Clinical trial NCT02826603
Conditions: Plaque Psoriasis
Keywords: Plaque psoriasis secukinumab ustekinumab ain457 ain457a
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-22; Completion date: 2018-07-09
Enrollment: 1114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Demonstrate superiority of secukinumab over ustekinumab in treatment of moderate to severe plaque psoriasis.

Detailed description:

Arms: arm 1: Secukinumab arm 2: Ustekinumab
Interventions: intervention 1: Secukinumab intervention 2: Ustekinumab
Intervention descriptions: intervention 1: 300mg, s.c. at randomization, Weeks 1, 2 and 3 and thereafter 4-weekly till Week 48 intervention 2: Per approved label, 45 mg or 90 mg s.c. based on subject weight (at randomization visit) to be administered at randomization, Week 4, 16, 28 and 40. At other timepoints subjects will receive placebo injections.

Protocol documents:
Prot_000.pdf: 
Global Clinical Development - General Medicine 
Secukinumab (AIN457) 
Clinical Trial Protocol [CAIN457A2326] / NCT02826603
A 52-week, multicenter, randomized, double-blind study of 
secukinumab (300 mg) to demonstrate efficacy as 
assessed by Psoriasis Area and Severity Index and 
Investigator’s Global Assessment after 12 weeks of 
treatment, compared to ustekinumab, and to assess long- 
term safety, tolerability, and efficacy in subjects with 
moderate to severe plaque psoriasis 
(CLARITY) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2015-002898-37 
Version number: 
v01 Clean 
Clinical trial phase: 
IIIb 
Release date: 
22-Apr-2016
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 03 (August 2015) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ....................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment 1.............................................................................................................................. 9 
Protocol summary .............................................................................................................. 10 
1 
Introduction ....................................................................................................................... 12 
1.1 
Background ............................................................................................................ 12 
1.2 
Purpose................................................................................................................... 14 
2 
Study objectives and endpoints ......................................................................................... 14 
2.1 
Primary objectives ................................................................................................. 14 
2.2 
Secondary objectives ............................................................................................. 14 
2.2.1 
Key secondary objectives ...................................................................... 14 
2.2.2 
Other secondary objectives ................................................................... 15 
 
 15 
2.4 
Objectives and related endpoints ........................................................................... 15 
3 
Investigational plan ............................................................................................................ 16 
3.1 
Study design ........................................................................................................... 16 
3.2 
Rationale for study design ..................................................................................... 18 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment .... 19 
3.4 
Rationale for choice of comparator ....................................................................... 19 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 19 
3.6 
Risks and benefits .................................................................................................. 19 
4 
Population .......................................................................................................................... 21 
4.1 
Inclusion criteria .................................................................................................... 21 
4.2 
Exclusion criteria ................................................................................................... 21 
5 
Treatment ........................................................................................................................... 24 
5.1 
Study treatment ...................................................................................................... 24 
5.1.1 
Investigational and control drugs .......................................................... 24 
5.1.2 
Additional treatment .............................................................................. 24 
5.2 
Treatment arms ...................................................................................................... 24 
5.3 
Treatment assignment and randomization ............................................................. 25 
5.4 
Treatment blinding ................................................................................................. 26 
5.5 
Treating the subject ................................................................................................ 27 


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5.5.1 
Subject numbering................................................................................. 27 
5.5.2 
Dispensing the study drug ..................................................................... 28 
5.5.3 
Handling of study and additional treatment .......................................... 28 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 29 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ......... 29 
5.5.6 
Rescue medication ................................................................................ 30 
5.5.7 
Concomitant medication ....................................................................... 30 
5.5.8 
Prohibited medication ........................................................................... 31 
5.5.9 
Emergency breaking of assigned treatment code .................................. 32 
5.6 
Study completion and discontinuation ................................................................... 33 
5.6.1 
Study completion and post-study treatment .......................................... 33 
5.6.2 
Discontinuation of study treatment ....................................................... 33 
5.6.3 
Withdrawal of informed consent ........................................................... 35 
5.6.4 
Loss to follow-up .................................................................................. 35 
5.6.5 
Early study termination by the sponsor ................................................. 35 
6 
Visit schedule and assessments ......................................................................................... 36 
6.1 
Information to be collected on screening failures .................................................. 40 
6.2 
Subject demographics/other baseline characteristics ............................................. 40 
6.2.1 
Demographics ....................................................................................... 40 
6.2.2 
Psoriasis medical history/previous psoriasis therapies .......................... 40 
6.2.3 
Smoking history .................................................................................... 41 
6.2.4 
Co-morbidities – cardiovascular medical history.................................. 41 
6.2.5 
Relevant medical history/current medical conditions ........................... 41 
6.2.6 
Prior and concomitant medications ....................................................... 41 
6.2.7 
Determination of tuberculosis status ..................................................... 41 
6.2.8 
Other baseline characteristics ................................................................ 44 
6.3 
Treatment exposure and compliance ..................................................................... 44 
6.4 
Efficacy .................................................................................................................. 44 
6.4.1 
Investigator’s Global Assessment (IGA mod 2011) ............................. 44 
6.4.2 
Assessment of total Body Surface Area (BSA) and Psoriasis Area 
and Severity Index (PASI) .................................................................... 45 
6.4.3 
Appropriateness of efficacy assessments .............................................. 47 
6.5 
Safety ..................................................................................................................... 47 
6.5.1 
Physical examination ............................................................................ 47 
6.5.2 
Vital signs .............................................................................................. 48 
6.5.3 
Height and weight ................................................................................. 48 
6.5.4 
Laboratory evaluations .......................................................................... 48 


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6.5.5 
Electrocardiogram (ECG) ..................................................................... 49 
6.5.6 
Pregnancy .............................................................................................. 50 
6.5.7 
Appropriateness of safety measurements .............................................. 50 
 
 50 
 
 50 
 
 51 
 
 51 
 
 51 
 
 51 
7 
Safety monitoring .............................................................................................................. 51 
7.1 
Adverse events ....................................................................................................... 51 
7.2 
Serious adverse events ........................................................................................... 53 
7.2.1 
Definition of SAE.................................................................................. 53 
7.2.2 
SAE reporting ........................................................................................ 54 
7.3 
Reporting of study treatment errors including misuse/abuse ................................. 55 
7.4 
Pregnancy reporting ............................................................................................... 55 
8 
Data review and database management ............................................................................. 55 
8.1 
Site monitoring ...................................................................................................... 55 
8.2 
Data collection ....................................................................................................... 56 
8.3 
Database management and quality control ............................................................ 56 
8.4 
Data Monitoring Committee .................................................................................. 57 
8.5 
Adjudication Committee ........................................................................................ 57 
9 
Data analysis ...................................................................................................................... 57 
9.1 
Analysis sets .......................................................................................................... 57 
9.2 
Subject demographics and other baseline characteristics ...................................... 58 
9.3 
Treatments ............................................................................................................. 58 
9.4 
Analysis of the primary variable(s)........................................................................ 59 
9.4.1 
Variable(s) ............................................................................................. 59 
9.4.2 
Statistical model, hypothesis, and method of analysis .......................... 59 
9.4.3 
Handling of missing values/censoring/discontinuations ....................... 60 
9.4.4 
Sensitivity analyses ............................................................................... 60 
9.5 
Analysis of secondary variables............................................................................. 60 
9.5.1 
Efficacy variables .................................................................................. 60 
 
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9.5.3 
Safety variables ..................................................................................... 63 
 
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9.6 
Interim analyses ..................................................................................................... 65 
9.7 
Sample size calculation .......................................................................................... 66 
9.8 
Power for analysis of key secondary variables ...................................................... 66 
10 Ethical considerations ........................................................................................................ 67 
10.1 
Regulatory and ethical compliance ........................................................................ 67 
10.2 
Informed consent procedures ................................................................................. 67 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 67 
10.4 
Publication of study protocol and results ............................................................... 68 
11 Protocol adherence ............................................................................................................ 68 
11.1 
Protocol amendments ............................................................................................. 68 
12 References ......................................................................................................................... 68 
13 Appendix 1: Clinically notable laboratory values and vital signs ..................................... 71 
 
 
List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 15 
Table 5-1 
Overview of treatment during the study – type and number of 
injections ............................................................................................... 25 
Table 5-2 
Prohibited medication ........................................................................... 31 
Table 6-1 
Assessment schedule ............................................................................. 37 
Table 6-2 
The IGA mod 2011 rating scale ............................................................ 45 
Table 6-3 
The PASI scoring system ...................................................................... 46 
Table 9-1 
Power to show superiority of secukinumab versus ustekinumab for 
co-primary endpoints ............................................................................. 66 
Table 9-2 
Power to show superiority of secukinumab versus ustekinumab for 
key secondary endpoints ....................................................................... 66 
 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 17 
Figure 6-1 
Tuberculosis screening flowchart .......................................................... 43 


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List of abbreviations 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
Bpm 
Beats per minute 
BSA 
Body Surface Area 
CFR 
US Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CPO 
Country Pharma Organization 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CTC 
Common Terminology Criteria 
DB 
Database 
 
 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of study 
EOT 
End of treatment (epoch) 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
hCG 
human chorionic gonadotropin 
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 
IFU 
Instructions For Use 
IGA mod 2011 
Novartis Investigator’s Global Assessment modified 2011 
IL 
Interleukin 
i.v. 
intravenous 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LFT 
Liver function test 
MedDRA 
Medical dictionary for regulatory activities 
OC/RDC 
Oracle Clinical/Remote Data Capture 
o.d. 
once a day 
PASI 
Psoriasis Area and Severity Index 
 


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SAE 
Serious Adverse Event 
s.c. 
subcutaneous, subcutaneously 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TB 
Tuberculosis 
TCS 
Topical corticosteroid 
TNF 
Tumor necrosis factor 
UV 
Ultraviolet 
WBC 
White blood cells 
WHO 
World Health Organization 
 


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Glossary of terms 
Cohort 
A specific group of patients/subjects fulfilling certain criteria 
Control drug 
Drugs(s) used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or 
evaluate comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study at which informed consent must 
be obtained (e.g. prior to starting any of the procedures described in the 
protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up 
Investigational drug 
The drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Subject ID 
A unique number assigned to each subject upon signing the informed 
consent 
Randomization number 
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment 
Study drug/treatment 
Any single drug or combination of drugs administered to the subject as 
part of the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
When the subject permanently stops taking study treatment prior to the 
defined study treatment completion date 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study 
Withdrawal of consent 
(WoC) 
Withdrawal of consent from the study is defined as when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study 
related contact, and does not allow analysis of already obtained biologic 
material 


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Amendment 1 
Amendment rationale 
Per the new protocol, all drug administrations will be performed at the site in order to 
minimize potential influence of subjects’ non-compliance at home administrations in this head 
to head study. 
Also, the Non-responder imputation method is updated. This change is in line with 
 
 recommendations to impute subjects with all post-baseline missing values as 
non-responders according to the Intent-to-treat (ITT) principle. 
At the time of amendment release, the study has not yet enrolled any subjects. 
 
Changes to the protocol 
The major changes are listed below: 
• All home visits (study treatment administrations at home) are converted to site visits 
(study treatment administrations at site). 
• Non-responder imputation method is updated. 
• Sensitivity analysis will also be performed on key secondary objectives. 
These changes were implemented throughout the relevant sections of the protocol. 
This protocol amendment also includes the correction of typographical and formatting errors 
and editorial changes for increased clarity of the text. 
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 for insertions. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes descri bed in this 
protocol amendment. 


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Protocol summary 
 
 
Protocol number 
CAIN457A2326 
Title 
A 52-week, multicenter, randomized, double-blind study of secukinumab 
(300 mg) to demonstrate efficacy as assessed by Psoriasis Area and 
Severity Index and Investigator’s Global Assessment after 12 weeks of 
treatment, compared to ustekinumab, and to assess long-term safety, 
tolerability, and efficacy in subjects with moderate to severe plaque 
psoriasis (CLARITY) 
Brief title 
Study of efficacy and safety of secukinumab compared to ustekinumab in 
subjects with plaque psoriasis 
Sponsor and Clinical 
Phase 
Novartis 
3b 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to confirm the superiority of secukinumab 
versus ustekinumab (weight based dosing, according to approved labelling) 
based on PASI 90 and IGA mod 2011 0/1 response rates at Week 12 in 
treatment of moderate to severe plaque psoriasis. 
Primary Objective(s) 
The primary objective of this study is to demonstrate the superiority of 
secukinumab 300 mg compared to ustekinumab in subjects with moderate 
to severe plaque psoriasis with respect to both PASI 90 and IGA mod 2011 
0/1 response at Week 12. Moreover, this study will assess the long-term 
efficacy, safety and tolerability of secukinumab versus ustekinumab over a 
period of 52 weeks. 
Secondary Objectives 
The key secondary objectives of the study are to demonstrate the 
superiority of secukinumab compared to ustekinumab with respect to: 
• PASI 75 response at Week 12 
• PASI 75 response at Week 4 
• PASI 90 at Week 16 
• PASI 100 at Week 16 
• IGA mod 2011 0/1 at Week 16 
• PASI 100 at Week 12 
• PASI 75 at Week 16 
• PASI 90 at Week 52 
Study design 
This is a multicenter, randomized, double-blind, active-controlled, parallel- 
group trial in approximately 1100 subjects with moderate to severe chronic 
plaque-type psoriasis. It is expected that subjects will be enrolled at 
approximately 200-250 study sites worldwide. 
The study consists of 3 epochs: screening (of at least 2 weeks and up to 4 
weeks), treatment epoch (of 52 weeks: from randomization to Week 52), 
and follow-up epoch (of 8 weeks: visits F4 and F8 to be conducted at 8 and 
12 weeks after last study treatment, for subjects with premature treatment 
discontinuation only). 
Population 
This study will randomize approximately 1100 male and female subjects 
aged ≥18 years. 
Key Inclusion criteria 
1. Subjects must give a written, signed and dated informed consent 


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2. Men or women must be at least 18 years of age at the time of screening 
3. Chronic plaque-type psoriasis present for at least 6 months before 
randomization 
4. Moderate to severe plaque psoriasis as defined at randomization by: 
• 
PASI score of ≥12 and 
• 
Body Surface Area (BSA) affected by plaque-type psoriasis ≥10% 
and 
• 
IGA mod 2011 ≥3 (based on a scale of 0–4) 
5. Candidate for systemic therapy, defined as having psoriasis 
inadequately controlled by: 
• 
Topical treatment (including topical corticosteroids) and/or 
• 
Phototherapy and/or 
• 
Previous systemic therapy 
Key Exclusion criteria 
1. Forms of psoriasis other than plaque psoriasis 
2. Drug-induced psoriasis 
3. Ongoing use of prohibited treatments 
4. Previous exposure to secukinumab or any other biologic drug directly 
targeting IL-17A or IL-17RA, or ustekinumab, or any therapies targeting 
IL-12 or IL-23 
5. Use of any other investigational drugs within 5 half-lives of the 
investigational treatment before study drug initiation 
6. Pregnant or nursing (lactating) women 
Study treatment 
o Investigational treatment 
• 
Secukinumab 150 mg, 1 ml liquid formulation in a pre-filled syringe 
o Reference treatment 
• 
Secukinumab placebo, 1 ml liquid formulation in a pre-filled syringe 
• 
Ustekinumab 45 mg, 0.5 ml liquid formulation in a pre-filled syringe 
Efficacy assessments 
• IGA mod 2011 
• PASI 
Key safety 
assessments 
• Adverse event monitoring 
• Physical examinations 
• Safety laboratory tests 
Data analysis 
The primary analysis method will be the logistic regression with treatment 
group; baseline bodyweight strata and baseline PASI score as explanatory 
variables. Odds ratios will be computed for comparisons of secukinumab 
dose regimens versus ustekinumab utilizing the logistic regression model 
fitted. In case of response rates of 0% or of 100% in one of the treatment 
groups, Fisher’s exact test will be applied. Confidence intervals for risk 
difference will be provided. 
Key words 
Plaque psoriasis, secukinumab, ustekinumab 


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1 
Introduction 
1.1 
Background 
Psoriasis is a chronic relapsing disease of the skin characterized by variable clinical features. 
The lesions are classified as erythemato-squamous, which indicates that both the vasculature 
(erythema) and the epidermis (increased scale formation) are involved. 
Plaque-type psoriasis (also called plaque or chronic plaque psoriasis) is the most frequent 
clinical presentation and therefore, also called psoriasis vulgaris. The erythematous plaques 
are well defined with sharp borders. The silvery grey scale on the surface of the lesions is 
easily removed. Sharply demarcated lesions can present on the extensor surfaces of the knees 
and elbows and on the trunk. Lesions are often symmetrically distributed. The size of the 
lesions is highly variable. Psoriasis may also occur exclusively on the scalp. Other 
manifestations of psoriasis are guttate, inverse, erythrodermic, nail and palmoplantar psoriasis. 
Extensive clinical experience with TNFα-inhibitors has been collected over the past 10 years 
and these agents are generally considered to be effective and relatively safe (Papp et al 2006). 
However, a substantial percentage of patients do not respond well to treatment with a TNFα - 
inhibitor. This inadequate response may imply either a primary unsatisfactory response (e.g. 
not achieving a decrease in Psoriasis Area and Severity Index (PASI) score of at least 50% 
after adequate duration of treatment), an initially adequate response that is lost over time 
(secondary failure) or intolerance for the TNFα-inhibitor. The percentage of patients with an 
inadequate response to TNFα-inhibitors can be as high as 40-60% (Van Lümig et al 2010). 
In routine medical practice, given the limited number of therapeutic agents available, it has 
become common practice to switch medications that are structurally distinct but 
therapeutically similar to achieve an improved clinical result or to restore a clinical result. 
Such therapeutic interchange is now being applied to biological agents to treat moderate to 
severe plaque psoriasis (Vender et al 2011). 
Studies have shown that a switch from one TNFα-inhibitor to another TNFα-inhibitor may be 
successful (Bissonnette et al 2010) although it remains largely unclear as to why such a switch 
can be effective. Possible explanations are: different mode of action or difference in binding 
site or binding affinity. Other possible explanations may include neutralizing antibodies 
directed against the first TNFα-inhibitor. 
However, most studies have shown that the response to a second or third TNFα -inhibitor is 
lower than that observed in patients who are treatment-naïve to TNFα-inhibitors. This 
phenomenon is most evident in patients who are primary non-responders to initial TNFα- 
inhibitor (Woolf et al 2010). In addition, an adequate response to the second or third TNFα - 
inhibitor can sometimes only be obtained or maintained by increasing the dose or the 
frequency of dose thereby increasing the likelihood of the occurrence of side effects ( Haitz 
and Kalb 2007). Thus, there remains a clinical need for alternative systemic therapies for the 
treatment of moderate to severe plaque psoriasis that combine robust short- and long-term 
efficacy with an acceptable safety profile. 


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The arrival of a new class of systemic, biological drugs such as usteki numab (interleukin (IL) 
12/23 inhibitor) has provided clinicians with more treatment options. Ustekinumab has shown 
good clinical efficacy in a number of well-designed Phase III studies (Leonardi et al 2008; 
Papp et al 2008). PASI response rates were better than those of etanercept and comparable to 
PASI response rates of infliximab and efficacy was generally maintained up to 3 years after 
initiation of treatment (Kimball et al 2012). 
One study showed good efficacy when patients were switched to ustekinumab after an 
inadequate primary response to etanercept. However, the ustekinumab response rate was 
lower in the previously treated etanercept inadequate responders (PASI 90 response rate 
23.4%) than in patients naïve for etanercept (44.7%). In addition, clinical response was only 
achieved with the highest dose of ustekinumab (90 mg) (Griffiths et al 2010). 
A number of IL-17A and IL-17RA inhibitors are being or have been investigated in Phase III 
studies for the treatment of a range of immune mediated inflammatory diseases , including 
plaque type psoriasis. With the approval of secukinumab for treatment of moderate-to-severe 
plaque psoriasis in patients who are candidates for systemic therapy or phototherapy, the first 
treatment option in this class became available for clinicians in major markets such as the 
United States, European Union, Japan, and Canada. 
Secukinumab (AIN457) is a recombinant high-affinity fully human monoclonal anti-human 
IL-17A antibody of the immunoglobulin (Ig) G1/κ-class. Secukinumab binds to human IL- 
17A and neutralizes the bioactivity of this cytokine. IL-17A is the central cytokine of a newly 
defined subset of inflammatory T cells, the Th17 cells which, in several animal models, are 
pivotal in multiple autoimmune and inflammatory processes. IL-17A is mainly produced by 
memory effector CD4+ and CD8+ T lymphocytes and is bei ng recognized as one of the 
principal pro-inflammatory cytokines in immune mediated inflammatory diseases. Its 
neutralization is expected to treat the underlying pathophysiology of immune mediated 
disease, and as a consequence provide relief of (psoriatic) symptoms. 
Secukinumab (Cosentyx®) with a recommended dose of 300 mg was approved in 2014 in 
Japan, in 2015 in the US, in the EU and in Switzerland for the treatment of moderate to severe 
plaque psoriasis in adults. Secukinumab is available as a powder for solution for injection, and 
as a solution of 150 mg in 1 mL for injection in pre-filled syringe or pre-filled pen. 
The Investigator’s Brochure (IB 2015) provides a more detailed review of the pre-clinical and 
clinical information on secukinumab. 
Secukinumab, which has a different mode of action to TNFα-inhibitors, has proven to be a 
suitable alternative for consecutive TNFα-inhibitor therapy after inadequate response to the 
previous TNFα-inhibitor. In two pivotal Phase 3 trials (ERASURE and FIXTURE), 
secukinumab was associated with a rapid reduction in psoriasis symptoms, elicited 
significantly greater PASI 75 rates and higher rates of 0 or 1 responses on the modified 
investigator's global assessment (IGA mod 2011) than placebo at Week 12, and with 
continued treatment was associated with sustained high response rates in a majority  of 
patients through Week 52. The FIXTURE study showed superior efficacy of secukinumab 
over the TNF inhibitor etanercept; PASI 75 at Week 12 being 77% with secukinumab 300 mg 
vs. 44% with etanercept and IGA mod 2011 0/1 being 62% with secukinumab 300 mg vs. 
27% with etanercept (Langley et al 2014). Furthermore, because secukinumab targets a 


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different interleukin (i.e., IL17A), it has also proved to be an alternative for ustekinumab, 
either as preferred “switch” drug or as a first line drug in the treatment of moderate to severe 
plaque psoriasis. 
In a recent 52-week, double blind study (CLEAR), secukinumab (79.0%) has proven to be 
superior to ustekinumab (57.6%) as assessed by PASI 90 response at Week 16 (p < 0.0001). 
The PASI 100 response rate at Week 16 was also significantly greater with secukinumab 
(44.3%) than ustekinumab (28.4%) (p < 0.0001). Thus, the study demonstrated that 
secukinumab was superior to ustekinumab in clearing skin of subjects with moderate to severe 
plaque psoriasis with a similar safety profile.
 
 
 
 
1.2 
Purpose 
The purpose of this study is to confirm the superiority of secukinumab versus ustekinumab 
(weight based dosing, according to approved labelling) based on PASI 90 and IGA mod 2011 
0/1 response rates at Week 12 in treatment of moderate to severe plaque psoriasis. 
Moreover, this study will assess the long-term efficacy, safety and tolerability of secukinumab 
versus ustekinumab over a period of 52 weeks to support the long-term use of secukinumab 
compared with ustekinumab in subjects suffering from moderate to severe plaque psoriasis. 
 
 
2 
Study objectives and endpoints 
2.1 
Primary objectives 
The co-primary objectives are: 
To demonstrate the superiority of secukinumab compared to ustekinumab in subjects with 
moderate to severe plaque psoriasis with respect to both PASI 90 and IGA mod 2011 0/1 
response at Week 12 
 
2.2 
Secondary objectives 
2.2.1 
Key secondary objectives 
o To demonstrate the superiority of secukinumab compared to ustekinumab in subjects 
with moderate to severe plaque psoriasis with respect to: 
• PASI 75 response at Week 12 
• PASI 75 response at Week 4 
• PASI 90 at Week 16 
• PASI 100 at Week 16 
• IGA mod 2011 0/1 at Week 16 
• PASI 100 at Week 12 


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• PASI 75 at Week 16 
• PASI 90 at Week 52 
2.2.2 
Other secondary objectives 
To investigate the clinical safety of secukinumab compared to ustekinumab as assessed by 
adverse event monitoring, vital signs, and clinical laboratory variables. 
 
 
2.4 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
 
 
OBJECTIVE 
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure 
Stat Analysis Section 
Primary 
To demonstrate the 
superiority of 
secukinumab compared 
to ustekinumab with 
respect to both PASI 90 
and IGA mod 2011 0/1 
response at Week 12 
Title: PASI 90 and IGA mod 2011 0/1 after 12 
weeks of treatment 
Unit of Measure: PASI, IGA mod 2011 
Description: PASI will be assessed/calculated 
as per usual standard. 
Section 9.4 
Investigator will assess severity of disease 
using a validated scale (IGA mod 2011) and 
rate the disease from a score of 0 (clear skin) to 
4 (severe disease). 
Time frame: Week 12 
Key Secondary 
To demonstrate the 
superiority of 
secukinumab compared 
to ustekinumab with 
Title: 
PASI 75 after 4, 12 and 16 weeks of treatment 
PASI 90 after 16 and 52 weeks of treatment 
Section 9.5 


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OBJECTIVE 
Endpoint Title, Description and Reporting 
Time Frame for analysis and Unit of Measure 
Stat Analysis Section 
respect to PASI 75 
response at Weeks 4, 
12 and 16; PASI 90, 
PASI 100, IGA mod 
2011 0/1 at Week 16; 
PASI 100 at Week 12; 
and PASI 90 at Week 
52 
PASI 100 after 12 and 16 weeks of treatment 
IGA mod 2011 0/1 after 16 weeks of treatment 
Unit of Measure: PASI, IGA mod 2011 
Description: PASI and IGA mod 2011 0/1 will be 
assessed at baseline and at regular intervals 
until Week 52. 
Time frame: Week 4, Week 12, Week 16, Week 
52 
Other Secondary 
To investigate the 
clinical safety and 
tolerability of 
secukinumab 300 mg in 
comparison to 
ustekinumab 
Endpoint: Clinical safety and tolerability. 
Unit of Measure: vital signs, clinical laboratory 
variables, adverse events monitoring 
Time frame: up to 52 weeks 
Section 9.5 
 
3 
Investigational plan 
3.1 
Study design 
This is a multicenter, randomized, double-blind, active-controlled, parallel-group trial in 
approximately 1100 subjects with moderate to severe chronic plaque-type psoriasis. It is 
expected that subjects will be enrolled at approximately 200-250 study sites worldwide. 
The study consists of 3 epochs: Screening (of at least 2 weeks and up to 4 weeks), Treatment 
epoch (of 52 weeks: from randomization to Week 52), and follow-up epoch (of 8 weeks: only 
for subjects with premature treatment discontinuation). An outline of the visits is presented 
Figure 3-1, while a detailed visit and assessment schedule can be found in Table 6-1. 
Safety and efficacy assessments will be performed according to the visit schedule (Table 6-1). 


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Figure 3-1 
Study design 
 
Screening 
Treatment epoch 
Follow-up2 
 
 
-4 to Rand. BSL 1 2 3 4 
8 
12 
16 
20 24 
28 32 
36 40 44 
EOT 
48   52 F4 
F8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BSL = Baseline; EOT = end of treatment epoch 
1 = ustekinumab dose is based on body weight at baseline; 45 mg for subject ≤ 100 kg; 90 mg for subject > 100 kg 
2 = for subjects with premature treatment discontinuation only 
= active dose administration; in order to keep the blind, subjects will receive placebo administrations at several 
time points (not shown in this study design figure) 
 
Screening (Screening to Randomization) 
The screening epoch of at least 2 weeks and up to 4 weeks will be used to assess the subject’s 
eligibility and to taper subjects off prohibited medications. 
 
Treatment Epoch (Randomization to Week 52) 
The Treatment Epoch is the period from randomization (baseline) through Week 52. At the 
start of the treatment epoch, eligible subjects will be randomized in a 1:1 ratio to one of the 
two double-blind treatment groups: secukinumab 300 mg s.c. and ustekinumab 45 mg or 90 
mg s.c. (depending upon weight at randomization). 
The last dose will be administered at Week 48. The planned end of treatment epoch visit 
[EOT] will be performed at Week 52. The Week 52 visit should be the last visit of the study 
for subjects who complete the treatment epoch. 
For all subjects who discontinue study treatment prematurely for any reason before the end of 
the treatment epoch the EOT visit should be performed approximately 4 weeks after their last 
dose of study drug and then subjects should enter the treatment free follow up epoch. 
 
Follow-up epoch 
Subjects who prematurely discontinue the treatment epoch will enter the treatment free 
follow-up epoch. The treatment free follow up visits (no study treatment administered during 
secukinumab 
300 mg 
ustekinumab 
45/90 mg
1
 
Randomization 


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the follow up epoch) should include F4 and F8 follow up visits. Follow up visit F4 is 
approximately 4 weeks after the EOT visit (that is 8 weeks after the last study treatment 
administration). Follow up visit F8 is approximately 8 weeks after the EOT visit (that is 12 
weeks after the last study treatment administration). 
 
3.2 
Rationale for study design 
The subject population will be described in more detail in the Section 4 below. 
The randomized, double-blind, parallel-group, and comparator-controlled design used in this 
study is aligned with previous studies performed in the indication of plaque psoriasis such as 
the ACCEPT study (Griffiths et al 2010), the PHOENIX 1 (Leonardi et al 2008) and the 
PHOENIX 2 studies (Papp et al 2008), the CLEAR study (Thaci et al 2015) as well as the 
European Medicines Agency (EMA) Guidelines for the Clinical Investigation of Medicinal 
Products Indicated for the Treatment of Psoriasis (CHMP/EWP/2454/02 2004). 
The co-primary endpoints being the PASI 90 and IGA mod 2011 0/1 response s have been 
chosen as these come closer to the total or almost total clearance of psoriatic lesions , the 
ultimate goal of treatment. The CHMP guidance indicates that a PASI 90 response is the “best 
evidence” of efficacy and is considered an appropriate measure of “Treatment Success”. 
Furthermore, PASI 90 seems to be the new treatment target in a new era with more  
efficacious biologics, since it is being used more frequently as primary endpoint in the more 
recent psoriasis trials. 
 
Finally, PASI 90 
response rates observed in the phase III studies were closer to the endpoint of “clear/almost 
clear skin” (IGA mod 2011 0/1) than PASI 75. Further, the study design and study endpoints 
have been discussed and agreed with the US FDA. 
The primary endpoint of the trial is at Week 12. This time point was chosen because the 
efficacy of psoriasis systemic treatment is generally establish ed between 12 and 16 weeks. 
The Week 12 timepoint was the timing of the primary endpoint used within the registration 
phase III programs for the approval of both secukinumab and ustekinumab, and is therefore 
used as the primary comparison. The Week 16 timepoint is used as a secondary endpoint, 
because that is the time point at which secukinumab reaches its highest efficacy. 
Furthermore, this study design also allows for the assessment of long-term (one full year) 
safety and efficacy of secukinumab 300 mg compared to ustekinumab administered according 
to its approved labeling. 
The study has a double-blind design to be aligned with the above listed guideline. Due to 
differences in the appearance of the packaging and the final dose forms of secukinumab and 
ustekinumab, precautions have been taken to ensure that investigators/site personnel and 
subjects remain blind to treatment allocation during entire treatment and follow-up epoch. The 
details are provided in Section 5.4 (Treatment blinding). 
The regular assessments of disease activity, clinical status and safety parameters ensure that 
safety is monitored closely and both the subject and the investigator have the opportunity to 
assess if their continued participation in the study is to their benefit. If the subject’s 
participation is deemed not to be of continued benefit by either the investigator or the subject, 
the subject may freely exit the study at any time. 


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3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
The dose regimens selected for secukinumab and ustekinumab are as per the approved label 
for the respective drugs in various countries i.e. 300 mg for secukinumab (the recommended 
dose within approved product labelling), and dosing per weight group for ustekinumab. 
The proposal is to use secukinumab at a dose of 300 mg administered subcutaneously with a 
weekly regimen (Baseline/randomization, Week 1, Week 2, and Week 3) followed by 
treatment every 4 weeks thereafter (starting at Week 4) per approved dose of secukinumab in 
moderate to severe plaque psoriasis. 
Ustekinumab will be administered at Baseline, Week 4 and then every 12 weeks as per the 
approved dose regimen for treatment of patients with moderate to severe plaque psoriasis: for 
patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks 
later, followed by 45 mg every 12 weeks; for patients weighing >100 kg (220 lbs), the 
recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. 
 
3.4 
Rationale for choice of comparator 
An active comparator arm has been chosen for this study rather than a placebo arm. 
Ustekinumab is a fully human monoclonal anti-human IL-12/23 antibody of the IgG1/κ-class 
which has been commercially available for a number of years and has proved to be a safe and 
efficacious treatment for moderate to severe plaque psoriasis. 
The efficacy of ustekinumab has been demonstrated in plaque psoriasis in a number of 
placebo-controlled trials including PHOENIX 1 and PHOENIX 2,  and  in  a  controlled  
Phase III trial versus etanercept (ACCEPT) (Leonardi et al 2008; Papp et al 2008; Griffiths et 
al 2010). PASI 90 response rates of approximately 42% were reported with ustekinumab 
(combined doses) in pivotal studies (PHOENIX 1, PHOENIX 2 and ACCEPT) after 12 weeks 
of treatment. 
Based on the available data, ustekinumab is considered as an established, appr opriate, and 
reliable comparator drug. It has been used as a comparator for secukinumab in a previous 
study (CAIN457A2317/CLEAR). This study, CLARITY, intends to confirm the comparative 
efficacy and safety observed in the CLEAR study. 
 
3.5 
Purpose and timing of interim analyses/design adaptations 
Week 16 analysis will be performed after all subjects have completed the Week 16 visit. 
Additional analyses may be performed to support health authority interactions as necessary. 
3.6 
Risks and benefits 
Secukinumab (Cosentyx®) with a recommended dose of 300 mg was initially approved in 
2014 in Japan, followed by other markets such as the US, EU, Canada and Switzerland for the 
treatment for moderate to severe plaque psoriasis in adults. The approved forms of 
secukinumab 150 mg are a powder for solution for injection, and as a solution for injection in 
pre-filled syringe or pre-filled pen. 


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Non-clinical studies and phase II and III clinical studies in adults have not shown any 
impediment to using secukinumab subcutaneously in man. In total 4546 patients with 
moderate to severe plaque psoriasis were included in studies in the registration prog ram. This 
included 3430 patients treated with secukinumab in 10 phase II/III studies, 2727 of whom 
were treated for at least 6 months and 2029 of whom were treated for at least 48 weeks. 
In adult studies, secukinumab has shown a very good efficacy profile in the treatment of 
moderate to severe chronic plaque psoriasis. Superiority of secukinumab 150 mg and 300 mg 
doses to placebo was demonstrated for the co-primary efficacy criteria of PASI 75 and IGA 
mod 2011 0 or 1 at 12 weeks in all 4 pivotal placebo -controlled trials (>62% for PASI 75  
and >48% for IGA mod 2011 0 or 1). Secukinumab at both doses was also found to be 
superior in efficacy compared to etanercept with a rapid onset of action in the etanercept and 
placebo-controlled studies, CAIN457A2302 and CAIN457A2303. The safety data from the 
completed and ongoing studies including AE and SAE data, laboratory parameters and 
immunogenicity data demonstrate a good safety profile which included an observed risk of 
infections in particular Candida infections and neutropenia (without association with serious 
infections) or 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, and only a few cases were timely associated with non-serious infections. 
The approved product labelling reflects the identified risks for the product; subsequent safety 
data including (1) AE data, laboratory parameters, available immunogenicity data from the 
completed studies, and (2) SAE data from the phase III studies do not highlight any new 
individual safety risk or particular pattern of event clustering. 
Subjects with pre-existing malignancies within the past 5 years are generally excluded from 
studies with secukinumab although there is no scientific basis to suggest that secukinumab 
would increase the risk for malignancies. Indeed, the majority of preclinical data, available in 
the literature, suggest that blocking IL-17A may actually prevent tumor growth. 
Based upon the results of toxicology studies which demonstrated a lack of effect of 
secukinumab on fertility and embryo-fetal development, women of childbearing potential can 
be included in studies with secukinumab, however, pregnancy should be avoided by proven 
effective measures. No contraceptive measures are required for males participat ing in studies 
with secukinumab. 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and close clinical monitoring. 
All quality, non-clinical pharmacology and toxicology data, as well as the available clinical 
efficacy and safety data for secukinumab are considered sufficient to expect a positive 
benefit/risk ratio for the treatment of moderate to severe plaque psoriasis with secukinumab. It 
is therefore considered appropriate to initiate this study. 
Additional information can be found in the IB for secukinumab. 


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4 
Population 
The study population will consist of a representative group of male and female subjects    
(≥18 years old) with moderate to severe plaque psoriasis that is inadequately controlled by 
topical treatments (including topical corticosteroids), ultraviolet (UV) light or systemic 
therapy (including biologic therapy) and requires systemic therapy. 
It is aimed to randomize a total of approximately 1,100 subjects in around 200 -250 centers 
worldwide. Subjects who drop out after they have been randomized will not be replaced. 
 
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. Subjects must be able to understand and comply with the requirements of the study and 
communicate with the investigator, and must give a written, signed and dated informed 
consent before any study related activity is performed. Where relevant, a legal 
representative will also sign the informed study consent according to local laws and 
regulations 
2. Men or women must be at least 18 years of age at the time of screening 
3. Chronic plaque-type psoriasis present for at least 6 months and diagnosed before 
randomization 
4. Moderate to severe plaque psoriasis as defined at randomization by: 
• PASI score of ≥12 and 
• Body Surface Area (BSA) affected by plaque-type psoriasis ≥10% and 
• IGA mod 2011 ≥3 (based on a scale of 0–4) 
5. Candidate for systemic therapy, defined as having psoriasis inadequately controlled by: 
• Topical treatment (including topical corticosteroids) and/or 
• Phototherapy and/or 
• Previous systemic therapy 
4.2 
Exclusion criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. No 
additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects. 
1. Forms of psoriasis other than plaque psoriasis (e.g., pustular psoriasis, erythrodermic and 
guttate psoriasis) 
2. Drug-induced psoriasis (e.g., new onset or current exacerbation from β-blockers, calcium 
channel inhibitors or lithium) 
3. Ongoing use of prohibited treatments. Washout periods detailed in the protocol must be 
adhered to (Table 5-2). Subjects not willing to limit UV light exposure (e.g., sunbathing 
and/or the use of tanning devices) during the course of the study will be considered not 
eligible for this study. 
Note: administration of live vaccines within 6 weeks prior to Randomization or during the 
study period is also prohibited. Further BCG vaccine should not be given for one year 


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prior to randomization or during treatment or for one year following discontinuation of 
treatment. 
4. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17A or 
IL-17RA, or ustekinumab 
5. Use of any other investigational drugs within 5 half-lives of the investigational treatment 
before study drug initiation or until the pharmacodynamics effect has returned to baseline, 
whichever is longer 
6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotropin (hCG) laboratory test 
7. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during the 
entire study or longer if required by locally approved prescribing information (e.g. 20 
weeks in EU). Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy), 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 subjects on the 
study, the vasectomized male partner should be the sole partner for that subject. 
• Barrier methods of contraception: condom or occlusive cap. For UK: with spermicidal 
foam/gel/film/cream/vaginal suppository. 
• Use of oral, injected or implanted hormonal methods of contraception or other forms 
or hormonal contraception that have comparable efficacy (failure <1%), e.g., hormone 
vaginal ring or transdermal hormone contraception or placement of an intrauterine 
device (IUD) or intrauterine system (IUS) 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
NOTE: 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 
• 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 is she considered not of child- 
bearing potential. 
8. Active ongoing inflammatory diseases other than psoriasis that might confound the 
evaluation of the benefit of secukinumab therapy. Also, underlying conditions (including, 


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but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, 
endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator 
significantly immunocompromises the subject and/or places the subject at unacceptable 
risk for receiving an immunomodulatory therapy. In addition, current severe progressive 
or uncontrolled diseases which render the subject unsuitable for the trial or puts the 
subject at increased risk, including any medical or psychiatric condition which, in the 
Investigator’s opinion, would preclude the participant from adhering to the protocol or 
completing the study per protocol. 
9. Investigator discretion should be used for subjects with pre-existing or recent-onset central 
or peripheral nervous system demyelinating disorders 
10. Presence of 
• Significant medical problems, including but not limited to the following: uncontrolled 
hypertension (systolic ≥ 160 mmHg and/or diastolic ≥ 95 mmHg), congestive heart 
failure (New York Heart Association [NYHA] status of class III or IV) 
• Serum creatinine level exceeding 2.0 mg/dL (176.8 µmol/L) 
• Total white blood cell (WBC) count <2,500/µL, platelets <100,000/µL, 
neutrophils <1500/µL or hemoglobin <8.5 g/dL, at screening 
11. Active systemic infections during the 2 weeks prior to randomization (exception: common 
cold) or any infection that reoccurs on a regular basis; investigator discretion should be 
used regarding subjects who have traveled or resided in areas of endemic mycoses, such 
as histoplasmosis, coccidioidomycosis or blastomycosis and for subjects with underlying 
conditions that may predispose them to infection, such as advanced or inadequately 
controlled diabetes 
12. History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis 
infection as defined by a positive or indeterminate QuantiFERON TB-Gold test (QFT) at 
screening. Subjects with a positive QFT test may participate in the study if a full 
tuberculosis work up (according to local practice/guidelines) completed within 12 weeks 
prior to randomization establishes conclusively that the subject has no evidence of active 
tuberculosis. If the presence of latent tuberculosis is established, then treatment must have 
been initiated and maintained according to local country guidelines for at least 4 weeks 
prior to randomization. 
13. Past medical history record of, or current infection with, human immunodeficiency virus 
(HIV), hepatitis B or hepatitis C prior to randomization 
14. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years (except for skin Bowen’s disease, or basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 12 weeks; carcinoma in situ of the cervix or non-invasive malignant colon polyps that 
have been removed) 
15. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins) 
16. History or evidence of ongoing alcohol or drug abuse, within the last 6 months prior to 
randomization 
17. History of hypersensitivity to any of study drug constituent 


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5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
The following study drugs will be used: 
• Investigational treatment 
o Secukinumab 150 mg, 1 ml liquid formulation in a pre-filled syringe 
• Control treatment 
o Secukinumab placebo, 1 ml liquid formulation in a pre-filled syringe 
o Ustekinumab 45 mg, 0.5 ml liquid formulation in a pre-filled syringe 
Investigational treatment: secukinumab 
Secukinumab for s.c. injection is provided in a pre-filled syringe containing 150 mg 
secukinumab. Each 300 mg dose is given as two s.c. injections of 150 mg. 
 
Control treatment: 
o 
Secukinumab placebo: secukinumab placebo to 150 mg secukinumab for s.c. injection 
is provided in a matching pre-filled syringe. Each pre-filled syringe contains a mixture 
of inactive excipients, matching the composition of the secukinumab 150 mg dose. 
o 
Ustekinumab is provided in a pre-filled syringe containing 45 mg of ustekinumab for 
s.c. injection. Subjects weighing >100 kg at baseline will receive a dose of 90 mg 
according to the label, which consists of two 45mg pre-filled syringes. 
Secukinumab pre-filled syringes 150 mg and secukinumab pre-filled syringes placebo will be 
supplied by Novartis. 
Ustekinumab pre-filled syringes 45 mg will be supplied by Novartis from US market source. 
All study drugs will be labeled appropriately. 
The removable cap of the secukinumab pre-filled syringe contains a derivative of natural 
rubber latex. Although no natural rubber latex is detected in the cap, the safe use of the 
secukinumab 1 mL pre-filled syringe in latex-sensitive individuals has not been studied. 
 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug and control drug are included in this trial. 
 
5.2 
Treatment arms 
Subjects will be randomized to one of the following two treatment arms in a ratio of 1:1. In 
order to achieve a balanced weight distribution in each treatment arm, randomization in these 
two arms will be stratified by body weight (≤100 kg and >100 kg) at baseline. 
o Secukinumab arm: will receive a dose of secukinumab 300 mg s.c. which consist of two 
injections of the 150 mg pre-filled syringes at a frequency shown in Table 5-1 
o Ustekinumab arm: 


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• Subjects weighing >100 kg at baseline will receive a dose of 90 mg ustekinumab s.c., 
which consists of two injections of the 45 mg pre-filled syringe at a frequency shown 
in Table 5-1 
• Subjects weighing ≤ 100 kg at baseline will receive a dose of 45 mg ustekinumab s.c., 
which consist of one injection of the 45 mg pre-filled syringe + one secukinumab 
placebo s.c. injection at a frequency shown in Table 5-1 
In addition, in order to  maintain the blind, placebo injections matching  the  secukinumab  
150 mg pre-filled syringe will be given to subjects in the ustekinumab arm at various time 
points, as can be seen in Table 5-1 so that all subjects will receive 2 s.c. injections at each 
dosing time point. 
Further, the pre-filled syringes for secukinumab and ustekinumab have a different outward 
appearance. Therefore, as this is a double-blind study, the dispensing and administration of  
the study treatments will be performed at the study site by suitably qualified unblinded 
personnel who are otherwise not involved in study conduct. Further details are provided in 
Section 5.3, Section 5.4 and Section 5.5. 
 
Table 5-1 
Overview of treatment during the study – type and number of 
injections 
 
Epoch 
Treatment* 
Week (relative to 
randomization) 
R 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Secukinumab 300 mg 
Active injection1 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Ustekinumab2 
Subject ≤ 100 kg 
Active injection2 
1 
- 
- 
- 
1 
- 
- 
1 
- 
- 
1 
- 
- 
1 
- 
- 
Placebo injection3 
1 
2 
2 
2 
1 
2 
2 
1 
2 
2 
1 
2 
2 
1 
2 
2 
Subject > 100 kg 
Active injection2 
2 
- 
- 
- 
2 
- 
2 
- 
- 
2 
- 
- 
2 
- 
- 
Placebo injection3 
- 
2 
2 
2 
- 
2 
2 
- 
2 
2 
- 
2 
2 
- 
2 
2 
1 Secukinumab 150 mg pre-filled syringes: subjects randomized to secukinumab will receive 2 active 
injections; 
2 Ustekinumab dose based on body weight at baseline: 45 mg for subject ≤ 100 kg (1 active injection); 
90 mg for subject > 100 kg (2 active injections) 
3 Secukinumab placebo pre-filled syringes 
* Treatment epoch is from randomization until Week 52 (last dose given at Week 48) 
 
5.3 
Treatment assignment and randomization 
At the Randomization Visit (Day 1), all eligible subjects will be randomized via IRT system 
to one of the two treatment arms. The unblinded pharmacist or other unblinded qualified site 
personnel will contact the IRT provider after the investigator has confirmed that the subject 
fulfills all the inclusion/exclusion criteria. The IRT system will assign a randomization 
number to the subject, which will be used to link the subject to a treatment arm, and will 


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dispense a unique medication number of investigational treatment to the subject. The 
randomization number will not be communicated to the user. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigat or staff. A 
subject randomization list will be produced by the IRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms. A separate medication list 
will be produced by or under the responsibility of Novartis Drug Supply Management using a 
validated system that generates unique medication numbers. The randomization scheme for 
subjects will be reviewed and approved by a member of the Audit Readiness, Validation & 
Randomization Group 
 
. 
Randomization will be stratified by body weight assessed at Day 1. Stratification ensures a 
balanced allocation of subjects to treatment groups within the two weight strata: “body weight 
≤100 kg” or “body weight >100 kg”. It is expected that approximately 40% of the subjects 
will be in the upper weight stratum. 
 
5.4 
Treatment blinding 
All data up to Week 16 will be collected with the Novartis clinical trial team (or delegates), 
investigators/site personnel evaluating subjects and subjects blinded to treatment allocation. 
The designated Novartis personnel will be unblinded following DB lock for the interim 
analysis after all subjects have completed Week 16. Field monitors/clinical research associates 
will remain blinded until after Final DB lock. All blinded site personnel, including the 
assessor performing the study assessments will remain blinded to individual treatment 
allocation until after Final DB lock using the following methods: 
o Randomization data will be kept strictly confidential until the time of unblinding, and 
will not be accessible by anyone else involved in the study with the following 
exceptions: 
• Specific vendors whose role in trial conduct requires their unblinding (e.g., IRT) 
• DSM (Drug Supply Management) 
o Study medication will be dispensed by an unblinded pharmacist (or other unblinded 
qualified site personnel) who is independent of those involved in the assessment of 
study subjects. In addition the unblinded pharmacist (or other unblinded qualified site 
personnel) will store study medication and keep medication records containing 
unblinded information in a separate area to which blinded staff would not have access. 
• Study treatments will be administered by an “independent study drug 
administrator”: an unblinded suitably qualified individual (nurse, physician, or 
other unblinded qualified site personnel) who is not responsible for any aspect of 
subject assessment or follow-up. The “Independent study drug administrator” 
could be the same person dispensing the drug if suitably qualified to perform 
both activities. 
o prior to the administration, the unblinded site personnel will put in 
place all methods e.g. physical barriers as agreed with the subject and 


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being available at the site to prevent subject seeing the appearance of 
their study treatment 
o the individual administering study treatment will be advised to refrain 
from making any comments to study staff or to other subjects regarding 
the appearance of study treatments 
o the procedural details relating to treatment blinding and blinded drug 
administration will be described in a manual which will be provided 
separately 
In the event that the packaging of a study treatment has a broken seal, this information will be 
documented in the IRT, along with a reason (if applicable) and the medication number so that 
the syringe will not be available to dispense to another subject. 
The appropriate personnel from the study site and Novartis will assess whether the study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason. Study treatment must be discontinued after emergency 
unblinding. 
However once a subject comes to the last study visit (Week 52 or F8 as applicable), (s)he will 
be unblinded ‘on demand’ to support an informed decision on how to manage the subject 
post-study. This will be a subject-by-subject approach and will be permitted only after Week 
16 DB lock is achieved. For subjects who withdraw consent earlier and do not attend the F8 
visit this could be done at the visit when he/she withdrew consent; however the information 
will not be shared with the subject before the Week 16 DB lock. When the subject is 
unblinded, the information should preferably not be shared with the investigator. Instead, it is 
preferred that the physician treating the subject after last study visit is a person not involved in 
the study conduct. The blinding is maintained beyond Week 16 to ensure reliable evaluation 
of efficacy and safety measures for the complete duration of treatment. 
 
5.5 
Treating the subject 
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems. 
 
5.5.1 
Subject numbering 
Each subject is uniquely identified by a Subject Number which is composed by the site 
number assigned by Novartis and a sequential number assigned by the investigator. Once 
assigned to a subject, the Subject Number will not be reused. 
Upon signing the informed consent form, the subject is assigned the next sequential number 
by the investigator. The investigator or his/her staff will contact the IRT and provide the 
requested identifying information for the subject to register them into the IRT. The site must 
select the CRF book with a matching Subject Number from the EDC system to enter data. 
If the subject is randomized but fails to be treated for any reason, the IRT must be notified 
within 2 days that the subject was not treated. The reason for not being treated will be entered 
on the Screening epoch Study Disposition CRF. 


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5.5.2 
Dispensing the study drug 
Each study site will be supplied by Novartis with secukinumab active and placebo treatment 
in packaging of identical appearance. 
Ustekinumab pre-filled syringes 45 mg will be supplied by the Novartis Drug Supply 
Management (DSM) team and should be dispensed as per label requirements. 
The secukinumab active and placebo and ustekinumab treatment packaging has a 2-part label. 
A unique medication number is printed on each part of this label which corresponds to one of 
the 2 treatment arms. The unblinded site pharmacist or unblinded qualified site personnel will 
identify the study drug package(s) to dispense to the subject by contacting the IRT and 
obtaining the medication number(s). Immediately before dispensing the package to the subject, 
the unblinded site pharmacist or unblinded qualified site personnel will detach the outer part  
of the label from the packaging and affix it to the source document (Drug Label Form) for that 
subject. 
 
5.5.3 
Handling of study and additional treatment 
 
5.5.3.1 
Handling of study treatment 
Study treatment must be received by designated unblinded site personnel at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
unblinded site personnel have access. Upon receipt, all study treatment must be stored 
according to the instructions specified on the labels. Clinical supplies are to be dispensed only 
in accordance with the protocol. Technical complaints are to be reported to the respective 
Novartis CPO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the subject except for the medication number. 
The study treatments, i.e. secukinumab pre-filled syringes (150 mg active/placebo) and 
ustekinumab pre-filled syringes (45 mg active) must be stored in a locked refrigerator at 2-
8°C (36-46°F), and protected from light and must be carefully controlled in accordance with 
regulations governing investigational medicinal products and local regulations. Study 
treatments should not be frozen. 
The unblinded pharmacist or other unblinded qualified site personnel 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 unblinded monitors during site visits 
or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the 
investigator will return all unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. 
 
5.5.3.2 
Handling of additional treatment 
Not applicable. 


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5.5.4 
Instructions for prescribing and taking study treatment 
All dosages prescribed and dispensed to the subject and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Secukinumab solution for s.c. injection, placebo secukinumab solution and ustekinumab 
solution for s. c. injection will be provided in pre-filled syringes (PFS). 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
All doses of study treatment are to be administered at the study site and should be performed 
after the study assessments for the visit have been completed. The first study treatment 
administration will occur at the randomization visit after inclusion/exclusion criteria have 
been confirmed, all study scheduled assessments have been performed and the scheduled 
blood samples have been drawn. 
At all study site visits when pre-dose blood samples have to be drawn (Table 6-1), the study 
treatment will be injected only after the blood samples have been taken. At all site visits when 
study assessments need to be done, all study assessments, 
 
 should be completed prior to the injection of 
study treatment. 
The study treatment solution must be injected in non-affected areas of the skin into the 
appropriate body site (thigh, abdomen, upper outer arm). If possible, throughout the trial 
administer the study treatment rotating the injection site from visit to visit and also for each 
injection at a given visit. 
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 the 
regulatory needs of the respective countries. 
The investigator must promote compliance by instructing the subject to attend the study visits 
as scheduled and by stating that compliance is necessary for the subject’s safety and the 
validity of the study. 
 
Study treatment administration 
All study treatment must be administered at the site and will be administered by unblinded 
site personnel not responsible for any aspect of subject assessment or follow-up (Section 5.4) 
Instructions mentioned in Section 5.4 must be followed to avoid unblinding. The type and 
number of injections to be administered are detailed in Table 5-1. 
 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Study treatment interruptions are not permitted. 
No dose adjustment of study treatment is permitted and there should be no interruption of the 
study treatment during the study. However a positive urine pregnancy test during the 
treatment epoch of the study requires immediate interruption of study treatment until serum β- 


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hCG is performed and found to be negative. If the serum β-hCG test is positive, study 
treatment must be definitively discontinued. 
If a dose (secukinumab or placebo secukinumab) was dispensed by IRT but not administered 
to a subject at a visit at which the subject attended, this deviation event must be recorded on 
the Dosage Administration Record CRF. 
 
5.5.6 
Rescue medication 
Use of rescue medication is not permitted during the study. 
 
5.5.7 
Concomitant medication 
All treatments administered during the 6 months prior to start of study treatment (including 
any treatments started during the screening epoch) for any reason NOT including psoriasis 
will be entered in the Prior and Concomitant Medication eCRF. The start date, end date, dose, 
unit, frequency, route and reason for administration or change are to be recorded. 
In addition, psoriasis treatments used from the time subject started to treat psoriasis will be 
reported on the Prior Psoriasis Therapy eCRF. All topical treatments, systemic treatments and 
phototherapies for psoriasis administered prior to Randomization Visit will be entered in the 
Prior Psoriasis Therapy eCRF page (Section 6.2.2). 
The investigator/qualified site staff should instruct the subject to notify the study site about 
any new medications that he/she takes after being enrolled into the study. All medications, 
procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the subject starts study treatment must be listed on the eCRF. 
 
5.5.7.1 
Permitted concomitant medications (not for psoriasis or psoriatic 
arthritis) 
Concomitant medications are allowed if not listed in Table 5-2. Dose adjustments of these 
medications should be avoided during the study. If a dose adjustment of these medications 
does occur, they must be recorded on the Prior and Concomitant Medication eCRF. 
Subjects who are receiving treatments known to worsen psoriasis (e.g. beta-blockers, lithium) 
should be on a stable dose for at least 4 weeks before Randomization Visit. 
Mild to moderate topical corticosteroids (TCS) are allowed only during the screening epoch if 
used only on the face, scalp, and/or genitoanal area. Subject should stop use of these TCS at 
least the day preceding the randomization visit. 
TCS will be allowed after the Week 16 visit (timing of analysis of several key secondary 
endpoints) to the last study visit, only if: 
o medication is started after the week 16 visit is completed; 
o medication is used for 14 consecutive calendar days or less; 
o medication is used for an indication other than psoriasis and not on the area 
affected with psoriasis. 
Use of these TCS must be recorded on the Concomitant Medication-Topical Corticosteroid 
eCRF. 


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5.5.7.2 
Permitted concomitant medications for psoriasis 
After the screening epoch, the use of concomitant medication for psoriasis in all body regions 
is restricted to bland emollients (not supplied by Novartis) and other non-medicated 
interventions (not listed in Table 5-2). Use of bland emollients must be recorded on the 
Concomitant medications eCRF. Use of any other non-medicated interventions must be 
recorded on the Procedures and Significant non-drug therapies eCRF. 
The definition of “bland” excludes all topical medications that contain pharmacologically 
active ingredients such as (but not limited to) lactic acid, salicylic acid, urea, α -hydroxy acids 
or fruit acids. 
The use of bland emollients should be avoided during the 12 hours preceding a scheduled 
study visit. 
 
5.5.8 
Prohibited medication 
Use of any treatments displayed in Table 5-2 that could confound the efficacy assessments are 
NOT allowed during the study for any indication and wash-out periods for these treatments 
are indicated in Table 5-2. If the use of these treatments is required, then the subject must 
NOT be randomized into the study. 
The investigator/qualified site staff must instruct the subject to notify them about any new 
treatments he/she takes after the start of the study treatment. All prohibited medications and 
significant non-drug therapies administered after the subject starts study treatment must be 
listed on eCRF. 
If a prohibited treatment listed in Table 5-2 was used during the study, the subject must 
discontinue use of the prohibited treatment if he/she wishes to continue in the study. At the 
discretion of the investigator/qualified site staff, if the subject’s use during the study of a 
prohibited treatment listed in Table 5-2 presents undue safety risk for the subject, the subject 
should be discontinued from study treatment according to Section 5.6.2. If the subject 
received a live virus vaccination during the study, the subject must discontinue study 
treatment and complete the end-of-treatment epoch visit (Week 52/EOT) and Follow-up visits 
F4 and F8. 
 
Table 5-2 
Prohibited medication 
Prohibited treatments1, 2 
Washout period 
(before 
  
Randomization Visit) 
 
Ustekinumab 
No prior use allowed 
 
Secukinumab 
No prior use allowed 
 
Any biologic drug directly targeting IL-17 or the IL-17 receptor (other than 
secukinumab e.g., brodalumab, ixekizumab) 
Any biologic directly targeting IL-12/23 other than ustekinumab (e.g. 
briakinumab) or IL-23 (e.g. guselkumab, tildrakizumab) 
No prior use allowed 
6 months 
Alefacept, efalizumab 
6 months 


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Biological 
immunomodulating 
agents 
other 
than 
above 
(e.g., adalimumab, etanercept, infliximab) 
Other systemic immunomodulating treatments3 
e.g., MTX, cyclosporine A, corticosteroids (oral, i.v., intramuscular, s.c., 
intra-articular, transdermal), cyclophosphamide 
12 weeks 
 
4 weeks 
Other systemic psoriasis treatments (e.g. retinoid, fumarates, apremilast) 
4 weeks 
Photo-chemotherapy (e.g., PUVA) 
4 weeks 
Phototherapy (e.g., UVA, UVB) 
2 weeks 
 
Topical treatment that is likely to impact signs and symptoms of psoriasis 
(e.g., corticosteroids4,5, vitamin D analogues, pimecrolimus, retinoids, 
salicylvaseline, salicylic acid, lactic acid, tacrolimus, tar, urea, α-hydroxy or 
fruit acids) 
2 weeks 
Live virus vaccinations6, 7 
6 weeks 
 
Any investigational treatment or participation in any interventional trial 
4 weeks or 5 half-lives 
(whichever is longer) 
 
Any other treatment known to worsen psoriasis (e.g., beta-blockers, calcium 
channel blockers, lithium) 
Stable at least 4 weeks 
before randomization 
 
1 If the prohibited treatment is being used during the study for any indication, the subject must discontinue use of 
the prohibited treatment if he/she wishes to continue in the study. 
2 In case of undue safety risk for the subject, the subject should discontinue study treatment at the discretion of 
the investigator/qualified site staff. 
3 Inhaled CS as well as corticosteroid drops in the eye or ear or nasal sprays with only a topical effect (e.g., to 
treat asthma) are not considered “systemic immunomodulating treatments” and are therefore acceptable as co- 
medication. 
4 Mild to moderate topical corticosteroids are allowed only during the screening epoch if used only on the face, 
scalp, and/or genitoanal area and should not be used at least the day preceding the randomization visit. 
5 Topical corticosteroids and other topical treatments will be allowed during treatment and follow-up epoch if (all 
must apply): 
• 
medication is started after the Week 16 visit is completed; and 
• 
medication is used for 14 consecutive calendar days or less; and 
• 
medication is used for an indication other than psoriasis and not on the area affected with psoriasis 
6 If the subject received a live virus vaccination during the study, the subject must discontinue study treatment. 
7 BCG vaccine should not be given for one year prior to randomization, during treatment and one year following 
discontinuation of treatment. 
 
Exposure to light 
Subjects need to be advised to limit exposure to ultraviolet (UV) light (including sunbathing 
and/or use of UV tanning devices) during the study to avoid possible effect on psoriasis. 
 
5.5.9 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 


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investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the inves tigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the Novartis monitor for the site and the Study Team that the code 
has been broken. 
It is the investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• study drug name (if available and applicable) 
• subject number 
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un - 
blinding can be performed at any time. 
Study treatment must be discontinued after emergency unblinding. 
The appropriate personnel from the study site and Novartis will assess whether study 
treatment should be discontinued for any subject whose treatment code has been broken 
inadvertently for any reason (except for ‘on-demand’ unblinding after completion of last study 
visit as mentioned in Section 5.4). 
Subjects who are discontinued from study treatment are requested to return for the end of 
treatment epoch visit (Week 52/EOT) and Follow-up visits F4 and F8. 
 
5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
A subject will be considered to have completed the study when (s)he has completed the last 
visit planned in the protocol. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care. 
 
5.6.2 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study drug is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the 
investigator. 
Subjects may voluntarily discontinue study treatment for any reason at any time. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would negatively impact the risk/benefit of trial participation. 
Study treatment must be discontinued under the following circumstances: 
• Subject wish 
• Withdrawal of consent 


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• Emergence of the following AEs: AEs that in the judgment of the investigator/qualified 
site staff, taking into account the subject’s overall status prevent the subject from 
continuing study treatment. 
• Any laboratory abnormalities that in the judgment of the investigator/qualified site staff, 
taking into consideration the subject’s overall status, prevent the subject from continuing 
study treatment. 
• Pregnancy (see Section 6.5.6 and Section 7.4) 
• Ongoing use of prohibited treatment per recommendations in Table 5-2 
• Any situation in which study participation might result in a safety risk to the subject 
• Emergency unblinding 
If discontinuation of study treatment occurs for any reason, the subject should NOT be 
considered withdrawn from the study. The subject should return to the site after 
discontinuation of study drug, for an End of Treatment (EOT) visit and Follow-up visits (F4 
and F8). Assessments detailed in the “End of Treatment visit” and Follow-up visits (F4 and 
F8) in Table 6-1 should be completed and recorded in the eCRF. The investigator must 
determine the primary reason for the subject’s premature discontinuation of study treatment 
and record this information on the eCRF. 
At the time of the study treatment discontinuation visit, IF it has been approximately 4 weeks 
post last dose of study treatment THEN the assessments described in EOT Visit Week 52 
should be completed at this visit. 
IF it has not been approximately 4 weeks post last dose of study treatment at the time of the 
study treatment discontinuation visit, THEN the subject should be scheduled to return 4 weeks 
post last dose for their EOT Visit Week 52 assessments. 
The investigator/qualified site staff must contact the IRT when the subject completes the EOT 
Visit Week 52 assessments to register the subject’s early completion of the study due to study 
treatment discontinuation. 
Further subject should also return for the final Follow-up visits, F4 (8 weeks after last study 
treatment) and F8 (12 weeks after last study treatment) as per Table 6-1. 
After study treatment discontinuation, at a minimum, the following data should be collected at 
site visits or via telephone visits: 
• new/concomitant treatments 
• Adverse Events/Serious Adverse Events 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If study drug discontinuation occurs because treatment code has been broken, please refer to 
Section 5.5.9 


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5.6.3 
Withdrawal of informed consent 
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a subject: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
and 
• Does not allow analysis of already obtained biologic material 
In this situation, the investigator must make every effort (e.g. telephone, e -mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and  
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should  be  made  as  detailed  in 
Table 6-1. 
 
5.6.4 
Loss to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be considered as lost to follow-up  
until the time point of his/her scheduled end of study visit has passed (i.e. planned Week 52 
visit). 
 
5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the 
subject must be seen as soon as possible and treated as a prematurely withdrawn subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator 
will be responsible for informing the Institutional Review Board/Independent Ethics 
Committee (IRBs/IECs) of the early termination of the trial. 


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6 
Visit schedule and assessments 
Table 6-1 lists all of the assessments and indicates with an “X” when the visits are performed. 
An ‘S’ indicates the data for that assessment are in the source documents at the site. 
Subjects should be seen for all visits on the designated day or as closely as possible to the 
original planned visit schedule. Every effort should be made to respect the time frame for any 
visits, particularly the Week 4, Week 12, Week 16 and Week 52 visit. 
If for any reason the subject is a screen failure, the subject may be rescreened. There is no 
restriction on the number of times a potential subject may be rescreened or on how much time 
must pass from the date of screen failure and the date of rescreening. 
IF a subject rescreens for the study, THEN the subject must sign a n ew ICF and be issued a 
new subject number prior to any screening assessment being conducted for the subject under 
the new screening subject number. For all subjects, the investigator/qualified site staff will 
record if the subject was rescreened on the rescreening CRF and any applicable screening 
numbers the subject was issued prior to the current screening number. 
The date of the new informed consent signature must be entered on the Informed consent CRF 
to correspond to the new screening subject number. For rescreening, all screening assessments 
must be performed per protocol, except for the tuberculosis (TB) work up, if applicable, if 
performed not more than 12 weeks before randomization. 
If the date of a TB work up is less than 12 weeks from the projected randomization date, then 
it is not required that the TB work up be repeated. However, the subject must repeat the 
QuantiFERON test performed by the central laboratory. 
During the treatment epoch, subjects may be seen at an unscheduled visit, e.g. if they 
experience deterioration of psoriasis or suspected AEs. During these unscheduled visits, study 
treatment will NOT be administered. 
For subjects who discontinue study treatment prematurely b efore the end of the treatment 
epoch for any reason other than withdrawal of informed consent or lost to follow up, the 
Week 52 (planned EOT) visit must be performed. 
Further such subjects should also return for the additional Follow-up visits F4 and F8 (8 and 
12 weeks after last study treatment respectively, see Table 6-1). 
If a subject refuses to return for these assessments or is unable to do so, every effort should be 
made to contact them, or a knowledgeable informant, by telephone or by sending appropriate 
correspondence (i.e. certified letter) immediately. At this contact, the safety (e.g. potential 
occurrence of AEs or SAEs) and the primary reason for the subject’s premature withdrawal 
should be determined. Documentation of attempts to contact the subject should be recorded in 
the subject source documents. 


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Table 6-1 
Assessment schedule 
 
Epochs 
Screen Treatment 
FU 
Unscheduled 
visit10
Week (relative to randomization) 
≥-4 to 
≤-2 
R 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
 
48 
52 
EOT 
F48 
F88 
Assessment Day 
≥ - 28 
to ≤ - 
14 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
NA 
NA 
NA 
Obtain informed consent 
X 
Demographics 
X 
Inclusion/exclusion criteria1 
X 
X 
Smoking history 
X 
Psoriasis: medical history/previous psoriasis 
therapies 
X 
Cardiovascular medical history 
X 
Other medical history and prior medications 
X 
Concomitant medications 
Update as necessary 
(s)AE assessment 
Update as necessary 
Physical examination 
S 
S 
S 
S 
S 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory sampling: safety panel2 
(Clinical chemistry, hematology) 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 


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Epochs 
Screen Treatment 
FU 
Unscheduled 
visit10
Week (relative to randomization) 
≥-4 to 
≤-2 
R 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
 
48 
52 
EOT 
F48 
F88 
Assessment Day 
≥ - 28 
to ≤ - 
14 
1 
8 
15 
22 
29 
57 
85 
113 
141 
169 
197 
225 
253 
281 
309 
337 
365 
NA 
NA 
NA 
Fasting labs: fasting plasma glucose and lipid 
panel2 
X 
X 
QuantiFERON® TB-Gold In-tube test3 
X 
X 
Serum pregnancy test4 
X 
X 
Urine pregnancy test (local)5 
X 
X 
X 
ECG (standard 12-lead)6 
S 
S 
PASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BSA 
X 
X 
IGA mod 2011 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization via IRT 
X 
Administer study treatment at study site7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete screening epoch eCRF 
X 
Complete end of treatment epoch eCRF 
X 
Complete Follow-up epoch eCRF9 
X 
(s)AE: (serious) adverse event; BSA: Body Surface Area; ECG: electrocardiogram; eCRF: electronic case report form; IGA: Investigator’s Global Assessment; IRT: 
interactive response technology; PASI: Psoriasis Area and Severity Index; R: randomization; TB: tuberculosis 
X = assessment to be recorded on clinical database; S = assessment to be recorded on source documentation 


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1. These assessments are supported by and stored within the source documentation. Data relating to inclusion/exclusion criteria are captured in the corresponding 
eCRF 
2. Samples will be shipped to the central laboratory for analysis 
3. A repeat QuantiFERON® TB-Gold In-Tube test is recommended if the result of the first QuantiFERON® TB-Gold In-Tube test is “indeterminate”. The subject must be 
referred for a follow-up tuberculosis workup (as per local guidelines) if either the first or the repeat test is “positive” or if the results of both tests are “indeterminate”. If 
the first test is indeterminate, the investigator may decide not to repeat the test and to proceed directly to the workup, though this is not recommended. The subject 
will not be eligible for randomization if “active tuberculosis is present “or if “latent tuberculosis is present” and is untreated according to local guidelines 
4. Only for females of child-bearing potential. 
5. In the event of a positive urine pregnancy test, study treatment must be withheld and a serum pregnancy test performed at the same visit. A urine pregnancy test is 
not required for a woman who is sterile or who is post-menopausal. 
6. Any clinically significant ECG findings need to be reported in CRF as medical history or AE (depending upon time of assessment relative to Screening). 
7. Study medication must be prepared and administered by suitably qualified unblinded personnel who are not responsible for any aspect of subject assessment or 
follow-up. 
8. F4 and F8 visits are follow-up visits only for subjects who prematurely discontinue. F4 visit is to be conducted 8 weeks after last dose of study treatment (4 weeks after 
EOT visit) and F8 visit is to be conducted 12 weeks after last dose of study treatment (8 weeks after EOT visit). 
9. Follow-up visits will be conducted only for subjects who prematurely discontinued study treatment. 
10. Unscheduled visit: The assessment(s) performed at an unscheduled visit are at the investigator’s discretion. 


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6.1 
Information to be collected on screening failures 
All subjects who sign the informed consent but discontinue prior to randomization at 
Randomization Visit are considered to be screen failures. 
If a subject discontinues prior to randomization, the IRT provider must be notified within 5 
days, and the reason for the subject not being randomized will be entered on the Screening 
Phase Disposition eCRF. The Screening visit date, the Demography eCRF, the Informed 
Consent eCRF, the Inclusion/Exclusion eCRF, and the subject rescreening eCRF (if 
applicable) must be completed. The AE eCRF should be completed for any SAEs that 
occurred during the screening epoch. Adverse events that are not SAEs will be followed by 
the investigator and collected only in the source data. The withdrawal of consent eCRF must 
be completed if consent was withdrawn during the screening epoch before the subject was 
randomized. 
For all subjects who sign the informed consent and entered into the next epoch of the study, 
all AEs occurring after the informed consent is signed will be recorded on the AE eCRF. 
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
 
6.2 
Subject demographics/other baseline characteristics 
All Baseline assessments should be performed prior to first study treatment administration. 
These may be in the screening epoch (e.g. demographics) or at the Randomization Visit 
 
 depending on the assessment. 
 
6.2.1 
Demographics 
Subject demographic and baseline characteristic data will be collected at the screening visit. 
Data to be collected on all subjects include: date of birth, age, sex, race, ethnicity, as well as 
height and weight. 
Subject weight (stratification variable) will be reassessed at Randomization visit, prior to 
randomization. 
 
6.2.2 
Psoriasis medical history/previous psoriasis therapies 
Disease history will be collected at the screening visit. The information to be collected and 
entered in the Psoriasis History eCRF and Prior Psoriasis Therapy eCRF includes the 
following: 
o The start date of plaque psoriasis 
o The previous treatments of psoriasis (including previous use of biologic therapies, as 
well as phototherapy and/or photo chemotherapy) and the reason for discontinuation 
of each therapy 
o The presence of psoriatic arthritis and the date of first diagnosis 


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6.2.3 
Smoking history 
The current and/or previous use of tobacco products as well as the estimated number of pack- 
years based on the approximate consumption per year will be recorded in Smoking History 
eCRF. Non-smokers will be advised to not start smoking during the study. 
 
6.2.4 
Co-morbidities – cardiovascular medical history 
Any information pertaining to cardiovascular medical history assessed prior to randomization 
should be reported in the Cardiovascular History eCRF. 
 
6.2.5 
Relevant medical history/current medical conditions 
Relevant medical history (including family history) and current medical conditions, not 
including psoriasis or psoriatic arthritis, prior to signing of the informed consent will be 
recorded in the eCRF. Whenever possible, diagnoses and not symptoms will be recorded. 
Significant findings that are observed after the subject has signed the informed consent form 
and that meet the definition of an AE must be recorded in the AE eCRF. 
 
6.2.6 
Prior and concomitant medications 
Concomitant medications and prior medications taken over the 6 months preceding study 
enrollment will be captured at the screening visit, and updated at the randomization visit in the 
Prior and Concomitant Medication eCRF. 
 
6.2.7 
Determination of tuberculosis status 
Determination of tuberculosis (TB) status will be required before administration of study 
treatment and should be performed as defined by local guidelines. TB status must be 
determined by medical history, signs, symptoms, and TB testing (QuantiFERON-TB Gold 
assay). 
Any significant findings will be recorded in the Medical History eCRF, as necessary. 
 
QuantiFERON TB-Gold In-Tube assay 
A QuantiFERON® TB-Gold In-Tube assay will be performed to assess the TB status at 
screening for all subjects. This test will only be used to determine subject’s eligibility for the 
trial. The test will be used to screen the subject population for latent tuberculosis infection 
(Doherty et al 2008). 
This blood-based assay is specific for Mycobacterium tuberculosis and is not influenced by 
previous Bacillus Calmette-Guérin vaccination or exposure to other Mycobacteria species. 
Furthermore, this test, in contrast to the purified protein derivative (PPD) skin test, is also 
insensitive to a booster effect since the subject is not exposed to the vaccine. The assay 
measures the production of interferon-gamma and presents it relative to a negative and a 
positive control sample (Manuel and Kumar 2008). 


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The QuantiFERON®-TB Gold assay test will be supplied by the central laboratory. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the laboratory manual. 
o If the test result is negative, the subject may be randomized 
o If the test result is positive, the investigator should perform workup for the test result 
per local procedures. If a TB workup was conducted prior to the screening the subject, 
results of the workup can be used to assess eligibility if the workup was conducted 
within 12 weeks prior to randomization. 
• Subjects positive for latent TB per workup may be randomized to the trial if 
sufficient treatment has been initiated according to local routine clinical practice 
and will be maintained for the prescribed duration 
• Subjects positive for active TB per workup are not eligible for the study 
• Subjects negative for TB (no signs of latent or active TB) per workup may be 
randomized to the trial 
o If the test result is indeterminate, it is recommended to repeat the test once. The 
investigator may decide to skip the repetition of the test and proceed directly to the 
workup (this is however not recommended). If a TB workup was conducted prior to 
the screening the subject, results of the workup can be used to assess eligibility if the 
workup was conducted within 12 weeks prior to randomization. 
• If the second test is negative, the subject may be randomized 
• If the second test is positive or indeterminate, the investigator should perform 
workup per local guidelines. Subject positive for latent TB per workup may be 
randomized to the trial if sufficient treatment has been initiated according to local 
routine clinical practice and will be maintained for the prescribed duration. The 
subject will not be eligible for randomization if “active tuberculosis is present” or 
“latent tuberculosis is present” and is untreated per local guidelines. 
• Subjects negative for TB per workup (no signs of latent or active TB) may be 
randomized to the trial if the workup was conducted within 12 weeks prior to 
randomization. 


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Figure 6-1 
Tuberculosis screening flowchart 


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6.2.8 
Other baseline characteristics 
Baseline characteristic data to be collected on all subjects include (see also Table 6-1): 
12-lead ECG (at screening), vital signs, hematology, clinical chemistry, physical examination, 
height, weight, past medical history record of HIV, Hepatitis B or C status, 
 as well as 
assessments of PASI, BSA and IGA mod 2011. A serum pregnancy test will be performed for 
women of childbearing potential. 
All laboratory assessments are central except where indicated. 
 
6.3 
Treatment exposure and compliance 
All doses of study treatment administration will be recorded on the appropriate Dosage 
Administration Record eCRF page. Up to the Final DB lock, compliance will be assessed by 
unblinded field monitor at each visit using syringe (secukinumab, ustekinumab and 
secukinumab placebo) counts and empty medication boxes/outer packaging and information 
provided by the unblinded pharmacist or qualified site personnel responsible for treatment 
dispensation and preparation of the study medication. 
 
6.4 
Efficacy 
All efficacy assessments should be performed prior to the administration of study treatment. 
The recommended order for the efficacy assessments is described below. 
• Efficacy assessments 
The efficacy assessments should be completed in the following recommended order. In all 
cases, the assessor will be blind to treatment allocation: 
• IGA mod 2011 
• PASI 
All remaining study visit procedures (e.g., laboratory sample collection, vital signs 
measurements) must be completed prior to administration of study treatment. 
 
6.4.1 
Investigator’s Global Assessment (IGA mod 2011) 
The IGA mod 2011 will be conducted for overall psoriatic disease as indicated in Table 6-1. It 
is recommended that the same evaluator conducts the assessment throughout the study 
wherever possible. 
Subjects require an IGA mod 2011 score at randomization of 3 or 4 in order to participate in 
the study. Based on this scale, a subject will be considered as an IGA 0 or 1 responder if they 
achieve a score of 0 or 1, and improve by at least 2 points on the IGA scale at a given time 
point compared to their score at randomization (baseline). 
The IGA mod 2011 rating scale for overall psoriatic disease is shown in Table 6-2. 


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The IGA mod 2011 used in this study is static, i.e. it refers exclusively to the subject’s 
disease state at the time of the assessments, and does not attempt a comparison with any of the 
subject’s previous disease states, whether at baseline or at a previous visit. 
The IGA mod 2011 score will be recorded in the eCRF. 
 
Table 6-2 
The IGA mod 2011 rating scale 
Score 
Short 
description 
Detailed description 
 
0 
Clear 
No signs of psoriasis. Post-inflammatory hyperpigmentation may be 
present 
1 
Almost clear 
Normal to pink coloration of lesions; no thickening; no to minimal 
focal scaling 
2 
Mild 
Pink to light red coloration; just detectable to mild thickening; 
predominantly fine scaling 
3 
Moderate Dull bright red, clearly distinguishable erythema; clearly 
distinguishable to moderate thickening; moderate scaling 
4 
Severe 
Bright to deep dark red coloration; severe thickening with hard 
edges; severe/coarse scaling covering almost all or all lesions 
 
Note: Involvement of nails is not part of the assessment 
 
6.4.2 
Assessment of total Body Surface Area (BSA) and Psoriasis Area and 
Severity Index (PASI) 
The investigator or trained qualified designee will complete the PASI assessment as indicated 
in Table 6-1. Whenever possible, the same evaluator should perform this assessment at all 
visits. 
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of 
areas affected, including head, trunk, upper limbs and lower limbs (see below for full details 
of the PASI assessment). The following calculations will be done: Each reported percentage 
will be multiplied by its respective body region corresponding factor (head = 0.1, trunk = 0.3, 
upper limbs = 0.2, lower limbs = 0.4). The resulting four percentages will be added up to 
estimate the total BSA affected by plaque-type psoriasis. 
The PASI scoring system is further described in Table 6-3. 
A PASI score (Fredriksson and Pettersson 1978; Weisman et al 2003; Gottlieb et al 2005) will 
be derived as indicated in Table 6-3. The head, trunk, upper limbs and lower limbs are 
assessed separately for erythema, thickening (plaque elevation, induration), and scaling 
(desquamation). The average degree of severity of each sign in each of the four body regions 
is assigned a score of 0-4. The area covered by lesions on each body region is estimated as a 
percentage of the total area of that particular body region. Further practical details to help with 
the assessment are provided below: 
1. The neck is assessed as part of the head 
2. The axillae and groin are assessed as part of the trunk 
3. The buttocks are assessed as part of the lower limbs 
4. When scoring the severity of erythema, scales should not be removed. 


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Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 
10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score is calculated 
using the formula: 
PASI = 0.1(EH+IH+DH)AH + 0.2(EU+IU+DU)AU + 0.3(ET+IT+DT)AT + 0.4(EL+IL+DL)AL 
The keys for the letters are provided in Table 6-3. 
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0. 
The baseline value for analysis of the PASI is collected at the Randomization Visit on the 
PASI score eCRF. 
Subjects require a total BSA affected by plaque-type psoriasis of 10% or more and a PASI 
score of 12 or more at randomization to be eligible for this study. 
 
Table 6-3 
The PASI scoring system 
 
Body 
region 
Erythema (E) 
Thickening 
(plaque elevation, 
induration, I) 
Scaling 
(desquamation, D) 
Area score 
(based on true 
area%, A)* 
Head (H)† 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=no involvement 
1=>0-<10% 
2=10-<30% 
3=30-<50% 
4=50-<70% 
5=70-<90% 
6=90-100% 
Trunk (T)‡ 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=none 
1=slight 
2=moderate 
3=severe 
4=very severe 
0=no involvement 
1=>0-<10% 
2=10-<30% 
3=30-<50% 
4=50-<70% 
5=70-<90% 
6=90-100% 
Upper 
0=none 
0=none 
0=none 
0=no involvement 
limbs (U) 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=>0-<10% 
2=10-<30% 
3=30-<50% 
4=50-<70% 
5=70-<90% 
6=90-100% 
Lower 
0=none 
0=none 
0=none 
0=no involvement 
limbs (L)§ 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=slight 
2=moderate 
3=severe 
4=very severe 
1=>0-<10% 
2=10-<30% 
3=30-<50% 
4=50-<70% 
5=70-<90% 
  
6=90-100% 
 
*Percentage (not score) of body region (not whole body) affected will be entered in the eCRF 
†Neck is assessed as part of the Head (H) body region 


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‡Axillae and groin are assessed as part of the Trunk (T) body region 
§Buttocks are assessed as part of the Lower limbs (L) body region 
 
Definitions of efficacy variables based on PASI 
The following definitions will be used in this study based on the CHMP guidelines for 
psoriasis (CHMP/EWP/2454/02 2004): 
o PASI 50 response (partial response): subjects achieving ≥50% improvement 
(reduction) in PASI score compared to baseline are defined as PASI 50 responders 
o PASI 75 response: subjects achieving ≥75% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 75 responders 
o PASI 90 response: subjects achieving ≥90% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 90 responders 
o PASI 100 response/remission: complete clearing of psoriasis (PASI=0) 
6.4.3 
Appropriateness of efficacy assessments 
PASI scores outcome measures, the assessment of the severity of the psoriasis symptoms and 
the extent to which the subject’s body area is affected by the disease, is mandated by the EMA 
for the clinical investigation of medicinal products for the treatment of psoriasis 
(CHMP/EWP/2454/02 2004). 
As indicated in Section 6.4.1, the IGA mod 2011 scale has been developed by Novartis in 
collaboration with health authorities, in particular the FDA. It is based on the previous version 
of the scale which was used in Phase II secukinumab studies, and has been used in all phase 
III studies. In the modified scale, the two “very severe” and “severe” have been condensed 
into a single category, “severe” and the explanations/descriptions of the points on the scale 
have been improved to ensure appropriate differentiation between the points. 
 
6.5 
Safety 
From Day 1, all blood draws and safety assessments must be performed prior to study 
treatment administration. Appropriate safety assessments (e.g., evaluation of AEs and SAEs) 
should be repeated after dosing with study treatment. 
 
6.5.1 
Physical examination 
A physical examination, including general appearance, will be performed as indicated in 
Table 6-1. 
If indicated, based on medical history and/or symptoms, additional exams will be performed 
at the discretion of the investigator. 
If possible, assessments for an individual subject should be performed by the same member of 
the study site staff throughout the study. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that are present prior to the subject signing informed consent 
must be included in the Medical History eCRF. Significant findings made after the signing of 


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the informed consent which meet the definition of an AE must be recorded on the AE eCRF 
(Section 7). 
 
6.5.2 
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed as indicated in 
Table 6-1. 
After the subject has been sitting for five minutes, with back supported and both feet placed 
on the floor, systolic and diastolic blood pressure will be measured twice (measurements 
separated by 1 to 2 minutes) using a validated device with an appropriately sized cuff and 
each BP measurement will be recorded in the source (Mancia et al 2007). In case the cuff 
sizes available are not large enough for the subject’s arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. Both measurements will be 
entered on the Vital Signs eCRF. 
If possible, assessments should be performed by the same study site staff member throughout 
the study. 
Normal blood pressure will be defined as a systolic pressure of 90 to <120 mmHg, and a 
diastolic blood pressure of 60 to <80 mmHg under the measurement conditions outlined 
above. Notable blood pressure will be hypertension (systolic blood pressure of ≥140 mmHg 
and/or diastolic blood pressure of ≥90 mmHg) or hypotension (systolic blood pressure of 
<90 mmHg and/or a diastolic blood pressure of <60 mmHg). A blood pressure indicative of 
prehypertension (systolic blood pressure of 120 to <140 mmHg and/or diastolic blood 
pressure of 80 to <90 mmHg) will not be regarded as notable (Chobanian et al 2003). 
A normal pulse rate will be defined as a rate of 60 to 100 beats per minute (bpm) under the 
measurement conditions outlined above. Notable pulse rates are a rate below 60 bpm 
(bradycardia) or above 100 bpm (tachycardia). 
Whether action needs to be taken to address notable vital signs will be decided by the 
investigator, taking into account the overall status of the subject. No specific action  is 
foreseen as part of the study protocol. 
 
6.5.3 
Height and weight 
Height and body weight will be measured as indicated in Table 6-1. 
Height and body weight will be measured in indoor clothing, but without shoes. 
If possible, body weight assessments should be performed by the same study site staff 
member and using the same scale throughout the study. The body weight recorded at 
Randomization visit will be used to stratify the subject population for randomization. 
 
6.5.4 
Laboratory evaluations 
Subjects should avoid smoking within the hour preceding the blood draws. 
A central laboratory will be used for analysis of all specimens unless noted otherwise. Details 
on the collections, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the Laboratory Manual. 


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For the identification of notable values, the laboratory manual should be consulted. 
Whether action needs to be taken to address notable laboratory values will be decided by the 
investigator, taking into account the overall status of the subject. No specific action  is 
foreseen as part of the study protocol. 
 
6.5.4.1 
Hematology 
Hematology assessments will include hemoglobin, hematocrit, red blood cell count, white 
blood cell count with differential (neutrophils including bands, lymphocytes, monocytes, 
eosinophils, basophils) and platelet count. Hematology assessments will be measured at all 
scheduled study visits specified in Table 6-1. 
 
6.5.4.2 
Clinical chemistry 
Serum chemistry will include blood urea nitrogen (BUN), creatinine, total bilirubin, alanine 
transaminase (ALT)/serum glutamic pyruvate transaminase (SGPT), aspartate transaminase 
(AST)/serum glutamic oxaloacetic transaminase (SGOT), gamma glutamyl transpeptidatse 
(GGT), alkaline phosphatase. Serum chemistry will be measured at all scheduled study visits 
specified in Table 6-1. Fasting plasma glucose and fasting lipids will be measured at baseline 
visit. 
 
6.5.4.3 
Urinalysis 
Dipsticks will be provided by the central laboratory to the study sites for local urinalysis 
assessments. The sites will record the results in the Local Lab Results-Urinalysis eCRF page 
for each subject. Standard dipstick measurements for specific gravity, protein, glucose, pH, 
blood, urine blood (non-hemolyzed), urine blood (hemolyzed), bilirubin, ketones, WBC will 
be done at screening as indicated in Table 6-1. If needed conditional microscopy assessments 
will be done. 
 
6.5.5 
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position. The preferred sequence of 
cardiovascular data collection during study visits is ECG collection first, followed by vital 
signs, and blood sampling. The Fridericia QT correction formula (QTcF) should be used for 
clinical decisions. 
A standard single 12-lead ECG will be collected at screening visit (Table 6-1). The 
investigator/qualified site staff must review and initial the tracing. The original ECGs 
appropriately signed, should be collected and archived at the study site. 
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, and filed in the study site source documents. For any ECGs with subject safety 
concerns, two additional ECGs should be performed to confirm the safety finding. Clinically 
significant abnormalities should be recorded on the relevant section of the (cardiovascular) 
medical history/AE CRF/e(CRF) page as appropriate. 


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6.5.6 
Pregnancy 
A serum β-hCG test will be performed at screening in all pre-menopausal women who are not 
surgically sterile. 
All women of childbearing potential will also have a urine pregnancy test performed locally at 
baseline. 
Any woman with a confirmed positive pregnancy test during screening is not eligible for 
randomization. 
A positive urine pregnancy test during the treatment epoch of the study requires immediate 
interruption of study treatment until serum β-hCG is performed and found to be negative. If 
the serum β-hCG test is positive, study treatment must be definitively discontinued, as 
described in Section 5.6.2. 
 
6.5.7 
Appropriateness of safety measurements 
The safety assessments selected in this study are reliable and standard measures for a biologic 
immunomodulating agent in adult subjects with psoriasis. 
 
 
 


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7 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 


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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patient with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
• the severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
• its relationship to the study treatment (suspected: no/yes), 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of SAE) 
• action taken regarding study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• no action taken (e.g. further observation only) 
• study treatment temporarily interrupted 
• study treatment permanently discontinued due to this adverse event 
• concomitant medication given 
• non-drug therapy given 
• subject hospitalized/subject’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it is judged 
to be permanent, and assessment must be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
Worsening of psoriasis in this study is evaluated via the use of PASI, IGA mod 2011 
 
 and is not expected to be captured as an AE in the eCRF. Exceptions 


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include cases when a) a new type of psoriasis is diagnosed e.g. guttate psoriasis or b) the 
worsening of psoriasis is so severe that a qualitatively different status is reached. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB 2015). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and has then to be discussed with the subject. 
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis. 
 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 


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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 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
 
7.2.2 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 12 weeks following the last administration of study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. Any 
SAEs experienced after 12 week period following the last administration of study treatment 
should only be reported to Novartis if the investigator suspects a causal relationship to study 
treatment. 
All SAEs reported up to the subject’s last visit will be reported in the AE eCRF. SAEs beyond 
the last visit will only be recorded in the Novartis Drug Safety and Epidemiology database. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form. The investigator must assess the relationship to 
study treatment, complete the SAE Report Form in English, and submit it within 24 hours 
after awareness of the SAE to Novartis. Detailed instructions regarding the submission 
process and requirements for signature are listed in the investigator folder provided to each 
site. Follow-up information should be provided using SAE Report Form stating that this is a 
follow-up to a previously reported SAE. 
Follow-up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the treatment code was broken or not and whether the subject 
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 


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committees in accordance with EU Guidance 2011/C 172/01 or with national regulatory 
requirements in participating countries. 
 
7.3 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety DB irrespective of it being associated with an AE/SAE. 
 
 
Treatment error 
type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
 
 
7.4 
Pregnancy reporting 
To ensure subject safety, each pregnancy occurring after signing the informed consent must  
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should  
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. During 


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the study, Novartis employs several methods of ensuring protocol and GCP compliance and 
the quality/integrity of the sites’ data. The field monitor will visit the site to check the 
completeness of subject records, the accuracy of entries on the (e)CRFs, the adherence to the 
protocol and to Good Clinical Practice and the progress of enrollment. Key study personnel 
must be available to assist the field monitor during these visits. Continuous remote  
monitoring of each site’s data may be performed by a centralized Novartis CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis Clinical Teams to assist with trial 
oversight. The investigator must maintain source documents for each subject in the study, 
consisting of case and visit notes (hospital or clinic medical records) containing demographic 
and medical information, laboratory data, electrocardiograms, and the results of any other 
tests or assessments. All information on CRFs must be traceable to these source documents in 
the subject's file. The investigator must also keep the original informed consent form signed 
by the subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
In addition, the unblinded field monitor will be responsible for monitoring unblinded  
activities performed by unblinded site personnel, including regular checks that the study 
treatment is being stored, prepared, dispensed and accounted for based on documentation filed 
that only unblinded personnel would have access to. 
 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the OC/RDC 
system. Designated investigator site staff will not be given access to the system until they 
have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After DB 
lock, the investigator will receive copies of the subject data for archiving at the investigational 
site. 
 
8.3 
Database management and quality control 
Novartis staff [or CRO working on behalf of Novartis] review the data entered into the CRFs 
by investigational staff for completeness and accuracy and instruct the site personnel to make 
any required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff is required to respond to the query and 
confirm or correct the data. If the electronic query system is not used, a paper Data Query 


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Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to Novartis staff that will make the correction to the DB. The signed copy of the Data 
Query Form is kept at the investigator site. 
Concomitant medications entered into the DB will be coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system.  
Concomitant procedures, non-drug therapies and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
ECGs will be read locally. Any clinically significant findings will be reported as 
(cardiovascular) medical history or AE depending upon timing of ECG assessment compared 
to screening. 
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the DB has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the DB after that time can only be made after written agreement by Novartis Development 
management. 
 
8.4 
Data Monitoring Committee 
Not applicable. 
 
8.5 
Adjudication Committee 
Not applicable. 
 
9 
Data analysis 
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before 
publication or presentation. 
 
9.1 
Analysis sets 
The following analysis sets will be used in this trial: 
Randomized set: The randomized set will be defined as all subjects who were randomized. 
Unless otherwise specified, misrandomized subjects (misrandomized in IRT) will be excluded 
from the randomized set. 


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Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set 
to whom study treatment has been assigned. Following the intent-to-treat principle, subjects 
will be analysed according to the treatment assigned at randomization. 
Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment epoch. Subjects will be analyzed according to treatment received. 
For subject demographics and other baseline characteristics analyses will be based on the 
randomized set, unless otherwise specified. 
Treatment groups for analyses for data will include: 
• secukinumab 
• ustekinumab 
9.2 
Subject demographics and other baseline characteristics 
Demographics and baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristic 
variables for each treatment group and for all subjects in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and for all subjects. 
 
Medical history 
Any condition entered as medical history or current medical conditions at baseline will be 
coded using the MedDRA dictionary. Medical history will be summarized by system organ 
class and preferred term in the MedDRA dictionary. Summaries for psoriasis specific medical 
history will be provided as well. 
 
9.3 
Treatments 
Study treatments 
The analysis of study treatment data will be based on the safety set. 
The number of active and placebo injections will be summarized by treatment group by means 
of contingency tables. 
The duration of exposure to study treatment will also be summarized by treatment group. In 
addition, the number of subjects with exposure of at least certain thresholds (e.g., any 
exposure, ≥1 week, ≥2 weeks, ≥3 weeks, ≥4 weeks, ≥8 weeks, etc.) will be displayed. 
 
Prior and concomitant treatments 
Prior and concomitant treatments will be summarized by treatment group in separate tables  
for the safety set. 
Prior treatments are defined as treatments taken and stopped prior to first dose of study 
treatment. Any treatment given at least once between the day of first dose of randomized 


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study treatment and the last day of study visit will be a concomitant treatment, including those 
which were started pre-baseline and continued into the treatment epoch. 
Treatments will be presented in alphabetical order, by ATC codes and main groups. Tables 
will also show the overall number and percentage of subjects receiving at least one treatment 
of a particular ATC code and at least one treatment in a particular anatomical main group. 
Psoriasis specific prior treatments will be presented as well including number of prior 
systemic and biologic psoriasis therapies as well as reason for discontinuation. 
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized. 
 
9.4 
Analysis of the primary variable(s) 
Details of the testing strategy are provided in Section 9.4.2. 
9.4.1 
Variable(s) 
Primary variable 
The co-primary efficacy variables are PASI 90 response at Week 12 and IGA 0 or 1 response 
at Week 12. The analysis of the co-primary variables will be based on the FAS. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
Primary endpoint 
The co-primary endpoints of this study are the proportion of subjects with PASI 90 response 
and IGA 0 or 1 response at Week 12 with secukinumab compared with ustekinumab. 
The statistical hypothesis for PASI 90 response at Week 12 and IGA 0 or 1 response at Week 
12 is that secukinumab is not superior to ustekinumab in the proportion of subjects with PASI 
90 response and IGA 0 or 1 response at Week 12. 
Let pjdenote the proportion of PASI 90 responders at Week 12 for treatment group j and rj 
denote the proportion of IGA 0 or 1 responders at Week 12 for treatment group j, j = 1,0. 
where 
• 
0 corresponds to ustekinumab 
• 
1 corresponds to secukinumab 
The following hypothesis will be tested: 
H1: p1 − p0 ≤ 0 versus HA1: p1 − p0 > 0, 
H2: r1 − r0 ≤ 0 versus HA2: r1 − r0 > 0 
In other words: 
H1: Secukinumab is not superior to ustekinumab with respect to PASI 90 response at Week 12 
H2: Secukinumab is not superior to ustekinumab with respect to IGA 0 or 1 response at Week 
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The primary analysis method will be the logistic regression with treatment group; baseline 
bodyweight strata and baseline PASI score as explanatory variables. Odds ratios will be 
computed for comparisons of secukinumab dose regimens versus ustekinumab utilizing the 
logistic regression model fitted. In case of response rates of 0% or of 100% in one of the 
treatment groups, Fisher’s exact test will be applied. Confidence intervals for risk difference 
will be provided. 
The hypotheses H1 and H2 will both be tested at level 2.5% (one-sided),  and  significant 
results will only be achieved if both tests are rejected. i.e., if only one hypothesis is rejected 
and the other hypothesis is not rejected, superiority of secukinumab has not been 
demonstrated. 
 
9.4.3 
Handling of missing values/censoring/discontinuations 
The following imputation methods will apply to the missing data: 
o Response variables based on PASI score and IGA mod 2011 categories will be 
imputed with multiple imputations (MI) method as primary imputation method. 
Multiple imputation (MI) is a simulation based approach where missing values are 
replaced by multiple Bayesian draws from the conditional distribution of missing data 
given the observed data and covariates, creating multiple completed data sets. These 
completed data sets can then be analyzed using standard methods. Within this analysis 
the PASI score or IGA mod 2011 categories will be imputed and response variables 
will be derived based on the imputed scores. In the multiple imputation analysis the 
response status will be imputed based on the individual treatment arm information. 
o Non-responder imputation will be used as sensitivity method: Missing values with 
respect to response variables based on PASI score and IGA 2011 categories will be 
imputed with non-response regardless to the reason for missing data (e.g. premature 
study discontinuation, missed visit, administrative issues), exceptions will apply to the 
following: 
• If a subject dropped out of the study prior to last scheduled visit and being 
responders consecutively at least for two preceding visits, the subject will be 
imputed as responder for the last scheduled visit. 
• If a subject who was responder at visit x-1 and visit x+1 but has missing data at 
visit x, then the subject will be imputed for visit x, except for the missing data at 
last visit in the treatment period. 
 
9.4.4 
Sensitivity analyses 
Sensitivity analyses will be performed as follows: 
Co-primary variables and key secondary variables will be evaluated using the logistic 
regression as described in primary analysis method with non-responder imputations. 
 
9.5 
Analysis of secondary variables 
9.5.1 
Efficacy variables 
The key secondary endpoints of this study are planned as follow: 


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o speed of onset (PASI 75 at Week 4) 
o PASI 75, PASI 90, PASI 100 and IGA 0/1 at Week 16 
o PASI 75 and PASI 100 at Week 12 
o PASI 90 at Week 52 
Testing strategy 
The following hypotheses will be tested sequentially and are included in the hierarchical 
testing strategy and type-I-errors will be set such that a family-wise type-I-error of α = 2.5% 
(one-sided) is kept: 
Co-primary objectives: H1 to H2 (see Section 9.4.2) 
Key secondary objectives: 
o H3: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 12 
o H4: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 4 
o H5: secukinumab is not superior to ustekinumab with respect to PASI 90 response at 
Week 16 
o H6: secukinumab is not superior to ustekinumab with respect to PASI 100 response at 
Week 16 
o H7: secukinumab is not superior to ustekinumab with respect to IGA 0 or 1 response at 
Week 16 
o H8: secukinumab is not superior to ustekinumab with respect to PASI 100 response at 
Week 12 
o H9: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 16 
o H10: secukinumab is not superior to ustekinumab with respect to PASI 90 response at 
Week 52 
The graphical approach of (Bretz et al. 2009) for sequentially rejective testing procedures is 
used to illustrate the testing strategy: 


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The efficacy variables involved in the above testing strategy will be analyzed analogously to 
the primary endpoints at Week 12. i.e., the logistic regression model with treatment group, 
baseline bodyweight strata and baseline PASI score 
. Odds ratios will 
be computed for comparisons of secukinumab versus ustekinumab utilizing the logistic 
regression model fitted. 
The testing sequence will continue to H3 at α (one-sided) only if both H1 and H2 have been 
rejected at α (one-sided). Similarly, the testing sequence will continue to H4 at α (one-sided) 
only if H3 testing has been rejected. In case, H9 has been rejected at α (one-sided), the 
corresponding alpha (α) will be passed to the next hypotheses corresponding H10. 
 
 


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9.5.3 
Safety variables 
All safety evaluations will be performed on the Safety set. 


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Adverse events 
Treatment emergent AEs (events started after the first dose of study treatment and within 84 
days after the last study treatment, or events present prior to the first dose of study treatment 
but increased in severity based on preferred term within 84 days after the last study treatment) 
will be summarized. Only primary paths within MedDRA will be considered for AE reporting. 
AEs will be summarized by presenting, for each treatment group, the number and percentage 
of subjects having any AE, having an AE in each primary system organ class and having each 
individual AE (preferred term). Summaries will also be presented for AEs by severity and for 
study treatment related AEs. If a subject reported more than one AE with the same preferred 
term, the AE with the greatest severity will be presented. If a subject reported more than one 
AE within the same primary system organ class, the subject will be counted only once with 
the greatest severity at the system organ class level, where applicable. 
Confidence intervals for relative frequencies will be derived as well according to the score 
method including continuity correction by Newcombe (Newcombe 1998). 
Separate summaries will be provided for death, SAE, other significant AEs leading to 
discontinuation and AEs leading to study treatment discontinuation. 
A graphical display of relative frequencies within system organ classes will be presented. 
 
Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry). Descriptive summary statistics for the change from 
baseline to each study visit will be presented. These descriptive summaries will be presented 
by test group, laboratory test and treatment group. Change from baseline will only be 
summarized for subjects with both baseline and post baseline. 
For each parameter, the maximum change from baseline within each study epoch will be 
analyzed analogously. 
In addition, shift tables will be provided for all parameters based on Common Toxicity grade 
Criteria (CTC). For these shift tables, the normal laboratory ranges will be used to evaluate 
whether a particular laboratory test value was normal, low, or high relative to the baseline 
value. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented for most extreme values post-baseline. 
 
Vital signs 
Analysis of the vital sign measurements using summary statistics for the change from baseline 
for each post-baseline visit will be performed. These descriptive summaries will be presented 
by vital sign and treatment group. Change from baseline will only be summarized for subjects 
with both baseline and post-baseline values. 
 


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9.6 
Interim analyses 
Week 16 analysis will be performed after all subjects have completed Week 16 visit. 
Additional analyses may be performed to support health authority interactions as necessary. 


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At the End of Study, a final analysis of all data collected up to last study visit (Week 52 or F8 
as applicable) will be performed when all subjects have completed the last study visit. 
 
9.7 
Sample size calculation 
The total sample size is 1100 subjects, i.e. using a balanced randomization 550 subjects will 
be randomized to each treatment group. 
The secukinumab dose regimen versus ustekinumab with respect to the co-primary endpoint 
PASI 90 and IGA 0/1 at Week 12 are tested at α=2.5% (one-sided). The response rates are 
computed based on CLEAR (CAIN457A2317) study data. The assumed response rates and 
power are shown in Table 9-1. The power calculations are based on chi-square test (nQuery 
Advisor 7.0, two group chi-square test of equal proportions). 
 
Table 9-1 
Power to show superiority of secukinumab versus ustekinumab for 
co-primary endpoints 
 
 
Endpoints 
Secukinumab 300 mg 
Response (%) 
Ustekinumab 
Response (%) 
Power 
PASI 90 at Week 12 
66% 
52% 
>99% 
IGA 0/1 at Week 12 
77% 
64% 
>99% 
Note: one-sided type-I-error=2.5%, N=550 per group 
If the assumed PASI 90 response rate at week 12 for secukinumab is 66% and for 
ustekinumab is 52%, the power to reject the corresponding null hypothesis is greater than 
99%. Similarly, if the assumed IGA 0/1 response rate at week 12 for secukinumab is 77% and 
for ustekinumab is 64%, the power to reject the corresponding null hypothesis is also greater 
than 99%. Details for other key secondary endpoints are provided in Table 9-2. 
 
9.8 
Power for analysis of key secondary variables 
The secukinumab dose regimen versus ustekinumab with respect to the key secondary 
endpoints are tested at α=2.5% (one-sided). The response rates are computed based on 
unpublished CLEAR (CAIN457A2317) study data. 
 
Table 9-2 
Power to show superiority of secukinumab versus ustekinumab for 
key secondary endpoints 
 
 
Endpoints
Secukinumab 300 mg 
Ustekinumab 
Power 
Response (%) 
Response (%) 
PASI 75 at Week 12 
88% 
79% 
97% 
PASI 75 at Week 4 
47% 
21% 
>99% 
PASI 90 at Week 16 
74% 
55% 
>99% 
PASI 100 at Week 16 
40% 
24% 
>99% 
IGA 0/1 at Week 16 
80% 
65% 
>99% 
PASI 100 at Week 12 
34% 
23.5% 
96% 


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Endpoints
Secukinumab 300 mg 
Ustekinumab 
Power 
Response (%) 
Response (%) 
PASI 75 at Week 16 
90% 
82% 
96% 
PASI 90 at Week 52 
70% 
60.5% 
90% 
Note: one-sided type-I-error=2.5%, N=550 per group 
 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US CFR 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in 
the Declaration of Helsinki. 
 
10.2 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the 
subject. In cases where the subject’s representative gives consent, the subject must be 
informed about the study to the extent possible given his/her understanding. If the subject is 
capable of doing so, he/she must indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (e.g. all of the procedures described in the 
protocol). The process of obtaining informed consent must be documented in the subject 
source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
Women of childbearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
must not be entered in the study. 
 
10.3 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g., advertisements) and any other written information to be provided to subjects. 


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Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made. 
 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report  
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results. 
 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected  
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
 
11.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate 
hazard to subjects may be implemented immediately provided the health authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7 (Safety Monitoring) must be followed. 
 
12 
References 
References are available upon request 


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Bissonnette R, Bolduc C, Poulin Y et al (2010) Efficacy and safety of adalimumab in patients 
with plaque psoriasis who have shown an unsatisfactory response to etanercept. J Am Acad 
Dermatol; 63: 228-34 
Bretz F, Maurer W, BrannathW, Posch M (2009) A graphical approach to sequentially 
rejective multiple test procedures. Statistics in Medicine; 28: 586-604. 
Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint 
National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood 
Pressure; National High Blood Pressure Education Program Coordinating Committee (2003) 
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure: the JNC 7 report. Hypertension; 42: 1206-52. 
Committee for medicinal products for human use (CHMP), European Medicines Agency for 
the Evaluation of Medicines for Human Use. (2004) Guideline on clinical investigation of 
medicinal products indicated for the treatment of psoriasis. CHMP/EWP/2454/02 corr. 
document. London, UK. 
Doherty SD, Van Voohes A, Lebwohl MG (2008) National Psoriasis Foundation consensus 
statement on screening for latent tuberculosis infection in patients with psoriasis treated with 
systemic and biologic agents. J Am Acad Dermatol; 59(2): 209-17. 
Fredriksson T and Pettersson U (1978) Severe psoriasis-oral therapy with a new retinoid. 
Dermatologica; 157: 238-44. 
Gottlieb A, Griffiths CEM, Ho VC, et al (2005) Efficacy and tolerability of oral pimecrolimus 
in the treatment of moderate to severe chronic plaque type psoriasis: a double-blind, 
multicentre, randomized dose-finding trial. Br J Dermatol; 152: 1219-27. 
Griffiths CEM, Strober BE, Kerkhof, van de P, et al (2010) Comparison of ustekinumab and 
etanercept for moderate-to-severe Psoriasis. N Engl J Med; 362: 118-28. [ACCEPT]. 
Haitz KA, Kalb RE (2007). Infliximab in the treatment of psoriasis in patients previously 
treated with etanercept. J Am Acad Dermatol; 57: 120-5. 
Investigator’s Brochure for secukinumab (Sep 2015) 
Kimball AB, Gordon KB, Fakharzadeh S, et al (2012) Long-term efficacy of ustekinumab in 
patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 
years. Br J Dermatol; 166(4): 861-72. 
Langley RG, Elewski BE, Lebwohl M, et al (2014) Secukinumab in plaque psoriasis: results 
of two phase 3 trials. N Engl J Med; 371 (4):326–338. 
Leonardi CL, Kimball AB, Papp KA et al (2008) Efficacy and safety of ustekinumab, a 
human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results 
from a randomised, double-blind, placebo-controlled trial. Lancet; 371: 1665-74. [Phoenix 1] 
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, et al. (2007) Guidelines for the 
Management of Arterial Hypertension: The Task Force for the Management of Arterial 
Hypertension of the European Society of Hypertension (ESH) and of the European Society of 
Cardiology (ESC). J Hypertens; 25:1105-87. 


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Manuel O, Kumar D (2008) QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Diagn; 8(3): 247-56. 
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-72. 
Papp KA (2006) The long-term efficacy and safety of new biological therapies for psoriasis. 
Arch Dermatol. Res; 298(1): 7–15. 
Papp KA, Langley RG, Lebwohl M et al (2008) Efficacy and safety of ustekinumab, a human 
interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a 
randomised, double-blind, placebo-controlled trial. Lancet; 371: 1675-84. [Phoenix 2] 
Thaçi D, Blauvelt A, Reich K et al (2015) Secukinumab is superior to ustekinumab in clearing 
skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled 
trial. J Am Acad Dermatol; 73(3):400-9. 
Van Lümig PPM, Lecluse LLA, Driessen RJB et al (2010) Switching from etanercept to 
adalimumab is effective and safe: results in 30 patients with psoriasis with primary failure, 
secondary failure or intolerance to etanercept. Br J Dermatol; 163; 838-846 
Vender RV (2011) An open-label, prospective cohort pilot study to evaluate the efficacy and 
safety of etanercept in the treatment of moderate to severe plaque psoriasis in patients who 
have not had an adequate response to adalimumab. J. Drugs Dermatol; 10(4): 396-402 
Weisman S, Pollack CR, Gottschalk RW (2003) Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat; 14: 158-165. 
Woolf RT, Smith CH, Robertson K et al (2010) Switching to adalimumab in patients with 
moderate to severe psoriasis who have failed on etanercept: a retrospective case cohort study 
Br J Dermatol; 163, 889-892. 


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13 
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 6.5.2. 
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 subject. 
 
Liver Function and Related Variables 
o ALT (SGPT): 
> 3 x Upper Limit of Normal (ULN) 
o AST (SGOT): 
> 3 x ULN 
o Total bilirubin: 
> 1.5 x ULN 
o Alkaline phosphatase: 
> 2 x ULN 
Renal Function 
o Creatinine (serum): 
> 1.5 x ULN 
Hematology Variables 
o Hemoglobin: 
≥ 20 g/L decrease from baseline 
o Platelet count: 
< Lower Limit of Normal (LLN) 
o White blood cell count: 
< 0.8 x LLN 
o Neutrophils: 
< 0.9 x LLN 
o Eosinophils: 
> 1.1 x ULN 
o Lymphocytes: 
> 1.1 x ULN 

SAP_001.pdf: 
Clinical Development
AIN457/ Secukinumab/Cosentyx®
CAIN457A2326 / NCT02826603
A 52-week, multicenter, randomized, double-blind study of 
secukinumab (300 mg) to demonstrate efficacy as 
assessed by Psoriasis Area and Severity Index and 
Investigator’s Global Assessment after 12 weeks of 
treatment, compared to ustekinumab, and to assess long-
term safety, tolerability and efficacy in subjects with 
moderate to severe plaque psoriasis (CLARITY)
Statistical Analysis Plan (SAP)
Author:
Statistician, 
Document type:
SAP Documentation
Document status:
Final v2.0
Release date:
18-Jul-2018
Number of pages:
51
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)
16-
May-
2016
Prior to 
FPFV
Creation 
of 
final
version
1.0
First version
NA
9-Nov-
2017
Prior to 
PEA
Creation 
Amendement 
1.0 version

Change to present one-sided p-values 
instead of two-sided p-values.

Update visit window derivation 

Update the subgroup analysis 
 
.

Update Section 2.4.1.2 Multiple 
assessments within visit windows

Update Section 2.5.3 Handling of 
missing 
values/censoring/discontinuations: add 
pure NRI method

 

Drop figure for adverse events.

Modify liver events definition.
10-
Apr-
2018
Prior to 
final 
analysis
Creation 
Amendment 
2.0 version 


Update wording ’Previous Non-biologic 
systemic Therapy’.

Update RAP M7.1 and M7.2 to TFL 
shell and RAP M8 to PDS. 

Update Table 2-9 per eCRS.

Update typo on “ALT or AST>3xULN & 
TBL >2xULN & ALP <2xULN    
(Potential Hy’s Law)”.

For time to event analysis, add 
treatment comparison and update 
treatment interval.


Drop some of the safety analysis

Drop subgroup analysis other than 
weight



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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................8
2.2
Analysis sets ............................................................................................................9
2.2.1
Subgroup of interest ..............................................................................10
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................20
2.5.3
Handling of missing values/censoring/discontinuations.......................21
2.5.4
Supportive analyses...............................................................................21
2.6
Analysis of the key secondary objective ...............................................................22
2.6.1
Key secondary endpoint........................................................................22
2.6.2
Statistical hypothesis, model, and method of analysis..........................22
2.6.3
Handling of missing values/censoring/discontinuations.......................23
2.7
Analysis of secondary efficacy objective(s)..........................................................23
2.7.1
Secondary endpoints .............................................................................23
2.7.2
Statistical hypothesis, model, and method of analysis..........................23
2.7.3
Handling of missing values/censoring/discontinuations.......................24
2.8
Safety analyses.......................................................................................................24
2.8.1
Adverse events (AEs)............................................................................24
2.8.2
Deaths....................................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................29
29
29


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29
30
30
2.14
Interim analysis......................................................................................................32
3
Sample size calculation .....................................................................................................32
4
Change to protocol specified analyses ..............................................................................33
5
Appendix ...........................................................................................................................33
5.1
Imputation rules.....................................................................................................33
5.1.1
Study drug.............................................................................................33
5.1.2
AE date imputation ...............................................................................33
5.1.3
Concomitant medication date imputation .............................................35
5.1.4
Other imputations..................................................................................36
5.2
AEs coding/grading ...............................................................................................36
5.3
Laboratory parameters derivations ........................................................................37
5.4
Statistical models...................................................................................................37
5.4.1
Analysis of continuous data ..................................................................37
5.4.2
Analysis of binary (and categorical) data..............................................37
5.4.3
Logistic regression ................................................................................38
5.4.4
Multiple imputations for response variables.........................................38
5.4.5
Analysis of time-to-event data ..............................................................41
5.4.6
Crude incidence and related risk estimates ...........................................42
5.4.7
Exposure adjusted incidence rate and related risk estimates ................44
5.5
Rule of exclusion criteria of analysis sets..............................................................45
45
45
6
Reference...........................................................................................................................47


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List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BSA
Body surface area
CHMP 
Committee for medicinal products for human use 
CSR
Clinical study report
CTCAE 
Common Terminology Criteria for Adverse Events
ECG
Electrocardiogram
eCRF
Electronic case report/record form
FAS
Full analysis set
FDA
United States Food and Drug Administration
GGT
Gamma-glutamyl transferase
HGB
Hemoglobin
IGA
Investigator’s global assessment
IGA mod 2011
Novartis Investigator’s Global Assessment modified 2011
IRT
Interactive response technology
LLN
Lower Limit of Normal
MACE
Major Adverse Cardiovascular Event
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
NMQ
Novartis MedDRA Query
NovDTD
Novartis Drug and Therapy Dictionary
PASI
Psoriasis Area and Severity Index
PD
Protocol deviation
PT
Preferred Term
RMP
Risk Management Plan
SAS
Statistical analysis software
SAE
Serious adverse event
SPP
Safety Profiling Plan
SOC
System Organ Class
TBL
Total bilirubin
TEAE
Treatment Emergent Adverse Event
ULN
Upper Limit of Normal
WBC
White blood cell


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1
Introduction
Data will be analyzed by Novartis according to the data analysis section (section 9) of the study 
protocol which is available in Appendix 16.1.1 of the CSR. Important information is given in 
the following sections and details are provided, as applicable, in Appendix 16.1.9 of the CSR.
This document covers statistical and analytical plans for CAIN457A2326 (CLARITY) study
with reference to the study protocol amendment 1 and the project standard analysis plans 
1.1
Study design
This is a multicenter, randomized, double-blind, active-controlled, parallel-group trial in 
approximately 1100 subjects with moderate to severe chronic plaque-type psoriasis.
Randomization will be stratified by body weight collected at baseline, ≤100 kg (220 LB) or > 
100 kg (220 LB). Subjects will be randomized using a 1:1 ratio into one of the treatment groups 
below:

Secukinumab arm: will receive a dose of secukinumab 300 mg, which consist of two 
injections of  the 150 mg pre-filled syringes;

Ustekinumab arm: 

Subjects weighing > 100 kg (220 LB) at baseline will receive a dose of 90 mg 
ustekinumab which consists of two injections of 45 mg pre-filled syringes;

Subjects weighing ≤100 kg (220 LB) at baseline will receive a dose of 45 mg 
ustekinumab which consist of one injection of the 45 mg pre-filled syringe + one 
secukinumab placebo
In addition, in order to maintain the blind, placebo injections matching secukinumab 150 mg 
pre-filled syringes will be given to subjects in ustekinumab arm.
The following study periods will be considered for analysis:

Screening period (before Randomization) 

Treatment period (Randomization to Week 52, last dose at Week 48), including
follow-up period (F4 and F8 visits) for prematurely discontinued subjects 
Of note: data from follow-up period (i.e., treatment free follow-up period after EOT visit, which 
includes F4 and F8 visits) for prematurely discontinued subjects will be included in the analysis 
of treatment period.
The primary analysis will be performed at the time of Week 16 interim DBL. Treatment period 
up to Week 16 will be presented for the W16 interim analysis and all data will be presented for 
the final analysis.
1.2
Study objectives and endpoints
The primary objective of this study is to confirm the superiority of secukinumab versus 
ustekinumab with respect to PASI 90 and IGA mod 2011 0 or 1 response rates at Week 12 in 
treatment of moderate to severe plaque psoriasis.


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The secondary objectives are to demonstrate the superiority of secukinumab versus 
ustekinumab with respect to:

PASI 75 response at Week 12

PASI 75 response at Week 4

PASI 90 response at Week 16

PASI 100 at Week 16

IGA mod 2011 0/1 at Week 16

PASI 100 at Week 12

PASI 75 at Week 16

PASI 90 at Week 52
Furthermore, additional aspects of long-term efficacy, safety and tolerability of secukinumab 
versus ustekinumab over a period of 52 weeks will be investigated.
Table 1-1
Primary, secondary 
 variables
Variable
Type
PASI 90 response at Week 12 (compared to Ustekinumab)
primary
IGA 0/1 response at Week 12 (compared to Ustekinumab)
primary
PASI 75 response at Week 12
secondary
PASI 75 response at Week 4
secondary
PASI 90 response at Week 16
secondary
PASI 100 response at Week 16
secondary
IGA 0/1 response at Week 16
secondary
PASI 100 response at Week 12
secondary
PASI 75 response at Week 16
secondary
PASI 90 response at Week 52
secondary
2
Statistical methods
2.1
Data analysis general information
Novartis will be performing both a Week 16 interim analysis and final analysis (Week 52). 
Statistical software SAS version 9.4 or later will be used.
Data up to Week 16 will be presented for the Week 16 interim analysis and all data will be 
presented in the final analysis.


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Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies.
If not otherwise specified, p-values will be presented as one-sided for hypothsis testings and as 
two-sided for other analysis. Two-sided 95% confidence intervals will be displayed. If not 
otherwise specified, hypothesis testings will be based on one-sided p-values that the treatment 
effect is in favor of Secukinumab. The level of significance will be set to 2.5% (one-sided, 
family-wise type-I-error). 95% confidence intervals will not be used for decision making; they 
will only be used for estimation and will therefore always be two-sided.
All listings will be presented by treatment sequence.
Footnotes on outputs will be kept to a minimum also for outputs not covered in 
 
Footnotes will generally be provided for

abbreviations used in the output; abbreviations used on several outputs, e.g. for listings in 
Appendix 16.2 can be presented on a separate page and do not have to be repeated as 
footnotes on each listing

sorting order of categories, e.g. for sorting within MedDRA (Medical Dictionary for 
Regulatory Activities) hierarchy levels

MedDRA version used for reporting of MedDRA coded data
Footnotes will generally NOT be given for

units displayed on the output

interpretation of results (e.g. “odds ratio larger 1 favors active treatment”)

information that can be retrieved from the statistical section of the clinical study report 
(CSR) unless it is not identifiable from the output, e.g.

explanation of analysis model used unless results of more than one model are 
displayed on an output

derivations of variables (e.g. BMI will not be explained on a footnote)

information that will be provided in the clinical study protocol and/or methods section of 
the CSR (e.g. baseline definition if this is specified in the statistical section of the CSR)
2.1.1
General definitions
2.1.1.1
Study treatment
The following study drugs will be used:

Investigational treatment
o
Secukinumab 150 mg, 1 ml liquid formulation in a pre-filled syringe

Control treatment
o
Secukinumab placebo, 1 ml liquid formulation in a pre-filled syringe
o
Ustekinumab 45 mg, 0.5 ml liquid formulation in a pre-filled syringe


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2.1.1.2
Study Day 1 and other study days
The first day of administration of randomized study treatment (first dose) is defined as Study 
Day 1 or Day 1. 
All other study days will be labeled relative to Day 1. For event dates on or after Day 1, study 
day for a particular event date is calculated as [Date of event] – [Date of first dose]+1, i.e., Day 
2, Day 3, etc., will be one day, two days, etc., after Day 1, respectively. For the dates before 
Day 1, study day for an event date is calculated as [Date of event] – [Date of first dose], i.e., 
Day -1, Day -2, etc., will be one day, two days, etc., before Day 1, respectively. Duration of an 
event will be calculated as (Event end date – Event start date + 1).
The descriptor “Day 0” will not be used.
2.1.1.3
Screening, baseline and post-baseline definitions
Screening refers to any procedures (e.g., checking inclusion and exclusion criteria) performed 
prior to the date of first dose of study treatment (for safety analysis) or prior to the randomization 
date (for efficacy analysis). Per protocol, subject informed consent must be obtained prior to 
performing any study related activity. The date of signing informed consent is the start date of 
screening period. Any assessment obtained during the screening period will be labeled
screening assessment. Assessments made on Day 1 may occur before or after the randomization 
or the first dose. Further information will be found in [PDS].
For efficacy analyses, baseline is the last assessment (including unscheduled visits) obtained on 
or before the randomization day. All assessments obtained after randomization are considered 
as post-baseline unless otherwise specified.
For safety analyses, baseline is the last assessment (including unscheduled visits) obtained on 
or before the first dose day of study treatment. All assessments obtained after the first dose of 
study treatment are considered as post-baseline unless otherwise specified.
2.1.1.4
Day of last dose of randomized study treatment
The date of last dose will be collected via the CRF. The subject’s exposure will be calculated 
considering the end of treatment period visit (e.g., treatment completion visit). If a subject 
discontinued early, then the last dose + 84 days or the last visit during the follow-up period
whichever occurs earlier is considered.
On-treatment is defined as assessments within last dose plus 84 days.
2.2
Analysis sets
The following analysis sets will be used for the data analysis. 
Randomized set: The randomized set will be defined as all subjects who were randomized at 
baseline visit. Unless otherwise specified, misrandomized subjects will be excluded from the 
randomized set.
Misrandomized subjects are subjects who are screen-failures, but have been randomized by the 
investigator before eligibility was finally assessed, however have not been treated. If subjects 


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were re-screened and successfully randomized, they will be included in the randomized set 
according to the treatment assigned in the last randomization. 
Full analysis set (FAS): The FAS will be comprised of all subjects from the randomized set to 
whom study treatment has been assigned. Following the intent-to-treat principle, subjects will 
be analyzed according to the treatment assigned to at randomization. If the actual randomization 
stratum is different to the assigned stratum in IRT, the actual stratum will be used in analyses.
Of note, subjects excluded from the randomized set will be excluded from the FAS.
Safety set: The safety set includes all subjects who took at least one dose of study treatment
during the treatment period. Subjects will be analyzed according to treatment received. 
The treatment received will be set to the treatment randomized. But if a subject has received the 
wrong treatment during the entire study, the treatment received will be set to this wrong 
treatment. 
For those subjects who received erroneously the wrong treatment at least once, an additional 
listing will be prepared displaying adverse events occurred after the treatment errors.
2.2.1
Subgroup of interest
The co-primary endpoints and secondary endpoints will be evaluated using the subgroups
defined in Table 2-1. Subgroup analyses for the study endpoints are represented in Table 2-2.
Table 2-1
Subgroup definitions
Subgroup 
variables
Categories
Description
Label for 
outputs
Suffix for 
outputs*
Randomization 
weight strata
body weight stratum (≤100 kg, 
>100 kg)
Weight 
strata
a
Table 2-2
Subgroup analyses
Endpoint/analysis
Randomization
weight strata
Previous psoriasis 
therapy*
Co-primary endpoints:
   PASI 90 response at Week 12
X
X
   IGA 0/1 response at Week 12
X
X
Secondary endpoints:
   PASI 75 response at Week 12
X
X
   PASI 75 response at Week 4
X
X
   PASI 90 response at Week 16
X
X
   PASI 100 response at Week 16
X
X
   IGA 0/1 response at Week 16
X
X
   PASI 100 response at Week 12
X
X
   PASI 75 response at Week 16
X
X
   PASI 90 response at Week 52
X
X
Note: presented are only those endpoints that need subgroup analyses.


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*: only for “Previous <biologic/systemic/non-biologic systemic> therapy” and embedded subgroup “failure” and 
non-biologic therapy failure “at least two failures”.
2.3
Patient disposition, demographics and other baseline 
characteristics
The summaries will be shown for the following treatment groups:

AIN457 300 mg, Ustekinumab, Total
The following common background and demographic variables will be analyzed:
Continuous variables:
o
Age (which is derived from year of birth and the Informed consent date)
o
Height
o
Weight
o
Body mass index (BMI)
Categorical variables:
o
Age categories (<65 years, 65 years and older, 75 years and older)
o
Gender
o
Race
o
Ethnicity
o
Smoking status at baseline
o
Weight categories (≤100 kg, > 100 kg)
Psoriasis-specific baseline characteristics and history of disease will be summarized as well: 
baseline PASI, baseline PASI (≤20, >20), baseline total BSA, baseline IGA mod 2011 score (at 
least mild, moderate, severe), severity of psoriasis (CHMP guidelines, mild (total BSA <10% 
and PASI < 10), moderate ((PASI ≥10 or total BSA≥10%) and PASI ≤20 and total BSA ≤20%), 
severe (total BSA >20% or PASI > 20)), psoriatic arthritis (yes, no), time since diagnosis of
psoriasis, time since diagnosis of psoriatic arthritis, previous exposure to biologic systemic 
psoriasis therapy, previous exposure to systemic psoriasis therapy, previous exposure to non-
biologic systemic psoriasis therapy, previous failure to biologic systemic psoriasis therapy, 
previous failure to systemic psoriasis therapy, previous failure to non-biologic systemic 
psoriasis therapy (including phototherapy and photo- chemotherapy)
Body Mass Index (BMI) will be calculated using the following formula:
BMI = (body weight in kilograms) / (height in meters)2
For BMI, height and body weight the last value prior to randomization is used. If there is no 
weight recorded prior to taking of study treatment, BMI will be missing.
Of note: subject’s height will not be remapped according to the analysis visit window.
Unless otherwise specified, summary statistics will be presented for continuous variables for 
each treatment group and for all subjects (total) in the randomized set. The number and 
percentage of subjects in each category will be presented for categorical variables for each 
treatment group and all subjects (total) in the randomized set.


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Any condition entered on the Relevant medical history / current medical conditions CRF will 
be coded using the MedDRA dictionary. They will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) of the MedDRA dictionary.
Summaries for cardiovascular medical history will be summarized by categories. 
Summaries for family medical history will be summarized by categories and treatment group.
Smoking history will be summarized by treatment group.
Unless otherwise specified, analyses will be based on the randomized set.
2.3.1
Patient disposition
The number of subjects screened will be presented. In addition, the reasons for screen failures 
will be provided. The number and percentage of subjects in the randomized set who completed 
study periods and who discontinued the study prematurely (including the reason for 
discontinuation) will be presented for each treatment group and all subjects.
For each protocol deviation, the number and percentage of subjects for whom the deviation
applies will be tabulated.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The analysis of study treatment data will be based on the safety set.
The number of secukinumab, secukinumab placebo and ustekinumab injections will be 
summarized by treatment group by means of contingency tables.
In case it cannot be identified from the data collected or assumed from the planned treatment 
whether an injection contained placebo or ustekinumab, it will be assumed that the syringe
contained ustekinumab. This applies for example to the ustekinumab treatment group for 
subjects with baseline body weight ≤100 kg (in which subjects should receive both an 
ustekinumab and a placebo injection) if only one injection is given. If the medication pack 
number is not available, it will be assumed that the ustekinumab injection was applied.
If this scenario occurs for subjects in the secukinumab treatment group or in the ustekinumab 
treatment group with baseline body weight > 100 kg, when subjects should receive two identical 
injections, it will be assumed that they received secukinumab or secukinumab placebo or 
ustekinumab, respectively, as planned.
The duration of exposure to study treatment will be summarized by treatment group. In addition, 
the number of subjects with exposure of at least certain time thresholds will be displayed. The 
following categories will be presented: “any exposure”, “≥1 week” “≥4 weeks”, “≥12 weeks”, 
“≥16 weeks”, “≥20 weeks”, “≥24 weeks”, “≥28 weeks”, “≥40 weeks” and “≥52 weeks”.
Duration of exposure will be defined as the time from first dose of study medication to the last 
dose plus 84 days or last visit (including follow-up visits) whichever occurs earlier. i.e., for 
subjects who discontinued or have their last visit earlier than 84 days, the end of study treatment 


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exposure will be the date of the last study visit in the follow-up period or in the corresponding 
treatment period.
Duration of exposure (days) = min (‘end of treatment period’ date, last dose date +84) – first 
dose date +1
Duration of exposure (years) = duration of exposure (days) / 365.25
Duration of exposure (100 subject years) = duration of exposure (years) / 100
The analyses of duration of exposure described above will be done for the treatment period up 
to Week 16 for the interim analysis, with the last category “≥16 weeks”.
2.4.1.1
Visit window
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows were created to 
cover the complete range of days within the study. The visit windows are shown in Table 2-3. 
In this table, the days are counted since the first dose of study treatment (study days) for safety 
assessments, and the days are counted since the date of randomization for efficacy assessments. 
These visit windows apply to measurements taken at every visit. For assessments collected less 
often different visit windows will be applied as detailed below.
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows. E.g., if the Week 4 visit of a subject is delayed and occurs on Day 60 instead 
of on Day 29, it will be re-aligned to visit window Week 12. In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below.
Table 2-3
Assessment windows for scheduled visits 
Analysis Visit
Week
Scheduled Day
Visit Window
Baseline
BSL
1
-28 days to Day 1*
Week 1
1
8
Day 2-18
Week 4
4
29
Day 19-57
Week 12
12
85
Day 58-99
Week 16
16
113
Day 100-155
Week 28
28
197
Day 156-239
Week 40
40
281
Day 240-323
Week 52
52
365
Day 324-421
* Baseline measurement before the first drug administration for safety assessments and before the randomization 
for efficacy assessments.
For parameters which are not collected at every visit (e.g. weight, laboratory, 
), visit 
windows defined in Table 2-3 will be combined. For example, if a parameter is measured at 
Week 12 and Week 28 only, Week 12 visit window will extend from Day 2 to Day 99 
(combining Week 1 to Week 12 visit windows), Week 28 will extend from Day 100 to Day 239


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(combining Week 13 to Week 28). If more than one assessment falls into the interval, the rules 
defined in Section 2.4.1.2 below are applied.
Of note: subject’s height will not be remapped according to the analysis visit window.
The analysis visit will be used for listing of visit and period for safety data. If a visit falls after 
the last visit window (after Day 421) it is not assigned an analysis visit and will be listed under 
label “After Week 52”.
2.4.1.2
Multiple assessments within visit windows
When there are multiple assessments in a particular visit window, the following rules are applied 
to select one value “representing” the subject in summary statistics in a visit window (See Table 
2-4).
For baseline assessment definition see Section 2.1.1.3. For post-baseline visit windows the 
following applies (unless otherwise specified):

for quantitative variables, the closest to the actual visit is chosen (if two assessments have 
the same distance, then the earlier one will be chosen); 

for qualitative variables, the worst record is selected. It is noted that in the analyses 
performed, worst case is always well defined (e.g., for urine protein values “+” and “++”, 
the worst case is defined as “++”),

in case qualitative variables are based on quantitative variables, e.g. PASI 90 response, the 
visit will be assigned to the quantitative variable, and this visit will be used for the derived 
qualitative variable.
Table 2-4
Rules for selecting values for analysis within a given visit window
Timing of measurement
Type of data
Rule
Baseline
All data
See Section 2.1.1.3.
Post-baseline efficacy
All data except for 
e.g., 
PASI, IGA
The measurement closest to the target 
day will be used. In the event two 
measurements are taken equally apart 
(e.g., 1 day before target date and 1 day 
after), the earlier one will be used.
If two measurement are taken on the 
same day then select the first one using 
eCRF visit number.
If two measurement have been taken on 
the same day and same visit then select 
the worst.


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Timing of measurement
Type of data
Rule
Post-baseline safety
Summary visit information 
(e.g. laboratory values, vital 
signs, etc.)
The (non-missing) measurement closest 
to the target day will be used. In the event 
two measurements are taken equally 
apart (e.g., 1 day before target date and 1 
day after), the earlier one will be used.
If two measurements are taken on the 
same day then select the first one (using 
the time).
If two measurements are taken on the 
same date/time then use the first eCRF 
visit number (assuming this is the planned 
visit).If two measurements are taken on
the same date/time/eCRF visit number
then take the average value of these two 
results.
Post-baseline safety 
Notable abnormalities (e.g. 
vitals signs) and CTCAE 
grades for laboratory values
The most extreme measurement in the 
window will be used. Note this means a 
subject can have a notably high and 
notably low measurement within an 
analysis period.
2.4.2
Prior, concomitant and post therapies
Medications will be identified using Novartis Drug and Therapy Dictionary (NovDTD)
including Anatomical Therapeutic Chemical (ATC) code. Prior and concomitant treatments will 
be summarized by treatment group for the safety set unless otherwise specified. Concomitant 
treatments will be displayed for the treatment period.
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Medications will be presented in alphabetical order, by ATC codes and grouped by anatomical 
main group (the 1st level of the ATC codes). Tables will also show the overall number and 
percentage of subjects receiving at least one drug of a particular ATC code and at least one drug 
in a particular anatomical main group. 
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment. Any medication given at least once between the day of first dose of randomized study 
treatment, and last dose plus 84 days or last (including follow-up visits) whichever occurs 
earlier will be a concomitant medication, including those which were started pre-baseline and 
continued into the treatment period. 
Psoriasis specific summaries of prior and/or concomitant medication will be presented as in 
Table 2-5, but as well for topical, phototherapy and photochemotherapy (yes/no) using the 
randomized set.
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized.


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Prior or concomitant medication will be identified based on recorded or imputed start and end 
dates of medication taken. Further rules will be given in Section 5.
Drug contraindication will be summarized by drug type and treatment group.
Table 2-5
Subgroups based on the previous psoriasis therapy
Level 1
description
Level 1 
outcome
Level 2 
description
Level 2 outcome
previous 
therapy
yes/no
systemic
no
yes
number
1
2
>=3
failure*
no
yes
biologic
no
yes
failure*
no
yes
type of previous biologic
anti-p40
no
yes
anti-TNF
no
yes
non-biologic 
systemic
no
yes
failure*
no
yes
failure* to at 
least 2
no
yes
only selected subgroups will be used for reporting
*: at least one therapy with lack of primary efficacy or lack of secondary efficacy or lack of tolerability
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The co-primary endpoints are PASI 90 response and IGA 0 or 1 response at Week 12. The 
analysis of the primary variables will be based on the FAS.
2.5.1.1
Definition of PASI and related variables
The investigator or trained qualified designee will complete the PASI assessments. Whenever 
possible, the same evaluator should perform this assessment at all visits.
The total BSA affected by plaque-type psoriasis will be estimated from the percentages of areas 
affected, including head, trunk, upper limbs and lower limbs (see below for PASI assessment). 
The following calculations will be done: each reported percentage will be multiplied by its 
respective body region corresponding factor (head = 0.1, trunk = 0.3, upper limbs = 0.2, lower 
limbs = 0.4). The resulting 4 percentages will be added up to estimate the total BSA affected 
by plaque-type psoriasis. The PASI scoring system is further described in Table 2-6.


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A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 2-6. The head, trunk, upper limbs and lower limbs are assessed 
separately for erythema, thickening (plaque elevation, induration), and scaling (desquamation). 
The average degree of severity of each sign in each of the four body regions is assigned a score 
of 0-4. The area covered by lesions on each body region is estimated as a percentage of the total 
area of that particular body region. Further practical details help the assessment:
1. The neck is assessed as part of the head.
2. The axillae and groin are assessed as part of the trunk.
3. The buttocks are assessed as part of the lower limbs.
4. When scoring the severity of erythema, scales should not be removed.
Because the head and neck, upper limbs, trunk and lower limbs correspond to approximately 
10%, 20%, 30% and 40% of the body surface area, respectively, the PASI score will be
calculated using the formula:
PASI = 0.1 (Eh + Ih + Dh)Ah + 0.2 (Eu + Iu + Du)Au + 0.3 (Et + It + Dt)At + 0.4 (El + Il + Dl)Al,
where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, and h, 
u, t, and l denote head, upper extremities, trunk, and lower extremities, respectively (see Table 
2-6).
PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72.0.
The investigator is responsible for collecting the components or scoring signs and total regional 
area for all visits. PASI and total BSA calculations will be done by investigator at screening 
and randomization only; The PASI scores after randomization will be calculated by Novartis 
and will be used in the analysis and for derivation of PASI response values (see below). 


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Table 2-6
The PASI scoring system
Body 
region
Erythema (E)
Thickening
(plaque elevation,
induration, I)
Scaling 
(desquamation, 
D)
Area score
(based on true 
area %, A)*
Head (H)†
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = no involvement
1 = >0-<10%
2 = 10-<30%
3 = 30-<50%
4 = 50-<70%
5 = 70-<90%
6 = 90-100%
Trunk (T)‡
0=none 
1=slight 
2=moderate
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = no involvement
1 = >0-<10%
2 = 10-<30%
3 = 30-<50%
4 = 50-<70%
5 = 70-<90%
6 = 90-100%
Upper 
limbs (U)
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = no involvement
1 = >0-<10%
2 = 10-<30%
3 = 30-<50%
4 = 50-<70%
5 = 70-<90%
6 = 90-100%
Lower 
limbs (L)§
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0=none 
1=slight 
2=moderate 
3=severe
4=very severe
0 = no involvement
1 = >0-<10%
2 = 10-<30%
3 = 30-<50%
4 = 50-<70%
5 = 70-<90%
6 = 90-100%
*
Percentage (not score) of body region (not whole body) affected will be entered in the eCRF.
†
Neck is assessed as part of the Head (H) body region.
‡
Axillae and groin are assessed as part of the Trunk (T) body region.
§
Buttocks are assessed as part of the Lower limbs (L) body region.
The following definitions are possible efficacy evaluations that can be used in clinical trials in 
psoriasis (CHMP/EWP/2454/02, 2004): 

PASI 50 response: subjects achieving ≥ 50% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 50 responders

PASI 75 response: subjects achieving ≥ 75% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 75 responders

PASI 90 response: subjects achieving ≥ 90% improvement (reduction) in PASI score 
compared to baseline are defined as PASI 90 responders

PASI 100 response / remission: complete clearing of psoriasis (PASI=0)


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2.5.1.2
Definition of IGA mod 2011 score and IGA mod 2011 0 or 1 response
The IGA mod 2011 rating scale for overall psoriatic disease (shown in Table 2-7) has been 
developed based on a previous version of the scale used in secukinumab phase II studies, and 
has been updated in collaboration with health authorities (in particular the FDA). The 
explanations/descriptions of the points on the scale have been improved to ensure appropriate 
differentiation between the points. It is recommended that the same evaluator conducts the 
assessments throughout the study whenever possible.
The IGA mod 2011 used in this study is static, i.e., it refers exclusively to the subject’s disease 
state at the time of the assessments, and does not attempt a comparison with any of the subject’s 
previous disease states, whether at baseline or at a previous visit.
Table 2-7
The IGA mod 2011 rating scale
Score
Short Description
Detailed Description
0
Clear
No signs of psoriasis. Post-inflammatory hyperpigmentation may 
be present.
1
Almost clear
Normal to pink coloration of lesions; no thickening; no to minimal 
focal scaling.
2
Mild
Pink to light red coloration; just detectable to mild thickening; 
predominantly fine scaling.
3
Moderate
Dull bright red, clearly distinguishable erythema; clearly 
distinguishable to moderate thickening; moderate scaling.
4
Severe
Bright to deep dark red coloration; severe thickening with hard 
edges; severe / coarse scaling covering almost all or all lesions.
Note:  Involvement of nails is not part of the assessment.
Subjects require an IGA mod 2011 score at randomization of 3 or 4 in order to participate in 
the study. Based on this scale, subjects will be considered as IGA mod 2011 0 or 1 responder
if they achieve a score of 0 or 1 and improve by at least 2 points on the IGA mod 2011 scale 
compared to baseline.
2.5.1.3
Overview of analysis methods of efficacy variables
An overview of statistical analyses and methods applied to psoriasis efficacy variables is given 
in Table 2-8.
Table 2-8
Overview of analysis methods for efficacy variables
Variable(s)
Summary 
statistics for 
binary/
categorical data 
Logistic 
regression
Summary 
statistics for 
continuous 
data
Time-to-
event 
analysis
Graphs
PASI 90 response at Week 12
X
X
X*
IGA 0/1 response at Week 12
X
X
X*
PASI 75 response at Week 12
X
X
X*
PASI 75 response at Week 4
X
X
PASI 90 response at Week 16
X
X
X*
PASI 100 response at Week 16
X
X
X*
IGA 0/1 response at Week 16
X
X
X*
PASI 100 response at Week 12
X
X
X*


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Variable(s)
Summary 
statistics for 
binary/
categorical data 
Logistic 
regression
Summary 
statistics for 
continuous 
data
Time-to-
event 
analysis
Graphs
PASI 75 response at Week 16
X
X
X*
PASI 90 response at Week 52
X
X
* dot plot; 
2.5.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis for PASI 90 response and IGA 0 or 1 response at Week 12 is that 
secukinumab is not superior to ustekinumab in the proportion of subjects with PASI 90 response 
and IGA 0 or 1 response at Week 12.
Let pj denote the proportion of PASI 90 responders at Week 12 for treatment group j and rj
denote the proportion of IGA 0 or 1 responders at Week 12 for treatment group j; 
j=0, 1, where 

0 corresponds to ustekinumab,

1 corresponds to secukinumab.
The following hypotheses will be tested:
   
H: H1H2 versus HA: HA1HA2
H1: p1 – p0 ≤ 0 versus HA1: p1 – p0 > 0,
   
H2: r1 – r0 ≤ 0 versus HA2: r1 – r0 > 0,
In other words:
H:
secukinumab is not superior to ustekinumab with respect to either PASI 90 response at 
Week 12 or IGA 0 or 1 response at Week 12 or both
H1: secukinumab is not superior to ustekinumab with respect to PASI 90 response at Week 12
H2: secukinumab is not superior to ustekinumab with respect to IGA 0 or 1 response at 
Week 12
The primary analysis method for PASI 90 and IGA 0 or 1 response at Week 12 will be evaluated
using logistic regression model with treatment group, body weight stratum (≤100 kg, >100 kg)
and baseline PASI score as explanatory variables (see Section 5 Appendix). Odds ratios will be 


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computed for comparisons of secukinumab versus ustekinumab utilizing the logistic regression 
model fitted. In case of non-convergence, risk difference (95% confidence interval) between 
secukinumab and ustekinumb and p-value get from t-test will be provided.
The hypotheses H1 and H2 will both be tested at α level = 2.5% (one-sided) and significant 
results will only be achieved if both hypotheses are rejected (i.e., if only one hypothesis is 
rejected and the other hypothesis is not rejected, superiority of secukinumab cannot be 
demonstrated).
The primary analysis set will be the FAS.
Summary statistics and figures will be provided as described in Section 5.4.6. Details in 
sensitivity analysis are provided in Section 2.5.4.
2.5.3
Handling of missing values/censoring/discontinuations
Response variables based on PASI score and IGA mod 2011 categories will be imputed with 
multiple imputation (MI) as primary imputation method for the missing values.
Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Within this analysis the PASI score or IGA mod 2011 
categories will be imputed and response variables will be derived based on the imputed scores. 
In the multiple imputation analysis the response status will be imputed based on the individual 
treatment arm information.
Modified non-responder (mNRI) imputation and pure non-responder (pNRI) imputation will be 
used as a sensitivity method: Missing values with respect to response variables based on PASI 
score and IGA 2011 categories will be imputed with non-response regardless to the reason for 
missing data (e.g. premature study discontinuation, missed visit, administrative issues).
Exceptions for modified non-responder imputation method will apply to the following:

If a subject dropped out of the study prior to last scheduled visit and being responder 
consecutively at least for two preceding visits, the subject will be imputed as 
responder for the last scheduled visit.

If a subject who was responder at visit x-1 and visit x+1 but has missing data at visit x, 
then the subject will be imputed as responder for visit x only if visit x-1 or visit x+1 are 
scheduled 4 weeks or less from visit x. Otherwise missing data at visit x will be imputed 
with non-response, except for the missing data at last visit in the treatment period.
Summary tables for PASI scores and IGA mod 2011 categories will be imputed using MI and
LOCF method.
Note: Only PASI and IGA mod 2011 based response variables are imputed with multiple 
imputation or non-response imputation, other response variables 
 
will be imputed with LOCF. 
2.5.4
Supportive analyses
Sensitivity analyses will be performed as follows:


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(A) Co-primary endpoints (PASI 90 and IGA 0 or 1 response at Week 12) and key secondary 
endpoints will be evaluated using the logistic regression as described in primary analysis 
method with pure non-responder (pNRI) imputation and modified non-responder (mNRI) 
imputations instead of multiple imputation for missing values. 
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
The key secondary endpoints of this study are planned as follow:

speed of onset (PASI 75 at Week 4) 

PASI 75, PASI 90, PASI 100 and IGA 0/1 response at Week 16

PASI 75 and PASI 100 at Week 12

PASI 90 at Week 52
The null hypotheses for secondary objectives are as follows:
o
H3: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 12
o
H4: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 4
o
H5: secukinumab is not superior to ustekinumab with respect to PASI 90 response at 
Week 16
o
H6: secukinumab is not superior to ustekinumab with respect to PASI 100 response at 
Week 16
o
H7: secukinumab is not superior to ustekinumab with respect to IGA 0 or 1 response at 
Week 16
o
H8: secukinumab is not superior to ustekinumab with respect to PASI 100 response at 
Week 12
o
H9: secukinumab is not superior to ustekinumab with respect to PASI 75 response at 
Week 16
o
H10: secukinumab is not superior to ustekinumab with respect to PASI 90 response at 
Week 52
2.6.2
Statistical hypothesis, model, and method of analysis
The following hypotheses will be tested sequentially and are included in the hierarchical testing 
strategy and type-I-error will be set such that a family-wise type-I-error of α = 2.5% (one-sided) 
is kept. The graphical approach of (Bretz et al. 2009) for sequentially rejective testing 
procedures is used to illustrate the testing strategy:


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Figure 2-1
Testing strategy
The secondary efficacy variables involved in the above testing strategy will be analyzed 
analogously to the primary endpoints. i.e., logistic regression model with treatment group, body 
weight stratum (≤100 kg, >100 kg) and baseline PASI score as explanatory variables. Odds 
ratios will be computed for comparisons of secukinumab versus ustekinumab utilizing the 
logistic regression model fitted.
The testing sequence will continue to H3 at α (one-sided) only if both H1 and H2 have been 
rejected at α (one-sided). Similarly, the testing sequence will continue to H4 at α (one-sided) 
only if H3 testing has been rejected. In case, H9 has been rejected at α (one-sided), the 
corresponding alpha (α) will be passed to the next hypotheses corresponding H10.
2.6.3
Handling of missing values/censoring/discontinuations
See Section 2.5.3.
2.7
Analysis of secondary efficacy objective(s)
No other secondary efficacy objectives were analyzed.
2.7.1
Secondary endpoints
Not applicable.
2.7.2
Statistical hypothesis, model, and method of analysis
Not applicable.


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2.7.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.8
Safety analyses
All safety analyses will be based on the safety set. Only those visits which were pre-planned in 
the protocol will be reported in tables and figures for safety variables.
Treatment groups for evaluation
The summaries of evaluation will be reported for treatment period up to Week 16 for the Week 
16 interim analysis and all data for the final analysis. The following groups will be used:

AIN457 300 mg: all subjects who are randomized to secukinumab group

Ustekinumab: all subjects who are randomized to ustekinumab group
Safety analyses will be performed on treatment received or actual treatment (See Section 
5.4.2, Safety Set).
2.8.1
Adverse events (AEs)
For adverse events and other binary safety variables crude incidence and exposure time-
adjusted incidence will be derived as described below and summarized in Table 2-8. 
All adverse events are summarized based on treatment emergent only. The definition for 
“treatment emergent” is as below:

events started after the first dose of study medication or events present prior to the first 
dose of study medication but increased in severity based on preferred term 

and started prior to the last dose plus 84 days (inclusive)
All adverse events will be listed with “treatment emergent” flag displayed.
Table 2-8
Overview of analyses on some safety endpoints
Analysis period
AEs & 
SPP/RMP 
risks
(special AE 
interest)
SAEs
AEs-SMQ
AEs by 
severity
study treatment
related AEs, 
death & other 
significant AEs
notables 
(lab/vitals)
Treatment 
period
(up to Week 16)
•crude 
incidence
•crude 
incidence
•crude 
incidence
•crude 
incidence
•crude 
incidence
•crude 
incidence
Treatment
period(including 
all data)
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
• crude 
incidence
• crude 
incidence
*Note, Exposure adjusted incidence rates will be provided and follow the guideline as below:

Primary SOC level for AE and SAE

Level 1 for risks and SMQ


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
PT level for SAE

PT level for AE  ≥2% or incidence rate per 100 subject years ≥5.0 in AIN457 300 mg 
or Ustekinumab treatment group

Other selected AEs of special interest on lower levels (e.g. PT or SMQ level 2), if 
appropriate
The crude incidence of treatment emergent adverse events will be presented for the treatment
period up to Week 16 for W16 interim analysis, and treatment period including all data for final 
analysis. The crude incidence of treatment emergent adverse events will be summarized by 
primary System Organ Class (SOC) and Preferred Term (PT). Confidence intervals for the 
crude rate will be derived using the score method including continuity correction (Newcombe 
1998) as described in Section 5.4.6. In addition, exposure time-adjusted incidence rates will be 
provided for the treatment period including all data (see Section 5.4.7).
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of subjects having at least one AE, having an AE in each primary system organ class 
and having each individual AE (preferred term). Summaries will also be presented for AEs by 
severity and for study treatment related AEs. If a particular AE ‘severity’ is missing, this 
variable will be listed as missing and treated as missing in summaries. If a subject reported more 
than one adverse event with the same preferred term, the adverse event with the greatest severity 
will be presented. If a subject reported more than one adverse event within the same primary 
system organ class, the subject will be counted only once with the greatest severity at the system 
organ class level, where applicable. 
Adverse events will also be reported separately by standardized or customized MEdDRA 
queries (SMQ or CMQ/NMQ). The MedDRA version used for reporting the adverse events will 
be described in a footnote.
The most common adverse events reported (z % in any group for each preferred term in the 
table by SOC and PT or z % in any group for each SMQ table) will be presented in descending 
frequency according to its incidence in secukinumab group starting from the most common 
event. Here threshold value z is set to 2 (%) but it may be updated following review of the dry 
run outputs.
Separate summaries will be provided for deaths, serious adverse events, other significant 
adverse events leading to discontinuation and adverse events leading to dose adjustment or 
interruption.
Algorithms for date imputations will be provided in Section 5.
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures.
The adverse events occurred after the treatment errors in those subjects who received 
erroneously the wrong treatment at least once, will be listed.
2.8.1.1
Adverse events of special interest / grouping of AEs
Crude incidence rate and exposure adjusted incidence rates for adverse events of special interest 
will be provided as in Table 2-9.


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Table 2-9
Table of AEs of special interest
Special AE interest:
Notes (All levels are displayed)
Inflammatory bowel disease [STANDARD](NMQ) (narrow)
Include Crohns (PT) and Ulcerative colitis 
(PT) and others
Opportunistic infections [FINGOLIMOD](CMQ)
Candida infections (HLT)
Herpes viral infections (HLT)
Both Oral and other are included
Staphylococcal infections (HLT)
MACE (MI, Stroke, Cardiovascular death) [AIN457](NMQ)
Malignant or unspecified tumours (SMQ)
Including BCC, SCC in SMQ
Malignant or unspecified tumours (SMQ excl BCC and SCC) 
[AIN457](NMQ)
Upper respiratory tract infections (HLT)
Other safety topics of interest, such as risks defined in the Safety Profiling Plan, Risk 
Management Plan or topics of interest regarding signal detection or routine analysis are defined 
in the Program Case Retrieval Sheet that is stored in CREDI at the path 
 
Crude rate of important identified and potential risks from Case Retrieval Sheet will be provided 
for all (non-serious and serious) cases and for all serious cases. Exposure-time adjusted rates 
will be provided for treatment period including all data for all (non-serious and serious) cases
and for all serious cases. In addition, listings will be provided for the related AE risks.
Risk measures and confidence intervals will be derived according to Section 5.
The version of the Case Retrieval Sheet used for the analyses will be described in a footnote. 
This includes MedDRA version and Novartis MedDRA Query (NMQ) dictionary date. 
Important note: For the evaluation of risks primary and secondary system organ classes of the 
MedDRA dictionary will be considered.
2.8.2
Deaths
Separate summary and listing will be provided for deaths.
2.8.3
Laboratory data
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry).
Descriptive summary statistics for the change from baseline to each study visit will be presented 
by laboratory test and treatment group. Change from baseline will only be summarized for 
subjects with both baseline and post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
Only “on-treatment” laboratory data will be summarized (i.e. assessments within last dose plus 
84 days). All laboratory data will be listed with “on-treatment” flag displayed. If two 
measurements are taken on the same date/time/CRF visit then use the average of two 
assessments.


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For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. The numerical 
part of the reported result will be treated as the actual LLQ or ULQ. These laboratory values 
will be displayed in listings using the standard unit with the reported sign (“<” or “>”).”
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the most extreme laboratory test value within a treatment 
period. For the shift tables, the normal laboratory ranges will be used to evaluate whether a 
particular laboratory test value is normal, low, or high (including category “high and low”). 
These summaries will be presented by laboratory test and treatment group. Subjects with 
abnormal laboratory values will be listed and values outside the normal ranges will be flagged.
The following laboratory parameters will be analyzed with respect to numerical Common 
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-10: hemoglobin, 
platelets, white blood cell count, neutrophils, lymphocytes, creatinine, total bilirubin (TBL), 
gamma-glutamyl 
transferase
(GGT), 
alanine 
aminotransferase 
(ALT), 
aspartate 
aminotransferase (AST), alkaline phosphatase (ALP).
The number and percentage of subjects with CTCAE grade newly occurring or worsening after 
baseline will be presented. These summaries will be split into hematology and chemistry.
Table 2-10
CTCAE grades for laboratory parameters to be analyzed
CTCAE v4.0 Term
Grade 1 
Grade 2 
Grade 3 
Grade 4 
HGB decreased 
(Anemia)
<LLN – 100 g/L
<100 – 80 g/L
<80 g/L
Life-threatening
consequences;
urgent
intervention
Platelet count
decreased
<LLN – 75.0 x10e9 /L
<75.0 - 50.0 x10e9 /L
<50.0 – 25.0 x10e9 /L
<25.0 x 10e9 /L
White blood cell 
decreased
<LLN - 3.0 x 10e9 /L
<3.0 - 2.0 x 10e9 /L
<2.0 - 1.0 x 10e9 /L
<1.0 x 10e9 /L
Neutrophil count 
decreased
<LLN - 1.5 x 10e9 /L
<1.5 - 1.0 x 10e9 /L
<1.0 - 0.5 x 10e9 /L
<0.5 x 10e9 /L
Lymphocyte count 
decreased
<LLN - 0.8 x 10e9/L
<0.8 - 0.5 x 10e9 /L
<0.5 - 0.2 x 10e9 /L
<0.2 x 10e9 /L
Creatinine increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 6.0 x ULN
>6.0 x ULN
TBL increased
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALT increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
AST increased
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
ALP increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
Shift tables will be presented comparing baseline laboratory result (CTCAE grade) with the 
worst results (expressed in CTCAE grade) during the treatment phase analyzed. Of note, 
baseline will be defined as last assessment prior to first dosing in initial treatment phase. If no 
pre-treatment value exists, also a value recorded after first dose can be used as baseline if it was 
collected on the same day as first dose, see Section 2.1.1.3.
Exposure time adjusted incidence for subjects with newly occurring neutropenia of CTCAE 
grade >=2 will be summarized and listed in the listing.


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The number and percentage of subjects with newly occurring liver enzyme abnormalities will 
also be summarized based on the event criteria given in Table 2-11.
Table 2-11
Liver-related events
Parameter
Criterion
ALT
>3xULN; >5xULN; >8xULN;>10xULN, >20xULN
AST
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN; >20xULN
TBL
>1xULN;>1.5xULN; >2xULN; >3xULN,
ALP
>1.5xULN;>2xULN; >3xULN; >5xULN
ALT or AST & 
TBL
ALT or AST>3xULN & TBL >1.5xULN;
ALT or AST>3xULN & TBL >2xULN;
ALT or AST >5xULN & TBL >2xULN;
ALT or AST >8xULN & TBL >2xULN;
ALT or AST >10xULN & TBL >2xULN;
ALT or AST >20xULN & TBL >2xULN;
ALP & TBL
ALP >3xULN & TBL >2xULN
ALP >5xULN & TBL >2xULN
ALT or AST & 
TBL & ALP
1)
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN    (Potential Hy’s 
Law)
Note: elevated ALP may suggest obstruction as a consequence of gall bladder or 
bile duct disease; ALP may also be increased in malignancy. FDA therefore terms 
Hy’s Law cases as indicators of pure hepatocellular injury. This does not mean 
that cases of ALT or AST >3xULN & TBL >2xULN & ALP >2xULN may not result 
in severe DILI.
2)
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN  (Potential Hy’s 
Law) or reported Hy’s Law case
Note: “Hy’s Law case” is a lower level term in MedDRA (10070546) and may be 
reported as AE.
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g., a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5xULN.
Individual subject data listings will be provided for subjects with notably abnormal laboratory 
values (reference to Protocol Amendment 1, Appendix 1) and newly occurring or worsening 
abnormal laboratory data by CTC grades. Data of subjects with newly occurring liver enzyme 
abnormalities will be listed in an additional listing.
Fasting laboratory tests including fasting plasma glucose and fasting lipids will be evaluated 
only at screening. No analysis will be done for these measurements.
For urinalysis, standard dipstick measurements for specific gravity, protein, glucose, pH, blood, 
urine blood (non-hemolyzed), urine blood (hemolyzed), bilirubin, ketones, WBC will be done 
at screening. No analysis will be done for these measurements.


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2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
A standard 12-lead ECG will be performed at screening to assess the eligibility of subjects. No 
analysis will be done for ECG measurements.
2.8.4.2
Vital signs
There will be two measurement of vital sign at each visit. The averaged value will be used for 
analysis.
Analysis in vital sign measurement using descriptive summary statistics for the change from 
baseline for each post-baseline visit will be performed by vital sign and treatment group. 
Change from baseline will only be summarized for subjects with both baseline and post-baseline 
values and will be calculated as:
change from baseline = post-baseline value – baseline value
Only “on-treatment” vital signs will be summarized (i.e. assessments within last dose plus 84 
days). All vital signs will be listed with “on-treatment” flag displayed.
The number and percentage of subjects with newly occurring notable vital signs will be 
presented. Criteria for notable vital sign abnormalities are provided in Table 2-12 below. A 
listing of subjects with newly occurring notably abnormal vital signs will be provided.
Table 2-12
Criteria for notable vital sign abnormalities
Vital sign (unit)
Notable abnormalities
Systolic blood pressure (mmHg)
>= 140 mmHg or < 90 mmHg
Diastolic blood pressure (mmHg)
>=90 mmHg or <60 mmHg
Pulse (bpm)
> 100 bpm or <60 bpm


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2.14
Interim analysis
Week 16 interim analysis will be performed after all subjects have completed Week 16 visit.
Additional analyses may be performed to support health authority interactions as necessary.
At the End of Study, a final analysis of all data collected up to last study visit (Week 52 or F8 
as applicable) will be performed when all subjects have completed the last study visit.
3
Sample size calculation
The total sample size is 1100 subjects, i.e. using a balanced randomization 550 subjects will be 
randomized to each treatment group.
The secukinumab dose regimen versus ustekinumab with respect to the co-primary endpoints
PASI 90 and IGA 0/1 at Week 12 are tested at α=2.5% (one-sided). The response rates are 
computed based on CLEAR (CAIN457A2317) study data. The assumed response rates and 
power are shown in. The power calculations are based on chi-square test (nQuery Advisor 7.0, 
two group chi-square test of equal proportions).
Table 3-1
Power to show superiority of secukinumab versus ustekinumab for 
co-primary endpoints
Endpoints
Secukinumab 300 mg
Response (%)
Ustekinumab 
Response (%)
Power
PASI 90 at Week 12
66%
52%
>99%
IGA 0/1 at Week 12
77%
64%
>99%
Note: one-sided type-I-error=2.5%, N=550 per group
If the assumed PASI 90 response rate at week 12 for secukinumab is 66% and for ustekinumab 
is 52%, the power to reject the corresponding null hypothesis is greater than 99%. Similarly, if 
the assumed IGA 0/1 response rate at week 12 for secukinumab is 77% and for ustekinumab is 
64%, the power to reject the corresponding null hypothesis is also greater than 99%. Details for 
other key secondary endpoints are provided in Table 3-2.
The secukinumab dose regimen versus ustekinumab with respect to the secondary endpoints 
are tested at α=2.5% (one-sided). The response rates are computed based on unpublished 
CLEAR (CAIN457A2317) study data.


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Table 3-2
Power to show superiority of secukinumab versus ustekinumab for 
secondary endpoints
Endpoints
Secukinumab 300 mg
Response (%)
Ustekinumab
Response (%)
Power
PASI 75 at Week 12
88%
79%
97%
PASI 75 at Week 4
47%
21%
>99%
PASI 90 at Week 16
74%
55%
>99%
PASI 100 at Week 16
40%
24%
>99%
IGA 0/1 at Week 16
80%
65%
>99%
PASI 100 at Week 12
34%
23.5%
96%
PASI 75 at Week 16
90%
82%
96%
PASI 90 at Week 52
70%
60.5%
90%
Note: one-sided type-I-error=2.5%, N=550 per group
4
Change to protocol specified analyses
A pure non-responder (pNRI) imputation for the primary endpoints will be provided as 
supportive analyses.
5
Appendix
Summary statistics for continuous variables will include N, mean, standard deviation, minimum, 
lower quartile, median, upper quartile, maximum. Summary statistics for discrete variables will 
be presented in contingency tables and will include absolute and relative frequencies.
If not otherwise specified, p-values will be presented as one-sided for hypothsis testings and as 
two-sided for other analysis. Two-sided 95% confidence intervals will be displayed.
Hypothesis testings will be based on one-sided p-values that treatment effect is in favor of 
Secukinumab. The level of significance will be set to 2.5% (one-sided, family-wise type-I-error).
5.1
Imputation rules
5.1.1
Study drug
Any partial dates will be imputed as follows:
We take the earlier day of 

The last day in the month and 

The end day of the corresponding epoch
5.1.2
AE date imputation
Impute AE end date:


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1. If the AE end date ‘month’ is missing, the imputed end date should be set to the earliest of 
the (min (last visit date, last dose date + 84 days), 31DECYYYY, date of death). 
2. If the AE end date ‘day’ is missing, the imputed end date should be set to the earliest of the 
(min (last visit date, last dose date + 84 days), last day of the month, date of death). 
3. If AE ‘year’ is missing or AE is ongoing, the end date will not be imputed. 
Impute AE start date:
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
1. If the AE start date ‘year’ value is missing, the date uncertainty is too high to impute a 
rational date. Therefore, if the AE year value is missing, the imputed AE start date is set to 
NULL. 
2. If the AE start date ‘year’ value is less than the treatment start date year value, the AE 
started before treatment. Therefore: 
a. If AE ‘month’ is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE ‘month’ is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 


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b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month start 
point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than 
the (imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end 
date. 
5.1.3
Concomitant medication date imputation
Impute CM end date:
1. If CM end day is missing and CM month/year are non-missing then impute CM day as the 
minimum of treatment end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as the 
minimum of treatment end date and the end of the year (31DECYYYY). 
3. If imputed CM end date is less than the CM start date, use the CM start date as the imputed 
CM end date. 
Impute CM start date:
1. If the CM start date year value is missing, the imputed CM start date is set to one day prior 
to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year point 
(01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start point 
(01JanYYYY). 


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b. Else if the CM month is not missing, the imputed CM start date is set to the month 
start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start date 
month, then the imputed CM start date is set to one day prior treatment start date. 
b. Else if the CM month is less than the treatment start date month, the imputed CM 
start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed CM 
start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM 
end date. 
5.1.3.1
Prior therapies date imputation
See Section 5.1.3.
5.1.3.2
Post therapies date imputation
See Section 5.1.3.
5.1.4
Other imputations
Only PASI and IGA mod 2011 based response variables are imputed with multiple imputation 
or non-response, other response variables 
 will be imputed with 
LOCF.
For laboratory test values below Lower Level of Quantification (LLQ) or above Upper Level 
of Quantification (ULQ) will be imputed as LLQ or ULQ value, respectively. The numerical 
part of the reported result will be treated as the actual LLQ or ULQ. These laboratory values 
will be displayed in listings using the standard unit with the reported sign (“<” or “>”).”
5.2
AEs coding/grading
Adverse events will also be coded according to MedDRA dictionary, using a narrow search.
The MedDRA version used for reporting the adverse events will be described in a footnote.


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Safety topics of interest, such as risks defined in the Safety Profiling Plan, Risk Management 
Plan or topics of interest regarding signal detection or routine analysis are defined in the 
Program Case Retrieval Sheet that is stored in CREDI 
 
5.3
Laboratory parameters derivations
See Section 2.8.3.
5.4
Statistical models
5.4.1
Analysis of continuous data
Summary statistics (including N, mean, standard deviation, minimum, lower quartile, median, 
upper quartile, maximum) will be provided for continuous data by visit and treatment group. 
For PASI score, 
summary statistics will be derived for absolute and 
percentage changes from baseline.
5.4.2
Analysis of binary (and categorical) data
Summary statistics for discrete variables will be presented in contingency tables and will 
include absolute and relative frequencies. If applicable, confidence intervals will be derived as 
well based on the score method including continuity correction [Newcombe (1998)]:
With z as (1-alpha/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-
alpha/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 
Then the lower limit is for 























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is for 























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
For response variables (e.g. for IGA mod 2011 0 or 1, PASI 75, PASI 50, PASI 90 and PASI 
100 response) the ustekinumab adjusted response rates (risk difference) including 95% 
confidence interval will be derived by visit.
Figures will be provided for PASI 75 response (upper left) PASI 90 response (upper right), 
PASI 100 response (lower left) and IGA mod 2011 0 or 1 response (lower right) at Week 12 
and Week 16 as dot plots displaying treatments on the x-axis and point estimates including 95% 
confidence intervals on the y-axis. 
p
q

1

,
0
for
0
,0



p
L
p

,
1
for
1
,1



p
U
p


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For time courses of response variables, the point estimate at each time point including 95% 
confidence interval will be plotted.
5.4.3
Logistic regression
Binary outcome variables, including PASI 50 / 75 / 90 / 100 response and IGA mod 2011 0 or 
1 response, will be evaluated using a logistic regression model with treatment regimen, body
weight stratum and baseline PASI score. Odds ratios will be computed for comparisons of 
secukinumab versus ustekinumab utilizing the logistic regression model fitted.
If response rates are 0% or 100% in one of the treatment groups odds ratio estimate and p-values 
will not be displayed in outputs, but “-” will be shown.
The odds ratio will be calculated such that an odds ratio >1 is favorable for secukinumab. Using 
PROC GENMOD to calculate the confidence interval for the odds ratios assumes asymptotic 
normality of the Wald estimate for the regression coefficient. The 95% confidence interval for 
the regression parameter of the active treatment effect relative to control(s) will be calculated 
using an exponential transformation to create the confidence interval for the odds ratio.
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests from Type III analyses. In the SAS procedure PROC GENMOD, a Type III analysis 
will be performed by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT.
Logistic regression will be applied to response variables at each visit.
If logistic regression model does not converge the following steps will be performed:
1. Run the PROC GENMOD procedure with EXACT statement; 
2. If convergence not reached, remove the covariates from the model one by one until 
convergence is reached; start with removing weight stratum, followed by baseline PASI; 
3. If convergence not reached, perform Fisher’s exact test.
It should be noted that this model might not converge if response rates are too low.
For subgroup analyses of PASI 50, PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 
response, the logistic regression model will be fitted with treatment group, body weight stratum 
(≤100 kg, >100 kg) and baseline PASI score as explanatory variables. Odds ratios will be 
computed for comparisons of secukinumab versus ustekinumab utilizing the logistic regression 
model fitted. In case of non-convergence, Fisher’s exact test will be performed.
Of note, for the subgroup analysis by body weight, the weight stratum variable will not be fitted 
in the logistic regression model.
5.4.4
Multiple imputations for response variables
Primary and secondary endpoints will be evaluated by Logistic regression and odds ratio 
estimate as described in the primary analysis method with multiple imputations for missing 
values. In addition, logistic regression analysis for PASI 50, PASI 75, PASI 90, PASI 100 and 
IGA mod 2011 0 or 1 response by visits will be analyzed using multiple imputation method.
In the multiple imputations analysis the response status will be imputed based on the individual 
treatment arm information.


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Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods. Rubin (1987) presented rules how to combine the multiple 
sets of estimates to produce overall estimates and confidence intervals that adequately 
incorporate missing data uncertainty. 
Missing values for the ‘change from baseline PASI score’ and ‘IGA mod 2011 score’ will be 
imputed simultaneously based on an underlying joint normal distribution and using a Markov 
Chain Monte Carlo (MCMC) method. The change from baseline in PASI score appears to 
follow closer to a normal distribution than the actual PASI score. Assuming normality for the 
‘IGA mod 2011 score’ is motivated by Schaefer (1997), where it was shown that the 
multivariate normal approximation for the imputation of incomplete categorical and binary data 
is robust. 
The imputations will be done separately for each treatment group including baseline weight, 
failure to at least one previous biologic (yes/no), and number of previous systemic therapies as 
additional covariates. 
Summary statistics for PASI 50, PASI 75, PASI 90, PASI 100, and IGA mod 2011 0 or 1
response by visit will be presented in contingency tables with multiple imputations method.
The number of imputations will be set to 100, the seed for the random function will be set to 
4572326 for this study. To generate the multiple imputed data sets, the SAS procedure MI can 
be used as follows:
The input data set <pasi_iga> should have one record per subject with baseline PASI score and 
IGA mod 2011 score as well as all changes from baseline PASI and post-baseline IGA mod 
2011 score.
ODS LISTING CLOSE;
ODS OUTPUT MissPattern=msgpat VarianceInfo=varinfo ParameterEstimates=param;
PROC MI DATA=<pasi_iga> OUT=<impdata> SEED=457<studycode> NIMPUTE=100;
VAR <baseline weight> <failure to at least one biologic> 
     <number of previous systemic therapies> 
     <baseline PASI> <baseline IGA> 
     <change from baseline PASI week 1> - <change from baseline PASI week primary endpoint>
     <IGA week1> - <IGA week primary endpoint>;
  BY <treatment group>;
RUN;
ODS LISTING;
Programming notes:

The SAS procedure MIANALYZE expects a variable called “_IMPUTATION_ which 
is generated by the MI procedure. It might be needed to set the SAS option 
“VALIDVARNAME=UPCASE” temporarily in the program before the MI call, this 
option should be reset after the MIANALYZE call to VALIDVARNAME=V6. 

In case there are no missings in one treatment group, the MI procedure does not 
impute any values. In this case the corresponding data need to be imputed manually 
outside PROC MI and added to the dataset <impdata>.


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The imputed data are saved in data set <impdata>. The outcomes of interest, i.e. the PASI
50/75/90/100 response and IGA mod 2011 0 or 1 response will be calculated, e.g. as follows:
DATA <impdata2>;
SET <impdata>;
IF <change from baseline PASI week primary endpoint>/<baseline PASI>=0.90 THEN <PASI 90 response> =1;
ELSE <PASI 90 response>=0;
<…repeat for all PASI response…>
IF <baseline IGA> >=3 THEN DO;
     IF <IGA week primary endpoint> < 1.5 THEN <IGA 0/1 response> =1;
ELSE IF <IGA week primary endpoint> >=1.5 THEN <IGA 0/1 response> =0;
ELSE PUT "E" "RROR:" stysid1a=;
END;
ELSE IF <baseline IGA>=2 THEN DO;
     IF <IGA week primary endpoint> < 0.5 THEN <IGA 0/1 response> =1;
ELSE IF <IGA week primary endpoint> >=0.5 THEN <IGA 0/1 response> =0;
ELSE PUT "E" "RROR:" stysid1a=;
END;
ELSE <IGA 0/1 response> =0;
RUN;
The treatment differences for each imputed data set will then be evaluated by Logistic 
regression and ODDS ratio as described in Section 5.4.6.2. This analysis will be done by 
_IMPUTATION_ for the comparison to the ustekinumab treatment group. The model should
be estimating response probability = 1 by using DESECENDING option. Using the ESTIMATE
option in the GENMOD procedure and the ODS OUTPUT data set “Estimates” provides the 
estimate for the odds ratio and confidence intervals.
PROC GENMOD <option>;
CLASS <stratum> <treatment>;
MODEL <response> = <explanatory variables> / link=logit dist=bin type3;
BY <by-variables);
ESTIMATE “OR. AIN 300 mg VS. Ustekinumab” <treatment> 1 -1/exp; 
ODS OUTPUT Estimates=Estimates;
RUN;
The MIANALYZE procedure expects the parameter estimate in the variables ESTIMATE, and 
the corresponding standard error in the variable STDERR. Measurements can be obtained from 
“Estimates” dataset by selecting the row with ODDS ratio estimates. 
Data <modified dataset>;
  set Estimates;
  if substr(label,1,3)= “Exp”;
  ESTIMATE=LBetaEstimate;
  STDERR=StdErr;
  effect= “OR”;
  if missing(ESTIMATE) or missing(STDERR) then delete;
RUN;
The estimates and standard errors based on the 100 imputed data are then combined by applying 
Rubin’s rules for multiple imputed data sets, see Little and Rubin (2002). 


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Programming notes: 

The variables ESTIMATE and STDERR in the input data set for the MIANALYZE 
procedure may not be missing. Records with missing values need to be deleted and the 
variable _IMPUTATION_ needs to be renumbered and regenerated since for each by-
group the procedure expects consecutive numbers starting at 1.

The ESTIMATE and STDERR in terms of odds ratios from logistic regressions will be 
transformed to follow a normal distribution before MIANALYZE procedure. They will
be transformed back to Odds Ratio to get the corrected ESTIMATE and corresponding 
CIs.  
The SAS procedure MIANALYZE will be applied as follows:
Step 1:
DATA <modified dataset_t>;
SET <modified dataset>;
estimate=log(ESTIMATE);
stderr=(log(LBETAUPPERCL)-log(LBETALOWERCL))/(2*1.96);
RUN ;
ODS LISTING CLOSE;
ODS OUTPUT ParameterEstimates=<results> VarianceInfo=<varinfo> ModelInfo=<modelinfo>;
PROC MIANALYZE PARMS=<modified dataset>;
  BY <by-variables>;
  MODELEFFECTS estimate;
  Stderr stderr;
RUN;
ODS LISTING;
data <results_back>;
set <results>;
estimate=exp(ESTIMATE);
LCLMEAN=estimate*exp(-1.96*stderr);
UCLMEAN=estimate*exp(+1.96*stderr);
RUN ;
5.4.5
Analysis of time-to-event data
Number and percentage of subjects with a clinical event based on the number of subjects in the 
analysis set at risk as denominator will be provided by treatment group. 
Median time to event (i.e., loss of PASI 90, IGA 0/1 response) and quartiles including 95% 
confidence intervals will be provided. The confidence intervals will be based on log-log 
transformation (PROC LIFETEST option conftype=log-log). In addition, for pre-specified time 
intervals the following will be presented in an output: 

for each treatment group and time interval: subjects at risk, subjects with event, 
subjects with event divided by subjects at risk, cumulative subjects with event and 
cumulative event probability including 95% confidence interval.

for treatment comparisons the hazard ratio derived via Cox regression as well as log-
rank test and Wilcoxon test.


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The pre-specified time intervals for different treatment periods are as follows: 
Treatment period: “>12 weeks to <=16 weeks”, “>16 weeks to <=28 weeks”, “>28 weeks to 
<=40 weeks”, and “>40 weeks”.
For the statistical appendix, the subjects identifier, the time to event, the number of subjects 
with an event, number of subjects remaining at risk in the treatment group in the analysis set, 
estimate of the event rate and its estimated standard error, as estimable, will be provided for 
each treatment group using the SAS procedure LIFETEST.
Subjects at risk, timepoint “0” and censoring will be defined as described in Table 5-1 below:
Table 5-1
Time to event: definition of risk set, timing and censoring by variable
Variable:
Time to
Risk set
Time = 0
Time of 
event
Censoring
Psoriasis 
ConMed
Informative  
censoring
Loss of 
PASI 90
All PASI 90
responders at 
Week 12 per 
analysis visit 
AND at least 
have one PASI 
assessments 
after Week 12
Week 12 
per 
analysis 
visit
Date of 1st
visit with
loss of 
PASI 90
observed
End of 
treatment 
period as 
per CRF 
disposition 
page
Censor (if 
Anti-
psoriasis 
ConMed 
taken 
before the 
event)
Study 
phase 
discontinu-
ation with 
reason 
“lack of 
efficacy”
Loss of 
IGA 0/1
All IGA 0/1
responders at 
Week 12 per 
analysis visit 
AND at least 
have one IGA
assessments 
after Week 12
Week 12 
per 
analysis 
visit
Date of 1st
visit with
loss of 
IGA 0/1 
observed
End of 
treatment 
period as 
per CRF 
disposition 
page
Censor (if 
Anti-
psoriasis 
ConMed 
taken 
before the 
event)
Study 
phase 
discontinu-
ation with 
reason 
“lack of 
efficacy”
Time-to-event will be derived as: 

date of event minus date of time=0 plus 1 day for subjects experiencing the event or

date of censoring minus date of time=0 plus 1 day for subjects not experiencing the 
event
5.4.6
Crude incidence and related risk estimates
5.4.6.1
Crude incidence and 100*(1-α)% confidence interval
For n subjects, each at risk to experience a certain event with probability π, the crude incidence 
is estimated as p=x/n, where x is the number of subjects with the event.
Absolute and relative frequencies will be displayed as well as 95% confidence interval for the 
relative frequency based on the score method including continuity correction (Newcombe 1998). 
With z as (1-α/2)-quantile of the standard normal distribution (SAS: z=PROBIT(1-alpha/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 
.
p
q

1


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Then the lower limit is























2
2
2
2
1
4
1
2
1
2
,0
max
z
n
nq
p
n
z
z
z
np
L
and the upper limit is























2
2
2
2
1
4
1
2
1
2
,1
min
z
n
nq
p
n
z
z
z
np
U
.
Note: if p = 0 then L = 0 and if p = 1 then U = 1.
If appropriate, an exact 100*(1-α)% confidence interval (Clopper-Pearson 1934) will be 
obtained by using the SAS procedure PROC FREQ with the EXACT BINOMIAL statement. 
However, the confidence interval derived via the score method including continuity correction 
will be the default in safety analyses.
5.4.6.2
Relative risk and 100*(1-α)% confidence interval
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event with probability π1 and π0 respectively, the relative risk is estimated as p1/p0 with p1=x1/n1
and p0=x0/n0.
An asymptotic 100*(1-α)% confidence interval on the relative risk will be based on the back-
transformed large sample confidence limits on the log-transformed relative risk estimate which 
are obtained by application of the delta-method and Slutzky’s theorem (Lachin 2000). The SAS 
procedure PROC FREQ with option RELRISK in the TABLES statement will be used to 
provide the asymptotic 100*(1-α)% confidence interval on the relative risk. The estimate is not 
computed if either x1 or x0 equals 0. In this case, or if the crude incidences are low in both 
groups, the relative risk will be approximated by the odds ratio for which an exact confidence 
interval will be obtained as specified in Section 5.4.6.3. If the relative risk is not well 
approximated by the odds ratio but asymptotic normality is questionable, STATXACT will be 
used.
5.4.6.3
Odds ratio and 100*(1-α)% confidence interval
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g. ustekinumab) with n0 subjects at risk, of whom x1 and x0 experience a certain event with 
probability π1 and π0 respectively, the odds ratio is estimated as
)
1
/(
)
1
/(
0
0
1
1
p
p
p
p


with p1= x1/n1 and 
p0=x0/n0. A conditional exact 100*(1-α)% confidence interval will be obtained by using the 
SAS procedure PROC FREQ with statement EXACT OR.


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5.4.6.4
Risk difference and 100*(1-α)% confidence interval
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g., placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0. 
Exact unconditional confidence limits for the risk difference will be obtained with SAS 
procedure PROC FREQ and option RISKDIFF in the TABLES statement, specifying the 
RISKDIFF option also in the EXACT statement. 
5.4.7
Exposure adjusted incidence rate and related risk estimates
5.4.7.1
Exposure adjusted incidence rate and 100*(1-α)% confidence interval
It will be assumed that for each of n subjects in a clinical trial the time tj (j=1,...,n) to the first 
occurrence of a certain 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 occurrences of an event will be modeled to follow 
approximately a Poisson process with constant intensity θ. The rate parameter θ will be 
estimated as λ=D/T, where 



n
j
jt
T
1
and D is the number of subjects with at least one event. 
Conditionally on T, an exact 100*(1-α)% confidence interval for a Poisson variable with 
parameter θT and observed value D can be obtained based on (Garwood, 1936), from which an 
exact 100*(1-α)% confidence interval for D/T will be derived as follows (Sahai, 1993; Ulm, 
1990):
Lower confidence limit   
for D>0, 0 otherwise,
Upper confidence limit 
where
k
c ,

is the αth quantile of the Chi-square distribution with k degrees of freedom.
5.4.7.2
Exposure-adjusted event rate and 100*(1-α)% confidence interval
For each of n subjects tj (j=1,...,n) specifies the exposure time. The number of occurrences of 
an treatment emergent event will be modeled to follow approximately a Poisson process with 
constant intensity θ. The rate parameter θ will be estimated as λ=D/T, where 



n
j
jt
T
1
and D 
is the number of events (episodes). Conditionally on T, an exact 100*(1-α)% confidence interval 
for a Poisson variable with parameter θT and observed value D can be obtained based on 
(Garwood, 1936), from which an exact 100*(1-α)% confidence interval for D/T will be derived 
as follows (Sahai, 1993; Ulm, 1990):
Lower confidence limit   
for D>0, 0 otherwise,
T
c
L
D
2
,
2
/
5.0


T
c
U
D
2
2
,2
/
1
5.0




T
c
L
D
2
,
2
/
5.0




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Upper confidence limit 
where
k
c ,

is the α th quantile of the Chi-square distribution with k degrees of freedom.
5.5
Rule of exclusion criteria of analysis sets 
Protocol deviations for exclusion from analysis sets are defined in Table 5-2. 
Table 5-2
Subject classification rules
Analysis set
PD Categories Codes that 
cause subject to be excluded
Non-PD criteria that cause a 
subject to be excluded
Randomization set
NA
Misrandomized subject
FAS (Full Analysis Set) 
DVSPID: INCL02a; OTH15
Misrandomized subject
Safety
DVSPID: INCL02a; OTH15
Subjects who did not take any 
study treatment
INCL02a: ICF missing or not signed
OTH15: Severe ICH-GCP non-compliance of study site
T
c
U
D
2
2
,2
/
1
5.0






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6
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