐1−𝛼/2,2𝐷+2
𝑇
  
where 𝑐𝛼𝑘 , is the αth quantile of the Chi-square distribution with k degrees of freedom. 
Table 5-1 
Examples for calculating exposure time for incidence rates (IR) 
1st treatment / 
total exposure 
time 
2nd treatment / total 
exposure time 
AE event onset (in 
days from study 
start) 
Exposure for IR 
Placebo / 100 
days 
AIN457 / 200 days 
Day 50 (during 1st 
treatment) 
Placebo: 50 days 
 
 
Day 110 (10 days into 
2nd treatment) 
AIN457: 10 days 
Any AIN: 10 days 
 
 
5.5 
Rule of exclusion criteria of analysis sets  
Exclusion criteria of analysis sets are complementary to those used for corresponding analysis 
set definitions (see Section 2.2 [Analysis Sets]). 
5.6 
Appendix A: Calculation rules 
Not applicable. 


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5.7 
Appendix C: Patient-reported Outcome Scoring 
rules/Forms/Instruments 
GO-QoL scoring (calculation rule used in eCRF) 
Questions are scored as follows: 
• “Yes severely / very much” → 1 point 
• “Yes a little” → 2 points 
• “No not at all” → 3 points 
Subscores are derived on the following logic: 
1. Calculation of two raw scores from 8 to 24 points: adding points for the questions of each 
subscale (question 1 to 8 and 9 to 16). For questions 1 and 2, the answers `no driver's 
license' or `never learned to ride a bike' are scored as a missing value. 
2. Transforming raw scores to total scores from 0 to 100 according to the formula: 
• If response is provided to fields 1 to 8 then Score 1 = [(raw score - 8)/16] *100 
• If response is provided for at least 4 fields then Score 1 ={[(raw score - #)/(2 * 
#) ]*100}, where # is the number of completed items. 
• If response to 5 fields is missing then derive 'Score 1' as missing value. 
 
 


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5.8 
Disclosure reporting 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on <on- 
treatment/treatment emergent> AEs which are not SAEs with an incidence greater than 5% and 
on <on-treatment/treatment emergent> SAEs and SAE suspected to be related to study 
treatment will be provided by Cohort, treatment, system organ class and preferred term on the 
SAF. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment/ non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
 
6 
References 
Garwood, F (1936) Fiducial limits for the Poisson distribution. Biometrika, 46; 441–453. 
Newcombe, RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872.  
Sahai H, Khurshid Anwer (1993) Confidence intervals for the mean of a poisson distribution: 
a review. Biom J, 35 (7); 857-867. 
Ulm K (1990) A simple method to calculate the confidence interval of a standard mortality 
ratio. American Journal of Epidemiology, 131(2); 373-375.