Clinical trial NCT03668613
Conditions: Moderate to Severe Chronic Plaque-type Psoriasis
Keywords: pediatric secukinumab plaque psoriasis AIN457A Skin condition skin disease itching condition psoriasis vulgaris relapsing/remitting psoriasis immune-mediated systemic disease skin lesions red skin lesions scaly patches papules plaques itching
Sponsor: Novartis Pharmaceuticals
Start date: 2018-08-29; Completion date: 2023-09-12
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was an open-label, parallel-group, two-arm, multicenter study in pediatric subjects aged 6 years to less than 18 years, at randomization, with moderate to severe chronic plaque psoriasis. 84 subjects (most with moderate severity) were enrolled. Subjects were stratified by weight and disease severity.

Detailed description:
This was an open-label, parallel group, two-arm, multi-center, trial in pediatric subjects aged 6 years to less than 18 years, at randomization, with moderate to severe chronic, plaque psoriasis. The study consists of 3 periods: screening (up to 4 weeks), treatment (Week 208) and post-treatment follow-up (Week 224).

Approximately 80 subjects (at least 60 subjects with moderate psoriasis) were planned to be enrolled in about 40 centers worldwide and targeted to have at least 5 subjects in the \< 25kg body weight, and at least 10 subjects in each of the other two weight groups (25-\< 50 kg and ≥ 50 kg). Adolescents (12-\< 18 years) and children (6-\< 12 years) were included from the beginning of this study, since the DMC had approved already the enrollment of children (6-\< 12 years) in the study CAIN457A2310 (NCT02471144). Subjects received the appropriate dose based on their body weight category.

For the statistical analysis for outcome measures 1 and 2, there was no 'within study' control arm. A historical placebo control was obtained using data from qualifying trials and used as the comparator for the primary and key secondary endpoint analysis. This was in line with the guidance from and discussions with Health Authorities including FDA and EMA (PDCO), which suggested reducing placebo exposure as well as overall clinical trial burden for the pediatric population and accepted an extrapolation approach (EMA 2012). Historical placebo data included in this study were based on clinical appropriateness and alignment of definitions (endpoints, clinical disease population and time point of assessment). Integrated in the analysis were placebo data from Novartis-reported secukinumab adult placebo-controlled studies (CAIN457A2302 (NCT01544595 and NCT01365455), CAIN457A2303 (NCT01544595 and NCT01358578), CAIN457A2308 (NCT01555125) and CAIN457A2309 (NCT01636687)) and pediatric placebo-controlled study CAIN457A2310. In addition, pediatric placebo-controlled study data from the literature on other biologics (e.g. etanercept, ustekinumab) were utilized (Paller et al 2008, Landells et al 2015).

If the subject moved into a higher or lower weight group at two consecutive visits with weight measurements during the maintenance (from Week 12 onwards as assessed at 4 weekly visits or during extension treatment period (as assessed at scheduled site visits), then the subject was dosed according to the new (higher or lower) weight group respectively.

Arms: arm 1: secukinumab low dose arm 2: secukinumab high dose
Interventions: intervention 1: secukinumab low dose intervention 2: secukinumab high dose
Intervention descriptions: intervention 1: dose depends on the weight group intervention 2: dose depends on the weight group

Protocol documents:
Prot_002.pdf: 
Global Clinical Development - General Medicine 
Secukinumab (AIN457) 
Clinical Trial Protocol CAIN457A2311 / NCT03668613
A randomized, open-label, multicenter trial to assess the 
efficacy of subcutaneous secukinumab after twelve weeks 
of treatment, and to assess the long-term safety, 
tolerability and efficacy in subjects from 6 to less than 18 
years of age with moderate to severe chronic plaque 
psoriasis 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2017-004515-39 
Version number: 
01 (Amendment 1) Clean 
Clinical trial phase: 
III 
Release date: 
25-Sep-2020
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.4 (May 2017) 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ......................................................................................................................... 6 
List of figures ....................................................................................................................... 6 
List of abbreviations ............................................................................................................. 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 (25-Sep-2020) .................................................................................................... 11 
Protocol summary .............................................................................................................. 13 
 
Introduction ........................................................................................................................ 16 
1.1 
Background ............................................................................................................ 16 
1.2 
Purpose ................................................................................................................... 18 
 
Study objectives and endpoints .......................................................................................... 19 
2.1 
Objectives and related endpoints ............................................................................ 19 
 
Investigational plan ............................................................................................................ 20 
3.1 
Study design ........................................................................................................... 20 
3.2 
Rationale for study design ...................................................................................... 22 
3.3 
Rationale for dose/regimen, route of administration and duration of treatment ..... 23 
3.4 
Rational for choice of comparator .......................................................................... 24 
3.5 
Purpose and timing of interim analyses/design adaptations ................................... 24 
3.6 
Risks and benefits .................................................................................................. 24 
 
Population .......................................................................................................................... 25 
4.1 
Inclusion criteria ..................................................................................................... 25 
4.2 
Exclusion criteria ................................................................................................... 26 
 
Treatment ........................................................................................................................... 28 
5.1 
Study treatment ...................................................................................................... 28 
5.1.1 
Investigational and control drugs ........................................................... 28 
5.1.2 
Additional treatment .............................................................................. 28 
5.2 
Treatment arms ....................................................................................................... 28 
5.3 
Treatment assignment and randomization .............................................................. 29 
5.4 
Treatment blinding ................................................................................................. 30 
5.5 
Treating the subject ................................................................................................ 30 
5.5.1 
Subject numbering ................................................................................. 30 
5.5.2 
Dispensing the study drug ..................................................................... 31 
5.5.3 
Handling of study and additional treatment ........................................... 32 
5.5.4 
Instructions for prescribing and taking study treatment ......................... 32 
5.5.5 
Permitted dose adjustments and interruptions of study treatment .......... 33 


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5.5.6 
Rescue medication ................................................................................. 33 
5.5.7 
Prior and Concomitant medication ........................................................ 33 
5.5.8 
Prohibited medication ............................................................................ 35 
5.5.9 
Emergency breaking of assigned treatment code ................................... 36 
5.6 
Study completion and discontinuation ................................................................... 36 
5.6.1 
Study completion and post-study treatment ........................................... 36 
5.6.2 
Discontinuation of study treatment ........................................................ 37 
5.6.3 
Withdrawal of informed consent ........................................................... 38 
5.6.4 
Loss to follow-up ................................................................................... 38 
5.6.5 
Early study termination by the sponsor ................................................. 39 
 
Visit schedule and assessments .......................................................................................... 39 
6.1 
Information to be collected on screening failures .................................................. 47 
6.2 
Subject demographics/other baseline characteristics .............................................. 47 
6.2.1 
Demographics ........................................................................................ 47 
6.2.2 
Psoriasis medical history / Previous psoriasis therapy ........................... 47 
6.2.3 
Relevant medical history / current medical conditions .......................... 47 
6.2.4 
Determination of Tuberculosis status .................................................... 48 
6.2.5 
Other baseline characteristics ................................................................ 51 
6.3 
Treatment exposure and compliance ...................................................................... 51 
6.4 
Efficacy .................................................................................................................. 51 
6.4.1 
Investigator Global assessment (IGA mod 2011) .................................. 51 
6.4.2 
Assessment of total body surface area (BSA) and psoriasis area 
safety index (PASI) ............................................................................... 52 
 
 54 
6.4.4 
Appropriateness of efficacy assessments ............................................... 54 
6.5 
Safety ..................................................................................................................... 55 
6.5.1 
Physical examination ............................................................................. 55 
 
 55 
6.5.3 
Vital signs .............................................................................................. 56 
6.5.4 
Height and weight .................................................................................. 56 
6.5.5 
Laboratory evaluations .......................................................................... 56 
6.5.6 
Electrocardiogram (ECG) ...................................................................... 58 
6.5.7 
Immunogenicity ..................................................................................... 58 
6.5.8 
Pregnancy and assessments of fertility .................................................. 59 
6.5.9 
Appropriateness of safety measurements ............................................... 60 
6.6 
Other assessments .................................................................................................. 60 


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6.6.1 
Clinical Outcome Assessments (COAs) ................................................ 60 
6.6.2 
Resource utilization ............................................................................... 61 
6.6.3 
Pharmacokinetics ................................................................................... 62 
6.6.4 
Other biomarkers ................................................................................... 62 
 
Safety monitoring ............................................................................................................... 62 
7.1 
Adverse events ....................................................................................................... 62 
7.2 
Serious adverse events ........................................................................................... 64 
7.2.1 
Definition of SAE .................................................................................. 64 
7.2.2 
SAE reporting ........................................................................................ 65 
7.3 
Liver safety monitoring .......................................................................................... 66 
7.4 
Renal safety monitoring ......................................................................................... 66 
7.5 
Reporting of study treatment errors including misuse/abuse .................................. 66 
7.6 
Pregnancy reporting ............................................................................................... 67 
 
Data review and database management ............................................................................. 67 
8.1 
Site monitoring ....................................................................................................... 67 
8.2 
Data collection ....................................................................................................... 68 
8.3 
Database management and quality control ............................................................. 68 
8.4 
Data Monitoring Committee .................................................................................. 69 
8.5 
Adjudication Committee ........................................................................................ 69 
 
Data analysis ...................................................................................................................... 69 
9.1 
Analysis sets ........................................................................................................... 69 
9.2 
Subject demographics and other baseline characteristics ....................................... 70 
9.3 
Treatments .............................................................................................................. 70 
9.4 
Analysis of the primary variable(s) ........................................................................ 70 
9.4.1 
Primary Variable(s) ............................................................................... 71 
9.4.2 
Statistical model, hypothesis, and method of analysis ........................... 71 
9.4.3 
Handling of missing values/censoring/discontinuations ........................ 71 
9.4.4 
Sensitivity analyses ................................................................................ 72 
9.5 
Analysis of secondary variables ............................................................................. 72 
9.5.1 
Efficacy variables .................................................................................. 72 
9.5.2 
Safety variables ...................................................................................... 72 
9.5.3 
Resource utilization ............................................................................... 74 
9.5.4 
Health-Related Quality of Life .............................................................. 74 
9.5.5 
Pharmacokinetics ................................................................................... 74 
9.5.6 
DNA ...................................................................................................... 74 
9.5.7 
Biomarkers ............................................................................................ 74 


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9.5.8 
PK/PD .................................................................................................... 74 
9.6 
Analysis of exploratory variables ........................................................................... 74 
9.7 
Interim analyses ..................................................................................................... 75 
9.8 
Sample size calculation .......................................................................................... 75 
 Ethical considerations ........................................................................................................ 76 
10.1 
Regulatory and ethical compliance ........................................................................ 76 
10.2 
Informed consent procedures ................................................................................. 77 
10.3 
Responsibilities of the investigator and IRB/IEC .................................................. 78 
10.4 
Publication of study protocol and results ............................................................... 78 
10.5 
Quality Control and Quality Assurance .................................................................. 78 
 Protocol adherence ............................................................................................................. 78 
11.1 
Protocol amendments ............................................................................................. 79 
 References .......................................................................................................................... 80 
 Appendix 1: Clinically notable laboratory parameters ...................................................... 83 
 Appendix 2: Blood collection log for pharmacokinetics and immunogenicity ................. 85 
 86 
 Appendix 4: Weight and recommended blood volumes .................................................... 87 


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List of tables 
Table 2-1 
Objectives and related endpoints ........................................................... 19 
Table 5-1 
Number of injections per visit per treatment arm .................................. 29 
Table 5-2 
Disease severity classification ............................................................... 30 
Table 5-3 
Prohibited medication ............................................................................ 35 
Table 6-1 
Assessment schedule (Year 1) ............................................................... 41 
Table 6-2 
Assessment schedule - Years 2-4 (continued) ....................................... 44 
Table 6-3 
IGA mod 2011 scale .............................................................................. 52 
Table 6-4 
PASI scoring system .............................................................................. 53 
Table 6-5 
Recommended Dimensions for Blood Pressure Cuff Bladders ............. 56 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................... 66 
Table 9-1 
Treatment groups for analyses .............................................................. 69 
Table 9-2 
Predictive placebo response rates for this study from model of 
historical data ........................................................................................ 76 
Table 14-1 
Blood collection log for pharmacokinetics ............................................ 85 
Table 14-2 
Blood Collection for Immunogenicity ................................................... 85 
Table 16-1 
Total blood volume, 1% and 3% of total blood volume by weight 
assuming 85mL per kg total blood volume ........................................... 87 
List of figures 
Figure 3-1 
Study design .......................................................................................... 20 
Figure 3-2 
Average concentration for the proposed low dose and high dose 
secukinumab arms ................................................................................. 23 
Figure 6-1 
Tuberculosis screening flowchart .......................................................... 50 


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List of abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BDR 
Bioanalytical Data Report 
BP 
Blood Pressure 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CDLQI 
Children’s Dermatology Life Quality Index 
COVID-19 
Coronavirus disease of 2019 
CFR 
Code of Federal Regulations 
CRF 
Case Report/Record Form (paper or electronic) 
CPO 
Country Pharma Organization 
CRO 
Contract Research Organization 
CS 
Corticosteroid 
CTC 
Common Toxicity Criteria 
DMC 
Data Monitoring Committee 
DS & E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report/Record Form 
eg 
Example 
eGFR 
estimated Glomerular Filtration Rate 
EMA 
European Medical Association 
EOT 
End of Treatment 
EOF 
End of Follow-up 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma –glutamyl transferase 
hCG 
Human chorionic gonadotropin 
HIV 
Human Immunodeficiency Virus 
HrQoL 
Health-related Quality of Life 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IGA 
Investigator Global Assessment 


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IgG 
Immunoglobulin G 
IL 
Interleukin 
IQS 
Integrated Quantitative Sciences 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IN 
Investigator Notification 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LLN 
Lower Limit of Normal 
LOCF 
Last Observation Carried Forward 
MACE 
Major Adverse Cardiovascular Events 
MAP 
Meta-analytical-prediction 
MedDRA 
Medical dictionary for regulatory activities 
MI 
Myocardial Infarction 
PASI 
Psoriasis Area and Severity Index 
PDCO 
Pediatric Committee of the European Medicines Agency 
PPD 
Purified Protein derivative 
PFS 
Pre-filled syringe 
PK 
pharmacokinetic 
PRO 
Patient reported outcome 
PS 
Patient Safety 
PUVA 
Photochemotherapy (eg psoralen + UVA treatment) 
QFT 
QuantiFERON TB-Gold test 
QM 
Quality Management 
R 
Randomization 
rpm 
Rate per minute 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sc 
subcutaneous 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SST 
Serum Separator Tube 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
tuberculosis 
TBL 
Total Bilirubin 
TCS 
Topical corticosteroids 
Th17 
T helper 17 cells 
ULN 
Upper Limit of Normal 
UV 
Ultraviolet 
UVA 
Ultraviolet A, long wave 400 nm–315 nm 
UVB 
Ultraviolet B, medium wave 315 nm–280 nm 
Vs 
Versus 
WBC 
White blood cells / leukocytes 


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WHO 
World Health Organization 
WoC 
Withdrawal of Consent 


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Glossary of terms 
 
Cohort 
A specific group of subjects/subjects fulfilling certain criteria 
Historical control 
drug 
Drugs(s) used from historical data to act as a comparator to evaluate 
comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the subject in a time unit (eg 100 mg once 
a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care. 
Enrollment 
Point/time of subject entry into the study at which informed consent must be 
obtained (eg prior to starting any of the procedures described in the protocol) 
Investigational 
drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug” or “investigational medicinal product.” 
Medication pack 
number 
A unique identifier on the label of each investigational drug package 
Subject/subject 
ID 
A unique number assigned to each subject upon signing the informed consent 
Period 
The subdivisions of the trial design (eg Screening, Treatment, Follow-up) which 
are described in the Protocol. Periods define the study phases and will be used 
in clinical trial database setup and eventually in analysis 
Randomization 
number 
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource. 
Study drug/ 
treatment 
Any single drug or combination of drugs administered to the subject as part of 
the required study procedures; includes investigational drug (s), 
placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation 
(TD) 
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date 
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study 
Withdrawal of 
study consent 
(WoC) 
Withdrawal of consent from the study 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 (25-Sep-2020) 
Amendment rationale 
The rationale for the amendment is to introduce a level of flexibility in drug dispensation, 
protocol assessment and visit schedule if a major health care event requires it (i.e. COVID-19 
pandemic) allowing patients to remain in the trial and continue treatment while being 
monitored for safety. 
The purpose of these changes is to reduce the risk of exposure for patients and site staff and 
potentially the risk of transmission of infectious diseases (e.g. COVID-19). 
These changes are limited to the duration of COVID-19 pandemic or of any other major health 
care event and must be done in accordance with the local rules and regulations relevant to 
pandemic containment measures. 
Further to the above, minor corrections, clarifications and editorial changes were undertaken in 
the protocol. 
Changes to the protocol: 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The Amendment includes changes: 
• Due to COVID-19 pandemic or any other pandemic 
• Allowing shipment of study medication to patient's home (Section 5.5.2) 
• Alternative options visits (Sections 6, 6.5, 7.1) 
• Local laboratory testing for safety purposes (Section 6.5.5) 
• Home Pregnancy testing (Section 6.5.8) 
• Remote PRO collection (Section 6.6.1.1) 
• Informed Consent Form (Section 10.2) 
• Home Nursing Informed Consent Form (Section 10.2) 
• Significant Update to Original Protocol: 
• Added Inflammatory Bowel Disease as an example for discontinuation ofstudy 
treatment (Section 5.6.2). 
• ICF (Section 10.2) 
• To manage inconsistencies and provide clarifications in the original protocol 
• clarify prior medication (Section 5.5.7) 
• correct data collection to source only (weight in IRT, Table 6-1; Table 6-2) 
• Imputation method (Section 9.4.3) 
• Remove sensitivity analysis (Section 9.4.4) 
• Add growth/weight 
 to Safety Section 9.5.2 
• As well as other miscellaneous minor corrections, modifications and text adjustments 
• Modification in Protocol summary secondary objectives. 


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• Modification in footnote 13 of Table 6-1. 
• Modification in Urine pregnanacy test, 
weight in IRT and footnote 10 
in Table 6-2. 
• Modification in Section 9.5.4. 
• Modification in Section 9.6. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
This protocol amendment is considered substantial. However many countries participating in 
this study have released Urgent Safety Measure guidance stating that certain changes to a 
protocol due to the COVID-19 pandemic are permissible by notification or by non-substantial 
amendment. Therefore the final determination of the protocol classification will be done on a 
country by country basis based on the latest local HA guidance. 
COVID-19 related measures may/will be implemented immediately and prior to IRB/IEC and 
HA approvals. Submission for review and approval to IRB/IEC and Health Authorities should 
occur as early as possible.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 described in this protocol amendment. 


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Protocol summary 
Protocol number 
CAIN457A2311 
Full Title 
A randomized, open-label, multicenter trial to assess the efficacy of SC 
Secukinumab after twelve weeks of treatment, and to assess the long-term safety, 
tolerability and efficacy in subjects from 6 to less than 18 years of age with 
moderate to severe chronic plaque psoriasis 
Brief title 
Study to assess the efficacy, safety, tolerability and PK of secukinumab in subjects 
6 to less than 18 years of age with moderate to severe chronic plaque psoriasis 
Sponsor 
and 
Clinical 
Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this study is to assess the efficacy of secukinumab at Week 12, 
based on both Psoriasis Area and Severity Index (PASI) 75 and Investigator’s 
Global Assessment (IGA) mod 2011 0 or 1 response rates in children and 
adolescents aged 6 to less than 18 years at randomization with moderate to severe 
chronic plaque psoriasis who are candidates for systemic therapy. 
This study will provide efficacy, safety and pharmacokinetic data to support the 
extension of label of secukinumab to include children and adolescents (6 years to 
< 18 years) with moderate to severe chronic plaque psoriasis. 
The study will assess the long-term efficacy, safety and tolerability of 
secukinumab over a period of up to 4 years to support the long-term use of 
secukinumab in pediatric patients. 
Primary Objective(s) 
To evaluate the efficacy of secukinumab in pediatric subjects aged 6 years to less 
than 18 years old with moderate to severe chronic plaque psoriasis with respect to 
PASI 75 and IGA mod 2011 0 or 1 response (co-primary endpoints) at Week 12, 
compared to placebo (historical control). 
Secondary Objectives 
Objective 1: To evaluate the efficacy of secukinumab in pediatric subjects aged 6 
years to less than 18 years old with moderate to severe chronic plaque psoriasis 
with respect to PASI 90 at Week 12, compared to placebo (historical control). 
Objective 2: To investigate the clinical safety and tolerability of secukinumab as 
assessed by growth, weight gain, vital signs, clinical laboratory variables, 
Electrocardiogram and AE monitoring 
Objective 3: To evaluate the pharmacokinetics of secukinumab doses in subjects 
Study design 
Multi-center, open label, parallel group, two arm study. 
Three periods, screening (up to 4 weeks), treatment (of 208 weeks) and follow-up 
(of 16 weeks) 
Population 
Approximately 80 pediatric subjects aged 6 years to less than 18 years with 
moderate to severe chronic plaque psoriasis will be enrolled. 
Key Inclusion criteria 
Written informed assent and parental permission obtained at screening. Subjects 
reaching the age of consent during the study, will need to also sign the 
corresponding study Informed Consent. 
Must be 6 to less than 18 years of age at the time of randomization. 


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Moderate to Severe plaque psoriasis, defined as a PASI score ≥ 12, and IGA mod 
2011 score of ≥ 3, and Body Surface Area (BSA) involvement of ≥ 10%, at 
randomization 
History of plaque psoriasis for at least 3 months before randomization 
Subject being regarded by the investigator to be a candidate for systemic therapy 
because of: 
inadequate control of symptoms with topical treatment, and/or 
failure to respond to or tolerate previous systemic treatment and/or ultraviolet 
therapy 
Key Exclusion criteria 
Forms of psoriasis other than chronic plaque-type (eg pustular, erythrodermic and 
guttate psoriasis), active at randomization 
Female subjects of childbearing potential (menarchal or becoming menarchal 
during the study) who do not agree to abstinence or, if sexually active, do not agree 
to the use of contraception. 
Active ongoing inflammatory diseases other than psoriasis that might confound 
the evaluation of the benefit of secukinumab therapy 
Underlying condition (including, 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. 
History of an ongoing, chronic or recurrent infectious disease, or evidence of 
tuberculosis infection. 
History of lymphoproliferative disease or any known malignancy or history of 
malignancy of any organ system within the past 5 years prior to screening. 
Active systemic infections during the last two weeks prior to randomization and 
any infections that reoccur on a regular basis. 
Study treatment 
Secukinumab prefilled syringes available as 75 mg /0.5 mL and 150 mg/1 ml will 
be provided by Novartis in an open-label fashion. 
Efficacy assessments 
Investigator’s Global Assessment (IGA mod 2011) 
Psoriasis Area and Severity Index (PASI) 
Key safety assessments 
Adverse Events 
Physical Exam 
Vital Signs 
Height and Weight 
Laboratory evaluations (hematology, clinical chemistry, urinalysis) 
ECG 
Pregnancy and assessments of fertility 
Other assessments 
Pharmacokinetics 
Immunogenicity IG 


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Children’s Dermatology Life Quality Index (CDLQI) 
Data analysis 
PASI 75 response at Week 12 and IGA 0 or 1 response at Week 12 will be 
evaluated and compared to historical placebo control. The secondary variable of 
PASI 90 response at Week 12 will be analyzed in the same way as the primary 
variable. Efficacy analysis will report the Bayesian posterior of the log-odds ratio 
between the secukinumab treatment groups and the historical placebo control. The 
median, 95% CI and the probability of a positive treatment difference of the 
posterior logs odds ratio will be presented. The co-primary efficacy variables and 
secondary efficacy variables will be analyzed using the Full Analysis Set (FAS). 
Key words 
Pediatric, psoriasis, children, adolescents, secukinumab 


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Introduction 
1.1 
Background 
Psoriasis is a chronic relapsing inflammatory skin disease with an estimated prevalence of 0.32% 
in children under the age of 18 in 1996 (National Center for Health Statistics of the Centers for 
Disease Control and Prevention 1996). Since then, more epidemiologic studies have provided 
estimates on the prevalence of psoriasis in children in Europe and the United States of America. 
• In the United Kingdom, prevalence of psoriasis was 0.55% in children aged 0 to 9 years 
and 1.37% in children and adolescents aged 10 to 19 years, with a higher prevalence in 
girls than in boys (Gelfand et al 2005). 
• In Germany, 0.71% of children were affected by psoriasis and the prevalence increased 
from 0.12% at the age of 1 year to 1.2% at the age of 18 years (Augustin et al 2010). 
• Results from a survey among dermatologists and general practitioners in the Netherlands 
suggested a prevalence of 0.37% in children aged 0 to 10 years, and 1.09% in children 
aged 11 to 19 years (de Jager et al 2009). 
• In the USA, a Southern California study in children enrolled in an integrated health plan 
reported a 0.30% prevalence of psoriasis in children aged 2 to 19 years. The prevalence 
increased consistently after 5 years of age and was higher in females than in males. 
Stratification by gender (males vs. females) and age group yielded an overall prevalence 
of 0.17 % vs 0.21%; ages 2-5 years, 0.03% vs. 0.04%; ages 6-11 years, 0.16% vs. 0.15%; 
ages 12-19 years, 0.25% vs. 0.33% (Wu et al 2011). 
The incidence of psoriasis in childhood in the US has been shown to increase with increasing 
age but also in recent years the incidence of psoriasis in children increased significantly from 
29.6 per 100,000 in 1970-1974 to 62.7 per 100,000 in 1995-1999 (Tollefson et al 2010). 
Plaque psoriasis affects 80% to 90% of all psoriasis subjects of all age-groups (Griffiths and 
Barker 2007, Pariser et al 2007) and hence is the most common variant in pediatric subjects. 
Most children manifest with plaque psoriasis in patterns similar to adult subjects, with lesions 
localized to the scalp, post auricular region, elbows, and knees; however, lesions in children are 
often smaller, thinner, and less scaly than those seen in adults. Involvement of the face and 
flexural regions is more common in children than adults, and psoriatic lesions in the diaper area 
are prevalent during infancy. 
As in adults, pediatric psoriasis is frequently associated with significant co-morbidities like 
diabetes mellitus, Crohn’s disease, obesity, and hypertension, and high cholesterol, 
psychological and psychiatric impact. The overall rate of comorbid conditions in psoriasis 
subjects under 20 years of age is double that of their peers who do not have psoriasis (Augustin 
2010). A pediatric study using an international cohort of psoriasis subjects found that a 
significantly higher percentage of children with psoriasis showed excess adiposity (37.9% vs. 
20.5%) or obesity (20.2% vs. 7.3%), significantly higher than the general pediatric population 
(Paller et al 2013). 
The psychological impact of psoriasis can be particularly traumatic to children and adolescents. 
In children with at least one of 12 different skin diseases, children with psoriasis reported the 
greatest impairment to quality of life. Itch or pain was reported in the same study as the most 


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significant problem affecting their Health-related Quality of Life (HrQoL) (Beattie 2006). 
Psoriasis, a debilitating and disfiguring skin condition, is an independent risk factor for 
psychiatric comorbidities in children and adolescents. Compared with a matched psoriasis-free 
control cohort in a study based on health services claims data in the USA, pediatric subjects had 
approximately 25% to 30% greater risks of being given a diagnosis of any psychiatric disorder, 
depression, or anxiety subsequent to the psoriasis diagnosis (Kimball et al 2012). 
Due to the higher prevalence of plaque psoriasis in children compared to other types and the 
significant physical and psychological burden it carries in the pediatric population, Novartis 
plans to study secukinumab in the treatment of plaque psoriasis in patients from 6 to less than 
18 years of age. 
The treatments for psoriasis have expanded over the past decade though in children treatment 
is frequently off-label. The use of topical therapy in childhood is the first line of treatment for 
skin-limited disease. With chronicity of illness and in more severe cases, phototherapy and 
systemic therapy are added to help induce remission (Silverberg 2009). 
Topical therapies represent the vast majority of prescriptions (57 to 91%), while systemic agents 
are rarely used (4%), and biologics being even more rarely used (0.4%) (Wu 2011, Kimball 
2012). Commonly used topical treatments for psoriasis include corticosteroids, coal tar, 
anthralin, calcipotriol either alone or in combination with topical steroids, tazarotene and 
calcineurin inhibitors (Burden 1999, Farber 1999, Benoit 2007). None of these treatments have 
been approved for the treatment of psoriasis in children below 12 years of age. Phototherapy is 
extensively used in adults and is a treatment option for some children with widespread plaques. 
Narrow-Band-Ultraviolet B (UVB) is considered the first-line phototherapy because it is 
similarly effective as Psoralen + Ultraviolet A (PUVA), more convenient, and less carcinogenic 
(Van Weelden 1990). PUVA therapy is not generally recommended in children, but may be 
used with caution in adolescents (Burden 1999). 
Systemic therapy is usually considered if the disease is moderate to severe in intensity, and not 
adequately controlled by topical therapies. Systemic treatments approved for use in adult 
psoriasis include acitretin, methotrexate, cyclosporine, and biologics. Acitretin is approved for 
subsets of psoriatic pediatric patients in some European Union (EU) countries and Switzerland. 
However cyclosporine and methotrexate are not currently approved for the treatment of 
children/adolescents suffering from psoriasis. 
Use of methotrexate, cyclosporine, retinoids (particularly acitretin), and, with a much lower 
frequency, dapsone and hydroxyurea has been reported in the literature (Zappel 2004; Benoit 
2007). Most experience has been reported with retinoids, but the potential effect on bone growth 
and teratogenicity limit their use in children and adolescents. Use of cyclosporine and 
methotrexate is limited by their adverse event (AE) profile (kidney dysfunction, hypertension 
and liver dysfunction, respectively). Reports on the use of biologics in pediatric patients are 
scarce (Benoit 2007). 
Amongst biologics, etanercept and ustekinumab have been approved not so long ago in US for 
moderate to severe psoriasis in pediatric patients (ustekinumab only for adolescents that is 
children 12 years or older). In Europe, apart from etanercept and ustekinumab (ustekinumab 
only for adolescents), adalimumab has also been approved recently but only for severe psoriasis 


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in children from 4 years of age. The details are available in respective prescribing information 
/ summary of product characteristics. 
In summary, a very limited number of systemic drugs for the treatment of psoriasis are approved 
for children, and the few approved drugs all have limitations. There is a high medical need to 
evaluate the treatment of psoriasis in patients less than 18 years of age where controlled studies 
are mostly missing (Burden 1999; Farber 1999; Benoit 2007; Paller et al 2008). 
Secukinumab (AIN457) is a recombinant high-affinity fully human monoclonal anti-human 
Interleukin-17A (IL-17A) antibody of the Immunoglobulin IgG1/κ-class. Secukinumab binds 
to human IL-17A and neutralizes the bioactivity of this cytokine. IL-17A is the central 
lymphokine of a newly defined subset of inflammatory T cells, the T helper 17 cells which, in 
several animal models, are pivotal in several autoimmune and inflammatory processes. IL-17A 
is mainly produced by memory effector CD4+ and CD8+ T lymphocytes. IL-17A is being 
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 symptoms. 
Based on the natural history of psoriasis and the similar clinical features and histology in adults 
and pediatric population (Burden 1999; Farber 1999; Benoit 2007), it is expected that a human 
monoclonal antibody such as secukinumab will have an identical mode of action in children 
when compared to adults. It is also expected that the exposure-response to secukinumab in 
pediatric psoriasis patients would be similar to the exposure-response relationship observed in 
adults. 
Now that efficacy and safety have been demonstrated in adults in a comprehensive phase II/III 
program, it seems appropriate that the pediatric population can be exposed to secukinumab in 
long term studies with a dosing regimen that is extrapolated from the adult efficacious dose. 
Currently, another clinical trial (CAIN457A2310) with secukinumab is already ongoing in 
pediatric patients with severe psoriasis. This planned trial (CAIN457A2311) will assess 
efficacy, safety and pharmacokinetics of secukinumab in moderate psoriasis (pediatric) patients 
as well as a few severe psoriasis patients. 
1.2 
Purpose 
The purpose of this study is to assess the efficacy of secukinumab at Week 12, based on both 
PASI 75 and IGA mod 2011 0 or 1 response rates in children and adolescents aged 6 to less 
than 18 years at randomization with moderate to severe chronic plaque psoriasis who are 
candidates for systemic therapy. 
This study will provide efficacy, safety and pharmacokinetic data to support the extension of 
label of secukinumab to include children and adolescents (6 years to <18 years) with moderate 
to severe chronic plaque psoriasis. 
Moreover, this study will assess the long-term efficacy, safety and tolerability of secukinumab 
over a period of up to 4 years to support the long-term use of secukinumab in pediatric patients. 


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Study objectives and endpoints 
2.1 
Objectives and related endpoints 
Table 2-1 
Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s) 
To evaluate the efficacy of secukinumab in 
pediatric subjects aged 6 years to less than 18 
years old with moderate to severe chronic 
plaque psoriasis with respect to PASI 75 and 
IGA mod 2011 0 or 1 response (co-primary 
endpoints) at Week 12, compared to placebo 
(historical control). 
Proportion of subjects who achieved PASI 75 and 
IGA mod 2011 0 or 1 response at Week 12 in 
each secukinumab treatment group (low dose and 
high dose). Placebo data are obtained from adult 
secukinumab placebo-controlled trials and 
pediatric placebo-controlled trials with 
secukinumab or other biologics 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
To evaluate the efficacy of secukinumab in 
pediatric subjects with respect to PASI 90 at 
Week 12, compared to placebo (historical 
control). 
Proportion of subjects who achieved PASI 90 
response at Week 12 in each secukinumab 
treatment group (low dose and high dose). 
Placebo data are obtained from adult placebo- 
controlled trials and pediatric placebo-controlled 
trials 
To investigate the clinical safety and tolerability 
of secukinumab as assessed by growth, weight 
gain, vital signs, clinical laboratory variables, 
ECGs, and adverse event monitoring 
Height and weight, vital signs, laboratory 
evaluations, ECG and adverse events 
To evaluate the pharmacokinetics of 
secukinumab in pediatric subjects 
Secukinumab concentration in serum at various 
time points 
Exploratory Objective(s) 
Endpoint(s) for exploratory objective(s) 
To investigate the effects of treatment with 
secukinumab with respect to changes in 
CDLQI over time up to End of Treatment 
Absolute and percentage change from baseline of 
CDLQI score over time up to End of Treatment 
To investigate the effects of treatment with 
secukinumab with respect to CDLQI 0 or 1 
score over time, up to End of Treatment 
Proportion of subjects achieving CDLQI 0 or 1 
over time up to End of Treatment 


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Exploratory Objective(s) 
Endpoint(s) for exploratory objective(s) 
To investigate the development of 
immunogenicity against secukinumab 
Development of anti-Drug Antibodies (ADA) to 
secukinumab 
 
Investigational plan 
3.1 
Study design 
This is an open-label, parallel-group, two-arm, multi-center, trial in pediatric subjects aged 6 
years to less than 18 years, at randomization, with moderate to severe chronic, plaque psoriasis. 
Approximately 80 subjects (at least 60 subjects with moderate severity) will be enrolled. It is 
expected that subjects will be enrolled in about 40 centers worldwide. It will be targeted to have 
at least 5 subjects in the < 25kg weight, and at least 10 subjects in each of the other two weight 
groups. 
Figure 3-1 
Study design 
 
 
The study consists of 3 periods: screening (up to 4 weeks), treatment (of 208 weeks) and post- 
treatment follow-up (of 16 weeks). An outline of the visits is presented in Figure 3-1 while a 
detailed visit and assessment schedule can be found in Table 6-1, Table 6-2. 


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Screening Period 
The screening period of up to 4 weeks will be used to assess eligibility of the subjects and to 
taper subjects off prohibited medication. 
Treatment Period 
The treatment period is defined as randomization to Week 208. In this period the endpoints are 
assessed and subjects are followed for long-term safety and efficacy. Subjects will be 
randomized using 1:1 ratio into either secukinumab low dose or secukinumab high dose. 
Randomization will be stratified by body weight (< 25kg, 25-< 50 kg, ≥ 50kg) and disease 
severity (either moderate (PASI score 12-<20 and IGA 3 or 4 or PASI score ≥ 20 and IGA 3) 
or severe (PASI score ≥ 20 and IGA of 4), collected at Randomization Visit. The study aims to 
recruit at least 60 subjects with moderate disease severity and approximately 20 subjects with 
severe disease severity. It will be targeted to have at least 5 subjects in the < 25kg weight, and 
at least 10 subjects in each of the other two weight groups. Subjects will receive the appropriate 
dose based on their body weight category. If a subject moves into a higher or lower weight 
group at two consecutive visits with weight measurements during the maintenance (from Week 
12 onwards as assessed at 4 weekly visits or during extension treatment period (as assessed at 
scheduled site visits), the subject will receive dosing according to the new (higher or lower) 
weight group respectively. The dose will be adapted starting from the visit of the second 
consecutive weight change. 
Adolescents (12-< 18 years) and children (6-< 12 years) can be included from the beginning of 
this study, since the DMC has approved already the enrollment of children (6-< 12 years) in 
study CAIN457A2310. 
All subjects will visit the study site at Randomization (Day 1) and at Weeks 1, 2, 3, 4, 8, 12, 16 
during which they will receive either high-dose or low-dose secukinumab treatment sub- 
cutaneously. Additionally, subjects will visit the site at Weeks 13, 14, 15 to provide blood 
samples for pharmacokinetics. 
During the Treatment period subjects will receive treatment of the assigned secukinumab dose 
every 4 weeks. However during Weeks 16-52 site visits will be scheduled every 8 weeks and 
from Weeks 64-208 site visits will be scheduled every 12 or 16 weeks, to minimize the burden 
on the subject. Subjects will have the option to receive treatment between scheduled visits at 
home, following instructions provided to the subject (if ≥12 years old), parent or caregiver. 
Subjects who discontinue study treatment for any reason before the end of the Treatment Period 
(Week 208) should have the Week 208 visit assessments performed approximately 4 weeks 
after their last dose of secukinumab. The subject will then enter the treatment–free Follow-up 
Period. 
Follow-up Period 
The treatment-free follow-up visits will be at Week 212, Week 216 and Week 224 (End Of 
Follow-up/EOF). Subjects who complete or discontinue the treatment early are expected to 
perform the complete treatment-free follow-up period unless they start another systemic anti- 
psoriatic treatment. In this case they do not need to continue with the remaining follow-up 


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visits but will be expected to return to the site after the start of the systemic treatment and 
perform the EOF visit. 
3.2 
Rationale for study design 
The rationale behind this design is based on a full extrapolation approach. Novartis’ proposal 
for a pediatric extrapolation approach is based on the Food and Drug Administration draft 
guidance, General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and 
Biological Products, which is also reflected in ICH E11 (R1) guidance and an European Medical 
Association reflection Paper on extrapolation of efficacy and safety in pediatric medicine 
development (ICH 2000; FDA 2014; EMA 2016; ICH 2016). 
Its intent is to minimize exposure of children to placebo and to overall clinical trial burden while 
leveraging the broad clinical information available from secukinumab trials in adult subjects as 
well as ongoing pediatric trial CAIN457A2310. This approach is considered appropriate due to 
the substantial similarity of the disease between the adults and pediatric population (Augustin 
2010, Feldman and Krueger 2005, Griffiths 2007, Kimball 2012, Langley et al 2005, Leman 
and Burden 2001, Paller et al 2008, Pariser 2007, Tollefson 2014) as well the similarity of 
exposure-response, which will be validated in the small population of children and adolescents 
of this study. The similarity of disease characteristics of psoriasis between adult and pediatric 
subjects has been described extensively. 
Following consultation with Health Authorities (FDA and EMA (PDCO) for overall pediatric 
program, the open label, design with no control arm was chosen for this particular study. 
Collection of pharmacokinetic information for pediatric subjects based on age and/or weight 
strata was recommended. In principle, if pediatric doses matching adult exposures are 
reasonably identified, then an uncontrolled open-label trial in pediatric subjects to collect safety 
and efficacy data can be acceptable. An interim PK analysis of data from the ongoing 
CAIN457A2310 trial (a double-blind placebo controlled and single blind active-controlled 
study in pediatric subjects with severe psoriasis) showed that pediatric trough concentrations 
for the weight and dose groups studied are consistent with the predictions from a population PK 
model in psoriasis patients (data on file; see Section 3.3 for more details). 
The present study is being conducted to collect long term safety data and evaluate efficacy and 
pharmacokinetics in children. The efficacy data collected in this uncontrolled study will be 
compared with historical placebo data obtained from the adult program with secukinumab and 
pediatric placebo-controlled trials with other biologics. If data from CAIN457A2310 (pediatric 
subjects with severe psoriasis) are available when this study report is created, the placebo 
efficacy data may also be used in the efficacy analysis of study CAIN457A2311. 
Finally, the lower age of enrollment has been limited to 6 years since the prevalence of psoriasis 
in the 0 to less than 6 age group is very low (with the highest prevalence published of 0.3%) 
and the proportion of children with a severe condition in need of a systemic treatment is 4%, 
giving a final prevalence of the condition to be about 1 per 10,000 in this age group. 


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3.3 
Rationale for dose/regimen, route of administration and duration 
of treatment 
The dose selection for secukinumab in pediatric psoriasis subjects is based on the completed 
phase III program in adults as well as on modeling and simulation based on the results from 
adult phase II/III studies. Secukinumab 300 mg and 150 mg are selected based on evidence 
from adult phase III studies that demonstrated both doses to be safe and effective in treating 
moderate to severe plaque psoriasis. 
The same doses were also selected for the first and ongoing pediatric study CAIN457A2310 
which is a double-blind placebo controlled and single blind active-controlled study in pediatric 
subjects with severe psoriasis. 
The proposed doses for the high dose and low dose secukinumab arms are based on a 
population-PK model that has been built based on the pool of key phase II/III adult trials to 
predict exposure of secukinumab according to various body weights. This dosing rationale 
assumes that the concentration-response relationship and disease characteristics (onset, severity, 
progression) in children are similar to adults with no major differences in target expression of 
IL-17A. Therefore, similar PK concentration profiles across the adult and pediatric populations 
will achieve comparable response. 
Figure 3-2 
Average concentration for the proposed low dose and high dose 
secukinumab arms 
 
Extrapolation of the exposure in children / adolescents in a bodyweight range down to 20 kg to 
allow maintaining exposure levels similar to those observed in adults with 50 kg body weight 
led to selection of 75mg, 150 mg and 300 mg within weight categories as follows: 
• Subjects ≥50 kg: 150 mg (low dose group) or 300 mg (high dose group) 
• Subjects 25 kg to < 50 kg: 75 mg (low dose group) or 150 mg (high dose group) 
• Subjects < 25 kg: 75 mg (for both dose groups in order to ensure no overly high exposures 
in this sub-population). 


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Interim PK data from 23 secukinumab-treated subjects in the age range of 12 to 17 years old 
from study CAIN457A2310 have been evaluated (data on file). The observed pediatric trough 
concentrations are consistent with model predictions for the weight and dose groups studied. 
These data, therefore, support the selected dosing regimen from a safety and efficacy point of 
view for study CAIN457A2310 and for the present study CAINA457A2311. 
3.4 
Rational for choice of comparator 
No comparator drug is included in this study. Historical placebo data from qualifying trials will 
be used as the control for primary and key secondary endpoint analysis as discussed in Section 
9.4. This is in line with guidance from and discussions with Health Authorities including FDA 
and EMA (PDCO) which suggested reducing placebo exposure as well as overall clinical trial 
burden for pediatric population and suggest/accept use of extrapolation approach. 
3.5 
Purpose and timing of interim analyses/design adaptations 
There are two planned interim analysis. An interim analysis, including the primary endpoint 
(Week 12) analysis will be conducted when all subjects have completed the Week 16 visit or 
the premature treatment discontinuation visit. Another interim analysis will be performed when 
all subjects have completed the Week 52 visit or the premature treatment discontinuation visit. 
Additional analyses may be performed to support health authority interactions, as necessary. 
Thereafter, efficacy and safety data collected after Week 52 until the end of study may be 
reported yearly in separate reports. 
Trial modifications are not planned based on any interim analysis. 
3.6 
Risks and benefits 
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures and by close clinical monitoring. 
Biologics are being considered a safe and effective option for treating psoriasis in the pediatric 
population as they are convenient to use, requiring less frequent dosing than traditional systemic 
agents such as methotrexate, cyclosporine, and acitretin. In addition, they lack many of the 
potential end-organ toxicities of traditional agents because of their targeted action. 
Results from non-clinical studies and phase II and III clinical studies in adults did not reveal a 
safety concern that would preclude the use of secukinumab in children. In adult studies, 
secukinumab has shown a very good efficacy profile in the treatment of moderate to severe 
chronic plaque psoriasis. The safety data from the completed and ongoing studies, including 
Adverse Event and Serious Adverse Event data, laboratory parameters and immunogenicity 
data, demonstrate a good safety profile. 
Known risks of secukinumab administration includes an increased risk of infections, in 
particular candida infections, neutropenia and hypersensitivity reactions that can be seen with 
administration of any foreign proteins. Most of the infections were non-serious upper 
respiratory tract infections and candidiasis, mild to moderate in severity, clinically manageable 
and did not lead to treatment discontinuation. Cases of neutropenia were uncommon, generally 


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mild to moderate and transient and did not lead to treatment discontinuation, and only a few 
cases were timely associated with non-serious infections. 
Potential risks for subjects on secukinumab may include malignancies, major adverse 
cardiovascular events (MACE), Crohn’s disease, immunogenicity, and interactions with live 
vaccines. 
Since the immune system was shown to reach adult levels of maturation by 6 years of age 
(Comans-Bitter et al 1997), no adverse effects of secukinumab on development of this system 
are expected in this trial’s pediatric population (age 6 to < 18 years). Consequently, no 
additional risks of infections, malignancies, or impact on peripheral competent immune cells 
over those described for adults are anticipated for this pediatric group. 
A potential for increased exposure of secukinumab at lower body weights has been suggested 
by the analysis of population pharmacokinetic data. Consequently, weight category based 
dosing has been instituted to ensure that exposure levels of secukinumab are comparable across 
all weight groups in the study population. 
No adverse effects are anticipated with respect to linear bone growth and development given 
the absence of bone findings in knock-out mice (Kokubu et al 2008) and in toxicology studies 
with secukinumab. Height, to measure linear growth, will be monitored throughout the study. 
Prior to participating in a clinical trial with secukinumab, participants should consider 
completion of all age appropriate immunizations according to immunization guidelines. 
Subjects treated with secukinumab should not receive live vaccines. Non-live vaccinations 
received during secukinumab treatment may not elicit an immune response sufficient to prevent 
disease (refer to Table 5-3). 
 
Population 
The study population will consist of male and female subjects age 6 to less than 18 years of age 
(at the start of study treatment) with moderate to severe plaque psoriasis who are candidates for 
systemic treatment. 
The investigator must ensure that all subjects being considered for the study meet the following 
eligibility criteria. No additional exclusions should be applied by the investigator, in order that 
the study population will be representative of all eligible subjects. 
Approximately 80 subjects (at least 60 with moderate psoriasis) will be randomized in 
approximately 40 centers worldwide. Since a 15% screening failure rate is expected, 
approximately 95 subjects will be screened. 
4.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. Written informed assent and parental permission (age as per local law) obtained at 
screening before any assessment is performed. Of note, if subjects reach age of consent 
(age as per local law) during the study, at that time they will need to also sign the 
corresponding study Informed Consent. 
2. Must be 6 to less than 18 years of age at the time of randomization. 


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3. Moderate to Severe plaque psoriasis, defined as a PASI score ≥ 12, and IGA mod 2011 
score of ≥ 3, and BSA involvement of ≥ 10%, at randomization 
4. History of plaque psoriasis for at least 3 months before randomization 
5. Subject being regarded by the investigator to be a candidate for systemic therapy because 
of: 
• inadequate control of symptoms with topical treatment, and/or 
• failure to respond to or tolerate previous systemic treatment and/or UV 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/subjects. 
1. Forms of psoriasis other than chronic plaque-type (eg, pustular, erythrodermic and guttate 
psoriasis), active at randomization. 
2. Drug-induced psoriasis (ie new onset or current exacerbation from beta-blockers, calcium 
channel blockers or lithium) 
3. Ongoing use of prohibited treatments as mentioned in Table 5-3 (Washout periods as 
detailed in Table 5-3 have to be adhered to). 
4. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or 
the IL-17 receptor, 
5. Use of any other investigational treatment within 30 days for small molecules or within a 
period of 5 half-lives of the investigational treatment from randomization, or until the 
expected pharmacodynamic effect has returned to baseline, whichever is longer. 
6. History of severe hypersensitivity reaction or anaphylaxis to any biological agent (human 
monoclonal antibody or soluble receptor) 
7. Pregnant or nursing (lactating) females, 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 
8. Female subjects of childbearing potential and/or who are at least 12 years of age; defined 
as all women physiologically capable of becoming pregnant, unless they are using 
effective methods of contraception during dosing and for 16 weeks after stopping study 
treatment (or longer if local label requires it (eg in EU 20 weeks), (menarchal or becoming 
menarchal during the study) who do not agree to abstinence or, if sexually active, do not 
agree to the use of contraception. Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 


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• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For United Kingdom: with spermicidal foam/gel/film/cream/ 
vaginal suppository 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral contraception women should have been stable on the same pill for 
a minimum of 3 months before taking investigational drug. 
In case local regulations deviate from the contraception methods listed above, local 
regulations apply and will be described in the Informed Consent Form 
9. Active ongoing inflammatory diseases other than psoriasis that might confound the 
evaluation of the benefit of secukinumab therapy 
10. Underlying condition (including, 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. 
11. Investigator discretion should be used for subjects with preexisting or recent-onset central 
or peripheral nervous system demyelinating disorders 
12. Subjects with an estimated Glomerular Filtration Rate (eGFR), estimated by the Schwartz 
equation, of < 60 mL/min/1.73 m2 at screening. Assessment may be repeated once, two or 
more days later, and if eGFR value ≥ 60, subject may be included at the discretion of the 
investigator. 
13. Subjects with total White Blood Cell count < 2,500/μL, or platelets < 100,000/μL or 
neutrophils < 1,500/μL or hemoglobin < 8.5 g/dL at screening 
14. Active systemic infections during the last two weeks (exception: common cold) prior to 
randomization and any infections that reoccur on a regular basis. Investigator/qualified 
site staff 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 poorly controlled diabetes 
15. History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis 
infection as defined by a positive central laboratory test result at screening. Subjects with a 
positive test result may participate in the study if further work up (according to local 
practice/guidelines) establishes conclusively that the subject has no evidence of active 
tuberculosis. If presence of latent tuberculosis is established, then treatment must have 
been initiated and maintained according to local country guidelines prior to 
randomization. 


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16. Past medical history record of, or known current infection with Human Immunodeficiency 
Virus, hepatitis B or hepatitis C at screening 
17. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years prior to screening, 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. 
18. Plans for administration of live vaccines during the study period or within 6 weeks prior to 
randomization. 
19. 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. 
20. Hypersensitivity or allergy to any of the ingredients of study treatment 
21. History or evidence of ongoing alcohol or drug abuse, within the last 24 weeks before 
randomization. 
22. Subjects not willing to limit UV light exposure (eg, sunbathing and/or the use of tanning 
devices) during the course of the study. 
23. Unwillingness to undergo repeated venipuncture or subcutaneous injections. 
 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
Secukinumab prefilled syringes available as 75mg/0.5ml and 150mg/1ml will be provided by 
Novartis in an open-label fashion. 
Syringes will be labeled as: 
• AIN457 75mg/0.5 mL or 
• AIN457 150mg/1mL 
5.1.2 
Additional treatment 
No additional treatment beyond investigational drug is included in this trial. 
5.2 
Treatment arms 
Subjects will be randomized using a 1:1 ratio at the Randomization visit to two treatment 
arms, secukinumab low dose or secukinumab high dose. Subjects will receive sc dose 
according to the weight category (< 25 kg, 25- < 50kg, ≥ 50 kg). 
Subjects in the two secukinumab arms weighing ≥ 50kg will receive 150 mg (low dose group) 
and 300 mg (high dose group), 25 to < 50 kg will receive 75mg (low dose group) and 150 mg 
(high dose group) and < 25kg will receive 75mg for both dose groups as summarized in the 
Table 5-1 below. Subjects will be receiving one sc injection at each drug administration of either 
secukinumab 75 mg or 150 mg Pre-filled Syringe (PFS) according to their treatment group. 


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Only the subjects in the ≥ 50 kg high dose treatment groups will be receiving two sc injections 
of 150 mg secukinumab at each administration. 
Secukinumab low dose group: 
According to the weight category, sc secukinumab 75 mg (in < 25 kg and 25 to < 50 kg) or 150 
mg (≥ 50 kg) injections will be administered at Randomization, Weeks 1, 2, 3, 4 and thereafter 
every 4 weeks during the entire treatment period of the study until Week 204. After Week 16, 
treatment which occurs outside of the site visits, may be administered at home every 4 weeks, 
either by subject (self-injection is allowed for subjects ≥ 12 years ) or parent/caregiver. If 
subject/parent does not feel confident in performing treatment administration at home they are 
still allowed to receive study treatment administration at site. 
Secukinumab high dose group: 
According to the weight category, sc secukinumab 75 mg (in < 25 kg), 150 mg (in 25 to < 50 
kg) or 2 x 150 mg (≥ 50 kg) injections will be administered at Randomization, Weeks 1, 2, 3, 
4 and thereafter every 4 weeks during the entire treatment period of the study until Week 204. 
After Week 16, treatment which occurs outside of the site visits, may be administered at home 
every 4 weeks, either by subject (self-injection is allowed for subjects ≥ 12 years ) or 
parent/caregiver. If subject/parent does not feel confident in performing treatment 
administration at home they are still allowed to receive study treatment administration at site. 
Table 5-1 
Number of injections per visit per treatment arm 
 
Weight 
Dose (PFS) 
Number of injections at each dosing 
<25 kg 
- low dose 
75 mg 
1 
-high dose 
75mg 
1 
25 to <50 kg - low dose 
75 mg 
1 
-high dose 
150 mg 
1 
≥50 kg 
- low dose 
150 mg 
1 
-high dose 
300mg 
2 
5.3 
Treatment assignment and randomization 
At Randomization (Day 1) all eligible subjects/subjects will be randomized via Interactive 
Response Technology (IRT) to one of the two treatment arms. The investigator or his/her 
delegate will contact the IRT after confirming that the subject fulfills all the inclusion/exclusion 
criteria. The subject number, the weight of the subject, the age and any relevant information 
related to severity, as described in the user manual, will be entered. The IRT will assign a 
randomization number to the subject, which will be used to link the subject to a treatment arm 
and will specify a unique medication number for the first package of study drug to be dispensed 
to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. 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 


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arms, which in turn are linked to medication numbers. A separate medication list will be 
produced by or under the responsibility of Novartis Drug Supply Management using a validated 
system that automates the random assignment of medication numbers to packs containing the 
investigational drug(s). 
Stratification 
Randomization will be stratified by disease severity and body weight collected at 
Randomization Visit. This stratification ensures balanced allocation of subjects to treatment 
groups within the disease severity and weight strata. 
The weight strata will be “body weight < 25 kg”, “25 kg ≤ body weight < 50 kg” or “body 
weight ≥ 50 kg” and disease severity strata (refer to Table 5-2). Stratification by disease severity 
and body weight will occur at Randomization Visit. 
Table 5-2 
Disease severity classification 
 
IGA 
PASI score 
Psoriasis severity 
3 
12-< 20 
Moderate 
3 
≥ 20 
Moderate 
4 
12-< 20 
Moderate 
4 
≥ 20 
Severe 
It will be targeted to have at least about 5 subjects in the < 25kg weight, and at least about 10 
subjects in each of the other two weight groups. 
The randomization scheme for subjects will be reviewed and approved by a member of the 
Integrated Quantitative Sciences Randomization Group. 
5.4 
Treatment blinding 
Medication will be labeled in an open-label fashion. Blinding requirements are not applicable 
for any of the parties involved. 
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 assigned by Novartis. The subject 
number is composed of a site number and a sequential subject number. 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 
available in the electronic data capture (EDC) system. 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 eCRF book with a matching Subject Number in the 
EDC system to enter data. 


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If the subject fails to be treated for any reason, the IRT must be notified within 2 days that the 
subject was not treated. The reason for not being treated will be entered on the appropriate 
Screening period eCRF. 
5.5.2 
Dispensing the study drug 
Each study site will be supplied by Novartis with study treatment. 
At all visits where secukinumab is dispensed, the IRT system will allocate a unique medication 
number which will be transmitted to the pharmacist (or other qualified site personnel) 
responsible for dispensation of study treatments. The pharmacist (or other qualified site 
personnel) will then identify the study treatment package(s) to administer to the subject 
corresponding to the medication number(s). The study drug packaging has a 2-part label. The 
unique medication number is printed on each part of this label. Immediately before preparation 
of the study treatment, the pharmacist (or other qualified site personnel) will detach the outer 
part of the label from the packaging and affix it to the source document for that subject’s unique 
subject number. These documents will be kept in a secured location as appropriate. The study 
treatment will be administered by study nurse/ qualified site personnel individual. 
During the COVID-19 pandemic or similar major health care disruption that limits or prevents 
on-site study visits, delivery of study drug directly to a participant’s home is generally permitted 
in the event the Investigator has decided that an on-site visit by the participant is no longer 
appropriate or possible, and that it is in the interest of the participant’s health to administer the 
study treatment even without performing an on-site visit. The dispatch of study drug from the 
site to the participant’s home remains under the accountability of the Investigator. 
At the site level, the agreement with approval of the Principal Investigator, Independent Ethics 
Committee/ Institutional Review Board (IEC/IRB) and any other Board as appropriate should 
be in place to implement home delivery. 
Home administration of secukinumab 
After Week 16, subjects/custodians will be expected to perform home administrations of 
secukinumab at the time points specified in the protocol, when they are not visiting the site for 
other trial related procedures. Subjects/custodians must be previously trained by site staff 
regarding the administration of secukinumab PFS. 
It must be noted that subjects 12- < 18 years of age can self-inject only under caregiver or health 
care professional supervision. Subjects < 12 years of age are not allowed to self –inject at any 
time. 
If the subject or custodian is not confident to administer medication at home, subjects should 
visit the site every 4 weeks and according to the visit schedule to have the administrations 
performed there by the site staff. Alternatively, if possible, local arrangements can be done for 
a trained nurse to administer medication to the subject at home. This person must be sufficiently 
trained. 
For home administrations the pharmacist/ qualified site personnel will dispense, via IRT, an 
appropriate number of investigational treatment packages and detach outer part of the label 
from the packaging as indicated above. The custodians/subjects will record the date(s) of 


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administration at home and will return the used PFS and packaging at their next visit to the site. 
Site staff are to transcribe this information into the appropriate Dosage Administration Record 
eCRF. 
The used PFS should be disposed immediately after use in a sharps container OR according to 
the requirements of the respective countries and brought back to site. Subjects will be asked to 
return all unused PFS the latest at the completion of the study or at the time of discontinuation 
of the investigational treatment. Detailed instructions will be provided separately. 
5.5.3 
Handling of study and additional treatment 
5.5.3.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees 
have access. Upon receipt, all study treatment must be stored according to the instructions 
specified on the labels. Clinical supplies are to be dispensed only in accordance with the 
protocol. Technical complaints are to be reported to the respective Novartis Country Pharma 
Organization Quality Assurance. 
Medication labels for secukinumab prefilled syringes will be in the local language and comply 
with the legal requirements of each country. They will include storage conditions for the 
investigational treatment but no information about the subject except for the medication number. 
They must be stored in a secured refrigerator at 2°C-8°C (36°F-46°F), and must be carefully 
controlled in accordance with regulations governing investigational medicinal products and 
local regulations. Study treatments should not be frozen and must be protected from light. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all used PFS and packaging at frequent intervals (i.e. at next scheduled study visit) and 
unused PFS and packaging latest at the end of the study or at the time of discontinuation of 
study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused PFS, 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. 
5.5.4 
Instructions for prescribing and taking study treatment 
All study treatments will be administered subcutaneously throughout the study. All doses of 
study treatments at scheduled site visits will be administered at the study site after the study 
assessments for the visit have been completed. Prior to administration to the subject, the study 
treatment will be dispensed by the qualified site personnel appointed at the study site. 
For home administrations the processes described earlier at Section 5.5.2 must be followed. 


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The first study treatment administration will occur at the Randomization Visit (Day 1), after all 
study scheduled assessments have been performed (and inclusion/exclusion criteria confirmed) 
and only after the scheduled blood samples have been drawn. Similarly, at each other visit, all 
study assessments should be completed prior to the administration of study treatment. 
Subjects will be administered study medication weekly for the first 4 weeks of the treatment 
period and then every 4 weeks until Week 204. 
During the Follow-up period, no study medication will be administered. 
Administration of secukinumab 
Secukinumab Solution for Subcutaneous Injection will be provided in Prefilled syringes (75 
mg/0.5 mL and 150 mg/1mL). 
The study treatment solution must be injected into non-affected areas of the skin. 
If possible, throughout the trial, the study treatment should be administered to body regions, 
changing the injection site from visit to visit, for example: right thigh, left thigh, right abdominal 
area, left abdominal area. 
Single prefilled syringes will be packed in individual boxes. The boxes containing the syringes 
with study treatment solution should be kept at 2 to 8°C (36°F to 46°F) and protected from light. 
They should not be frozen or shaken. Prior to administration the boxes containing the syringes 
with study treatment solution should be allowed to come to room temperature unopened for 
about 15-30 minutes before administration. Used syringes should be disposed immediately after 
use in a sharps container or according to the requirements of the respective countries. For home 
administration please refer to Section 5.5.2. 
Note: The removable cap of the secukinumab pre-filled syringe 1 mL and 0.5mL form 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 or 0.5 mL pre-filled syringe in latex-sensitive individuals has 
not been studied. 
All kits of study treatment assigned by the IRT will be recorded/databased in the IRT. 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment 
Investigational or other treatment dose adjustments and/or interruptions are not permitted. 
5.5.6 
Rescue medication 
Rescue medication for psoriasis is not permitted in this study 
5.5.7 
Prior and Concomitant medication 
Relevant treatments (excluding those for psoriasis) taken within 6 months from screening date 
must be entered in the Prior and Concomitant Medications eCRF. Any psoriasis treatments used 


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from the time subject started to treat psoriasis will be reported on the Prior psoriasis therapy 
eCRF and not in the prior and concomitant medications eCRF. 
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study. All medications, procedures and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the subject was enrolled into the study must be recorded in the appropriate CRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. 
5.5.7.1 
Permitted concomitant medications (not for psoriasis) 
Concomitant medications are allowed if not listed in Table 5-3. 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 Concomitant medications eCRF or the Procedures and 
Significant non-drug therapies eCRF. 
Subjects who are receiving treatments known to worsen psoriasis (eg beta-blockers) must be on 
stable dose for at least 4 weeks before Randomization Visit. 
Topical corticosteroids (TCS) and other topical treatments will be allowed from Week 12 visit 
and until the end of study only if: medication was started after the week 12 visit was completed 
AND medication was used for 14 consecutive calendar days or less AND medication was 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 medications TCS eCRF. 
There is no restriction on the use of anti-histamines or of corticosteroid drops used in the eye 
or ear during the study 
5.5.7.2 
Permitted concomitant medication for psoriasis 
After the screening period, 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 5-3). 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. 
A TCS treatment of mild or moderate activity is allowed for the face, scalp, and genitoanal area 
during the screening period, but not after the subject has been randomized. These TCS must not 
be used during the 12 hours preceding the Randomization study visit. Use of these TCS must 
be recorded on the Prior psoriasis therapy eCRF if they were used to treat psoriasis. If not used 
to treat psoriasis they should be entered in the TCS eCRF (Section 5.5.7.1). 


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5.5.8 
Prohibited medication 
Use of any treatments displayed in Table 5-3 that could confound the efficacy are NOT allowed 
during the study for any indication and wash-out periods for these treatments prior to 
randomization are indicated in the table. If the use of these treatments is required, then the 
subject should NOT be randomized into the study 
The investigator should instruct the subject to notify the study site 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 treatment with study treatment must be 
listed on appropriate eCRF. 
If a prohibited treatment listed in Table 5-3 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, if the subject’s use during the study of a prohibited treatment 
listed in Table 5-3 presents undue safety risk for the subject, the subject should be discontinued 
from study treatment as per Section 5.6.2. If the subject received a live vaccination during the 
study, the subject must discontinue study treatment. 
During the screening period, subjects will be allowed to use some active topical treatments for 
any indication in the following body regions: face, scalp, and genitoanal area. The active topical 
treatments are limited to: mild or moderate potency corticosteroid. The subject must stop use 
of these topical corticosteroids (TCS) at least 12 hours preceding the Randomization visit. 
For all other body regions, a washout period of 2 weeks applies for all active topical treatments 
for any indication as indicated in Table 5-3 below 
The Sponsor will be notified if a prohibited treatment is taken while the subject is on study. 
Table 5-3 
Prohibited medication 
 
Prohibited Treatment 
Wash-out period up 
to Randomization 
Treatment 
Period1,2 
Secukinumab 
No prior use allowed 
Used as 
study 
treatment 
Any biologic drug directly targeting IL-17 or the IL-17 receptor 
(other than secukinumab [eg brodalumab, ixekizumab]) 
No prior use allowed 
Not 
allowed 
Any biologic directly targeting IL-12/23 or IL-23, eg 
briakinumab, stekinumab, guselkumab, tildrakizumab 
26 weeks 
Not 
allowed 
Alefacept, efalizumab 
26 weeks 
Not 
allowed 
Etanercept 
4 weeks 
Not 
allowed 
Biological immunomodulating agents other than above (eg, 
adalimumab, infliximab) 
12 weeks 
Not 
allowed 
Other systemic immunomodulating treatments 
(eg, methotrexate (MTX), cyclosporine A [CSA], 
corticosteroid, cyclophosphamide) 
4 weeks 
Not 
allowed 
Photochemotherapy (eg, PUVA) 
4 weeks 
Not 
allowed 


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Prohibited Treatment 
Wash-out period up 
to Randomization 
Treatment 
Period1,2 
Other systemic therapy for psoriasis (eg, retinoids, fumarates, 
apremilast) 
4 weeks 
Not 
allowed 
Any other investigational treatment or participation in any 
interventional trial 
4 weeks or 5 half- 
lives (whichever is 
longer) 
Not 
allowed 
Phototherapy (eg, UVA, UVB) 
2 weeks 
Not 
allowed 
Topical treatment3 for psoriasis or any other skin condition 
(eg, corticosteroids, vitamin D analogues, pimecrolimus, 
retinoids, salicylvaseline, salicylic acid, lactic acid, tacrolimus, 
tar, urea, α-hydroxy or fruit acids), except on the face, scalp, 
hands and feet and genitoanal area during screening 
2 weeks4 
Not 
allowed 5 
Live vaccinations 
6 weeks 
Not 
allowed 6 
1 If a prohibited treatment of psoriasis is used during the study, 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. 
3 Including intra-articular or peri-articular injections. Note that inhaled corticosteroids as well as corticosteroid drops in the eye or 
ear or nasal sprays are permitted. 
4 Mild to moderate topical corticosteroids are allowed only during the screening period if used only on the face, scalp, hands and 
feet and/or genitoanal area and if not used during at least 12hrs preceding the randomization visit 
5 Topical corticosteroids and other topical treatments will be allowed after Week 12 Visit only if (all must apply): 
•medication was started after the Week 12 visit was completed; 
•medication was used for 14 consecutive calendar days or less; 
•medication was used for an indication other than psoriasis and not on the area affected with psoriasis. 
6 If the subject received a live vaccination during the study, the subject must discontinue study 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 
Not Applicable as treatment is open label. 
5.6 
Study completion and discontinuation 
5.6.1 
Study completion and post-study treatment 
A subject will be considered to have completed the study when the subject has completed the 
Week 224 visit as per the protocol. For subjects who discontinue prior to this, the study 
completion corresponds to the last study visit of the subject or contact of the site with 
custodian/subject. Study completion for the study will occur when all randomized subjects have 
completed the study as stated above. 
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. 


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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/custodian or the 
investigator. 
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/custodian’s wish 
• Withdrawal of consent 
• Pregnancy (see Section 6.5.8 and Section 7.6) 
• Ongoing use of prohibited treatment as per recommendations in Table 5-3 
• 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, for example sepsis, or newly occuring or worsening 
Inflammatory Bowel Disease, including Crohn’s disease and ulcerative colitis. 
• Any laboratory abnormalities that in the judgment of the investigator/qualified site staff, 
and taking into consideration the subject’s overall status, prevents the subject from 
continuing study treatment. 
• Live vaccination 
• Any situation where study participation results in a significant risk to subject’s safety 
If discontinuation of study treatment occurs, the subject should NOT be considered withdrawn 
from the study. If the subject discontinued study treatment within the treatment period, the 
subject should return to the clinic after discontinuation of study drug, for Week 208 and 
Follow-up visits (Week 212, Week 216 and Week 224). 
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 at Week 208 visit in Table 6- 
2 should be completed and recorded in the eCRF. 
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 Week 208 visit. 
The investigator must determine the primary reason for the subject’s premature 
discontinuation of study treatment and record this along with the date treatment was stopped 
on the eCRF page. The investigator must also contact the IRT to register the subject’s 
discontinuation from study treatment. As mentioned above if subjects discontinues treatment 
early, subject is expected to perform the visits of the treatment –free follow up period. 
If the subject cannot or is unwilling to attend any further visit(s), the site staff should maintain 
regular telephone contact with the custodian/subject to obtain at least information on adverse 
events or concomitant medication. This telephone contact should preferably be done according 
to the study visit schedule. 


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Discontinuation from the treatment-free follow-up period 
Subsequently to the Week 208 visit the subject will be expected to return to the site and 
perform all visits of the treatment-free follow-up period as indicated in Table 6-2. 
If premature withdrawal occurs for any reason in the treatment-free period (follow-up period, 
Week 208-Week 224), the subject is expected to return to the site and perform all assessment 
of visit EOF /Week 224 (see Table 6-2). The investigator must make every effort to determine 
the primary reason for a subject’s premature withdrawal from the study and record this 
information on the relevant eCRF). 
Of note, if subjects start another systemic anti psoriatic treatment during follow up, they do not 
need to continue with the remaining follow-up visits but they will be expected to return to site 
after the start of the systemic treatment and perform Week 224 visit. 
5.6.3 
Withdrawal of informed consent 
Custodians/subjects may voluntarily withdraw consent for participation 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 (eg 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 the 
assessment table below. 
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 must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg dates of telephone 
calls, registered letters, etc. 


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5.6.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit risk assessment of participating in the study, practical reasons, or for 
regulatory or medical reasons (including slow enrolment). Should this be necessary, the subject 
must be seen as soon as possible and treated as a prematurely discontinued subject. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the subject’s interests. The investigator will 
be responsible for informing the Institutional Review Board/Independent Ethics Committee 
(IRBs/IECs) of the early termination of the trial. 
 
Visit schedule and assessments 
Subjects should be seen for all visits on the designated day or as closely as possible to the 
original planned visit schedule. 
During the COVID-19 pandemic or similar major health care disruption that limits or prevents 
on-site study visits, alternative methods of providing continuing care may be implemented 
Phone calls, virtual contacts (e.g. teleconsult) or visits by site staff or home nursing service to 
the participant´s home depending on local regulations and capabilities, can partially replace on- 
site study visits, for the duration of the pandemic/ health care disruption until it is safe for the 
participant to visit the site again. These contacts should occur on or around the scheduled visit 
dates (or more frequently if needed). Events qualifying for being reported in CRF should be 
entered as appropriate. Every effort should be made to complete all study visit assessments 
feasible per protocol. Special effort should be made to conduct the scheduled EOT and EOF 
visit on site. If it is not feasible to conduct the EOT and EOF visit on-site, at least phone contact 
or if possible visits to the patient´s home by site staff as mentioned previously should be 
attempted. 
Screening will be flexible in duration and will last up to a maximum of 4 weeks. During this 
time, the custodian(s) and subject will sign first the informed consent and assent form 
respectively, subject will then be evaluated for eligibility and will have all screening visit 
assessments done as indicated in Table 6-1. 
Table 6-1 and Table 6-2 list all study assessments and indicate with an “x” at which visits the 
assessments are performed. 
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 custodian/subject must sign a new ICF/assent form 
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 eCRF 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 eCRF to correspond to 
the new screening subject number. Informed Consent for a rescreened subject must be obtained 


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prior to performing any study related assessment or collecting any data for the Screening Visit. 
For rescreening, all screening assessments must be performed as 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 
tuberculosis test performed by the central laboratory. 
At the discretion of the investigator, laboratory assessments at randomization visit need not be 
performed if screening laboratory assessments were performed within 7 days from 
randomization. 
During the treatment period, subjects may be seen at an unscheduled visit, eg if they experience 
deterioration of psoriasis, or AEs that in the opinion of the investigator need intervention or 
repeated laboratory testing. During these unscheduled visits, study treatment will NOT be 
administered. The assessment(s) performed at an unscheduled visit are at the investigator’s 
discretion. 
Suggested order of assessments: 
Suggested guidelines for conduct of the visit assessments (as applicable) are below: 
• Subject to complete CDLQI at the study site prior to any study assessments. 
• Investigator to complete investigator assessments: 
• IGA mod 2011 
• PASI 
• Review of CDLQI data 
• Physical exam 
• All remaining study visit procedures (eg, AE and concomitant medication collection, 
laboratory sample collection, vital signs measurements, etc) must be completed and results 
reviewed by the investigator or qualified designee prior to study treatment dosing. 
• Enter PASI data into the source data worksheets and perform calculations as needed 
BEFORE contacting IRT at randomization Visit. 
• Contact IRT to register the subject visit, as applicable 
• Administration of study treatment, as applicable 


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Table 6-1 
Assessment schedule (Year 1) 
 
Period 
Scr 
Treatment Year 1 
Week 
-4-Ra 
Day 1 (R) 
1 
2 
3 
4 
8 
12 
13 
14 
15 
16 
24 
32 
40 
48 
52 
Day 
-28-Ra 
1 (R) 
8 
15 
22 
29 
57 
85 
92 
99 
106 
113 
169 
225 
281 
337 
365 
Obtain informed consent1 
x 
Subject demographics 
x 
Inclusion/ exclusion2 
S 
S 
Psoriasis history/prior therapies 
x 
Medical history and prior medications 
x 
Concomitant medications3 
update as necessary 
Surgeries and non-drug procedures 
update as necessary 
Physical Exam 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
Height4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (BP & pulse) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Labs: Hematology6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood chemistry6, Urinalysis(local) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tuberculosis test7 
x 
Serum pregnancy test(in females of 
childbearing potential) 6 
x 
Urine Pregnancy test8(local; in females of 
childbearing potential) 
x 
x 
x 
x 
ECG (standard 12-lead) 
x 
x 
x 
x 
Blood sample for immunogenicity(pre-dose)9 
x 
x 
x 
x 
Blood sample for PK (pre-dose)9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PASI 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IGA mod 2011 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Period 
Scr 
Treatment Year 1 
Week 
-4-Ra 
Day 1 (R) 
1 
2 
3 
4 
8 
12 
13 
14 
15 
16 
24 
32 
40 
48 
52 
Day 
-28-Ra 
1 (R) 
8 
15 
22 
29 
57 
85 
92 
99 
106 
113 
169 
225 
281 
337 
365 
CDLQI10 
x 
x 
x 
x 
x 
x 
(Serious) Adverse event assessment 
update as necessary 
Randomization via IRT 
x11 
Data entry of weight into IRT12 
x 
x 
x 
x 
x 
x 
x 
x 
Administration of study drug13 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Contact IRT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Scr= screening, R=randomization, PK=pharmacokinetics, ECG=Electrocardiogram, CDLQI= children’s dermatology life quality index, IRT=Interactive 
response technology, 
X=assessment entered or transferred into the clinical database. S= assessment only recorded in source 
a Before randomizing the subject, the site must ensure that all assessments of the screening visit have been performed, all lab results are available and 
subject is eligible. Special attention must be given to tuberculosis testing as results take longer to be available. 
1 Apart from the Informed consent for this study signed by parent(s) /legal representatives, assent form will be completed as appropriate by the pediatric 
subjects. 
2 These assessments are supported by and are stored with the source documentation. However, data regarding to which inclusion/exclusion criteria are 
met are captured on the appropriate eCRF 
3 Information on Topical Corticosteroid medication, that a subject may use, is entered in the concomitant medications-topical corticosteroids eCRF 
4 Measured standing and barefoot, using the same stadiometer. 
 
 
6 Samples will be shipped to and analyzed by the central lab. At the discretion of the investigator, laboratory assessments need not to be performed 
again at Day 1-Randomization (R) visit if screening labs were performed within 7 days from randomization. 
7 If the first tuberculosis central lab test is indeterminate, the investigator may choose to perform a second test (as part of an unscheduled visit) or refer 
the subject for tuberculosis workup per local guidelines. If the result of any tuberculosis central lab test is “positive” or the results of two sequential tests 
are “indeterminate”, the subject must be referred to have a tuberculosis workup per local guidelines (if no workup within 12 weeks prior to randomization 
is available). The subject will not be eligible for randomization if active tuberculosis is present or if latent tuberculosis is present and is untreated as per 
local guidelines. 
8 Urine pregnancy test will be performed locally. If there is a positive urine pregnancy test, study treatment must be withheld and a serum pregnancy test 
done at the same visit. Pregnancy tests will be performed in female subjects of child bearing potential, i.e. those who have started menstruation and/or 
are of age 12 or older. 


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9 Samples shipped by the sites will be stored at the central laboratory and then shipped to reference laboratories for analysis. Each PK and IG blood 
sample should be collected pre-dose between Day 1 (Randomization) and Wk 52. 
10 CDLQI will no longer be completed once subjects reach 18 years of age 
11 At Day 1- Randomization the PASI Score and BSA must be calculated by appropriate site staff prior to contacting IRT. The investigator must ensure 
subject meets all eligibility criteria before contacting IRT to randomize the subject. 
12 For every visit (including unscheduled), weight measured at that visit will be entered into IRT. 
13 Secukinumab will be dispensed at site visits. After Week 16 and until Week 52 monthly treatment which occurs outside the site visits, may be 
administered at home every 4 weeks, either by subject (self-injection is allowed for subjects ≥ 12 years ) or parent/caregiver. In case subject or parent 
does not feel confident in performing home administrations subjects will be allowed to continue to perform drug administrations at site. These home 
administrations in the first year occur at Wk 20, Wk 28, Wk 36, Wk 44. During the COVID-19 pandemic, or any other pandemic, study medication may be shipped 
to the patient’s home and administration should be completed at the scheduled timepoints. 


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Table 6-2 
Assessment schedule - Years 2-4 (continued) 
 
Period 
Treatment Period (years 2-4) 
Follow-up Periodb 
Unscheduled d 
Week 
64 
76 
88 
104 
116 
128 
140 
156 
168 
180 
192 
208 
EOT 
212 
216 
224 
EOF 
Day 
449 
533 
617 
729 
813 
897 
981 
1093 
1177 
1261 
1345 
1457 
1681 
1709 
1765 
Concomitant medications1 
Update as necessary 
x 
Surgeries and non-drug procedures 
Update as necessary 
x 
Physical Exam 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
s 
S 
S 
Height2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs (BP & pulse) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood Chemistry4, Urinalysis (local) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Urine Pregnancy test (local; in females of childbearing 
potential)5 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
ECG (standard 12-lead) 
x 
x 
x 
x 
x 
x 
x 
Blood sample for IG6 
x 
x 
x 
x 
x7 
Blood sample for PK6 
x 
x 
x 
x 
x7 
PASI 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
IGA mod 2011 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CDLQI8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


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Period 
Treatment Period (years 2-4) 
Follow-up Periodb 
Unscheduled d 
Week 
64 
76 
88 
104 
116 
128 
140 
156 
168 
180 
192 
208 
EOT 
212 
216 
224 
EOF 
Day 
449 
533 
617 
729 
813 
897 
981 
1093 
1177 
1261 
1345 
1457 
1681 
1709 
1765 
(Serious) Adverse event assessment 
Update as necessary 
x 
Data entry of weight into IRT9 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Contact IRT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Administration of Study Drug10 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
End of Treatment 
x 
Study completion 
x 
R=randomization, PK=pharmacokinetics, ECG=Electrocardiogram, CDLQI= children’s dermatology life quality index, IRT=Interactive response technology, 
X=assessment entered or transferred into the clinical database. S= assessment only recorded in source 
a During EOT visit, subjects will have their last assessments performed for treatment period. This visit will also be performed for all subjects who will discontinue early the 
treatment period. 
b Follow-up assessments are to be conducted for subjects who complete treatment period and for subjects who discontinue study treatment early 
c EOF assessments are to be conducted for subjects who complete treatment free follow up period and for subjects who discontinue this period early 
d The assessments performed at an unscheduled visit are at the investigator’s discretion 
1Information on Topical Corticosteroid medication, that a subject may use, is entered in the concomitant medications- topical corticosteroids eCRF 
2 Measured standing and barefoot, using the same calibrated stadiometer, 
 
4 Samples will be shipped to and analyzed by the central lab. 
5If there is a positive urine pregnancy test, study treatment must be withheld and a serum pregnancy test must be done at the same visit and sent to central lab. 
Pregnancy tests will be performed in female subjects of child bearing potential, that is those who have started menstruation and/or are of age 12 or older. 
6 Samples shipped by the sites will be stored at the central laboratory and then shipped to reference laboratories for analysis. Each PK and IG sample should be collected 
pre-dose for Week 52 to Week 208. 
7 An unscheduled IG and/or PK sample is collected only to replace an IG or PK sample not taken at a regular scheduled visit. In case unscheduled IG sample is taken, 
there should always be a matching unscheduled PK sample taken at the same time point. 
8 CDLQI will no longer be completed once subjects reach 18 years of age 


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9 For every visit, the weight measured at that visit will be entered into IRT 
10 Secukinumab will be dispensed at site visits. Between site visits, study medication will be administered every 4-weeks at home either by the subject (self-injection is 
allowed for subjects ≥ 12 years) or parent/caregiver until Week 204. In case subject or parent/caregiver does not feel confident in performing home administrations 
subjects will be allowed to continue to perform drug administrations at site. Home administrations in the years 2-4 occur at Wk 56, Wk 60, Wk 68, Wk 72, Wk 80, Wk 84, 
Wk 92, Wk 96, Wk 100, Wk 108, Wk 112, Wk 120, Wk 124, Wk 132, Wk 136, Wk 144, Wk 148, Wk 152, Wk 160, Wk 164, Wk 172, Wk 176, Wk 184, Wk 188, Wk 196, 
Wk 200, Wk 204. During the COVID-19 pandemic, or any other pandemic, study medication may be shipped to the patient’s home and administration should be 
completed at the scheduled timepoints. 


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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 Day 1 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 in the respective 
Disposition eCRF. The Screening visit date, the Demography eCRF, the Informed Consent 
eCRF, the Inclusion/Exclusion eCRF, and the subject rescreening eCRF must be completed. 
The AE eCRF should be completed for any SAEs that occurred during the screening period. 
Adverse events that are not SAEs will be followed by the investigator and collected only in the 
source data. The Death eCRF should be completed in the case of a death during the screening 
period. The withdrawal of consent eCRF must be completed if consent was withdrawn during 
the screening period before the subject was randomized. 
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 period (eg demographics) or at the Randomization Visit eg 
patient reported outcomes (PROs), depending on the assessment. 
6.2.1 
Demographics 
Data to be collected on all subjects include: age, sex, race, and ethnicity). 
6.2.2 
Psoriasis medical history / Previous psoriasis therapy 
Disease history will be collected at the screening visit. The information to be collected and 
entered in the Psoriasis History eCRF and Prior Psoriasis Therapies eCRF includes the 
following: 
• The date of first diagnosis of plaque psoriasis (by a physician) 
• The previous treatments of psoriasis (including previous use systemic therapies, biologic 
therapies, as well as phototherapy and/or photo chemotherapy or topical use) and the 
reason for discontinuation of each therapy 
• The presence of psoriatic arthritis and the date of first diagnosis (by a physician) 
6.2.3 
Relevant medical history / current medical conditions 
Relevant medical history and current medical conditions, not including psoriasis or psoriatic 
arthritis, prior to signing of the informed consent will be recorded in the Medical History 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. 
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. 


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6.2.4 
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 central lab testing. Any significant findings will 
be recorded in the relevant TB assessment eCRF and the Medical History eCRF, as necessary. 
A central lab testing 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. 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. Further 
information is available in Manuel and Kumar (2008). 
The tuberculosis 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. 
Refer to Figure 6-1 for guidance on subject eligibility with respect to TB testing. The results of 
a workup for a subject with a positive or indeterminate test must be recorded on the Tuberculosis 
assessment eCRF. 
• If the test result is negative, the subject may be randomized. 
• If the test result is positive, the investigator should perform workup for the test result as 
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. 
• 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. 
• 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. 
• If the test result is indeterminate, the investigator may repeat the test once or may 
proceed directly to perform workup for the test result as per local procedures. This 
action is at the discretion of the investigator. 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 
as 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 


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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 12 within weeks prior to 
randomization. 
If eligibility is being assessed with only 1 test result and a TB workup (i.e., no second TB test 
will be performed), the TB test to assess eligibility must have been done via the central 
laboratory for the study within the screening period (within 4 weeks prior to randomization) 
and TB workup will only be considered if it was completed within 12 weeks prior to 
randomization. 


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Figure 6-1 
Tuberculosis screening flowchart 
 


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6.2.5 
Other baseline characteristics 
Baseline characteristic data to be collected on all subjects include (all labs are central except 
where indicated): 
ECG, vital signs; hematology; clinical chemistry; local urinalysis; immunogenicity; PK; PASI; 
IGA mod 2011; CDLQI. A serum pregnancy test will be performed for females of child bearing 
potential or of at least 12 years of age at screening. 
6.3 
Treatment exposure and compliance 
All doses of study treatment administered will be recorded on the appropriate Dosage 
Administration Record eCRF page. Information on drug dispensing, administration, 
accountability will be collected in drug accountability logs and other documents as appropriate. 
For drug administrations at home subject will record relevant information at home which will 
then be transcribed at the corresponding documents at site including Dosage Administration 
Record eCRF page, 
Subject compliance to the study treatment should be assessed by qualified site personnel at each 
study visit using the study kits and documentation regarding study treatment dispensation and 
administration. 
Site compliance will also be assessed continuously during the conduct of the study by Novartis 
study personnel using medication kits and the corresponding documentation. 
6.4 
Efficacy 
All efficacy assessments should be performed prior to administration of study treatment. There 
are two co-primary efficacy variables in this study: PASI 75 response and IGA mod 2011 0 or 
1 response. 
The following order should be applied when performing the efficacy assessments during study 
visits: 
• Investigator’s Global Assessment (IGA mod 2011; scale from 0 – 4) 
• Psoriasis Area and Severity Index (PASI; score from 0 – 72) 
 
 
6.4.1 
Investigator Global assessment (IGA mod 2011) 
The IGA mod 2011 will be conducted for overall psoriatic disease as indicated in Table 6-1 and 
Table 6-2. It is recommended that the same evaluator conducts the efficacy assessment 
throughout the study whenever possible. 
The IGA mod 2011 rating scale for overall psoriatic disease is shown in Table 6-3 below. 
The IGA mod 2011 scale has been developed based on a previous version of the scale used in 
secukinumab phase II studies 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. 


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The IGA mod 2011 used in this study is static, ie, 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 6-3 
IGA mod 2011 scale 
 
 
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 
Based on this scale, a subject will be eligible to participate in the study if the subject has an IGA 
mod 2011 score at baseline of 3 or 4. 
Based on this scale, a subject will be considered an IGA mod 2011 0 or 1 responder if the 
subject achieves a score of 0 or 1 and improved by at least 2 points on the IGA mod 2011 scale 
compared to baseline. 
6.4.2 
Assessment of total body surface area (BSA) and psoriasis area safety 
index (PASI) 
The investigator or trained qualified designee will complete the PASI assessment as indicated 
in Table 6-1, Table 6-2. Whenever possible, the same evaluator should perform this efficacy 
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. 
A PASI score (Fredriksson and Petterson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 6-4. 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: 
• The neck is assessed as part of the head. 
• The axillae and groin are assessed as part of the trunk. 
• The buttocks are assessed as part of the lower limbs. 


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• When scoring the severity of erythema, scales should not be removed. 
Table 6-4 
PASI scoring system 
 
Body region 
Erythema (E) 
Thickening (I) 
(plaque 
elevation, 
induration) 
Scaling (D) 
(desquamation) 
Area score (A) 
(based on true area %)* 
Head (H)† 
0=none 
0=none 
0=none 
0 = no involvement 
1= slight 
1= slight 
1= slight 
1 = >0-<10% 
2= moderate 
2= moderate 
2= moderate 
2 = 10-<30% 
3= severe 
3= severe 
3= severe 
3 = 30-<50% 
4=very severe 
4=very severe 
4=very severe 
4 = 50- <70% 
5 = 70-<90% 
6= 90 -100% 
Trunk (T)‡ 
0=none 
0=none 
0=none 
0 = no involvement 
1= slight 
1= slight 
1= slight 
1 = >0-<10% 
2= moderate 
2= moderate 
2= moderate 
2 = 10-<30% 
3= severe 
3= severe 
3= severe 
3 = 30-<50% 
4=very severe 
4=very severe 
4=very severe 
4 = 50- <70% 
5 = 70-<90% 
6= 90-100% 
Upper limbs (U) 
0=none 
0=none 
0=none 
0 = no involvement 
1=slight 
1=slight 
1=slight 
1 = >0-<10% 
2=moderate 
2=moderate 
2=moderate 
2 = 10-<30% 
3=severe 
3=severe 
3=severe 
3 = 30-<50% 
4=very severe 
4=very severe 
4=very severe 
4 = 50- <70% 
5 = 70-<90% 
6 = 90-100% 
Lower limb (L)§ 
0=none 
0=none 
0=none 
0 = no involvement 
1=slight 
1=slight 
1=slight 
1 = >0-<10% 
2=moderate 
2=moderate 
2=moderate 
2 = 10-<30% 
3=severe 
3=severe 
3=severe 
3 = 30-<50% 
4=very severe 
4=very severe 
4=very severe 
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. 
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 


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The keys for the letters are provided in Table 6-4. 
PASI scores can range from a lowest value of 0, corresponding to no signs of psoriasis, up to a 
theoretic maximum of 72. 
The investigator or qualified designee is responsible for evaluating the subject and collecting 
the PASI components, scoring signs and total regional area. The PASI data will be entered into 
the PASI eCRF. 
Based on PASI, to be eligible, a subject must have a score of 12 or more at the Randomization 
Visit. 
Based on total BSA, to be eligible, a subject must have 10% or more total BSA involved at the 
Randomization Visit. 
Only if the above eligibility criteria and all other eligibility criteria are fulfilled should site 
contact IRT at the Randomization Visit to randomize the subject. 
Definitions of efficacy variables based on PASI 
The following definitions are used in this study (see CHMP guidelines for psoriasis 
(CHMP/EWP/2454/02 2004)): 
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) 
 
 
6.4.4 
Appropriateness of efficacy assessments 
The PASI score, 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 considered acceptable by health 
authorities (CHMP guideline on the treatment of psoriasis-CHMP/EWP/2454/02 2004) to 
assess efficacy in conjunction with Investigator’s Global Assessment (IGA). 


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6.5 
Safety 
All blood draws and safety assessments should be done prior to study treatment administration. 
Appropriate safety assessments (eg, evaluation of AEs and SAEs including injection site 
reactions) should be repeated after the dose is administered. 
During the COVID-19 pandemic or similar major health care disruption that limits or prevents 
on-site study visits, phone calls, virtual contacts (e.g. teleconsult), or visits by site staff or home 
nursing service depending on local regulations and capabilities may occur on or around 
scheduled protocol visit dates (or more frequently if needed). This will be done for safety 
monitoring and discussion of the subject´s health status until the subject can again visit the 
site. Case report forms (e.g. AEs, concomitant medications, procedures and non-drug therapies) 
should be updated as appropriate. 
6.5.1 
Physical examination 
A physical examination, including general appearance, skin, neck, eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, and extremities, and vascular and neurological systems 
will be performed as indicated in Table 6-1, Table 6-2. Investigator should pay special attention 
to any signs or symptoms of potential skin or mucosal candida infections. 
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 screening visit must be included in 
the Medical History screen on the subject’s eCRF. Significant findings made after the start of 
study (Day 1) that meet the definition of an adverse event must be recorded on the Adverse 
Event screen of the subject’s eCRF. 


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6.5.3 
Vital signs 
Vital signs (including blood pressure and pulse measurements) will be assessed at every 
scheduled visit as indicated in Table 6-1, Table 6-2. If possible, assessments should be 
performed by the same study site staff member throughout the study. 
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 a cuff that is appropriately sized for 
the subject’s arm circumference. The average of the two measurements will be entered on the 
Vital Signs eCRF. 
The Recommendations for the dimensions of Blood Pressure Cuff Bladders are noted in the 
following table. 
Table 6-5 
Recommended Dimensions for Blood Pressure Cuff Bladders 
 
Width [cm] 
Length [cm] 
Maximum Arm 
Circumference [cm]* 
Newborn 
4 
8 
10 
Infant 
6 
12 
15 
Child 
9 
18 
22 
Small adult 
10 
24 
26 
Adult 
13 
30 
34 
Large adult 
16 
38 
44 
*calculated so that the bladder can encircle even the largest arm by at least 80% 
Source: Feld and Corey H (2007): Hypertension in childhood, Pediatric in Review 28: 283-98 
Whether action needs to be taken to address notable vital signs will be decided by the 
investigator/qualified site staff, taking into account the overall status of the subject. No specific 
action is foreseen as part of the study protocol. 
6.5.4 
Height and weight 
Height and body weight will be measured at visits as in Table 6-1, Table 6-2. Height 
measurements (in indoor clothing, but without shoes, socks, hats or hair accessories interfering 
with assessment) will be made using a stadiometer that is calibrated on a regular basis. Height 
measurements will be performed twice and the reported height will be the mean of the 2 
measurements. 
If possible, body weight assessments (in indoor clothing, but without shoes) should be 
performed by the same study site staff member and using the same scale throughout the study. 
The body weight recorded at Randomization (Day 1) will be used to categorize the subject 
population at randomization to receive the corresponding doses in the high dose and low dose 
secukinumab groups. 
6.5.5 
Laboratory evaluations 
Subjects should avoid smoking within the hour preceding the blood draws. 


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A central laboratory will be used for analysis of all specimens listed below, 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. The blood volume drawn will 
be adjusted for pediatric subjects and will be stated in the laboratory manual. 
During the COVID-19 pandemic or a major healthcare disruption that limits or prevents on-site 
study visits and central lab sampling, performing the safety lab tests locally will be allowed in 
case it is needed to check safety parameters. Depending on local regulations, technical 
capabilities and following any applicable training in the required process, qualified staff may 
visit the subject at home to draw blood/ urine samples if needed to check safety parameters. 
Clinically notable values for key laboratory tests are defined in Section 13, Appendix 1. For 
identification of pediatric abnormal values for all parameters, the laboratory manual must also 
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. 
6.5.5.1 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(neutrophils including bands, lymphocytes, monocytes, eosinophils, basophils) and platelet 
count will be measured at scheduled study visits, as specified in Table 6-1, Table 6-2. 
6.5.5.2 
Clinical chemistry 
Serum chemistry will include urea or BUN, creatinine, total bilirubin, AST (SGOT), ALT 
(SGPT), GGT, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorous, 
total protein, albumin, and uric acid. 
Serum chemistry will be measured at scheduled study visits as specified in Table 6-1, Table 6- 
2. 
6.5.5.3 
Estimated GFR 
In addition estimated Glomerular Filtration Rate (eGFR) as per Schwartz et al (Schwartz et al 
2009) will be calculated and reported by the Central Laboratory, whenever a serum creatinine 
is performed. 
The calculation is based on the following formula: 
eGFR (ml/min/1.73m2) = 0.413 x height (cm) / serum creatinine (mg/dl) 
Height will be provided by the site to the central lab. 
For eGFR, baseline value for the decrease from baseline criterion will be calculated as the 
average of values prior to the first dose (i.e. screening and baseline values). 


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6.5.5.4 
Urinalysis 
Urine Dipstick (local) 
A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. 
A semi-quantitative ‘dipstick’ evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, leukocytes and blood, micro albumin. 
Urinalysis will be measured locally at scheduled study visits as specified in Table 6-1, Table 6- 
2. 
6.5.6 
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed as indicated in Table 6-1, Table 6-2. When the ECG 
is performed at scheduled visits, the investigator will review and initial tracing, and store with 
the subject’s source documentation. All ECGs must be performed on the ECG machines 
provided to the study site. 
All ECGs will be independently reviewed by a central reader. Instructions for the collection and 
transmission of the ECGs to the independent reviewer will be provided in the ECG investigator 
manual. 
Even though there is no exclusion criterion specifically based on the ECG, the ECG performed 
at Screening must be reviewed for major abnormalities before dosing at the randomization visit. 
If the ECG findings are clinically relevant and would prevent the subject from participating in 
the study (taking into account the subject's overall status including medical history and 
concomitant medications), the subject should not receive treatment and should exit the study. 
If a clinically relevant abnormality is noted on the screening ECG it should be reported in the 
Medical History eCRF. Clinically relevant abnormalities noted after the screening ECG should 
be recorded as AEs. 
6.5.7 
Immunogenicity 
Blood samples for immunogenicity (anti-secukinumab antibodies) will be taken pre-dose by 
direct venipuncture at the scheduled time points as indicated in Table 6-1, Table 6-2 and 
Appendix 2, Table 14-2. Blood samples (approximately 2 mL) will be collected into serum 
separator tube (SST) tubes. The blood sample will be allowed to clot over a minimum of 30 
minutes at room temperature prior to harvesting of the serum. The serum will be obtained by 
centrifugation at approximately 2500 revolutions per minute (rpm) for 10 minutes, or within 
sufficient time and speed to allow formation of a clear supernatant layer. 
Serum samples will be split into 2 aliquots (labeled plain barrier polypropylene tubes) and then 
stored (within 30 minutes of serum collection by centrifugation) at approximately -70˚C to - 
20˚C prior to shipment on dry ice to the central laboratory. Shipment of stored aliquots from 
the site to the central lab should be on a pre-specified basis. To the extent possible, the site 
should send each aliquot of the sample to the central laboratory separately. The central lab will 
ship aliquots of the samples on dry ice to the analytical laboratory as per agreement with 
Novartis. Immunogenicity samples will only be disposed of after approval by the Sponsor. 


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The actual sample collection date and time will be entered on the relevant Blood collection for 
IG eCRF. In case unscheduled IG samples are taken, matching PK samples must be taken as 
well. 
A laboratory manual will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment. 
Tubes and labels will be provided by the central laboratory with study/sample type and sample 
number preprinted on the label. 
Further details on labeling of the immunogenicity samples can be found in Appendix 2, Table 
14-2 . 
Sample stability 
Due to the nature of the immunogenicity response, no real stability data can be given for 
immunogenicity samples. 
The serum samples will be transferred on dry ice (enough dry ice to avoid thawing) from the 
central laboratory to the analytical laboratory at Novartis or a designated Clinical Research 
Organization (CRO). 
Immunogenicity analytical method 
An electrochemiluminescence based method will be used for the detection of potential anti- 
AIN457 antibody formation. The detailed method description to assess immunogenicity will be 
described in the bioanalytical raw data of the study and in the respective Bioanalytical Data 
Report (BDR). 
6.5.8 
Pregnancy and assessments of fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric subjects who are menarchal or who become 
menarchal during the study. In this study pregnancy tests will be performed in female subjects 
who are menarchal or become menarchal during the study and/or are 12 years of age or older at 
the beginning or at any point during the study. Sites must ensure that pregnancy testing 
commences once any of these conditions are fulfilled. 
Serum pregnancy test will be performed for all females of child-bearing potential according to 
the schedule in Table 6-1, Table 6-2. 
During the COVID-19 pandemic or similar major health care disruption that limits or prevents 
female subjects of childbearing potential or at least of 12 years of age for on-site study visits, 
urine pregnancy test kits may be shipped or provided directly to the subject. After appropriate 
instruction, patients can perform the urine pregnancy test at home at the time points specified 
in the protocol and report the result to the site. It is important that patients perform the pregnancy 
test first and only if the test result is negative, they then should proceed with the administration 
of the study drug. 
A communication process should be established with the subject so that the site is informed of 
the pregnancy test results. 


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All menarchal girls and their parents/custodians should be informed about the potential risks of 
pregnancy and the need to prevent pregnancy during the study. It is important to be sensitive in 
introducing this issue, as understanding and comprehension of puberty, sexual activity, 
pregnancy and contraception is influenced by age, as well as factors such as precocity, socio- 
educational economic and familial background. These discussions with the subject and her 
parents/custodians are therefore best performed by investigators familiar with the pediatric 
subject and her family and should be guided by requirements of the local regulatory authorities. 
These discussions should take into account the socio-economic, cultural factors and religious 
beliefs of the adolescent participant and her family. The investigator should also discuss the 
management of the pregnancy test results with the subject and her parents/custodians. The 
privacy of the subject should be considered in accordance with the local law and ethics. 
Additional pregnancy tests may be performed at the investigator’s discretion during the study. 
Subjects becoming pregnant must be discontinued from study drug. However, a subject may 
choose to remain in the study should she become pregnant, and be followed in the treatment- 
free follow-up period as described in Table 6-1, Table 6-2. 
Female subjects of child-bearing potential who do not agree to abstinence and who are or might 
become sexually active must be informed of the need to prevent pregnancy, by using effective 
methods of contraception during dosing of study treatment and for a minimum of 16 weeks 
after stopping study treatment or longer if local label requires it (eg in EU 20 weeks). 
Details on contraception methods can be found in the Exclusion criteria, Section 4.2. 
It is recommended that the decision on the contraceptive method should be reviewed at least 
every 3 months to evaluate the individual need and compatibility of the method chosen. 
6.5.9 
Appropriateness of safety measurements 
The safety measures used in this study are reliable and relevant standard measures for a biologic 
immunomodulating agent in psoriasis. 
6.6 
Other assessments 
6.6.1 
Clinical Outcome Assessments (COAs) 
6.6.1.1 
Subject/Patient Reported Outcomes (PRO) 
The impact of psoriasis on various aspects of subject’s health-related quality of life (HRQoL) 
will be assessed by Children’s Dermatology Life Quality Index (CDLQI). 
The Children’s Dermatology Life Quality Index (Lewis-Jones and Finlay 1995) is a 10-item 
general dermatology disability index designed to assess health-related quality of life in pediatric 
subjects aged 4 to 16 years. It is self-explanatory and may be completed by the child with 
assistance from parents or caregivers as necessary. The 10 questions cover six areas of daily 
activities including symptoms and feelings, leisure, school or holidays, personal relationships, 
sleep and treatment. The questions are based on the preceding week to permit accurate recall. 


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Each question is answered on a 4-point Likert scale scored from 0 to 3. These are added to give 
a minimum score of 0 and maximum score of 30. A higher CDLQI score indicates greater 
degree of QoL impairment. 
CDLQI is available in two versions, text only and text with cartoons. The text only version will 
be used in this study. The mean completion time of the text version is 120 seconds. 
This questionnaire should be completed in the language the subject is most familiar with before 
any other clinical assessments, 
All subjects will complete the PRO questions via an electronic tablet. The questionnaire should 
be completed by the subject with the help of parent/custodian if and as needed. The site staff 
may help understand the questions, as necessary. The subject should be given sufficient space 
and time to complete the questionnaire. If subject experiences any difficulties with submission 
after they complete the PROs, the study staff should assist with submitting the PRO responses. 
Attempts should be made to collect responses to all PROs for all subjects, including from those 
who prematurely discontinue prior to the study evaluation completion visit, however, if 
subjects/subjects refuse to complete PROs, this should be documented in study source records. 
Subject’s refusal to complete study PROs are not protocol deviations. 
The study coordinator should check the questionnaire for completeness and encourage the 
subject to complete any missing responses before the clinical examination. Missing data will 
not be imputed. 
The CDLQI questionnaire will be completed by the subject as indicated in Table 6-1, Table 6- 
2. CDLQI will no longer be completed, once the subjects reach 18 years of age. 
During the COVID-19 pandemic or similar major health care disruption that limits or prevents 
on-site study visits, CDLQI questionnaire data may be collected remotely (e.g. via telephone 
interview of the subject) by qualified site personnel. This will depend on local regulations, 
technical capabilities and following any applicable training in the required process. 
Documentation of the procedure should follow the vendor emergency manual directives. 
Completed questionnaires will be reviewed and examined by the investigator, before the clinical 
examination, for responses that may indicate potential adverse events (AEs) or serious adverse 
events (SAEs). The investigator should review not only the responses to the questions in the 
questionnaires but also for any unsolicited comments written by the subject. If AEs or SAEs 
are confirmed, then the physician must record the events as per instructions given in Section 
7.1 and Section 7.2 of the protocol. 
6.6.1.2 
Performance Outcomes (PerfO) 
Not applicable 
6.6.1.4 
Proxy Reported Outcomes 
Not applicable 
6.6.2 
Resource utilization 
Not applicable 


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6.6.3 
Pharmacokinetics 
At all study sites, blood samples will be collected for pharmacokinetics (PK) at the scheduled 
visits as indicated in Table 6-1, Table 6-2. 
Pharmacokinetic samples will be obtained for all subjects. For a detailed description of the 
blood sampling schema, including time points, refer to the Blood Log in Appendix 2. 
All blood samples will be taken by direct venipuncture in a forearm vein. 
PK sample handling, labeling and shipment instructions 
Blood samples (1 mL,) will be collected into SST tubes. The blood sample will be allowed to 
clot over a minimum of 30 minutes at room temperature prior to harvesting of the serum. The 
serum will be obtained by centrifugation at approximately 2500 rpm for 10 minutes, or within 
sufficient time and speed to allow formation of a clear supernatant layer. Serum samples will 
be split into 2 aliquots (polypropylene tubes) and then stored (within 30 min of serum collection 
by centrifugation) at -20°C or -70°C (approximately) prior to shipment to the central laboratory. 
Shipment of stored aliquots from the site to the central lab should be on a pre-specified basis. 
To the extent possible, the site should send each aliquot of a sample to the central laboratory 
separately. The central lab will ship aliquots of the samples on dry ice to the analytical 
laboratory as per agreement with Novartis. PK samples will only be disposed of after approval 
by the Sponsor. 
The actual date and time of sample collection will be entered on the appropriate CRF page. 
Laboratory manuals will be provided by the central laboratory with detailed information on 
sample collection, sample handling and shipment. 
Tubes and labels will be provided by the central laboratory with study/sample type and sample 
number preprinted on the label. 
Further details on labeling of the pharmacokinetic samples can be found in Appendix 2 of the 
protocol. 
PK sample stability 
Secukinumab is stable in serum samples for at least 12 months at -20°C or 32 months at -80°C. 
6.6.4 
Other biomarkers 
Not applicable 
 
Safety monitoring 
7.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (eg, 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. 


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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 or scheduled phone/virtual contact during the study. Adverse events also may be 
detected when they are volunteered by the subject during or between visits or through physical 
examination findings, laboratory test findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subject with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for laboratory and other test abnormalities 
are included in Appendix 1. 
Adverse events must be recorded in the appropriate CRF capturing AEs 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 
• its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• whether it constitutes a serious adverse event (SAE - See Section 7.2 for definition of 
SAE) and which seriousness criteria have been met. 
• action taken regarding secukinumab treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• no action taken (eg further observation only) 
• 
secukinumab treatment interrupted/withdrawn 
• concomitant medication or non-drug therapy given 
• non-drug therapy given 
• subject hospitalized/subject’s hospitalization prolonged (see Section 7.2 for definition of 
SAE) 
• its outcome (not recovered/not resolved; recovered/resolved; recovered/resolved with 
sequelae; fatal; or unknown) 


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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 
CDLQI assessments and is not expected to be captured as an AE in the eCRF. Exceptions 
include cases when a) a new type of psoriasis is diagnosed eg 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). 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 IN or an 
Aggregate Safety Finding. New information might require an update to the informed consent 
and has then to be discussed with the subject. 
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires in-subject 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 out-subject 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, eg defined as an event that jeopardizes the subject or may require 
medical or surgical intervention. 


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All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 20 weeks after last dose was taken or until 30 days after 
the last study visit (whichever is later) must be reported to Novartis within 24 hours of learning 
of its occurrence. Any SAE reported until 20 weeks after last dose was taken or until End of 
study visit (whichever is later) must be recorded in the AE eCRF. SAEs beyond that date will 
only be recorded in the Novartis DS&E database. 
Any SAEs experienced after 30 days from end of study visit or 20 weeks after last dose was 
taken (whichever is later) should only be reported to Novartis if the investigator suspects a 
causal relationship to study treatment. Recurrent episodes, complications, or progression of the 
initial SAE must be reported as follow-up to the original episode, regardless of when the event 
occurs. This report must be submitted within 24 hours of the investigator receiving the follow- 
up information. An SAE that is considered completely unrelated to a previously reported one 
should be reported separately as a new event. 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 is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess the relationship of each SAE to study treatment, 
complete the SAE Report Form in English, and submit the completed form within 24 hours to 
Novartis. Detailed instructions regarding the submission process and requirements for signature 
are to be found in the investigator folder provided to each site. 
Follow-up information is submitted as instructed in the investigator folder. Each re-occurrence, 
complication, or progression of the original event must be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 


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resolved or continues, if and how it was treated, and whether the patient continued or withdrew 
from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Drug Safety and Epidemiology 
Department associate may urgently require further information from the investigator for health 
authority reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with EU 
Guidance 2011/C 172/01 or as per national regulatory requirements in participating countries. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning of its 
occurrence/receiving follow-up information. 
7.3 
Liver safety monitoring 
Not Applicable. 
 
7.4 
Renal safety monitoring 
Not Applicable. 
7.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the appropriate CRF, irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE. 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error 
type 
Document in CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 


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7.6 
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 should 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. 
 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and Good Clinical Practice (GCP) compliance and the quality/integrity of the sites’ 
data. The field monitor will visit the site to check the completeness of subject records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may 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. (Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs). 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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects/subjects will be disclosed. 


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8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRFs) using fully validated secure web-enabled software that conforms 
to US CFR 21 Part 11 requirements. Designated investigator site staff will not be given access 
to the system until they have been trained. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. 
Designated sites and investigator staff will enter the data required by the protocol into the EDC 
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 
database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site. 
8.3 
Database management and quality control 
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff is required to respond promptly to queries and 
to make any necessary changes to the data. 
Concomitant medications entered into the database will be coded using the Word Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. 
ECG readings will be processed centrally and the results will be sent electronically to Novartis. 
Randomization codes and data about all study drug dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis. 
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 


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locked. Any changes to the database after that time can only be made after written agreement 
by Novartis Development management. 
8.4 
Data Monitoring Committee 
An external data monitoring committee (DMC) will be appointed to monitor the safety of the 
study subjects. 
Details regarding the DMC process, responsibilities and membership will be available, as 
needed, in the relevant secukinumab DMC charter. 
8.5 
Adjudication Committee 
Not required. 
 
Data analysis 
Treatment groups for analyses will be presented as shown in Table 9-1. 
Table 9-1 
Treatment groups for analyses 
 
Weight Category 
Low dose secukinumab 
High dose secukinumab 
<25kg 
75mg 
75mg 
25-<50kg 
75mg 
150mg 
≥50kg 
150mg 
300mg 
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 at 
baseline visit. Unless otherwise specified, subjects with missing informed consent form as well 
as 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 
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. 
The subjects with severe GCP violation will not be included in the FAS. 
Of note, subjects excluded from the randomized set will be excluded from the FAS. 
Safety set: The safety set will include all subjects who took at least one dose of study drug 
during the treatment period. Subjects will be analyzed according to treatment received. 


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9.2 
Subject demographics and other baseline characteristics 
Demographics and baseline characteristics 
Summary statistics will be presented for continuous demographic and baseline characteristics 
variables by treatment group and for all subjects. The number and percentage of subjects in 
each category will be presented for categorical variables by treatment group. Summaries will 
be performed on the randomized set unless otherwise specified. 
Medical history 
All conditions entered as medical history or current medical condition at baseline will be coded 
using the MedDRA dictionary. These will be summarized by system organ class and preferred 
term of the MedDRA dictionary. In addition, summaries for psoriasis specific medical history 
will be provided. 
9.3 
Treatments 
Study treatment 
Exposure to study treatment will be summarized by treatment group on the safety population. 
The total number of injections per subject will be summarized in contingency tables and 
summary statistics will be performed on the duration of exposure. In addition, exposure will be 
categorized to certain time thresholds (eg any exposure, ≥ 1 week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 
weeks, ≥ 8 weeks, etc.) and the number of subjects within each category will be presented. 
Prior and concomitant medication(s) 
Prior and concomitant medications will be summarized by treatment group in separate tables. 
Prior medications are defined as medications taken and stopped prior to date of first dose of 
study treatment. Any medication given at least once between the day of first dose of randomized 
study treatment and the last day of study visit will be regarded as concomitant medication, 
including those which started pre-baseline and continued into the treatment period. 
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will also show the overall number 
and percentage of subjects receiving at least one medication of a particular ATC code and at 
least one medication in a particular anatomical main group. 
Psoriasis specific prior medication will be presented, and summary will include 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) 
This section will detail the statistical analysis of the primary endpoint. A Bayesian analysis has 
been chosen to allow the direct incorporation into the analysis of information about placebo 
response rates from historical data. 


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Data from four secukinumab adult placebo-controlled trials (CAIN457A2302, CAIN457A2303, 
CAIN457A2308 and CAIN457A2309) and pediatric placebo-controlled trials from other 
biologics (Paller 2008, Landells et al 2015) will be used to obtain a historical placebo control 
through the Bayesian meta-analytic-predictive (MAP) framework (Spiegelhalter et al 2004, 
Neuenschwander et al. 2010). CAIN457A2310 data will be used if they are reported prior to 
the present study. 
9.4.1 
Primary Variable(s) 
The co-primary efficacy variables are PASI 75 response at Week 12 and IGA mod 2011 0 or 1 
response at Week 12. A PASI 75 responder is defined as a subject achieving ≥ 75% 
improvement (reduction) in PASI score compared to baseline. A subject is considered as IGA 
mod 2011 0 or 1 responder if the subject achieves a score of 0 or 1 and improved from baseline 
by at least 3 points on the IGA mod 2011 scale if the subject enrolled into the study with a score 
of 4 and by at least 2 points on the IGA mod 2011 scale if the subject enrolled into the study 
with a score of 3. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
In order to evaluate the efficacy of secukinumab after 12 weeks, a Bayesian model will be fitted 
to the co-primary endpoint on secukinumab and placebo treatments. A Bayesian method has 
been chosen to allow the direct incorporation into the analysis of information about placebo 
response rates from historical data. These data will be used to calculate the Bayesian posterior 
of the log odds ratio between secukinumab and placebo treatment. For the log odds of the 
secukinumab treatment group a non-informative prior will be used, whilst the placebo treatment 
group log odds response rate will be represented though the MAP prior. The MAP prior will be 
derived from the historical placebo data using a logistic Bayesian mixed-effects model and will 
represent the predicted placebo log odds response rate for this trial. The analysis will report the 
median of the means, the 95% credible interval and the probability of a positive treatment effect 
of the posterior log odds ratio. Comparisons with placebo will be performed for the low and 
high dose group of secukinumab separately. Analysis of the co-primary variables will be based 
on the Full Analysis Set (FAS). 
9.4.3 
Handling of missing values/censoring/discontinuations 
 
The following imputation methods will apply to the missing data for analysis up to Week 52. 
• Pure non-responder imputation (includes Bayesian Primary endpoint analysis at Week 
12): Missing values with respect to response variables based on PASI score and IGA 
mod 2011 categories were to be imputed with non-response regardless to the reason for 
missing data (e.g. premature study discontinuation, missed visit, administrative issues). 
Patients with missing baseline or those with all post-baseline missing were to be imputed 
with non-response (in the secukinumab treatment groups). 
• Descriptive summaries on response variables based on PASI score and IGA mod 2011 
categories will be imputed with multiple imputations (MI) method as sensitivity 
imputation method. Multiple imputation (MI) is a simulation based approach where 


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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 (absolute change from baseline) 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. 
The following imputation methods will apply to the missing data for analysis of the long term 
data beyond Week 52: 
• Response variables based on PASI score and IGA mod 2011 categories will be 
generally be presented as ‘observed case’; i.e. all available data for each time point 
will be included in the analyses. 
• Summaries on multiple imputation will be provided as sensitivity analysis where 
appropriate. 
9.4.4 
Sensitivity analyses 
No sensitivity analysis is planned for the Bayesian primary endpoint analysis. 
9.5 
Analysis of secondary variables 
The secondary efficacy variable is PASI 90 response at Week 12 
9.5.1 
Efficacy variables 
The key secondary efficacy endpoint of this study is the proportion of subjects with a PASI 90 
response at Week 12. These data will be analyzed in the same way as the primary endpoint 
though a Bayesian framework, using a Bayesian mixed-effects model. Efficacy of secukinumab 
low and high dose compared to historical placebo control will be performed separately. 
Analyses will be based on the FAS population, and historical placebo data will be incorporation 
into the analysis as before through the MAP framework. 
Missing data will be handled with the same methods as primary endpoint analysis. 
9.5.2 
Safety variables 
All safety evaluations will be performed on the Safety set. 
Adverse events 
Treatment emergent adverse events will be summarized, and all AEs will be presented in the 
listings. 
AEs 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. 


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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. 
Separate summaries will be provided for death, serious adverse event, other significant adverse 
events leading to discontinuation and adverse events leading to dose adjustment (including 
study treatment discontinuation). A separate AE listing will be produced for subjects who 
reported a treatment deviation, where AEs occurring after treatment deviation will be flagged. 
Laboratory data 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(hematology, serum chemistry and urinalysis). 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. 
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low, or high for each visit value relative to whether or not the baseline value was normal, low, 
or high. These summaries will be presented by laboratory test and treatment group. Shifts will 
be presented for most extreme values post-baseline. 
Immunogenicity 
Immunogenicity data will be listed. 
Vital signs 
Analysis of 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. 
Only “on-treatment” vital signs will be summarized (i.e. assessments within last dose plus 84 
days). All information collected will be listed by subject where on treatment and abnormal 
values will be flagged. 
The number and percentage of subjects with newly occurring notable vital sign abnormalities 
will be presented. Further details on the criteria for notable abnormalities will be presented in 
the Statistical Analysis Plan. 
ECG 
Summary statistics will be presented for ECG variables by visit and treatment group. 


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Physical development 
Growth and weight changes will be summarised descriptively. 
 
. 
9.5.3 
Resource utilization 
Not applicable 
9.5.4 
Health-Related Quality of Life 
Children’s Dermatology Quality of Life Index (CDLQI) 
Seven scores will be derived from the CDLQI: the total score of each of the six dimensions 
(symptoms and feeling, leisure, school or holidays, personal relationships, sleep, treatment) as 
well as the total score over all items. The higher the score, the more quality of life is impaired. 
For each of the seven scores the percentage change from baseline will be derived. Summary 
statistics will be provided for absolute values as well as for the percentage change by visit and 
treatment group in contingency tables .(LOCF). 
9.5.5 
Pharmacokinetics 
All completed subjects with quantifiable pharmacokinetic (PK) measurements of secukinumab 
will be included in the pharmacokinetic data analysis. Serum concentrations will be expressed 
in mass per volume units. All concentrations below the limit of quantification or missing data 
will be labeled as such in the concentration data listings. PK concentrations will be summarized 
by visit and treatment group. In addition to mean, standard deviation, coefficient of variation, 
median and quartiles, the geometric mean and geometric coefficient of variation and n(log) will 
be presented. 
9.5.6 
DNA 
Not Applicable. 
9.5.7 
Biomarkers 
Not applicable 
9.5.8 
PK/PD 
Not applicable 
9.6 
Analysis of exploratory variables 
The following exploratory efficacy endpoints will be assessed: 


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PASI 75, PASI 90, PASI 100 and IGA 2011 0 or 1 response over time 
Number of subjects with PASI 75, PASI 90, PASI 100 and IGA mod 2011 0 or 1 response by 
treatment and visit will be presented in frequency contingency tables and will include absolute 
and relative frequencies. 
Figures will be provided displaying responder rates by treatment including confidence intervals. 
PASI score over time 
Summary statistics will be provided for absolute PASI scores as well as for percent change from 
baseline by treatment and visit. Figures will also be provided. 
9.7 
Interim analyses 
There are two planned interim analysis. An interim analysis of the data collected up until Week 
16, including the co-primary endpoint (at Week 12) will be performed after all subjects have 
completed either their Week 16 visit or the premature treatment discontinuation visit. Another 
interim analysis will be performed when all subjects have completed the Week 52 visit, (or 
premature treatment discontinuation visit). 
Additional analyses may be performed to support health authority interactions, as necessary. 
Thereafter, efficacy and safety data collected after Week 52 until the end of study may be 
reported yearly in separate reports. 
Trial modifications are not planned based on any interim analysis. 
9.8 
Sample size calculation 
The sample size for this study is calculated to ensure an adequate number of subjects for PK 
analyses and powered efficacy analyses. Approximately 80 pediatric subjects from 6 to less 
than 18 years of age at randomization will be recruited. Since a 15% screening failure rate is 


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expected, approximately 95 patients will be screened. The study will aim to recruit at least 60 
subjects with moderate severity and approximately 20 subjects with severe severity. 
Power calculations were performed to support the co-primary endpoints PASI 75 and IGA 0 or 
1 response at week 12, and secondary endpoint PASI 90 at week 12, versus placebo (historical 
control) for the low and high secukinumab dose regimens. Data from four adult placebo- 
controlled trials (CAIN457A2302, CAIN457A2303, CAIN457A2308 and CAIN457A2309) 
and pediatric placebo controlled trials (Paller et al 2008, Landells et al 2015) were used to 
estimate the historical placebo response rate. For study CAIN457A2310, a 10% response rate 
was assumed for PASI 75, IGA 0 or 1 and PASI 90 response for the placebo group. The power 
calculation was performed assigning pediatric data moderate heterogeneity and adult trial data 
substantial heterogeneity (Neuenschwander et al.2010), thus allowing pediatric trial data to be 
given twice the weight compared to adult trial data. All the calculations were performed in the 
R package RBesT (version 1.1) through the meta-analytical-predictive framework 
(Spiegelhalter et al. 2004, Neuenschwander et al. 2010), and the predicted response rate of the 
placebo group for this study are presented in Table 9-2 below by endpoint. 
Table 9-2 
Predictive placebo response rates for this study from model of 
historical data 
 
Endpoint 
Mean 
Standard 
Deviation 
Median 
95% CI 
IGA 0 or 1 
9% 
6% 
8% 
1-23% 
PASI 75 
10% 
6% 
9% 
2-25% 
PASI 90 
6% 
4% 
5% 
1-18% 
Requiring that the posterior probability of the log odds ratio difference between placebo and 
secukinumab exceeds with at least 97.5% zero leads to a power of approximately 99% for each 
co-primary endpoint when assuming a sample size of 40 pediatric patients per treatment group 
and true response rates of 10% and 65% for PASI 75 and 9% and 45% for IGA mod 2011 0 or 
1 response for placebo and secukinumab respectively. 
For the secondary endpoint of PASI 90 response, assuming a response rate of 6% and 39% for 
placebo and secukinumab respectively, the power to provide a posterior probability of at least 
97.5% that the PASI 90 response rate on secukinumab is greater than placebo at week 12 is 
approximately 99%. 
The assumed response rates for secukinumab are based on confirmatory efficacy in the adult 
phase III program (CAIN457A2302, CAIN457A2303, CAIN457A2308 and CAIN457A2309). 
 
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 


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Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
10.2 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent, or, if incapable of doing 
so, after such consent has been provided by a legally acceptable representative(s) of the patient. 
In cases where the patient’s representative gives consent, the patient should be informed about 
the study to the extent possible given his/her understanding. If the patient is capable of doing 
so, he/she should indicate assent by personally signing and dating the written informed consent 
document or a separate assent form. Informed consent must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the patient source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/ IEC, and a copy of 
the approved version must be provided to the Novartis monitor after IRB/IEC approval. 
In pediatric patients (< 18 years of age) parental permission and, whenever possible, child assent 
is needed instead of the procedure for informed consent used for research involving adults. In 
general, one or both parents or a guardian must be provided with the information ordinarily 
required for informed consent, so that they may decide whether to allow the child to participate, 
and children capable of assent must also express their willingness to participate. These forms 
will be submitted for IRB/IEC/REB approval. Subjects who turn 18 years of age during the 
trial must sign the general informed consent form. 
Women of child bearing potential should be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained. 
During the COVID-19 pandemic or similar major health care disruption that may challenge the 
ability to obtain a standard written informed consent due to limitations that prevent an on-site 
visit, the Investigator may conduct the informed consent discussion remotely (e.g. telephone, 
videoconference). Guidance issued by local regulatory bodies on this aspect prevails and must 
be implemented and appropriately documented (e.g. the presence of an impartial witness, 
sign/dating separate ICFs or assent forms by trial subject/ guardian and person obtaining 
informed consent, etc). 
In case Home Nursing (other than study treatment administration) is implemented during the 
COVID-19 pandemic or similar major health care disruption, a separate Home Nursing 
informed consent document must be used in addition to the study ICF. 


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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, 
informed consent form, consent form updates, subject recruitment procedures (eg, 
advertisements) and any other written information to be provided to subjects/subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
10.4 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results. 
10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 
Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
 
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/subjects should 
be administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction, data, information, observation 
would be incidentally collected, the investigator shall immediately disclose it to Novartis and 
not use it for any purpose other than the study, except for the appropriate monitoring on study 
participants. 


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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 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. 


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References 
References are available upon request 
Augustin M, Reich K, Glaeske G, et al (2010) Co-morbidity and age-related prevalence of 
psoriasis: analysis of health insurance data in Germany. Acta Derm Venereol; 90:147–151. 
Beattie PE and Lewis-Jones MS (2006). A comparative study of impairment of quality of life 
in children with skin disease and children with other chronic childhood diseases; Br J 
Dermatol 2006 Jul; 155(1), 145–151. 
Benoit S, Hamm H (2007) Childhood psoriasis. Clin Dermatol; 25(6):555–62. 
Blondell RD, Roster MB, Dave KC (1999) Disorders of puberty. Am Fam Physician; 
60(1):209-18, 223-4. 
Burden AD (1999); Management of psoriasis in childhood; CED, 24, 341–345. 
Comans-Bitter WM et al (1997) Immunophenotyping of blood lymphocytes in childhood. J 
Pediatr Volume; 130, Number 3: 388-393. 
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 
393document. London, UK. 
De Jager MEA et al (2009) Epidemiology and prescribed treatments in childhood psoriasis: A 
survey among medical professionals. Journal of Dermatological Treatment; 20:254–258. 
Doherty SD, Van Voohees 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): 209–217. 
EMA (2016) Reflection paper on extrapolation of efficacy and safety in paediatric medicine 
development http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory 
_and_procedural_guideline/2016/04/WC500204187.pdf (accessed on 14 June 2017). 
Farber EM, Nall ML, (1999); Childhood Psoriasis; Cutis 1999 Nov; 64(5): 309 -14. 
FDA (2014). General Clinical Pharmacology Considerations for Pediatric Studies for Drugs 
and Biological Products. https://www.fda.gov/downloads/drugs/guidances/ucm425885.pdf 
(accessed on 14 June 2017). 
Feld, Corey H (2007) Hypertension in childhood, Pediatric in Review: 28: 283-98. 
Feldman SR and Krueger GG (2005) Psoriasis assessment tools in clinical trials. Ann Rheum 
Dis; 64(Suppl 2):ii 65–8. 
Fredriksson T, Pettersson U (1978) Severe psoriasis – oral therapy with a new retinoid. 
Dermatologica; 157:238–44. 
Gelfand JM, Weinstein R, Porter SB et al (2005). Prevalence and Treatment of Psoriasis in the 
United Kingdom: A Population based Study; Arch Dermatol 2005; 141:1537-1541 
Gottlieb A, Griffiths CEM, Ho VC, et al (2005) Oral pimecrolimus in the treatment of 
moderate to severe chronic plaque type psoriasis: a double-blind, multicenter, randomized 
dose-finding trial. Br J Dermatol; 152:1219-27. 


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Griffiths CE, Barker JN (2007) Pathogenesis and clinical features of psoriasis. Lancet; 
370:263-271. 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (2000). Clinical Investigation of Medicinal Products in the 
Pediatric Population E11. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4 
/E11_Guideline.pdf (accessed on 14 June 2017). 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (2016). Addendum to ICH E11: Clinical Investigation of 
Medicinal Products in the Pediatric Population E11(R1). 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/ICH_ 
E11_R1_Step_2_25Aug2016_Final.pdf (accessed on 14 June 2017). 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (2003). Post-approval safety data management: definitions 
and standards for expedited reporting (ICH E2D). 2003. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step 
4/E2D_Guideline.pdf. Accessed January 23, 2018. 
Kimball AB et al (2012) Risks of developing psychiatric disorders in pediatric patients with 
psoriasis. J Am Acad Dermatol; 674:651-7. 
Kokubu T, et al (2008) Immunolocalization of IL-17A, IL-17B, and Their Receptors in 
Chondrocytes during Fracture Healing; J Histochem Cytochem; Volume 56(2): 89–95. 
Landells I, Marano C, Hsu MC, et al (2015). Ustekinumab in adolescent patients age 12 to 17 
years with moderate-to-severe plaque psoriasis: Results of the randomized phase 3 CADMUS 
study. J Am Acad Dermatol. 73:594-603. 
Langley RG, Krueger GG, Griffiths CE (2005) Psoriasis: epidemiology, clinical features, and 
quality of life. Ann Rheum Dis; 64:ii18-ii23. 
Leman J, Burden D (2001) Psoriasis in children: a guide to its diagnosis and management. 
Paediatr Drugs; 3(9):673–80 
Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): 
initial validation and practical use. Br J Dermatol 1995; 1326: 942-949. 
Manuel O, Kumar D (2008). QuantiFERON-TB Gold assay for the diagnosis of latent 
tuberculosis infection. Expert Rev Mol Diagn; 8(3): 247-56. 
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ (2010) Summarizing 
historical information on controls in clinical trials. Clinical Trials 7, 5-18. 
Paller AS et al (2008) Etanercept treatment for children and adolescents with plaque psoriasis. 
N Engl J Med; 358:241-51. 
Pariser DM, Bagel J, Gelfand JM et al (2007) National Psoriasis Foundation Clinical 
Consensus on Disease Severity. Arch Dermatol; 143: 239-242. 
Schwartz GJ, Munoz A, Schnei MF et al (2009). New equations to estimate GFR in children 
with CKD. J Am Soc Nephrol; 20:629-637. 
Silverberg NB (2009); Pediatric psoriasis; Ther Clin Risk Manag 2009;5 849–856. 


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Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical trials and 
Health-Care Evaluation. Chichester: John Wiley and Sons. 
 
Tollefson et al (2010) Incidence of psoriasis in children: a population- based study. J Am 
Acad Dermatol. 2010 Jun; 62(6):979-87. 
Tollefson M (2014) Diagnosis and management of psoriasis in children. Pediatr Clin North 
Am; 61(2):261-277. 
Weisman S, Pollack CR, Gottschalk RW (2003). Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat; 14: 158-165. 
Wu JJ et al (2011) Low prevalence of psoriasis among children and adolescents in a large 
multiethnic cohort in southern California. J Am Acad Dermatol 2011; 65: 957-64. 
Zappel K, Sterry W, Blume-Peytavi U (2004) Therapy options for psoriasis in childhood and 
adolescence. JDDG; 2004. 2:329 – 342. 


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Appendix 1: Clinically notable laboratory parameters 
The following criteria will be used to define expanded limits and notable abnormalities of key 
laboratory tests. 
Unless otherwise indicated, no specific action is pre-defined within this protocol to respond to 
specific abnormal laboratory values, as it will be decided by the investigator whether & which 
specific action needs to be taken to respond to any abnormal values, taking into account the 
overall status of the subject. 
Laboratory values 
Newly occurring selected notable laboratory abnormalities in pediatric patients at the time of 
the assessment: 
Biochemistry and Urinalysis 
• Alamine Aminotranferase (ALT)(SGPT): 
>Upper Limit of Normal () 
≥3 x ULN 
≥5 x ULN 
≥8 x ULN 
≥10 x ULN 
• Aspartate Aminotranferase (AST) (SGOT): 
>ULN 
≥3 x ULN 
≥5 x ULN 
≥8 x ULN 
≥10 x ULN 
• Total Bilirubin (TBL) 
>ULN, 
≥1.5xULN, 
≥ 2xULN 
• Alkaline Phosphatase (ALP) 
>ULN 
≥1.5xULN, 
≥2xULN, 
≥3x ULN 
≥5xULN 
• ALT and/or AST >3x-, 5x-, 10x ULN accompanied by TBL >2xULN 
• ALT or AST >3x ULN and TBL >2x-, and ALP >2 x ULN. 
• ALP >3x ULN and TBL >2x ULN 
• Gamma-Glutamyltransferase (GGT): 
>ULN 


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≥3 x ULN 
≥5 x ULN 
Hematology 
• Hemoglobin: 
• ≥ 20 g/L decrease from baseline, or 
• < 85 g/L for < 16 years of age 
• < 100 g/L for ≥ 16 years of age 
• Absolute neutrophils: 
• Grade 1: <LLN – 1.5 x 10E9/L 
• Grade 2: <1.5 – 1.0 x 10E9/L 
• Grade 3: <1.0 – 0.5 x 10E9/L 
• Grade 4: <0.5 x 10E9/L 
• Criteria based on CTC grades for platelet count: 
• Grade 1: <LLN – 75.0 x 10E9/L 
• Grade 2: <75.0 – 50.0 x 10E9/L 
• Grade 3: <50.0 – 25.0 x 10E9/L 
• Grade 4: <25.0 x 10E9/L 
• Criteria based on CTC grades for WBC: 
• Grade 1:<LLN – 3.0 x10E9/L 
• Grade 2:<3.0 – 2.0 x10E9/L 
• Grade 3:<2.0 – 1.0 x10E9/L 
• Grade 4: <1.0 x10E9/L 
• Absolute Lymphocytes: < LLN 
• Absolute Eosinophils: ≥ 1.1 x ULN 
• Absolute Eosinophils: ≥0.45 x 109/L 


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Appendix 2: Blood collection log for pharmacokinetics and 
immunogenicity 
Table 14-1 
Blood collection log for pharmacokinetics 
 
Visit 
Timepoint 
Volume 
Analyte 
 Sample 
number1 
PK collection 
number /Dose 
Reference ID1 
Randomization/Day 1 
Pre-dose 
1 mL 
AIN457 for PK 
1 
1 
Week 4 
Pre-dose 
1 mL 
AIN457 for PK 
2 
2 
Week 12 
Pre-dose 
1 mL 
AIN457 for PK 
3 
3 
Week 13 
168 hours2 
1 mL 
AIN457 for PK 
4 
3 
Week 14 
336 hours2 
1 mL 
AIN457 for PK 
5 
3 
Week 15 
504 hours2 
1 mL 
AIN457 for PK 
6 
3 
Week 16 
672 hours2 
1 mL 
AIN457 for PK 
7 
3 
Week 24 
Pre-dose 
1 mL 
AIN457 for PK 
8 
4 
Week 52 
Pre-dose 
1 mL 
AIN457 for PK 
9 
5 
Week 104 
Pre-dose 
1 mL 
AIN457 for PK 
10 
6 
Week 156 
Pre-dose 
1 mL 
AIN457 for PK 
11 
7 
Week 208 
672 hours3 
1 mL 
AIN457 for PK 
12 
8 
Week 224 
3360 hours3 
1 mL 
AIN457 for PK 
13 
8 
1 If a PK sample is collected at an unscheduled visit, the sample numbers will follow the pattern: 1001, 1002, etc. 
2 Scheduled time points for sample numbers 4, 5, 6, 7 (168, 336, 504 and 672 hours post-dose, respectively) refer 
to the last previous dose given at Week 12 (Dose Reference ID = 3) 
3 Scheduled time points for sample numbers 12 and 13 (672 and 3360 hours post-dose, respectively) refer to the 
last dose given at Week 204 (Dose Reference ID = 8) 
 
Table 14-2 
Blood Collection for Immunogenicity 
 
Visit 
Timepoint 
Volume 
Analyte 
Immunogenicity 
Sample number1 
Randomization/Day 1 
Pre-dose 
2 mL 
anti-AIN457 for IG 
501 
Week 16 
Pre-dose 
2 mL 
anti-AIN457 for IG 
502 
Week 24 
Pre-dose 
2 mL 
anti-AIN457 for IG 
503 
Week 52 
Pre-dose 
2 mL 
anti-AIN457 for IG 
504 
Week 104 
Pre-dose 
2 mL 
Anti-AIN457 for IG 
505 
Week 156 
Pre-dose 
2 mL 
Anti-AIN457 for IG 
506 
Week 208 
672 hours2 
2 mL 
Anti-AIN457 for IG 
507 
Week 224 
3360 hours2 
2 mL 
anti-AIN457 for IG 
508 
1 If an IG sample is collected at an unscheduled visit, the sample numbers will follow the pattern: 3001, 3002, 
etc. 
2 Scheduled time points for sample numbers 12 and 13 (672 and 3360 hours post-dose, respectively) refer to 
the last dose given at Week 204 


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Appendix 4: Weight and recommended blood volumes 
European Medicines Agency (EMA) recommendations for trial related blood loss (including 
any losses in the maneuver) in pediatric populations are that no more than 3% of total blood 
volume should be taken during a four week period and not more than 1% of total blood volume 
at a single time-point. At a total blood volume estimated at 80 to 90ml per kilogram (kg) body 
weight, this equates to 2.4mL to 2.7mL blood per kg body weight during a four week period, 
or 0.8mL to 0.9mL blood per kg at any one time. 
These recommended volumes must not be exceeded for any patient. Please use the information 
below to ensure that the recommended volumes are adhered to. 
Table 16-1 
Total blood volume, 1% and 3% of total blood volume by weight 
assuming 85mL per kg total blood volume 
 
Weight (Kg)
Total Blood Volume* 
1% Blood Volume* 
3% Blood Volume* 
(mL) 
(mL) 
(mL) 
5 
425 
4 
12 
10 
850 
8 
24 
15 
1275 
12 
36 
20 
1700 
17 
51 
25 
2125 
21 
63 
30 
2550 
25 
75 
35 
2975 
29 
87 
40 
3400 
34 
102 
45 
3825 
38 
114 
50 
4250 
42 
126 
55 
4675 
46 
138 
60 
5100 
51 
103 
65 
5525 
55 
165 
70 
5950 
59 
177 
75 
6375 
63 
186 
80 
6800 
68 
204 
*all blood volumes are rounded down 

SAP_003.pdf: 


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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)
26-Apr-
2019
Prior to 
week 16 
dry run 
Information 
shared at CSPD 
Further details added to 
Bayesian 
analysis. 
Updated code syntax to 
write and finalize placebo 
model ahead of lock
Added a figure for primary
and 
secondary 
key 
endpoint analysis 
2.5.2
26-Apr-
2019
Prior to 
week 16 
dry run 
Vital sign 
standard 
pediatric 
reference range 
assigned
Updated 
to 
reference 
ranges  
2.8.4.2
04-Jun-
2019
Prior to 
week 16 
dry run
Clarification
Efficacy 
subgroups 
for 
summary stats defined in a 
table
2.2.2
04-Jun-
2019
Prior to 
week 16 
dry run
2310 treatment 
label update, 
adhere to 
program 
standard 
Secukinumab treatment 
label updated to AIN457
04-Jun-
2019
Prior to 
week 16 
dry run
Clarification
Define PASI 90 as Key 
secondary 
Added endpoint time to 
PASI 75/90 up to week 12
1.2, 5.4.8
04-Jun-
2019
Prior to 
week 16 
dry run
To follow 
current process   
Remove PD summary by 
major and minor 
classification
2.3.1










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Table of contents
Table of contents .................................................................................................................7
List of abbreviations............................................................................................................9
1
Introduction .......................................................................................................................11
1.1
Study design...........................................................................................................11
1.1.1
Randomization ......................................................................................12
1.2
Study objectives and endpoints .............................................................................13
2
Statistical methods.............................................................................................................14
2.1
Data analysis general information .........................................................................14
2.1.1
General definitions................................................................................15
2.2
Analysis sets ..........................................................................................................16
2.2.1
Subgroup of interest ..............................................................................17
2.3
Patient disposition, demographics and other baseline characteristics ...................18
2.3.1
Patient disposition.................................................................................19
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................20
2.4.1
Study treatment / compliance................................................................20
2.4.2
Prior, concomitant and post therapies...................................................23
2.5
Analysis of the primary objective..........................................................................25
2.5.1
Primary endpoint...................................................................................25
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................32
2.5.4
Supportive analyses...............................................................................33
2.6
Analysis of the key secondary objective ...............................................................33
2.6.1
Key secondary endpoint........................................................................33
2.6.2
Statistical hypothesis, model, and method of analysis..........................33
2.6.3
Handling of missing values/censoring/discontinuations.......................33
34
2.8
Safety analyses.......................................................................................................35
2.8.1
Adverse events (AEs)............................................................................36
2.8.2
Deaths....................................................................................................39
2.8.3
Laboratory data .....................................................................................39
2.8.4
Other safety data ...................................................................................41
2.9
Pharmacokinetic endpoints....................................................................................44
2.10
PD and PK/PD analyses.........................................................................................45
45
2.12
Biomarkers.............................................................................................................46


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2.13
Other Exploratory analyses....................................................................................46
2.14
Interim analysis......................................................................................................46
3
Sample size calculation .....................................................................................................46
4
Change to protocol specified analyses ..............................................................................48
5
Appendix ...........................................................................................................................50
5.1
Imputation rules.....................................................................................................50
5.1.1
Study drug.............................................................................................50
5.1.2
AE date imputation ...............................................................................50
5.1.3
Concomitant medication date imputation .............................................51
5.2
AEs coding/grading ...............................................................................................53
5.3
Laboratory parameters derivations ........................................................................53
5.4
Statistical models...................................................................................................53
5.4.1
Analysis of continuous data ..................................................................53
5.4.2
Analysis of binary (and categorical) data..............................................54
5.4.3
Multiple imputations for response variables.........................................54
5.4.4
Crude incidence and related risk estimates...........................................56
5.4.5
Exposure adjusted incidence rate and related risk estimates ................57
5.4.6
Primary analysis....................................................................................57
5.4.7
Key secondary analysis.........................................................................58
5.4.8
Analysis of time-to-event data ..............................................................58
5.5
Rule of exclusion criteria of analysis sets..............................................................59
59
6
Reference...........................................................................................................................61


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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
CV
Coefficient of variation 
ECG
Electrocardiogram
eCRF
Electronic case report/record form
eGFR
FAS
Estimated glomerular filtration rate 
Full analysis set
FIR
First Interpretable Results
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
LLQ
LOCF
Lower Limit of Normal
Lower Level of Quantification
Last Observation Carried Forward
MACE
MAP
Major Adverse Cardiovascular Event
Meta-analytic-predictive
MCMC
Markov Chain Monte Carlo
MedDRA
MI
Medical Dictionary for Regulatory Activities
Multiple Imputation 
NMQ
Novartis MedDRA Query
NovDTD
Novartis Drug and Therapy Dictionary
PASI
PK
PsA
PsO
Psoriasis Area and Severity Index
Pharmacokinetics 
Psoriatic arthritis
Psoriasis
PD
PRO
Protocol deviation
Patient Reported Outcome
PT
QTc
QTcF
Preferred Term
Corrected QT interval
Fridericia corrected QTc
RMP
Risk Management Plan


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SAS
Statistical analysis software
SAE
Serious adverse event
SPP
Safety Profiling Plan
SOC
SMQ
System Organ Class
Standardized MedDRA Query 
TBL
Total bilirubin
TEAE
Treatment Emergent Adverse Event
ULN
ULQ
Upper Limit of Normal
Upper Level of Quantification
WBC
White blood cell


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1
Introduction
Data will be analyzed by Novartis according to the data analysis section 9 of the protocol,
which is available in Appendix 16.1.1 of the CSR.
This document contains the detailed statistical and analytical plans for full analyses of
CAIN457A2311 study with reference to the study protocol and the project
standard analysis plans AIN457A MAP. 
1.1
Study design
This is an open-label, parallel-group, two-arm, multi-center trial in pediatric subjects aged 6
years to less than 18 years with moderate to severe chronic plaque psoriasis.
Approximately 80 subjects (at least 60 patients with moderate severity) will be enrolled. It is
expected that subjects will be enrolled in about 40 centers worldwide. It will be targeted to 
have at least 5 subjects in the < 25 kg weight, and at least 10 subjects in each of the other two 
weight groups (25 - <50 kg and ≥50 kg). Subjects will receive the appropriate dose based on 
their body weight category. If a subject moves into a higher or lower weight group at two 
consecutive visits with weight measurements from Week 12 onwards, the subject will receive 
dosing according to the new (higher or lower) weight group respectively. The dose will be 
adapted starting from the visit of the second consecutive weight change.
The following study periods will be considered for analysis:
Screening Period
The screening period of up to 4 weeks will be used to assess eligibility of the subjects and to
taper subjects off prohibited medication.


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Treatment Period
The treatment period is defined as randomization to Week 208. In this period the endpoints 
are assessed and subjects are followed for long-term safety and efficacy. For safety analysis
this is defined a last dose + 84 days exposure.
Follow-up Period
The treatment-free follow-up visits will be at Week 212, Week 216 and Week 224 (End Of
Follow-up/EOF). Subjects who complete or discontinue treatment early are expected to
perform the complete treatment-free follow-up period unless they start another systemic 
antipsoriatic treatment. 
Of note: data from follow-up period for prematurely discontinued subjects will be included in 
the analysis of treatment period if appropriate.
Entire study period (Randomization to end of study (EOS)), including follow-up period 
(W212, W216 and W224 visits).
1.1.1
Randomization 
Randomization will be stratified by body weight (< 25 kg, 25-< 50 kg, ≥ 50 kg) and disease 
severity collected at baseline (moderate, severe) (refer to Table 1-1). Subjects will be 
randomized using 1:1 ratio into one of the following treatment groups according to their 
baseline body weight:

AIN457 low dose: 
o
Subjects weighing < 50 kg at baseline will receive a dose of 75 mg
administered as one injection of  the 75 mg pre-filled syringe
o
Subjects weighing ≥50 kg at baseline will receive a dose of 150 mg 
administered as one injection of  the 150 mg pre-filled syringe

AIN457 high dose: 
o
Subjects weighing < 25 kg at baseline will receive a dose of 75 mg 
administered as one injection of  the 75 mg pre-filled syringe
o
Subjects weighing 25-<50 kg at baseline will receive a dose of 150 mg 
administered as one injection of  the 150 mg pre-filled syringe
o
Subjects weighing ≥ 50 kg at baseline will receive a dose of 300 mg
administered as one two injections of the 150 mg pre-filled syringes
Table 1-1 Disease severity definition by IGA and PASI score
IGA score
PASI score 
Psoriasis severity
3 
12-< 20
Moderate
3 
≥ 20 
Moderate
4 
12-< 20 
Moderate
4 
≥ 20 
Severe
PASI: Psoriasis Area and Severity Index; IGA: Investigator Global Assessment




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Table 1-2
Primary, secondary 
 variables
Variable
Type
PASI 75 response at Week 12 (compared to historical placebo)
Co-primary
IGA 0/1 response at Week 12 (compared to historical placebo)
Co-primary
PASI 90 response at Week 12 (compared to historical placebo)
Key 
secondary
Height, weight, vital signs, laboratory evaluations , ECG over time 
secondary
Adverse events 
secondary
Secukinumab concentration in serum over time and derived PK parameters (AUC and Cmax)
secondary
2
Statistical methods
2.1
Data analysis general information
This document covers statistical and analytical plans for CAIN457A2311 with reference to 
study protocol and the project standard analysis plans (AIN457 MAP).
Novartis will be performing all analyses. Statistical software of R version 3.4.3 or later and SAS 
version 9.4 or later will be used.
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.
All listings will be presented by treatment sequence. 
Footnotes on outputs will be kept to a minimum also for outputs not covered in AIN457A MAP 
TFL shells.
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


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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 (body mass index) 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 75 mg, 0.5 ml liquid formulation in a pre-filled syringe
o
Secukinumab 150 mg, 1 ml liquid formulation in a pre-filled syringe
o
Secukinumab 300 mg, 2 x 1 ml liquid formulation in a pre-filled syringe
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


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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 randomization (day). All assessments obtained after randomization (day) 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 of study treatment. All assessments obtained after the first dose (day) 
of study treatment are considered as post-baseline unless otherwise specified.
Of note, baseline will be derived based on the randomization day or first dose day, exact 
randomization/dosing time is not considered.
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, for patient reported outcomes, laboratory assessments
and ECG if no pre-treatment value exists, values obtained after first dose of treatment can be 
used as baseline only if it was collected on the same day as first dose.
2.1.1.4
Day of last dose of randomized study treatment
The date of last dose will be collected via the electronic case report form (eCRF). 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.
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 
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 Interactive Response Technology system (IRT), 
the actual stratum will be used in analyses. Subjects reporting a severe GCP (good clinical 
practice) violation will be excluded from the FAS.
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. For safety summaries, subjects will be analyzed according to 


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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. If a subject has received intermittent wrong treatment, the treatment 
received will be set to the original randomized treatment.
For those subjects who received erroneously the wrong treatment at least once, an additional 
listing will be prepared flagging adverse events which occurred after the treatment deviation.
Protocol deviations leading to exclusion from analysis populations are defined in Table 5-2 in 
Section 5 Appendix.
The number of subjects in each analysis set will be presented for all treatment groups in efficacy 
and safety analyses, and for all subjects (total). The number of screened and screen failures 
subjects will also be shown for all subjects (total).
2.2.1
Subgroup of interest
The primary endpoint(s), selected secondary
endpoints and selected safety 
endpoints will be evaluated using the subgroups defined in Table 2-1 where appropriate. 
Subgroup analyses for the study endpoints are represented in Table 2.2. Analyses will be 
 presented as descriptive summaries. 
Table 2-1
Subgroups definitions
Subgroup 
variables
Categories
Label 
for 
outputs
Suffix
for 
outputs*
Randomization 
weight strata
body weight stratum 
(kg:<25, 25-<50, ≥50)
Weight 
strata
a
Randomization 
disease 
severity 
strata
Disease 
severity 
strata 
(moderate, severe)
Disease 
severity 
strata
b
Age group
(<12 years or ≥12 years)
Age 
group
c
Body weight and 
dose group
AIN457 75 mg and < 25 kg, 
AIN457 75 mg and 25--< 
50 kg, AIN457  150 mg and 
≥50 kg;   AIN457  150 mg 
and 25-< 50 kg, AIN457 
300 mg and≥50 kg
Body 
weight 
by dose 
group
d


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Table 2-2
Subgroup endpoints
Endpoint/analysis
Randomization strata 
including weight and 
disease severity
Age
Weight and by 
dose group
Adverse event
PK concentration data
X
X
X
X
Demography and 
backgroud characterics 
X
X
2.3
Patient disposition, demographics and other baseline 
characteristics
Summaries will be reported by the following treatment groups:
Treatment for analysis

AIN457 low dose 

AIN457 high dose

Total
The following common background and demographic variables will be analyzed:
Continuous variables:

Age in years (derived from year of birth and informed concent data, assuming date is 
July 1st since only year of birth is reported on the case report form (CRF))

Height

Weight

Body mass index (BMI)
Categorical variables:

Age categories (<12 years, 12 years and older)

Gender

Race

Ethnicity


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
Weight categories (<25 kg, 25-<50 kg, ≥50 kg)

Disease severity (moderate or severe)
Psoriasis specific baseline characteristics and history of disease will be summarized as well: 
baseline PASI, baseline PASI (≤20, >20), baseline total body surface area (BSA), baseline IGA 
mod 2011 score (moderate, severe), severity of psoriasis (as defined at randomization), 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). Summaries above will be repeated and presented separately by age group and 
body weight by dose group. 
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.
Time since diagnosis of psoriasis (PsO) and time since diagnosis of psoriatic arthritis (PsA) 
will be calculated using the following formula:
Time since diagnosis = (inform consent date –first diagnosis date + 1)/365.25
The first diagnosis date of PsO or PsA will be imputed according to the imputation rules in 
Section 4.1 of MAP
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.
Any condition entered on the relevant medical history / current medical conditions eCRF will 
be coded using the MedDRA dictionary. They will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) of the MedDRA dictionary.
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 failure 
will be provided. The number and percentage of subjects in the randomized set who completed 
study periods (treatment period and treatment free follow period) and who discontinued the 
study prematurely (including the reason for discontinuation) will be presented for each 
treatment group and all subjects.


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For each protocol deviation, the number and percentage of subjects for whom the deviation 
applies will be tabulated by randomized treatment groups on the FAS population. All substantial
protocol deviations will be displayed in the outputs. 
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 injections will be summarized by treatment group by means of 
contingency tables. 
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 (any exposure, ≥ 1 week, 
≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, and thereafter every 4 weeks, so ≥ 8 weeks, ≥ 12 weeks, etc.) 
will be displayed. 
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 last dose plus 84 days, the end of 
study treatment 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 reported for the treatment period
up to Week 16 for the PEA, with the last category “≥16 weeks”. Summaries on the entire 
treatment will be provided at Week 24 IA and thereafter. 
Also, subjects who changed dose due to change of weight group will be listed if required.
2.4.1.1
Visit window
Visit-windows will be applied to data summarized by visit. These will be based on study 
evaluation schedule and comprise a set of days around the nominal visit day. For any assessment, 
there are the protocol defined scheduled visits around which visit windows are created 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 


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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.
The analysis visit will be used for listing of visit and period for safety data. If a visit falls after 
the last visit window, it is not assigned an analysis visit and will be listed under label “After 
Week xxx”.
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 2-11
Week 2
2
15
Day 12-18
Week 3
3
22
Day 19-25
Week 4
4
29
Day 26-43
Week 8 
8
57
Day 44-71
Week 12
12
85
Day 72-99
Week 16
16
113
Day 100-141
Week 24
24
169
Day 142-197
Week 32
32
225
Day 198-253
Week 40
40
281
Day 254-309
Week 48
48
337
Day 310-351
Week 52
52
365
Day 352-407
Week 64
64
449
Day 408-491
Week 76
76
533
Day 492-575
Week 88
88
617
Day 576-673
Week 104
104
729
Day 674-771
Week 116
116
813
Day 772-855
Week 128
128
897
Day 856-939
Week 140
140
981
Day 940-1037
Week 156
156
1093
Day 1038-1135
Week 168
168
1177
Day 1136-1219
Week 180
180
1261
Day 1220-1303
Week 192
192
1345
Day 1304-1401
Week 208 (EOT)
208
1457
Day 1402-1471
Week 212
212
1485
Day 1472-1499
Week 216
216
1513
Day 1500-1541
Week 224 (EOF)
224
1569
Day 1542-1597
* Baseline measurement before the first drug administration for safety assessments and before 
the randomization for efficacy assessments.






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In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized.
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. Summaries will be based on 
the safety set. 
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


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2.5
Analysis of the primary objective
The primary analysis of the study is a Bayesian analysis, chosen to allow the direct 
incorporation into the analysis of information about placebo response rates from historical data.
Literature and internal Novartis pediatric and adult plaque psoriasis studies were reviewed to 
provide the basis for assessing efficacy compared to a historical placebo. All analyses included 
in this study are based on clinically appropriateness and alignment of definitions (endpoints, 
clinical disease population, and time point of assessment). Integrated in the analysis are data 
from four Novartis reported secukinumab adult placebo-controlled trials (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309) and pediatric study CAIN457A2310. 
Pediatric placebo-controlled trial data from literature on other biologics at study level data will
be utilized (Paller 2008, Landells et al 2015). A historical placebo control is obtained through 
the Bayesian meta-analytic-predictive (MAP) framework (Spiegelhalter et al 2004,
Neuenschwander et al. 2010). Further details on the historical data included are provided in 
Section 3 and Table 3.1. Note, placebo response rates for study CAIN457A2310 will be 
available prior to the reporting of this study and therefore utilized in this analysis.  
2.5.1
Primary endpoint
The co-primary efficacy variables are PASI 75 response at Week 12 and IGA mod 2011 0 or 
1 response at Week 12. Analysis of the primary variable will be performed on each treatment 
group (AIN457 high vs. historical placebo and AIN457 low dose vs. historical placebo) 
separately on the FAS population. 
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. 
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 2-5. 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:

The neck is assessed as part of the head.

The axillae and groin are assessed as part of the trunk.

The buttocks are assessed as part of the lower limbs.

When scoring the severity of erythema, scales should not be removed.








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Table 2-8
Overview of analysis methods for efficacy variables
Variable(s)
Summary of 
time to event 
Summary 
statistics for 
binary/
categorical data 
Bayesian 
Analysis 
Summary 
statistics for 
continuous 
data
Graphs
PASI 75 response at Week 12
X
X
X*
IGA 0/1 response at Week 12
X
X
X*
PASI 90 response at Week 12
X
X
X*
Time to PASI 75/90 at week 12 
X
X
* dot plot; ** time course plot
2.5.2
Statistical hypothesis, model, and method of analysis
The statistical hypothesis are that AIN457 high dose or AIN457 low dose is not superior to 
placebo from historical data in the proportion of subjects with PASI 75 response and IGA 0 or 
1 response at Week 12. Data from four adult placebo-controlled trials (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309) and pediatric placebo controlled trials 
(Paller et al 2008, Landells et al 2015 and CAIN457A2310) will be used to estimate the 
historical placebo response rate. 
The primary hypotheses of comparing AIN457 doses versus historical placebo data will be 
evaluated using a Bayesian model fitted to study level data. A Bayesian method has been chosen 
to allow the direct incorporation into the analysis of information about placebo response rates 
from historical data through a meta-analytic-predictive (MAP) prior. These historical data will 
include adult (data from repository CPOOL) and pediatric studies.   
First, a logistic regression Bayesian mixed-effects model is fitted to the historical placebo data, 
including terms study and population. This is built to predict efficacy outcomes of a future 
pediatric trial taking into account between trial heterogeneity of the control response rate. The 
adult studies are assigned a smaller weight in comparison to the pediatric studies. This is 
achieved through allocation to two distinct exchangeability strata which share a common 
population response rate, but differ in their between-trial heterogeneity parameter () . 
Moderate between-trial heterogeneity (with τ prior set as HalfNormal(0, 0.5)) was defined for 
pediatric trial data and substantial heterogeneity (with τ prior set as HalfNormal(0, 1)) was 
defined for adult trial data (Neuenschwander et al 2010), thus allowing pediatric trial data to be 
given a higher weight compared to adult trial data. From this model, the MAP prior is derived
on the logit scale, and represents the predicted placebo log odds of the pediatric trial, which is 
used in this study as the comparator. For each endpoint the model was fit using MCMC and the 
resulting posterior distributions forming the MAP prior are approximated with a parametric 


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distribution for each endpoint. As parametric distribution a mixture of normal distributions is 
used, since mixtures can arbitrarily exact approximate any target distribution (West M 1993). 
The number of mixture components is chosen automatically using lowest Akaike Information 
Criteria (AIC) as the criterion. This step is performed prior to the first database lock, and results 
per endpoint from the best fitting mixture model are presented in Table 2-9. 
Table 2-9
Information on placebo priors
Endpoint 
Mixture component 
1
Mixture component 
2
Mixture component 
3
IGA 0/1
  Weight 
  Mean
  SD
0.555
-3.337
1.0048
0.445
-2.741
0.5311
PASI 75
  Weight 
  Mean
  SD
0.361
-2.555
0.3866
0.351
-2.101
0.2910
0.288
-2.723
0.9029
PASI 90
  Weight 
  Mean 
  SD
0.774
-3.487
0.5944
0.226
-4.058
1.0976
A separate model for each endpoint is fitted on the log odds scale to active data from this study
with the term treatment.
These data will be used to calculate the Bayesian posterior of the log odds ratio between AIN457 
and placebo treatment response rate in this trial. For the log odds of the AIN457 treatment 
groups a non-informative prior will be used, whilst the placebo treatment group log odds 
response rate will be represented though the MAP prior as described above.. 
Both models described above are fitted separately on each efficacy endpoint (PASI 75, PASI 
90 and IGA 0/1) using MCMC in Stan version 2.17.1. The MCMC non-convergence Rhat 
diagnostic (Gelman and Rubin 1992) will be monitored for all model parameters. Rhat values 
much greater than 1.0 indicate sampling problems and the overall number of model parameters 
with a Rhat value greater than 1.1 will be documented if observed. It is expected there will be 
zero divergent transitions during the sampling phase of the used hamiltonian monte-carlo (HMC) 
algorithm implemented in Stan (Upadhyay et al 2015).


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The analysis will report the posterior of the mean log odds ratio as point estimate by its median, 
its 95% credible interval and the probability of a positive treatment effect which corresponds to
the level of evidence for a positive treatment effect. Comparisons with placebo will be 
performed for the AIN457 low and high dose group separately on each of the efficacy endpoints 
at week 12. 
Results from the posterior distribution will be plotted to provide a graphical representation. 
Analysis of the co-primary variables and key secondary endpoint will be based on the Full 
Analysis Set (FAS).
Notation
Indexes
	 ∈{1,2,3} labels endpoint PASI 75 (1), IGA 0/1 (2) or PASI 90 (3)
 ∈{1,2} labels AIN457 treatment arm low dose (1), high dose (2)
ℎ∈{1, … , } historical studies
(ℎ) ∈{1,2} population
pediatric historical studies have (ℎ) = 1
adult historical studies have (ℎ) = 2
Data

 responders in placebo group

 responders in active group

 patients in placebo group

 patients in active group
Parameters

 responder rate placebo

 responder rate placebo, log-odds

 population response rate placebo

 between-trial heterogeniety of trial specific intercept for placebo

 responder rate active

 responder rate active, log-odds

 treatment effect as log-odds-ratio with respect to placebo control group


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Model
Likelihood
,|,, , ∼Binomial(, = logit+,(,), ,)
 |  ,  ∼Binomial( = logit+,(), )
Hierarchical model (MAP)
,|, ,() ∼Normal(, ,()
/
)
,⋆|, ,, ∼Normal(, ,,
/ )
Treatment effect as log-odds ratio
 =  −,⋆
The final analysis will report for each endpoint 	 and treatment arm  the probability for a 
positive treatment effect 2(,3 > 0) and the median as a point estimate of the mean treatment 
difference of AIN457 low dose ( = 1) versus historical placebo and AIN457 high dose ( =
2) versus historical placebo, and the respective associated 95% credible interval of ,3. 
Priors

 ∼Normal(0, 2/) - overall intercept on log-odds scale

,3 ∼Normal(0, 2/) - response rate for active on log-odds scale

,() ∼HalfNormal80, ()
/
9 - between trial heterogeneity intercept

, = 1/2 - between trial heterogeneity pediatric data

/ = 1 - between trial heterogeneity adult data
2.5.3
Handling of missing values/censoring/discontinuations
Pure non-responder imputation (pNRI) will be used as the primary missing data imputation 
method for both Bayesian analysis at week 12 and descriptive summaries up to week 52.
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). Subjects with missing baseline or 
those with all post-baseline missing will be imputed with non-response. 
Missing data from this study for Bayesian analysis will be imputed in the SAS platform. A 
dataset with study level data is constructed in SAS and transferred to RBesT where the MAP 
analysis will be performed and the results transferred back to SAS for reporting activities. 




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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.
The summaries of evaluation will be reported for the entire treatment period, and where 
appropriate on the entire study period as well. 
Data will be presented by the following treatment groups:

AIN457 low dose: all subjects who were randomized to AIN457 low dose 

AIN457 high dose: all subjects who were randomized to AIN457 high dose 

Any AIN457 dose: data on AIN457 groups above pooled together 
Safety analyses will be performed on treatment received or actual treatment (See Section 2.2, 
Safety Set).
In general, the following guidelines are proposed for safety analysis unless stated otherwise:

Adverse events: Only treatment emergent records are reported in the tables, and listings 
have the “treatment emergent” flag displayed.

Laboratory data (including vital sign and ECG): 
o
by period summary statistics tables: only include “on-treatment” records in the 
tables, i.e., Assessments within last dose plus 84 days cutoff. Listings have the “on-
treatment” flag displayed.
o
by visit summary statistics tables: present all “on-treatment” visits, follow up visits 
(CRF visits) may be summarized separately if required.


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In addition to the treatment emergent/on-treatment safety summary, extended entire treatment/ 
study period safety analysis will be provided for AE records up to EOS and for LABs by visit 
summary statistics up to EOS.
Additional listing will be provided for AE that started after last dose + 84 days through to EOS. 
Entire treatment/study period
Entire treatment period = randomization to Week 208 (EOT); for safety analysis include FU 
period up to last dose + 84 days for early discontinued subjects.
Entire study period = randomization to end of study (EOS); includes follow up period (Week 
212, 216 and 224)
For evaluation of entire treatment/study period, AIN457 treatment groups will be pooled to 
“any AIN457”.
2.8.1
Adverse events (AEs)
Only treatment emergent adverse events are summarized. However all AEs are included in the 
listing with flags for treatment emergent. Non-treatment emergent adverse events may be 
summarized separately upon request.
Treatment emergent adverse events are defined as events started on or after the first dose of 
study medication or events present prior to the first dose of study medication but increased in 
severity on or after dosing based on preferred term and within last dose + 84 days (inclusive).
The crude incidence of treatment emergent adverse events will be summarized by primary 
system organ class and preferred term. Confidence intervals for the crude rate will be derived 
as described in Section 5 Appendix. In addition, exposure time-adjusted rates (incidence rate) 
including 95% confidence intervals may be provided, see also Error! Reference source not 
found.10. 
Table 2-10
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)
initial
(Day 1 -
week 16)
• crude 
incidence
• crude 
incidence
• crude 
incidence
• crude 
incidence
• crude 
incidence
• crude 
incidence
Entire treatment 
period
• crude 
incidence
• exp.time 
adjusted 
incidence
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
• crude 
incidence
• exp.time 
adjusted 
incidence*
• crude 
incidence
Entire study
• exp. time 
adjusted
Incidence*
• exp. time 
adjusted
Incidence*
*Extended safety summary will be provided for pediatrics trials with FU of 16 weeks


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* Please note that exposure adjusted incidence rates may be provided and follow the guideline 
as below:

Primary SOC level for AE and SAE

Level 1 for risks and SMQ

PT level for SAE

PT level for AE  ≥2% or incidence rate per 100 subject years ≥5.0 in AIN457 low dose 
or AIN457 high dose treatment group (may be updated following review of dry run 
outputs).

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 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 5.4.2. In addition, exposure time-adjusted incidence rates may be provided 
for the treatment period including all data (see Section 5.4.5).
Adverse events will be summarized by presenting, for each treatment group (including any 
AIN457), 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). The relative frequencies 
and 95% confidence intervals within each system organ class will be presented for adverse 
event and serious adverse event in a panel graph (for DMC only).
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.
The crude incidence of treatment emergent AEs may be repeated and presented by age, disease 
severity strata and by body weight strata subgroups.
The exposure time-adjusted incidence rate of treatment emergent AEs, SAEs and important 
identified or potential risks (level 1) in entire treatment period will be summarized, where data 
permits. Data will be reported by SOC and PT and presented by age, disease severity strata and 
body weight strata. Crude rate will also be evaluated. Summary by body weight and dose group 
may be evaluated in addition to the above.
Adverse events will also be reported separately by standardized or customized MedDRA
queries (SMQ or CMQ/NMQ). The MedDRA version used for reporting the study will be 
described in a footnote.


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The most common adverse events reported (≥z% in any group for each preferred term in the 
SOC-PT table or ≥z % in any group for each grouping term table) will be presented in 
descending frequency according to its incidence in total AIN457 group (combining both 
AIN457 treatment groups) 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 study treatment related adverse events, death, serious
adverse event, other significant adverse events leading to discontinuation and adverse events
leading to dose adjustment or interruption.
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE will be to be checked in a block e.g., among AE's in a ≤ 1 day gap block, 
if at least one SAE is occurring, then one occurrence is calculated for that SAE.
Algorithms for date imputations will be provided in Section 5 Appendix.
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures.
For those subjects who received erroneously the wrong treatment at least once, an additional
listing will be prepared displaying all adverse events for that subject and flag AEs that occurred 
after the first treatment error.
To meet the requirements for posting results to ClinicalTrials.gov and EudraCT, two further 
tables are produced and final reporting. Treatment emergent adverse events which are not 
serious adverse events with an incidence greater than X% and a summary for treatment 
emergent serious adverse events and SAE suspected to be related to study treatment. Summaries 
are presented by system organ class and preferred term on the safety set population. Here, the 
threshold value X is set to 2-5 (%) and may be updated following review of the dry run outputs.
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.
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.


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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).
The general guideline for laboratory summaries (including vital signs and ECGs in Section 
2.8.4.1 and 2.8.4.2) are as below:

all the summary of laboratory outputs (newly occurring notables, maximum changes, shift 
tables, by visit summary statistics) will be reported on all data collected up until end of 
study. Any summary presented by period will use the on-treatment definition i.e., include 
all assessments within last dose plus 84 days.

all records are displayed in the listing with the on-treatment flag. i.e., occurred within last 
dose plus 84 days- yes or no, as well as eCRF visits and period.
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
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 “>”).”
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline within treatment period will be summarized analogously. 
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.  


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The following laboratory parameters will be analyzed with respect to numerical Common
Terminology Criteria for Adverse Events (CTCAE) grades, given in Table 2-9: 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) and estimated glomerular filtration rate 
(eGFR).
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 2-11
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
eGFR
    >ULN – 2.5 x ULN
  <LLN –
60ml/min/1.73m2
>2.5 - 5.0 x ULN
<60-30 ml/min/1.73m2
>5.0 - 20.0 x ULN
<30-15 ml/min/1.73m2
>20.0 x ULN
<15 ml/min/1.73m2
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 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.
The number and percentage of subjects with newly occurring or worsening after baseline
(treatment emergent) liver enzyme abnormalities will be presented for the treatment period
based on the event criteria given in Table 2-12. For pooled DMC analysis 95% confidence will 
be provided. Standard laboratory change from baseline tables of liver function test by visit will 
be produced. 


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Table 2-12
Liver-related events
Parameter
Criterion
ALT
>ULN; >3xULN; >5xULN; >8xULN; >10xULN
AST
>ULN; >3xULN; >5xULN; >8xULN; >10xULN
ALT or AST
>3xULN; >5xULN; >8xULN; >10xULN
TBL
>ULN; >1.5xULN, >2xULN
ALP
>ULN;>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 &
TBL & ALP
ALP > 3x ULN & TBL > 2x ULN
ALP > 5x ULN & TBL > 2x ULN
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Potential Hy’s Law)
(ALT or AST > 3x ULN & TBL > 2x ULN & ALP < 2x ULN) or reported Hy's 
Law case
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN.
Individual subject data listings will be provided for subjects with newly occurring or worsening 
abnormal laboratory data. Data of subjects with newly occurring or worsening liver enzyme 
abnormalities will be listed in an additional listing.
For the DMC, a panel graph will be presented to display shift from baseline to maximum 
evaluation for each of the liver function test (including ALT, AST, ALP and TBL) by treatment. 
Similarly a graphical presentation of each hematology parameter (including Leukocytes, 
neutrophils, lymphocytes and platelets) will be presented to display shift of baseline to 
minimum evaluation based on CTCAE grades.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
The following quantitative variables may be summarized if requested: ventricular rate, RR 
interval, PR interval, QRS duration, QT interval, and corrected QT interval (QTc). Fridericia 
(QTcF) correction will be presented for QTc.


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Notable abnormal QTc will summarized by computing the number and percentage of subjects 
(including 95% confidence intervals for pooled DMC analysis) with:

QTc > 500 msec

QTc > 480 msec

QTc > 450 msec

QTc changes from baseline > 30 msec

QTc changes from baseline > 60 msec

PR > 250 msec
Summary statistics will be presented for ECG variables by visit and treatment group based on 
the entire study period. In addition, shift tables comparing baseline ECG interpretation (normal, 
abnormal, not available, total) with the worst on-treatment/study interpretation (normal, 
abnormal, not available, total) will be provided.
A listing of all newly occurring or worsening abnormalities (based on the treatment period/study 
period) will be provided, as well as a by-subject listing of all quantitative ECG parameters.
2.8.4.2
Vital signs
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
Vital signs will be summarized by visit based on the entire study period data. All vital signs 
will be listed with “on-treatment” flag displayed.
The number and percentage of subjects with newly occurring notable vital signs (within the 
treatment period) will be presented by treatment group. Subjects not meeting the following 
criteria at baseline but meeting at post-baseline are considered to be subjects with newly 
occurring abnormalities. Criteria for notable vital sign abnormalities are provided in Table 2-
13 below:
Table 2-13 Criteria for notable vital signs in pediatric patients
Age group
Systolic BP(mmHg)
Diastolic BP(mmHg)
Pulse (bpm)
6 -11 yrs
90-130
50-80
50-105
12-17 yrs
90-145
55-90
45-95
18 yrs and over
90-139
60-89
60-100


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If appropriate, data of subjects with newly occurring notable vital signs abnormalities will be
listed in an additional listing.
Of note, systolic and diastolic blood pressure will be measured twice (measurements separated 
by 1 to 2 minutes), the average will be entered on the Vital Signs eCRF and will be used in the 
analysis.
2.8.4.4
Growth and Physical development 
Body weight, height and BMI percentile will be summarized by treatment and visit.
Standard height, weight, and BMI curves will be obtained from the U.S. National Center of 
Health Statistics (www.cdc.gov/growthcharts) curves for ages up to 18 years. These growth 
curves will be used for all study subjects. The Center’s files contain the L, M, and SD 
parameters needed to generate exact percentiles as follows:


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; =
<=
>?
@
−1
A × CD
where X = physical measurement (e.g., patient’s weight, height, and BMI)
M = median
SD= standard deviation
L = the power in the Box-Cox transformation
Percentiles for each patient at each time point will be calculated using the SAS function 
PROBNORM(z). 
The number and percentages of subjects falling in low (i.e. <5), normal (i.e. 5-<95), or high 
(i.e. >= 95) growth percentiles will be summarized by treatment and visit. Shift from baseline
in growth percentile categories, i.e., low (i.e. <5), normal (i.e. 5-<95), or high (i.e. >= 95), will 
be summarized by treatment and visit.
2.9
Pharmacokinetic endpoints
All completed subjects with quantifiable pharmacokinetic (PK) measurements of secukinumab 
will be included in the pharmacokinetic data analysis.
Serum concentrations will be expressed in mass per volume units. All concentrations below the 
limit of quantification (BLQ) as well as missing data will be labeled as such in the concentration 
data listings. BLQ concentrations will be included in the summaries. Serum concentration data 
from patients who missed a dose or doses will be excluded at the following visit(s).
PK concentrations will be summarized by eCRF visit and treatment. PK concentrations will 
also be presented by visit (i.e., CRF visit), dose group (75 mg, 150 mg, 300 mg) and body 
weight categories at visit (<25 kg, 25 to <50kg, ≥50 kg). Per protocol, a subject will change 
into a higher or lower weight category and dose, when the subject’s weight moves into a 
different weight category for two consecutive visits. This change is assessed from Week 12, 
then at week 16 and bimonthly until week 52 and at trimonthly visits in the extension phase. If
such a change happens, in the PK summaries, at the concerned assessment points, the subject 
will be accounted in the new dose group (75 mg, 150 mg, 300 mg) and weight category group. 
In addition to mean, standard deviation (SD), coefficient of variation (CV), median and quartiles, 
the geometric mean and geometric coefficient of variation (CV) and n(log) will be presented. 
The formula for deriving the geometric mean and CV (%) is as following:

CV (%) = (SD/mean)*100,

geometric mean=exp( (sum of log transformed data) / number of non-missing data 
points after log transformation),

geometric CV = sqrt( exp( variance of log-transformed data)-1)*100.
In addition, sample number, concentration, sample date, elapse time since day of first 
secukinumab dose, reason excluding from analysis will be listed by treatment.
Values below lower limit of quantification/below detection limit will be imputed by 0.


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Pharmacokinetic derived parameters AUC84-112d, Tmax and Cmax will be summarized by 
treatment group (AIN457 low dose and AIN457 high dose). Descriptive summary statistics
include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, 
minimum and maximum. Derived pharmacokinetic parameters will be listed by treatment 
sequence.
2.10
PD and PK/PD analyses
Not applicable.


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2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
2.14
Interim analysis
A primary endpoint analysis of the data collected up until Week 16, including the co-primary 
endpoint (at Week 12) will be performed after the last subject completes  their Week 16 visit. 
Efficacy and safety data up to Week 16 visit for all subjects will be summarized. AE listing will 
be presented on the entire treatment period i.e. reports AE data collected until last subject week 
16 cut-off date.
To address comments from the health authorities an additional full analysis will be performed 
when all subjects have completed the Week 24 visit. 
A full analysis will be performed when all subjects have completed the Week 52 visit, (or
premature treatment discontinuation visit). Thereafter, efficacy and safety data collected after 
Week 52 until the end of study may be reported yearly in separate reports.
Additional analyses may be performed to support health authority interactions, as necessary.
Trial modifications are not planned based on any interim analyses No aggregated statistical 
analysis will be performed by actual treatment group prior to W16 PEA.
3
Sample size calculation
The sample size for this study is calculated to ensure an adequate number of subjects for PK
analyses and powered efficacy analyses. Approximately 80 pediatric subjects from 6 to less
than 18 years of age at randomization will be recruited. Since a 15% screening failure rate is
expected, approximately 95 patients will be screened. The study will aim to recruit at least 60
subjects with moderate severity and approximately 20 subjects with severe severity.
Power calculations were performed to support the co-primary endpoints PASI 75 and IGA 0 or
1 response at week 12, and secondary endpoint PASI 90 at week 12, versus placebo (historical
control) for the low and high secukinumab dose regimens. The low dose arm with smaller 
treatment effect is being considered in the power/sample size calculation.
Data from four adult placebo-controlled
trials (CAIN457A2302, CAIN457A2303, 
CAIN457A2308 and CAIN457A2309) and pediatric placebo controlled trials (Paller et al 2008, 


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Landells et al 2015) were used to estimate the historical placebo response rate. For study 
CAIN457A2310, a 10% response rate was assumed for PASI 75, IGA 0 or 1 and 8% for PASI 
90 response for the placebo group. The 95% upper quantile of predicted number of responders 
are 7, 7 and 6 subjects, respectively. The assumed placebo response rates were derived 
accordingly with 40 pediatrics for study CAIN457A2310. Refer to table 3.1 below.
Table 3-1 Placebo response rates from historical secukinumab placebo controlled 
trials 
Adult Placebo 
Endpoint 
Number of subjects with response/
Placebo response
controlled trial 
Number of subjects evaluable
rate (%)
CAIN457A2302
IGA 0 or 1 
6/246
2.4
PASI 75
11/246
4.5
PASI 90
3/246
1.2
CAIN457A2303
IGA 0 or 1 
9/324
2.8
PASI 75
16/324
4.9
PASI 90
5/324
1.5
CAIN457A2308
IGA 0 or 1 
0/59
0
PASI 75
0/59
0
PASI 90
0/59
0
CAIN457A2309
IGA 0 or 1 
0/61
0
PASI 75
2/61
3.3
PASI 90
0/61
0
Pediatric Placebo 
Endpoint 
Number of subjects with response/
Placebo response
controlled trial 
Number of subjects evaluable
rate (%)
Ustekinumab
PGA 0 or 1 
2/37
5.4
Dermatol 2015
PASI 75
4/37
10.8
(Age 12 to 17 years)
PASI 90
2/37
5.4
Etanercept NEJM
PGA 0 or 1 
14/105
13
2008
PASI 75
12/105
11
(Age 12 to 17 years)
PASI 90
7/105
7
CAIN457A2310
IGA 0 or 1
7/40
17.5
(estimation 
PASI 75
7/40
17.5
Includes 
PASI 90
6/40
15
simulation
uncertainty error)
The Meta-Analytic-Predictive (MAP) approach derives an informative prior from historical 
data which is discounted using a hierarchical model. When using the MAP approach to estimate 
the predicted placebo response rate, differential discounting was defined for two stratum: 
pediatric study data and adult study data. Moderate between-trial heterogeneity (with τ prior set 
as HalfNormal(0, 0.5)) was defined for pediatric trial data and substantial heterogeneity (with 


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τ prior set as HalfNormal(0, 1)) was defined for adult trial data (Neuenschwander et al.2010), 
thus allowing pediatric trial data to be given a higher weight compared to adult trial data. The 
prior distribution for the regression coefficient β was set as non-informative Normal (0, 2). The 
following Table 3-2 presents the summary statistics of the fitted mixtures of conjugate 
distribution to the sample. 
All the calculations were performed in the R package RBesT (version 1.3.1) through the meta-
analytical-predictive framework (Spiegelhalter et al. 2004, Neuenschwander et al. 2010).
Table 3-2 Predictive placebo response rates for this study from model of historical 
data
Endpoint 
Mean Standard Deviation 
Median 
95% Credible Interval
IGA 0 or 1 
9% 
6% 
8% 
1-23%
PASI 75 
10% 
6% 
9% 
2-25%
PASI 90 
6% 
4% 
5% 
1-18%
Based on confirmatory efficacy in the adult phase III program (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309), the PASI 75, IGA 0/1 and PASI 90 
response rate at week 12 was assumed as 65%, 45% and 39% for secukinumab. Non-
informative prior was set for secukinumab arm. A sample size of 40 pediatric patients from this 
study under each high or low secukinumab arm over predictive placebo response (Table 3-2) 
will lead to a power of approximately 99% for each co-primary endpoint and secondary 
endpoint. Details as following:

A sample size of 40 pediatric patients per treatment group and true response rates of 65% 
for PASI 75 and 45% for IGA mod 2011 0 or 1 response for secukinumab was assumed. 
For each co-primary endpoint there is approximately 99% power to detect a posterior 
probability of the log odds ratio difference between placebo and secukinumab to exceed
with at least 97.5%. 

Similarly, for the secondary endpoint of PASI 90 response there is approximately 99%
power to provide a posterior probability of at least 97.5% that the PASI 90 response rate 
on secukinumab is greater than placebo. This assumes a response rate of 39% for
secukinumab. 
4
Change to protocol specified analyses
The following are changes to protocol specified analysis:
Following HA recommendadtion to impute subjects with all post-baseline missing values as 
non-responders according to the intention to treat principal and to remain consistent with the 
adult studies and pediatric data used within the MAP analysis, the primary analysis will be 
performed on pure non-responder imputation and the MI dropped. Modified non-responder 
analysis may still be performed upon request from HA. No sensitivity analysis will be provided 
for the Bayesian analysis. For the descriptive summary of key efficacy endpoints, results using 
pure non-responder imputation as well as multiple imputation will be provided.  


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Week 16 PEA analysis constitutes the scope for delivering to DMC and an extended FIR 
requirement, thus a full analysis will not be performed as planned. Further to recent 
communications with the health authorities, additional outputs and an interim analysis at Week 
24 is added to support the pediatric submission. The following subgroup summaries are added
to the planned analyses: 

Summaries by age subgroup:<12 years or ≥ 12 years

Summaries by body weight strata:<25kg, 25-<50kg and ≥ 50kg 

Summaries by disease severity strata:moderate, severe 

Summaries by body weight and dose group:AIN457 – 75 mg and < 25 kg, AIN457 Low 
– 75 mg and ≥25 kg -< 50 kg, AIN457 Low – 150 mg and ≥50 kg;, AIN457 High – 150 
mg and ≥25 kg -< 50 kg, AIN457 High – 300 mg and ≥50 kg;
Safety summaries for exposure adjusted incidence rates may be prepared.
Pandemic reporting (COVID-19)
Data collected in this trial that is affected by the COVID-19 situation, can be expected to lead 
to difficulties in interpretation in the trial’s reporting. In recognition of these challenges, both 
FDA and EMA (and local regulatory authorities) have issued specific guidelines that request 
Novartis to collect the reasons for non-compliance and discontinuation of clinical trial elements 
related to COVID-19 in all ongoing trials. 
In adherance to these guidences, specific protocol deviations were added to capture data 
necessary to provide a summary of impact for the pandemic. 
The primary and key secondary objective of the study assesed at Week 12 are not impacted. 
These were reported prior to the pandemic, which emerged as the last few patients were
reaching week 52 visit. Therefore, notably missing data are not expected and imputations are 
considered reasonable for evaluating efficacy up to week 52. 
All protocol deviations for the study will be summarised together (i.e including COVID-19
specific PDs) as described in section 2.3.1. In addition, all protocol deviations from 1st March 
2020, that is considered to be the starting point of COVID-19 period (as per internal guidance 
for those countries participating in this study) will capture whether there was any relation to 
COVID-19 including a precise relationship status in regard to COVID-19 virus (such as health 
status related, site issues, quarantine of patient/lockdown, drug supply issue, patient concern, 
other or no relationship to COVID-19). The relationship status will be presented in the listing.
For patients with suspected/confirmed cases of COVID-19, separate listings may be provided 
for disposition, concomitant medications/proceduces and significant non drug therapies and 
adverse events (including COVID-19 testing with outcome results). Summaries of treatment 
emergent COVID-19 related adverse events may be presented if data permits. 


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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.
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:
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 + 140 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 + 140 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: 


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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. 
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:


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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). 
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.
5.1.3.3
First diagnosis date (Pso, PsA) imputation
1. If the first diagnosis day/ month are missing and the year is non-missing:






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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 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 
4572311 for this study. SAS proceduce MI will be used 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>;
EM converge=1E-2 MAXITER=5000;
MCMC PRIOR=RIDGE=2 ;
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>.
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>;


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IF <change from baseline PASI week primary endpoint>/<baseline PASI>=0.75 THEN <PASI 75 response> =1;
ELSE <PASI 75 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;
5.4.4
Crude incidence and related risk estimates
5.4.4.1
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 
.
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.
p
q

1


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5.4.5
Exposure adjusted incidence rate and related risk estimates
5.4.5.1
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.
5.4.6
Primary analysis
Example schematic code for Bayesian analysis of 2311 using dummy data
for PASI 75.
## model to fit placebo data 
tau.prior <- rbind(c(0, 0.5), c(0, 1))
set.seed(345652)
analysis_pbo_mc_pasi <- gMAP(cbind(r, n-r) ~ 1 | trial,
                             tau.strata=stratum,
                             family=binomial,
                             data=final_data_pbo,
                             tau.dist="HalfNormal",
                             tau.prior=tau.prior,
                             beta.prior=rbind(c(0,2)))
T
c
L
D
2
,
2
/
5.0


T
c
U
D
2
2
,2
/
1
5.0






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## model to fit the data of A2311
set.seed(34535214)
analysis_A2311_mc_pasi75 <- gMAP(cbind(r, n-r) ~ 0 + TREATMENT,
                                 family=binomial,
                                 data=active,
                                 tau.dist="Fixed",
                                 tau.prior=1E-6,
                                 beta.prior=matrix(c(0,0,2,2), 2, 2))
5.4.7
Key secondary analysis
As per section 5.4.6 but on the PASI 90 endpoint. 
5.4.8
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. 
Subjects without PASI 75/90 response will be considered as censored at Week 12.
Median time to event 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). The plot will include the number of subjects at risk for each treatment group 
at pre-specified timepoints, which are 0 to <=  4 weeks , >4 to <=8 weeks and 8 to <=12 weeks. 
Subjects at risk, timepoint “0” and censoring will be defined as described in Table 5-1 below:
Table 5-1
Variable:
Time to
Risk set
Time = 0
Time of 
event
Censoring
Psoriasis 
ConMed*
Informative  
censoring
PASI 
75/90 
response
All subjects 
randomized 
with baseline 
and post-
baseline data 
for PASI
Date of 
randomization
Date of 1st
visit with 
PASI 
75/90
response 
observed
Week 12
visit 
date/discont
inuation
date   
Censor (if 
ConMed 
taken 
before the 
event)
No
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


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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: INCL01; OTH12
Misrandomized subject
Safety
DVSPID: INCL01; OTH12
Misrandomized subject 
Subjects who did not take any 
study treatment
INCL01: ICF missing or not signed; in the case where ICF was obtained after initiating study 
procedures, subjects will be included in all analysis sets
OTH12: Severe ICH-GCP non-compliance of study site


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6
Reference
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika, 26; 404–413
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
Fredriksson T, 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,
multicenter, randomized dose-finding trial. Br J Dermatol; 152:1219-27.
Landells I, Marano C, Hsu MC, et al (2015). Ustekinumab in adolescent patients age 12 to 17
years with moderate-to-severe plaque psoriasis: Results of the randomized phase 3 CADMUS
study. J Am Acad Dermatol. 73:594-603.
Little, R.J.A and Rubin, D.B. (2002). Statistical Analysis with Missing Data. Wiley Series in 
Probabiliy and Statistics, Chapter 10
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ (2010) Summarizing
historical information on controls in clinical trials. Clinical Trials 7, 5-18.
Newcombe RG (1998) Two-sided confidence intervals for the single proportion: comparison 
of seven methods. Statistics in Medicine; 17: 857-872.
Paller AS et al (2008) Etanercept treatment for children and adolescents with plaque psoriasis. 
N Engl J Med; 358:241-51.
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley.
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical trials and 
Health-Care Evaluation. Chichester: John Wiley and Sons.
Weisman S, Pollack CR, Gottschalk RW (2003) Psoriasis disease severity measures: 
comparing efficacy of treatments for severe psoriasis. J Dermatolog Treat; 14: 158-165
Gelman Andrew, and Rubin Donald B.Rubin (1992) Inference from Iterative Simulation Using 
Multiple Sequences. Statistical Science; Vol 7, No. 4: 457-511.
Retrieved from http://dx.doi.org/10.1002/jrsm.1217
Satyanshu K. Upadhyay, Umesh Singh, Dipak K. Dey, Appaia Loganathan. Current Trends in 
Bayesian Methodology with Applications. 1st Edition .Chapman and Hall/CRC. Chapter 4 
West M (1993) Approximating posterior distributions by mixtures,  Journal of the Royal 
Statistical Society: Series B (Methodological), 55(2), 409–422


Clinical Development – General Medicine 
AIN457/Secukinumab 
AIN457A2311 / NCT03668613
A randomized, open-label, multicenter trial to assess the 
efficacy of subcutaneous Secukinumab after twelve weeks 
of treatment, and to assess the safety, tolerability and long-
term efficacy in subjects from 6 to less than 18 years of age 
with moderate to severe chronic plaque psoriasis 
Statistical Analysis Plan (SAP) Amendment 1 
Author: 
 (Trial Statistician) 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
27 Sept 2023 
Number of pages: 
56 
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) 
14-Dec-
2022 
Prior to 
Final lock 
Creation of 
final DBL SAP  
Clarification on methods 
to address missing data  
beyond Week 52 
2.7 
14-Dec-
2022 
Prior to 
Final lock 
Creation of 
final DBL SAP  
Clarification on data 
presenting for patients 
with suspected/confirmed 
cases of COVID-19  
4 
15-Sept-
2023 
Prior to 
Final lock 
Creation of 
amendment 1 
Adjusted the definition of  
dose and weight subgroup 
for the final analysis 
2.2.1 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.1.1 
Randomization ........................................................................................ 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 19 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 28 
2.5.4 
Supportive analyses ............................................................................... 28 
2.6 
Analysis of the key secondary objective ............................................................... 29 
2.6.1 
Key secondary endpoint ........................................................................ 29 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 29 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 29 
 
 29 
2.8 
Safety analyses....................................................................................................... 31 
2.8.1 
Adverse events (AEs) ............................................................................ 32 
2.8.2 
Deaths .................................................................................................... 34 
2.8.3 
Laboratory data ..................................................................................... 35 
2.8.4 
Other safety data ................................................................................... 37 
2.9 
Pharmacokinetic endpoints .................................................................................... 39 
2.10 
PD and PK/PD analyses ........................................................................................ 40 
 
 40 
2.12 
Biomarkers ............................................................................................................. 41 


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2.13 
Other Exploratory analyses.................................................................................... 41 
2.14 
Interim analysis ...................................................................................................... 41 
3 
Sample size calculation ..................................................................................................... 42 
4 
Change to protocol specified analyses .............................................................................. 44 
5 
Appendix ........................................................................................................................... 45 
5.1 
Imputation rules ..................................................................................................... 45 
5.1.1 
Study drug ............................................................................................. 45 
5.1.2 
AE date imputation ............................................................................... 45 
5.1.3 
Concomitant medication date imputation ............................................. 47 
5.2 
AEs coding/grading ............................................................................................... 49 
5.3 
Laboratory parameters derivations ........................................................................ 49 
5.4 
Statistical models ................................................................................................... 49 
5.4.1 
Analysis of continuous data .................................................................. 49 
5.4.2 
Analysis of binary (and categorical) data .............................................. 49 
5.4.3 
Multiple imputations for response variables ......................................... 50 
5.4.4 
Crude incidence and related risk estimates ........................................... 51 
5.4.5 
Exposure adjusted incidence rate and related risk estimates ................ 52 
5.4.6 
Primary analysis .................................................................................... 53 
5.4.7 
Key secondary analysis ......................................................................... 53 
5.4.8 
Analysis of time-to-event data .............................................................. 53 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 54 
 
 54 
6 
Reference ........................................................................................................................... 56 


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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 
 
CV 
 
Coefficient of variation  
ECG 
Electrocardiogram 
eCRF 
Electronic case report/record form 
eGFR 
FAS 
Estimated glomerular filtration rate  
Full analysis set 
FIR 
First Interpretable Results 
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 
LLQ 
LOCF 
Lower Limit of Normal 
Lower Level of Quantification 
Last Observation Carried Forward 
MACE 
MAP 
Major Adverse Cardiovascular Event 
Meta-analytic-predictive 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
MI 
Medical Dictionary for Regulatory Activities 
Multiple Imputation  
NMQ 
Novartis MedDRA Query 
NovDTD 
Novartis Drug and Therapy Dictionary 
PASI 
PK 
PsA 
PsO 
Psoriasis Area and Severity Index 
Pharmacokinetics  
Psoriatic arthritis 
Psoriasis 
PD 
PRO 
Protocol deviation 
Patient Reported Outcome 
PT 
QTc 
QTcF 
Preferred Term 
Corrected QT interval 
Fridericia corrected QTc 
RMP 
Risk Management Plan 


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SAS 
Statistical analysis software 
SAE 
Serious adverse event 
SPP 
Safety Profiling Plan 
SOC 
SMQ 
System Organ Class 
Standardized MedDRA Query  
TBL 
Total bilirubin 
TEAE 
Treatment Emergent Adverse Event 
ULN 
ULQ 
Upper Limit of Normal 
Upper Level of Quantification 
WBC 
White blood cell 
 
 
 
 
 


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1 
Introduction 
 
Data will be analyzed by Novartis according to the data analysis section 9 of the protocol, 
which is available in Appendix 16.1.1 of the CSR. 
This document contains the detailed statistical and analytical plans for full analyses of 
CAIN457A2311 study with reference to the study protocol and the project 
standard analysis plans AIN457A MAP.  
 
1.1 
Study design 
This is an open-label, parallel-group, two-arm, multi-center trial in pediatric subjects aged 6 
years to less than 18 years with moderate to severe chronic plaque psoriasis. 
 
Approximately 80 subjects (at least 60 patients with moderate severity) will be enrolled. It is 
expected that subjects will be enrolled in about 40 centers worldwide. It will be targeted to 
have at least 5 subjects in the < 25 kg weight, and at least 10 subjects in each of the other two 
weight groups (25 - <50 kg and ≥50 kg). Subjects will receive the appropriate dose based on 
their body weight category. If a subject moves into a higher or lower weight group at two 
consecutive visits with weight measurements from Week 12 onwards, the subject will receive 
dosing according to the new (higher or lower) weight group respectively. The dose will be 
adapted starting from the visit of the second consecutive weight change. 
 
 
The following study periods will be considered for analysis: 
 
Screening Period 
The screening period of up to 4 weeks will be used to assess eligibility of the subjects and to 
taper subjects off prohibited medication. 
 


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Treatment Period 
The treatment period is defined as randomization to Week 208. In this period the endpoints 
are assessed and subjects are followed for long-term safety and efficacy. For safety analysis 
this is defined a last dose + 84 days exposure. 
 
Follow-up Period 
The treatment-free follow-up visits will be at Week 212, Week 216 and Week 224 (End Of 
Follow-up/EOF). Subjects who complete or discontinue treatment early are expected to 
perform the complete treatment-free follow-up period unless they start another systemic 
antipsoriatic treatment.  
Of note: data from follow-up period for prematurely discontinued subjects will be included in 
the analysis of treatment period if appropriate. 
Entire study period (Randomization to end of study (EOS)), including follow-up period 
(W212, W216 and W224 visits). 
 
1.1.1 
Randomization  
Randomization will be stratified by body weight (< 25 kg, 25-< 50 kg, ≥ 50 kg) and disease 
severity collected at baseline (moderate, severe) (refer to Table 1-1). Subjects will be 
randomized using 1:1 ratio into one of the following treatment groups according to their 
baseline body weight: 
 
• AIN457  low dose:  
o Subjects weighing < 50 kg at baseline will receive a dose of 75 mg 
administered as one injection of  the 75 mg pre-filled syringe 
o Subjects weighing  ≥50 kg at baseline will receive a dose of 150 mg 
administered as one injection of  the 150 mg pre-filled syringe 
 
• AIN457 high dose:  
o Subjects weighing < 25 kg at baseline will receive a dose of 75 mg 
administered as one injection of  the 75 mg pre-filled syringe 
o Subjects weighing 25-<50 kg at baseline will receive a dose of 150 mg 
administered as one injection of  the 150 mg pre-filled syringe 
o Subjects weighing ≥ 50 kg at baseline will receive a dose of 300 mg 
administered as one two injections of the 150 mg pre-filled syringes  
 
Table 1-1 Disease severity definition by IGA and PASI score 
IGA score 
PASI score  
 
Psoriasis severity 
3  
 
12-< 20  
 
Moderate 
3  
 
≥ 20  
 
 
Moderate 


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4  
 
12-< 20  
 
Moderate 
4  
 
≥ 20  
 
 
Severe 
PASI: Psoriasis Area and Severity Index; IGA: Investigator Global Assessment 
1.2 
Study objectives and endpoints 
The primary objective of this study is to evaluate efficacy of AIN457 (low dose and high 
dose) compared to placebo (historical control) with respect to PASI 75 and IGA mod 2011 0 
or 1 response rates at Week 12 in treatment of moderate to severe plaque psoriasis. Historical 
placebo data from qualifying trials will be used as the control for primary and key secondary 
efficacy endpoint analyses. Further details are provided in Section 2.5. 
 
The secondary objectives for this study are as follows: 
• To evaluate the efficacy of secukinumab in pediatric subjects with respect to PASI 90 
at Week 12, compared to placebo (historical control) 
• To investigate the clinical safety and tolerability of secukinumab as assessed by growth, 
weight gain, vital signs, clinical laboratory variables, electrocardiogram (ECG), and 
adverse event monitoring 
• To evaluate the pharmacokinetics of secukinumab 
 
This study will provide efficacy and safety data to support a submission for the indication of 
moderate to severe plaque psoriasis. 
A summary of the primary, secondary 
 endpoints are listed in Table1-
2. 


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Table 1-2 
Primary, secondary 
 variables 
Variable 
Type 
PASI 75 response at Week 12 (compared to historical placebo) 
Co-primary 
IGA 0/1  response at Week 12 (compared to historical placebo) 
Co-primary 
PASI 90 response at Week 12 (compared to historical placebo) 
Key 
secondary 
Height, weight, vital signs, laboratory evaluations , ECG over time  
secondary  
Adverse events  
secondary 
Secukinumab concentration in serum over time and derived PK parameters (AUC and Cmax) 
secondary 
 
2 
Statistical methods 
2.1 
Data analysis general information 
This document covers statistical and analytical plans for CAIN457A2311 with reference to 
study protocol and the project standard analysis plans (AIN457 MAP).  
Novartis will be performing all analyses. Statistical software of R version 3.4.3 or later and SAS 
version 9.4 or later will be used. 
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. 
All listings will be presented by treatment sequence.  
Footnotes on outputs will be kept to a minimum also for outputs not covered in AIN457A MAP 
TFL shells.  
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 


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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 (body mass index) 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 75 mg, 0.5 ml liquid formulation in a pre-filled syringe 
o Secukinumab 150 mg, 1 ml liquid formulation in a pre-filled syringe 
o Secukinumab 300 mg, 2 x 1 ml  liquid formulation in a pre-filled syringe 
 
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 


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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 randomization (day). All assessments obtained after randomization (day) 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 of study treatment. All assessments obtained after the first dose (day) 
of study treatment are considered as post-baseline unless otherwise specified. 
Of note, baseline will be derived based on the randomization day or first dose day, exact 
randomization/dosing time is not considered. 
 
In general, a baseline value refers to the last measurement made prior to administration of the 
first dose of study treatment. However, for patient reported outcomes, laboratory assessments 
and ECG if no pre-treatment value exists, values obtained after first dose of treatment can be 
used as baseline only if it was collected on the same day as first dose. 
 
2.1.1.4 
Day of last dose of randomized study treatment 
The date of last dose will be collected via the electronic case report form (eCRF). 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. 
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 
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 Interactive Response Technology system (IRT), 
the actual stratum will be used in analyses. Subjects reporting a severe GCP (good clinical 
practice) violation will be excluded from the FAS. 
Of note, subjects excluded from the randomized set will be excluded from the FAS. 


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Safety set: The safety set includes all subjects who took at least one dose of study treatment 
during the treatment period. For safety summaries, 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. If a subject has received intermittent wrong treatment, the treatment 
received will be set to the original randomized treatment. 
For those subjects who received erroneously the wrong treatment at least once, an additional 
listing will be prepared flagging adverse events which occurred after the treatment deviation. 
Protocol deviations leading to  exclusion from analysis populations are defined in Table 5-2 in 
Section 5 Appendix. 
 
The number of subjects in each analysis set will be presented for all treatment groups in efficacy 
and safety analyses, and for all subjects (total). The number of screened and screen failures 
subjects will also be shown for all subjects (total).  
 
2.2.1 
Subgroup of interest 
The primary endpoint(s), selected secondary
 endpoints and selected safety 
endpoints will be evaluated using the subgroups defined in Table 2-1 where appropriate. 
Subgroup analyses for the study endpoints are represented in Table 2.2. 
 
  
Table 2-1 
Subgroups definitions 
Subgroup 
variables 
Categories 
Label 
for 
outputs 
Suffix 
for 
outputs* 
Randomization 
weight strata 
body weight stratum  
(kg:<25, 25-<50, ≥50) 
Weight 
strata 
a 
Randomization 
disease 
severity 
strata 
Disease 
severity 
strata 
(moderate, severe) 
Disease 
severity 
strata 
b 
Age group 
(<12 years or ≥12 years) 
Age 
group 
c 
Body weight and 
dose group* 
 AIN457 75 mg and < 25 kg, 
AIN457 75 mg and  25--< 
50 kg, AIN457  150 mg and 
≥ 50 kg;   AIN457  150 mg 
and 25-< 50 kg, AIN457 
300 mg and≥ 50 kg 
Body 
weight 
by dose 
group 
d 
 
 
 
 


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*In the final (Week 224) analysis, subjects will be accounted in their actual dose group and 
weight category group to evaluate doses adjusted to the body weight.  Per protocol, a subject 
will change into a higher or lower weight category and dose, when the subject’s weight moves 
into a different weight category for two consecutive visits. If such a change happens, starting 
from the next efficacy assessment after the dose change, the subject will be accounted in the 
new dose group (75 mg, 150 mg, 300 mg) and weight category group. 
 
Table 2-2 
Subgroup endpoints 
Endpoint/analysis 
Randomization strata  
including weight and 
disease severity 
Age 
Weight and by 
dose group 
Adverse event 
PK concentration data 
X 
 
X 
 
X 
X 
Demography and 
backgroud characterics  
X 
X 
 
 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Summaries will be reported by the following treatment groups: 
Treatment for analysis 
• AIN457 low dose   
• AIN457 high dose 
• Total 
 
The following common background and demographic variables will be analyzed: 
Continuous variables: 
• Age in years (derived from year of birth and informed concent data, assuming date is 
July 1st since only year of birth is  reported on the case report form (CRF)) 
• Height 
• Weight 
• Body mass index (BMI) 


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Categorical variables: 
• Age categories (<12 years, 12 years and older) 
• Gender 
• Race 
• Ethnicity 
• Weight categories (<25 kg, 25-<50 kg, ≥50 kg) 
• Disease severity (moderate or severe) 
 
Psoriasis specific baseline characteristics and history of disease will be summarized as well: 
baseline PASI, baseline PASI (≤20, >20), baseline total body surface area (BSA), baseline IGA 
mod 2011 score (moderate, severe), severity of psoriasis (as defined at randomization), 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). Summaries above will be repeated and presented separately by age group and 
body weight by dose group.  
 
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. 
 
Time since diagnosis of psoriasis (PsO) and time since diagnosis of psoriatic arthritis (PsA) 
will be calculated using the following formula: 
Time since diagnosis = (inform consent date –first diagnosis date + 1)/365.25 
The first diagnosis date of PsO or PsA will be imputed according to the imputation rules in 
Section 4.1 of MAP 
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. 
Any condition entered on the relevant medical history / current medical conditions eCRF will 
be coded using the MedDRA dictionary. They will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) of the MedDRA dictionary. 
Unless otherwise specified, analyses will be based on the randomized set. 


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2.3.1 
Patient disposition 
The number of subjects screened will be presented. In addition, the reasons for screen failure 
will be provided. The number and percentage of subjects in the randomized set who completed 
study periods (treatment period and treatment free follow period) 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 by randomized treatment groups on the FAS population. All substantial 
protocol deviations will be displayed in the outputs.   
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 injections will be summarized by treatment group by means of 
contingency tables.  
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 (any exposure, ≥ 1 
week, ≥ 2 weeks, ≥ 3 weeks, ≥ 4 weeks, and thereafter every 4 weeks, so ≥ 8 weeks, ≥ 12 weeks, 
etc.) will be displayed.  
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 last dose plus 84 days, the end of 
study treatment 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 reported for the treatment period 
up to Week 16 for the PEA, with the last category “≥16 weeks”. Summaries on the entire 
treatment will be provided at Week 24 IA and thereafter.   
Also, subjects who changed dose due to change of weight group will be listed if required. 
2.4.1.1 
Visit window 
Visit-windows will be applied to data summarized by visit. These will be based on study 
evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are the protocol defined scheduled visits around which visit windows are 
created to cover the complete range of days within the study. The visit windows are shown in 


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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. 
 
The analysis visit will be used for listing of visit and period for safety data. If a visit falls after 
the last visit window, it is not assigned an analysis visit and will be listed under label “After 
Week xxx”.  
 
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 2-11 
Week 2 
2 
15 
Day 12-18 
Week 3 
3 
22 
Day 19-25 
Week 4 
4 
29 
Day 26-43 
Week 8  
8 
57 
Day 44-71 
Week 12 
12 
85 
Day 72-99 
Week 16 
16 
113 
Day 100-141 
Week 24 
24 
169 
Day 142-197 
Week 32 
32 
225 
Day 198-253 
Week 40 
40 
281 
Day 254-309 
Week 48 
48 
337 
Day 310-351 
Week 52 
52 
365 
Day 352-407 
Week 64 
64 
449 
Day 408-491 
Week 76 
76 
533 
Day 492-575 
Week 88 
88 
617 
Day 576-673 
Week 104 
104 
729 
Day 674-771 
Week 116 
116 
813 
Day 772-855 
Week 128 
128 
897 
Day 856-939 
Week 140 
140 
981 
Day 940-1037 
Week 156 
156 
1093 
Day 1038-1135 
Week 168 
168 
1177 
Day 1136-1219 
Week 180 
180 
1261 
Day 1220-1303 
Week 192 
192 
1345 
Day 1304-1401 
Week 208 (EOT) 
208 
1457 
Day 1402-1471 


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Week 212 
212 
1485 
Day 1472-1499 
Week 216 
216 
1513 
Day 1500-1541 
Week 224 (EOF) 
224 
1569 
Day 1542-1597 
* 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 24 only, Week 12 visit window will extend from Day 2 to Day 99 
(combining Week 1 to Week 12 visit windows), Week 24 will extend from Day 100 to Day 
197 (combining Week 16 to Week 24). If more than one assessment falls into the interval, the 
rules defined in Section 2.4.1.2 below are applied. 
 
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 
   
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. 


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Timing of 
measurement 
Type of data 
Rule 
If two measurement have been taken 
on the same day and same visit then 
select the worst. 
 
 
 
 
 
 
  
 
 
 
 
 
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 take the average 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) and PT. 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 


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earlier will be a concomitant medication, including those which were started pre-baseline and 
continued into the treatment period.  
Seperate psoriasis specific summaries of prior and/or concomitant medication will be presented 
as in Table 2-5, but as well for topical, phototherapy and photo chemotherapy (yes/no) using 
the randomized set. 
In addition, medical procedures and significant non-drug therapies as coded in MedDRA will 
be summarized. 
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. Summaries will be based on 
the safety set.  
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 
 
 
 


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2.5 
Analysis of the primary objective 
 
The primary analysis of the study is a Bayesian analysis, chosen to allow the direct 
incorporation into the analysis of information about placebo response rates from historical data. 
Literature and internal Novartis pediatric and adult plaque psoriasis studies were reviewed to 
provide the basis for assessing efficacy compared to a historical placebo. All analyses included 
in this study are based on clinically appropriateness and alignment of definitions (endpoints, 
clinical disease population, and time point of assessment).  Integrated in the analysis are data 
from four Novartis reported secukinumab adult placebo-controlled trials (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309) and pediatric study CAIN457A2310.  
Pediatric placebo-controlled trial data from literature on other biologics at study level data will 
be utilized (Paller 2008, Landells et al 2015). A historical placebo control is obtained through 
the Bayesian meta-analytic-predictive (MAP) framework (Spiegelhalter et al 2004, 
Neuenschwander et al. 2010). Further details on the historical data included are provided in 
Section 3 and Table 3.1. Note, placebo response rates for study CAIN457A2310 will be 
available prior to the reporting of this study and therefore utilized in this analysis.   
2.5.1 
Primary endpoint 
The co-primary efficacy variables are PASI 75 response at Week 12 and IGA mod 2011 0 or 
1 response at Week 12. Analysis of the primary variable will be performed on each treatment 
group (AIN457 high vs. historical placebo and AIN457 low dose vs. historical placebo) 
separately on the FAS population.  
 
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.  
A PASI score (Fredriksson and Pettersson 1978, Weisman et al 2003, Gottlieb et al 2005) will 
be derived as indicated in Table 2-5. 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: 
• The neck is assessed as part of the head. 
• The axillae and groin are assessed as part of the trunk. 
• The buttocks are assessed as part of the lower limbs. 
• 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 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 performed by investigator at 
screening and randomization only. The PASI scores 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 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 
 
 
 
 
 


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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. 


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Table 2-8 
Overview of analysis methods for efficacy variables 
Variable(s) 
Summary of 
time to event  
Summary 
statistics for 
binary/ 
categorical data  
Bayesian 
Analysis  
Summary 
statistics for 
continuous 
data 
Graphs 
PASI 75 response at  Week 12 
 
X 
X 
 
X* 
IGA 0/1 response at Week 12 
 
X 
X 
 
X* 
PASI 90 response at  Week 12 
 
X 
X 
 
X* 
 
* dot plot; ** time course plot 
 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The statistical hypothesis are that AIN457  high dose or AIN457 low dose is not superior to 
placebo from historical data in the proportion of subjects with PASI 75 response and IGA 0 or 
1 response at Week 12. Data from four adult placebo-controlled trials (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309) and pediatric placebo controlled trials 
(Paller et al 2008, Landells et al 2015 and CAIN457A2310) will be used to estimate the 
historical placebo response rate.  
The primary hypotheses of comparing AIN457 doses versus historical placebo data will be 
evaluated using a Bayesian model fitted to study level data. A Bayesian method has been chosen 
to allow the direct incorporation into the analysis of information about placebo response rates 
from historical data through a meta-analytic-predictive (MAP) prior. These historical data will 
include adult (data from repository CPOOL) and pediatric studies.    
 
First, a logistic regression Bayesian mixed-effects model is fitted to the historical placebo data, 
including terms study and population. This is built to predict efficacy outcomes of a future 
pediatric trial taking into account between trial heterogeneity of the control response rate. The 
adult studies are assigned a smaller weight in comparison to the pediatric studies. This is 
achieved through allocation to two distinct exchangeability strata which share a common 
population response rate, but differ in their between-trial heterogeneity parameter 𝜏𝜏𝑠𝑠(ℎ) .  
Moderate between-trial heterogeneity (with τ prior set as HalfNormal(0, 0.5)) was defined for 
pediatric trial data and substantial heterogeneity (with τ prior set as HalfNormal(0, 1)) was 
defined for adult trial data (Neuenschwander et al 2010), thus allowing pediatric trial data to be 
given a higher weight compared to adult trial data. From this model, the MAP prior is derived 
on the logit scale, and represents the predicted placebo log odds of the pediatric trial, which is 
used in this study as the comparator. For each endpoint the model was fit using MCMC and the 
resulting posterior distributions forming the MAP prior are approximated with a parametric 


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distribution for each endpoint. As parametric distribution a mixture of normal distributions is 
used, since mixtures can arbitrarily exact approximate any target distribution (West M 1993).  
The number of mixture components is chosen automatically using lowest Akaike Information 
Criteria (AIC) as the criterion. This step is performed prior to the first database lock, and results 
per endpoint from the best fitting mixture model are presented in Table 2-9.   
Table 2-9 
Information on placebo priors 
Endpoint  
Mixture component 1 
Mixture  component 2 
Mixture component 3 
IGA 0/1 
  Weight  
  Mean 
  SD 
 
0.555 
-3.337 
1.0048 
 
0.445 
-2.741 
0.5311 
 
PASI 75 
  Weight  
  Mean 
  SD 
 
0.361 
-2.555 
0.3866 
 
0.351 
-2.101 
0.2910 
 
0.288 
-2.723 
0.9029 
PASI 90 
  Weight  
  Mean  
  SD 
 
0.774 
-3.487 
0.5944 
 
0.226 
-4.058 
1.0976 
 
 
A separate model for each endpoint is fitted on the log odds scale to active data from this study 
with the term treatment. 
These data will be used to calculate the Bayesian posterior of the log odds ratio between AIN457  
and placebo treatment response rate in this trial. For the log odds of the AIN457  treatment 
groups a non-informative prior will be used, whilst the placebo treatment group log odds 
response rate will be represented though the MAP prior as described above..  
Both models described above are fitted separately on each efficacy endpoint (PASI 75, PASI 
90 and IGA 0/1) using MCMC in Stan version 2.17.1. The MCMC non-convergence Rhat 
diagnostic (Gelman and Rubin 1992) will be monitored for all model parameters. Rhat values 
much greater than 1.0 indicate sampling problems and the overall number of model parameters 
with a Rhat value greater than 1.1 will be documented if observed. It is expected there will be 
zero divergent transitions during the sampling phase of the used hamiltonian monte-carlo (HMC) 
algorithm implemented in Stan (Upadhyay et al 2015). 
 
The analysis will report the posterior of the mean log odds ratio as point estimate by its median, 
its 95% credible interval and the probability of a positive treatment effect which corresponds to 
the level of evidence for a positive treatment effect. Comparisons with placebo will be 


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performed for the AIN457 low and high dose group separately on each of the efficacy endpoints 
at week 12.  
Results from the posterior distribution will be plotted to provide a graphical representation.  
Analysis of the co-primary variables and key secondary endpoint will be based on the Full 
Analysis Set (FAS).  
 
Notation 
Indexes 
𝑖𝑖∈{1,2,3} labels endpoint PASI 75 (1), IGA 0/1 (2) or PASI 90 (3) 
𝑗𝑗∈{1,2} labels AIN457 treatment arm low dose (1), high dose (2) 
ℎ∈{1, … , 𝐻𝐻} historical studies 
𝑠𝑠(ℎ) ∈{1,2} population 
pediatric historical studies have 𝑠𝑠(ℎ) = 1 
adult historical studies have 𝑠𝑠(ℎ) = 2 
Data 
• 𝑟𝑟 responders in placebo group 
• 𝑟𝑟෤ responders in active group 
• 𝑛𝑛 patients in placebo group 
• 𝑛𝑛෥ patients in active group 
Parameters 
• 𝜋𝜋 responder rate placebo 
• 𝜃𝜃 responder rate placebo, log-odds 
• 𝜇𝜇 population response rate placebo 
• 𝜏𝜏 between-trial heterogeniety of trial specific intercept for placebo 
• 𝜋𝜋෥ responder rate active 
• 𝜃𝜃෥ responder rate active, log-odds 
• 𝛿𝛿 treatment effect as log-odds-ratio with respect to placebo control group 
 
 
Model 
Likelihood 


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𝑟𝑟𝑖𝑖,ℎ|𝜋𝜋𝑖𝑖,ℎ, 𝑛𝑛𝑖𝑖,ℎ∼Binomial(𝜋𝜋𝑖𝑖,ℎ= logit−1(𝜃𝜃𝑖𝑖,ℎ), 𝑛𝑛𝑖𝑖,ℎ) 
𝑟𝑟෤𝑖𝑖| 𝜋𝜋෥𝑖𝑖, 𝑛𝑛෥𝑖𝑖∼Binomial(𝜋𝜋෥𝑖𝑖= logit−1(𝜃𝜃෥𝑖𝑖), 𝑛𝑛෥𝑖𝑖) 
Hierarchical model (MAP) 
𝜃𝜃𝑖𝑖,ℎ|𝜇𝜇𝑖𝑖, 𝜏𝜏𝑖𝑖,𝑠𝑠(ℎ) ∼Normal(𝜇𝜇𝑖𝑖, 𝜏𝜏𝑖𝑖,𝑠𝑠(ℎ)
2
) 
𝜃𝜃𝑖𝑖,⋆|𝜇𝜇𝑖𝑖, 𝜏𝜏𝑖𝑖,1 ∼Normal(𝜇𝜇𝑖𝑖, 𝜏𝜏𝑖𝑖,1
2 ) 
Treatment effect as log-odds ratio 
𝛿𝛿𝑖𝑖= 𝜃𝜃෥𝑖𝑖−𝜃𝜃𝑖𝑖,⋆ 
The final analysis will report for each endpoint 𝑖𝑖 and treatment arm 𝑗𝑗 the probability for a 
positive treatment effect 𝑃𝑃(𝛿𝛿𝑖𝑖,𝑗𝑗> 0) and the median as a point estimate of the mean treatment 
difference of AIN457 low dose (𝑗𝑗= 1) versus historical placebo and AIN457 high dose (𝑗𝑗=
2) versus historical placebo, and the respective associated 95% credible interval of 𝛿𝛿𝑖𝑖,𝑗𝑗.  
Priors 
• 𝜇𝜇𝑖𝑖∼Normal(0, 22) - overall intercept on log-odds scale 
• 𝜃𝜃෥𝑖𝑖,𝑗𝑗∼Normal(0, 22) - response rate for active on log-odds scale 
• 𝜏𝜏𝑖𝑖,𝑠𝑠(ℎ) ∼HalfNormal൫0, 𝑠𝑠𝑠𝑠(ℎ)
2
൯ - between trial heterogeneity intercept 
• 𝑠𝑠1 = 1/2 - between trial heterogeneity pediatric data 
• 𝑠𝑠2 = 1 - between trial heterogeneity adult data 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
 
Pure non-responder imputation (pNRI) will be used as the primary missing data imputation 
method for both Bayesian analysis at week 12 and descriptive summaries up to week 52. 
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). Subjects with missing baseline or 
those with all post-baseline missing will be imputed with non-response.  
 
 
Missing data from this study for Bayesian analysis will be imputed in the SAS platform. A 
dataset with study level data is constructed in SAS and  transferred to RBesT where the MAP 
analysis will be performed and the results transferred back to SAS for reporting activities.  
2.5.4 
Supportive analyses 
No sensitivity analyses will be performed for Bayesian analysis.  
 


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Multiple imputation (MI) will be used as a supportive analysis for the descriptive summary 
of key efficacy endpoints (see Section 5.4.3) up to week 52. It 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.
 
 
 In the multiple imputation 
analysis the response status will be imputed based on the individual treatment arm information. 
 
Of note: subjects with missing baseline or subjects with all post-baseline missing will be 
included in the multiple imputation analysis. 
 
The following methods will apply to analysis of the long term efficacy data beyond Week 52: 
• Reponses variables based on PASI score and IGA mod 2011 categories will generally be 
presented as ‘observed case’; i.e. all available data for each time point will be included in 
the analyses. 
• Multiple imputation will be used as sensitivity method if appropriate. In general, data will 
be summarised up to the timepoint where 30-40% values are missing in total.  
 
2.6 
Analysis of the key secondary objective 
2.6.1 
Key secondary endpoint 
The key secondary efficacy endpoint of this study is the proportion of subjects with a PASI 90 
response at Week 12.  
2.6.2 
Statistical hypothesis, model, and method of analysis 
These data will be analyzed in the same way as the primary endpoint though a Bayesian 
framework. 
Efficacy of AIN457 low and high dose compared to historical placebo data will be performed 
separately. Analyses will be based on the FAS population, and historical placebo data will be 
incorporation into the analysis as before through the MAP framework. 
2.6.3 
Handling of missing values/censoring/discontinuations 
Missing data will be handled with the same methods as primary endpoint analysis. The bayesian 
analysis will use pure non-responder imputation and no sensitivity analysis will be performed. 
Multiple imputation will be used as a sensitivity analysis for the descriptive summary of key 
secondary endpoints.  
 
 
 
 


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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. 
The summaries of evaluation will be reported for the entire treatment period, and where 
appropriate on the entire study period as well.  
Data will be presented by the following treatment groups: 
• AIN457  low dose: all subjects who were randomized to AIN457 low dose  
• AIN457 high dose: all subjects who were randomized to AIN457 high dose  
• Any AIN457 dose: data on AIN457 groups above pooled together  
 
Safety analyses will be performed on treatment received or actual treatment (See Section 2.2, 
Safety Set). 
In general, the following guidelines are proposed for safety analysis unless stated otherwise: 
• Adverse events: Only treatment emergent records are reported in the tables, and listings 
have the “treatment emergent” flag displayed. 
• Laboratory data (including vital sign and ECG):  
o by period summary statistics tables: only include “on-treatment” records in the 
tables, i.e., Assessments within last dose plus 84 days cutoff. Listings have the “on-
treatment” flag displayed. 
o by visit summary statistics tables: present all “on-treatment” visits, follow up visits 
(CRF visits) may be summarized separately if required. 
In addition to the treatment emergent/on-treatment safety summary, extended entire treatment/ 
study period safety analysis will be provided for AE records up to EOS and for LABs by visit 
summary statistics up to EOS.  
Additional listing will be provided for AE that started after last dose + 84 days through to EOS.  
Entire treatment/study period 
Entire treatment period = randomization to Week 208 (EOT); for safety analysis include FU 
period up to last dose + 84 days for early discontinued subjects. 
Entire study period = randomization to end of study (EOS); includes follow up period (Week 
212, 216 and 224) 


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For evaluation of entire treatment/study period, AIN457 treatment groups will be pooled to 
“any AIN457”. 
2.8.1 
Adverse events (AEs) 
Only treatment emergent adverse events are summarized. However all AEs are included in the 
listing with flags for treatment emergent. Non-treatment emergent adverse events may be 
summarized separately upon request. 
Treatment emergent adverse events are defined as events started on or after the first dose of 
study medication or events present prior to the first dose of study medication but increased in 
severity on or after dosing based on preferred term and within last dose + 84 days (inclusive).  
 
The crude incidence of treatment emergent adverse events will be summarized by primary 
system organ class and preferred term. Confidence intervals for the crude rate will be derived 
as described in Section 5 Appendix. In addition, exposure time-adjusted rates (incidence rate) 
including 95% confidence intervals may be provided, see also Table 2-10.  
Table 2-10 
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) 
initial 
(Day 1 -  
week 16) 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
• crude 
incidence 
Entire treatment  
period 
• crude 
incidence 
• exp.time 
adjusted 
incidence 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
• crude 
incidence 
• exp.time 
adjusted 
incidence* 
• crude 
incidence 
Entire study 
• exp. time 
adjusted 
Incidence* 
• exp. time 
adjusted 
Incidence* 
 
 
 
 
*Extended safety summary will be provided for pediatrics trials with FU of 16 weeks 
* Please note that exposure adjusted incidence rates may be provided and follow the guideline 
as below: 
• Primary SOC level for AE and SAE 
• Level 1 for risks and SMQ 
• PT level for SAE 
• PT level for AE  ≥ 2% or incidence rate per 100 subject years ≥ 5.0 in AIN457 low dose 
or AIN457 high dose treatment group (may be updated following review of dry run 
outputs). 
• Other selected AEs of special interest on lower levels (e.g. PT or SMQ level 2), if 
appropriate 


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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 5.4.2. In addition, exposure time-adjusted incidence rates may be provided 
for the treatment period including all data (see Section 5.4.5). 
 
Adverse events will be summarized by presenting, for each treatment group (including any 
AIN457), 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). The relative frequencies 
and 95% confidence intervals within each system organ class will be presented for adverse 
event and serious adverse event in a panel graph (for DMC only). 
 
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. 
 
The crude incidence of treatment emergent AEs may  be repeated and presented by age, disease 
severity strata and by body weight strata subgroups. 
 
The exposure time-adjusted incidence rate of treatment emergent AEs, SAEs and important 
identified or potential risks (level 1) in entire treatment period will be summarized, where data 
permits. Data will be reported by SOC and PT and presented by age, disease severity strata and 
body weight strata. Crude rate will also be evaluated. Summary by body weight and dose group 
may be evaluated in addition to the above.  
 
Adverse events will also be reported separately by standardized or customized MedDRA 
queries (SMQ or CMQ/NMQ). The MedDRA version used for reporting the study will be 
described in a footnote. 
 
The most common adverse events reported (≥z% in any group for each preferred term in the 
SOC-PT table or ≥z % in any group for each grouping term table) will be presented in 
descending frequency according to its incidence in total AIN457 group (combining both 
AIN457 treatment groups) 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 study treatment related adverse events, death, serious 
adverse event, other significant adverse events leading to discontinuation and adverse events 
leading to dose adjustment or interruption. 
If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 


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• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE will be to be checked in a block e.g., among AE's in a ≤ 1 day gap block, 
if at least one SAE is occurring, then one occurrence is calculated for that SAE. 
 
Algorithms for date imputations will be provided in Section 5 Appendix. 
 
For SAEs occurred during screening a listing will be prepared for all subjects screened including 
screening failures. 
 
For those subjects who received erroneously the wrong treatment at least once, an additional 
listing will be prepared displaying all adverse events for that subject and flag AEs that occurred 
after the first treatment error. 
To meet the requirements for posting results to ClinicalTrials.gov and EudraCT, two further 
tables are produced and final reporting. Treatment emergent adverse events which are not 
serious adverse events with an incidence greater than X% and a summary for treatment 
emergent serious adverse events and SAE suspected to be related to study treatment. Summaries 
are presented by system organ class and preferred term on the safety set population. Here, the 
threshold value X is set to 2-5 (%) and may be updated following review of the dry run outputs. 
 
 
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.  
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. 
 


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2.8.3 
Laboratory data 
The summary of laboratory evaluations will be presented for two groups of laboratory tests 
(hematology and serum chemistry).  
 
The general guideline for laboratory summaries (including vital signs and ECGs in Section 
2.8.4.1 and 2.8.4.2) are as below: 
 
• all the summary of laboratory outputs (newly occurring notables, maximum changes, shift 
tables, by visit summary statistics) will be reported on all data collected up until end of 
study. Any summary presented by period will use the on-treatment definition i.e., include 
all assessments within last dose plus 84 days. 
 
• all records are displayed in the listing with the on-treatment flag. i.e., occurred within last 
dose plus 84 days- yes or no, as well as eCRF visits and period. 
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 
 
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 “>”).” 
For each parameter, the maximum change (maximum decrease and maximum increase) from 
baseline within treatment period will be summarized analogously.  
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 2-9: 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) and estimated glomerular filtration rate 
(eGFR). 
 
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.  
 


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Table 2-11 
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 
 
eGFR 
    >ULN – 2.5 x ULN 
  <LLN – 
60ml/min/1.73m2 
>2.5 - 5.0 x ULN 
 
<60-30 ml/min/1.73m2 
>5.0 - 20.0 x ULN 
 
<30-15 ml/min/1.73m2 
>20.0 x ULN 
 
<15 ml/min/1.73m2 
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 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.  
 
The number and percentage of subjects with newly occurring or worsening after baseline 
(treatment emergent) liver enzyme abnormalities will be presented for the treatment period 
based on the event criteria given in Table 2-12. For pooled DMC analysis 95% confidence will 
be provided.  Standard laboratory change from baseline tables of liver function test by visit will 
be produced.  
 
Table 2-12 
Liver-related events 
 
Parameter 
Criterion 
 
ALT 
>ULN; >3xULN; >5xULN; >8xULN; >10xULN 
AST 
>ULN; >3xULN; >5xULN; >8xULN; >10xULN 
ALT or AST 
>3xULN; >5xULN; >8xULN; >10xULN 
TBL 
>ULN; >1.5xULN, >2xULN 
ALP 
>ULN;>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; 


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ALT or AST >8xULN & TBL >2xULN  
ALT or AST >10xULN & TBL >2xULN 
ALT or AST & 
TBL & ALP 
 
ALP > 3x ULN & TBL > 2x ULN 
ALP > 5x ULN & TBL > 2x ULN 
ALT or AST>3xULN & TBL >2xULN & ALP <2xULN (Potential Hy’s Law) 
(ALT or AST > 3x ULN & TBL > 2x ULN & ALP < 2x ULN) or reported 
Hy's Law case 
 
For a combined criterion to be fulfilled, all conditions have to be fulfilled on the same visit. The 
criteria are not mutually exclusive, e.g. a subject with ALT = 6.42xULN is counted for 
ALT >3xULN and ALT>5x ULN. 
 
Individual subject data listings will be provided for subjects with newly occurring or worsening 
abnormal laboratory data. Data of subjects with newly occurring or worsening liver enzyme 
abnormalities will be listed in an additional listing. 
  
For the DMC, a panel graph will be presented to display shift from baseline to maximum 
evaluation for each of the liver function test (including ALT, AST, ALP and TBL) by treatment. 
Similarly a graphical presentation of each hematology parameter (including Leukocytes, 
neutrophils, lymphocytes and platelets) will be presented to display shift of baseline to 
minimum evaluation based on CTCAE grades. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
The following quantitative variables may be summarized if requested: ventricular rate, RR 
interval, PR interval, QRS duration, QT interval, and corrected QT interval (QTc). Fridericia 
(QTcF) correction will be presented for QTc. 
 
Notable abnormal QTc will summarized by computing the number and percentage of subjects 
(including 95% confidence intervals for pooled DMC analysis) with: 
 
• QTc > 500 msec 
• QTc > 480 msec 
• QTc > 450 msec 
• QTc changes from baseline > 30 msec 
• QTc changes from baseline > 60 msec 
• PR > 250 msec 
 
Summary statistics will be presented for ECG variables by visit and treatment group based on 
the entire study period. In addition, shift tables comparing baseline ECG interpretation (normal, 
abnormal, not available, total) with the worst on-treatment/study interpretation (normal, 
abnormal, not available, total) will be provided. 


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A listing of all newly occurring or worsening abnormalities (based on the treatment period/study 
period) will be provided, as well as a by-subject listing of all quantitative ECG parameters. 
 
2.8.4.2 
Vital signs 
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 
 
Vital signs will be summarized by visit based on the entire study period data. All vital signs 
will be listed with “on-treatment” flag displayed. 
The number and percentage of subjects with newly occurring notable vital signs (within the 
treatment period) will be presented by treatment group. Subjects not meeting the following 
criteria at baseline but meeting at post-baseline are considered to be subjects with newly 
occurring abnormalities. Criteria for notable vital sign abnormalities are provided in Table 2-
13 below: 
 
Table 2-13 Criteria for notable vital signs in pediatric patients 
Age group 
Systolic BP(mmHg) 
Diastolic BP(mmHg) 
Pulse (bpm) 
6 -11 yrs 
 90-130 
 50-80 
 50-105 
12-17 yrs 
 90-145 
 55-90 
 45-95 
18 yrs and over 
 90-139 
 60-89 
 60-100 
 
If appropriate, data of subjects with newly occurring notable vital signs abnormalities will be 
listed in an additional listing. 
 
Of note, systolic and diastolic blood pressure will be measured twice (measurements separated 
by 1 to 2 minutes), the average will be entered on the Vital Signs eCRF and will be used in the 
analysis. 


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2.8.4.4 
Growth and Physical development  
Body weight, height and BMI percentile will be summarized by treatment and visit. 
 
Standard height, weight, and BMI curves will be obtained from the U.S. National Center of 
Health Statistics (www.cdc.gov/growthcharts) curves for ages up to 18 years. These growth 
curves will be used for all study subjects. The Center’s files contain the L, M, and SD 
parameters needed to generate exact percentiles as follows: 
 
𝑧𝑧=
ቀ𝑋𝑋
𝑀𝑀ቁ
𝐿𝐿
−1
𝐿𝐿× 𝑆𝑆𝑆𝑆 
where X = physical measurement (e.g., patient’s weight, height, and BMI) 
M = median 
SD= standard deviation 
L = the power in the Box-Cox transformation 
 
Percentiles for each patient at each time point will be calculated using the SAS function 
PROBNORM(z).  
The number and percentages of subjects falling in low (i.e. <5), normal (i.e. 5-<95), or high 
(i.e. >= 95) growth percentiles will be summarized by treatment and visit. Shift from baseline 
in growth percentile categories, i.e., low (i.e. <5), normal (i.e. 5-<95), or high (i.e. >= 95), will 
be summarized by treatment and visit.  
 
2.9 
Pharmacokinetic endpoints   
All completed subjects with quantifiable pharmacokinetic (PK) measurements of secukinumab 
will be included in the pharmacokinetic data analysis. 


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Serum concentrations will be expressed in mass per volume units. All concentrations below the 
limit of quantification (BLQ) as well as missing data will be labeled as such in the concentration 
data listings. BLQ concentrations will be included in the summaries. Serum concentration data 
from patients who missed a dose or doses will be excluded at the following visit(s). 
PK concentrations will be summarized by eCRF visit and treatment. PK concentrations will 
also be presented by visit (i.e., CRF visit), dose group (75 mg, 150 mg, 300 mg) and body 
weight categories at visit (<25 kg, 25 to <50kg, ≥50 kg). Per protocol, a subject will change 
into a higher or lower weight category and dose, when the subject’s weight moves into a 
different weight category for two consecutive visits. This change is assessed from Week 12, 
then at week 16 and bimonthly until week 52 and at trimonthly visits in the extension phase. If 
such a change happens, in the PK summaries, at the concerned assessment points, the subject 
will be accounted in the new dose group (75 mg, 150 mg, 300 mg) and weight category group.  
 
In addition to mean, standard deviation (SD), coefficient of variation (CV), median and 
quartiles, the geometric mean and geometric coefficient of variation (CV) and n(log) will be 
presented. The formula for deriving the geometric mean and CV (%) is as following: 
• CV (%) = (SD/mean)*100, 
• geometric mean=exp( (sum of log transformed data) / number of non-missing data 
points after log transformation), 
• geometric CV = sqrt( exp( variance of log-transformed data)-1)*100. 
 
In addition, sample number, concentration, sample date, elapse time since day of first 
secukinumab dose, reason excluding from analysis will be listed by treatment. 
 
Values below lower limit of quantification/below detection limit will be imputed by 0.  
 
Pharmacokinetic derived parameters AUC84-112d, Tmax and Cmax will be summarized by 
treatment group (AIN457 low dose and AIN457 high dose). Descriptive summary statistics 
include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, 
minimum and maximum. Derived pharmacokinetic parameters will be listed by treatment 
sequence. 
2.10 
PD and PK/PD analyses 
Not applicable. 
 
 
 


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2.12 
Biomarkers 
Not applicable. 
2.13 
Other Exploratory analyses 
2.14 
Interim analysis 
A primary endpoint analysis of the data collected up until Week 16, including the co-primary 
endpoint (at Week 12) will be performed after the last  subject completes  their Week 16 visit. 
Efficacy and safety data up to Week 16 visit for all subjects will be summarized. AE listing will 
be presented on the entire treatment period i.e. reports AE data collected until last subject week 
16 cut-off date.  
 
To address comments from the health authorities an additional full analysis will be performed 
when all subjects have completed the Week 24 visit.  
 


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A full analysis will be performed when all subjects have completed the Week 52 visit, (or 
premature treatment discontinuation visit). Thereafter, efficacy and safety data collected after 
Week 52 until the end of study may be reported yearly in separate reports. 
 
Additional analyses may be performed to support health authority interactions, as necessary. 
 
Trial modifications are not planned based on any interim analyses No aggregated statistical 
analysis will be performed by actual treatment group prior to W16 PEA. 
3 
Sample size calculation 
The sample size for this study is calculated to ensure an adequate number of subjects for PK 
analyses and powered efficacy analyses. Approximately 80 pediatric subjects from 6 to less 
than 18 years of age at randomization will be recruited. Since a 15% screening failure rate is 
expected, approximately 95 patients will be screened. The study will aim to recruit at least 60 
subjects with moderate severity and approximately 20 subjects with severe severity. 
 
Power calculations were performed to support the co-primary endpoints PASI 75 and IGA 0 or 
1 response at week 12, and secondary endpoint PASI 90 at week 12, versus placebo (historical 
control) for the low and high secukinumab dose regimens. The low dose arm with smaller 
treatment effect is being considered in the power/sample size calculation.  
 
Data from four adult placebo-controlled trials (CAIN457A2302, CAIN457A2303, 
CAIN457A2308 and CAIN457A2309) and pediatric placebo controlled trials (Paller et al 2008, 
Landells et al 2015) were used to estimate the historical placebo response rate. For study 
CAIN457A2310, a 10% response rate was assumed for PASI 75, IGA 0 or 1 and 8% for PASI 
90 response for the placebo group. The 95% upper quantile of predicted number of responders 
are 7, 7 and 6 subjects, respectively. The assumed placebo response rates were derived 
accordingly with 40 pediatrics for study CAIN457A2310. Refer to table 3.1 below.  
 
Table 3-1 Placebo response rates from historical secukinumab placebo controlled 
trials  
Adult Placebo   
Endpoint  
Number of subjects with response/ 
Placebo response 
controlled trial   
 
Number of subjects evaluable  
rate (%) 
CAIN457A2302 
IGA 0 or 1  
 
6/246 
 
 
 
 
2.4 
 
 
 
PASI 75 
 
11/246  
 
 
 
4.5 
 
 
 
PASI 90 
 
3/246 
 
 
 
 
1.2 
 
CAIN457A2303 
IGA 0 or 1  
 
9/324 
 
 
 
 
2.8 
 
 
 
PASI 75 
 
16/324  
 
 
 
4.9 
 
 
 
PASI 90 
 
5/324 
 
 
 
 
1.5 
 
CAIN457A2308 
IGA 0 or 1  
 
0/59 
 
 
 
 
0 
 
 
 
PASI 75 
 
0/59 
 
 
 
 
0 
 
 
 
PASI 90 
 
0/59 
 
 
 
 
0 


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CAIN457A2309 
IGA 0 or 1  
 
0/61 
 
 
 
 
0 
 
 
 
PASI 75 
 
2/61 
 
 
 
 
3.3 
 
 
 
PASI 90 
 
0/61 
 
 
 
 
0 
Pediatric Placebo  
Endpoint  
Number of subjects with response/ 
Placebo response 
controlled trial   
 
Number of subjects evaluable  
rate (%) 
Ustekinumab   
PGA 0 or 1  
 
2/37 
 
 
 
 
5.4 
Dermatol 2015 
PASI 75 
 
4/37 
 
 
 
 
10.8 
(Age 12 to 17 years) PASI 90 
 
2/37 
 
 
 
 
5.4 
 
Etanercept NEJM 
PGA 0 or 1  
 
14/105  
 
 
 
13 
2008  
 
PASI 75 
 
12/105  
 
 
 
11 
(Age 12 to 17 years) PASI 90 
 
7/105 
 
 
 
 
7 
 
CAIN457A2310  
IGA 0 or 1 
 
7/40 
 
 
 
 
17.5 
(estimation  
 
PASI 75 
 
7/40 
 
 
 
 
17.5 
Includes  
 
PASI 90 
 
6/40 
 
 
 
 
15 
simulation 
uncertainty error) 
 
 
The Meta-Analytic-Predictive (MAP) approach derives an informative prior from historical 
data which is discounted using a hierarchical model. When using the MAP approach to estimate 
the predicted placebo response rate, differential discounting was defined for two stratum: 
pediatric study data and adult study data. Moderate between-trial heterogeneity (with τ prior set 
as HalfNormal(0, 0.5)) was defined for pediatric trial data and substantial heterogeneity (with 
τ prior set as HalfNormal(0, 1)) was defined for adult trial data (Neuenschwander et al.2010), 
thus allowing pediatric trial data to be given a higher  weight compared to adult trial data. The 
prior distribution for the regression coefficient β was set as non-informative Normal (0, 2). The 
following Table 3-2 presents the summary statistics of the fitted mixtures of conjugate 
distribution to the sample.  
All the calculations were performed in the R package RBesT (version 1.3.1) through the meta-
analytical-predictive framework (Spiegelhalter et al. 2004, Neuenschwander et al. 2010). 
 
Table 3-2 Predictive placebo response rates for this study from model of historical 
data 
Endpoint  
Mean  Standard Deviation  
Median  
95% Credible Interval 
IGA 0 or 1  
9%  
 
6%  
 
8%  
 
 
1-23% 
PASI 75  
10%  
 
6%  
 
9%  
 
 
2-25% 
PASI 90  
6%  
 
4%  
 
5%  
 
 
1-18% 
 
Based on confirmatory efficacy in the adult phase III program (CAIN457A2302, 
CAIN457A2303, CAIN457A2308 and CAIN457A2309), the PASI 75, IGA 0/1 and PASI 90 
response rate at week 12 was assumed as 65%, 45% and 39% for secukinumab. Non-
informative prior was set for secukinumab arm. A sample size of 40 pediatric patients from this 


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study under each high or low secukinumab arm over predictive placebo response (Table 3-2) 
will lead to a power of approximately 99% for each co-primary endpoint and secondary 
endpoint. Details as following: 
• A sample size of 40 pediatric patients per treatment group and true response rates of 65% 
for PASI 75 and 45% for IGA mod 2011 0 or 1 response for secukinumab was assumed. 
For each co-primary endpoint there is approximately 99% power to detect a posterior 
probability of the log odds ratio difference between placebo and secukinumab to exceed 
with at least 97.5%.  
• Similarly, for the secondary endpoint of PASI 90 response there is approximately 99% 
power to provide a posterior probability of at least 97.5% that the PASI 90 response rate 
on secukinumab is greater than placebo. This assumes a response rate of 39% for 
secukinumab.  
4 
Change to protocol specified analyses 
The following are changes to protocol specified analysis: 
Following HA recommendadtion to impute subjects with all post-baseline missing values as 
non-responders according to the intention to treat principal and to remain consistent with the 
adult studies and pediatric data used within the MAP analysis, the primary analysis will be 
performed on pure non-responder imputation and the MI dropped. Modified non-responder 
analysis may still be performed upon request from HA. No sensitivity analysis will be provided 
for the Bayesian analysis. For the descriptive summary of key efficacy endpoints, results using 
pure non-responder imputation as well as multiple imputation will be provided.   
Week 16 PEA analysis constitutes the scope for delivering to DMC and an extended FIR 
requirement, thus a full analysis will not be performed as planned. Further to recent 
communications with the health authorities, additional outputs and an interim analysis at Week 
24 is added to support the pediatric submission. The following subgroup summaries are added 
to the planned analyses:  
• Summaries by age subgroup:<12 years or ≥ 12 years  
• Summaries by body weight strata:<25kg, 25-<50kg and ≥ 50kg  
• Summaries by disease severity strata:moderate, severe  
• Summaries by body weight and dose group:AIN457 – 75 mg and < 25 kg, AIN457 Low 
– 75 mg and ≥ 25 kg -< 50 kg, AIN457 Low – 150 mg and ≥ 50 kg;, AIN457 High – 150 
mg and ≥ 25 kg -< 50 kg, AIN457 High – 300 mg and ≥ 50 kg; 
Safety summaries for exposure adjusted incidence rates may be prepared. 
 
Pandemic reporting (COVID-19) 
Data collected in this trial that is affected by the COVID-19 situation, can be expected to lead 
to difficulties in interpretation in the trial’s reporting. In recognition of these challenges, both 
FDA and EMA (and local regulatory authorities) have issued specific guidelines that request 


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Novartis to collect the reasons for non-compliance and discontinuation of clinical trial elements 
related to COVID-19 in all ongoing trials.  
In adherance to these guidences, specific protocol deviations were added to capture data 
necessary to provide a summary of impact for the pandemic.  
The primary and key secondary objective of the study assesed at Week 12 are not impacted. 
These were reported prior to the pandemic, which emerged as the last few patients were 
reaching week 52 visit. Therefore, notably missing data are not expected and imputations are 
considered reasonable for evaluating efficacy up to week 52.   
All protocol deviations for the study will be summarised together (i.e including COVID-19 
specific PDs) as described in section 2.3.1. In addition, all protocol deviations from 1st March 
2020, that is considered to be the starting point of COVID-19 period (as per internal guidance 
for those countries participating in this study) will capture whether there was any relation to 
COVID-19 including a precise  relationship status in regard to COVID-19 virus (such as health 
status related, site issues, quarantine of patient/lockdown, drug supply issue, patient concern, 
other or no relationship to COVID-19). The relationship status will be presented in the listing. 
For patients with suspected/confirmed cases of COVID-19, separate summaries and/or listings 
may be provided for disposition, concomitant medications/proceduces and significant non drug 
therapies and adverse events (including COVID-19 testing with outcome results). Summaries 
of treatment emergent COVID-19 related adverse events may be presented if data permits.  
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. 
 
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: 
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 + 140 days), 31DECYYYY, date of death).  


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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 + 140 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.  
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).  


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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).  
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:  


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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. 
5.1.3.3 
First diagnosis date (Pso, PsA) imputation 
1. If the first diagnosis day/ month are missing and the year is non-missing: 
a. If the year part of the first diagnosis date is equal to the year part of the inform 
consent date, then the imputed first diagnosis date is set to the year start point 
(01JanYYYY). 
b. Otherwise the imputed first diagnosis date is set to the mid-year point 
(01JulYYYY). 
 
2. If the first diagnosis day is missing and the month/year are non-missing: 
a. If the month and year part of the first diagnosis date is equal to the month and year 
part of the inform consent date, then the imputed first diagnosis date is set to the 
month start point (01MONYYYY). 
b. Otherwise the imputed first diagnosis date is set to the mid-month point 
(15MONYYYY). 
5.1.3.4 
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. 
 
 
 
 
 
 


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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 “>”).” 
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. 
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. 
5.3 
Laboratory parameters derivations 
Not applicable.  
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. If 
applicable, means +/- SE will be plotted. 
 
 
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
 
 
p
q
−
=1
(
),
0
for
0
,0
=
=
>
p
L
p
(
),
1
for
1
,1
=
=
<
p
U
p


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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.  
For time courses of response variables, the point estimate at each time point including 95% 
confidence interval will be plotted. 
5.4.3 
Multiple imputations for response variables 
Descriptive summaries for 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. 
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 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 
4572311 for this study. SAS proceduce MI will be used 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> 


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<baseline PASI> <baseline IGA> 
<change from baseline PASI week 1> - <change from baseline PASI week primary endpoint> 
<IGA week1> - <IGA week primary endpoint>; 
EM converge=1E-2 MAXITER=5000; 
MCMC PRIOR=RIDGE=2 ; 
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>. 
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>=0.75 THEN <PASI 75 response> =1; 
ELSE <PASI 75 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; 
 
 
 
5.4.4 
Crude incidence and related risk estimates 
5.4.4.1 
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).  


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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 
. 
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. 
5.4.5 
Exposure adjusted incidence rate and related risk estimates 
5.4.5.1 
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 ,
α  is the αth quantile of the Chi-square distribution with k degrees of freedom. 
p
q
−
=1
T
c
L
D
2
,2
/
5.0
α
=
T
c
U
D 2
2
,
2
/
1
5.0
+
−
=
α


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5.4.6 
Primary analysis  
 
Example schematic code for Bayesian analysis of 2311 using dummy data 
for PASI 75. 
 
## model to fit placebo data  
 
tau.prior <- rbind(c(0, 0.5), c(0, 1)) 
 
set.seed(345652) 
analysis_pbo_mc_pasi <- gMAP(cbind(r, n-r) ~ 1 | trial, 
                             tau.strata=stratum, 
                             family=binomial, 
                             data=final_data_pbo, 
                             tau.dist="HalfNormal", 
                             tau.prior=tau.prior, 
                             beta.prior=rbind(c(0,2))) 
 
 
 
## model to fit the data of A2311 
set.seed(34535214) 
analysis_A2311_mc_pasi75 <- gMAP(cbind(r, n-r) ~ 0 + TREATMENT, 
                                 family=binomial, 
                                 data=active, 
                                 tau.dist="Fixed", 
                                 tau.prior=1E-6, 
                                 beta.prior=matrix(c(0,0,2,2), 2, 2)) 
 
 
 
 
5.4.7 
Key secondary analysis 
As per section 5.4.6 but on the PASI 90 endpoint.  
5.4.8 
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.  
Subjects without PASI 75/90 response will be considered as censored at Week 12. 
 
Median time to event 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). The plot will include the number of subjects at risk for each treatment group 
at pre-specified timepoints, which are 0 to <=  4 weeks , >4 to <=8 weeks and 8 to <=12 weeks.  


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Subjects at risk, timepoint “0” and censoring will be defined as described in Table 5-1 below: 
Table 5-1 
Variable: 
Time to 
Risk set 
Time = 0 
Time of 
event 
Censoring 
Psoriasis 
ConMed* 
Informative  
censoring 
PASI 
75/90 
response 
All subjects 
randomized 
with baseline 
and post-
baseline data 
for PASI 
Date of 
randomization 
Date of 1st 
visit with 
PASI 
75/90 
response 
observed 
Week 12 
visit 
date/discont
inuation 
date    
Censor (if 
ConMed 
taken 
before the 
event) 
No 
 
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 
 
5.5 
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: INCL01; OTH12 
Misrandomized subject 
Safety 
DVSPID: INCL01; OTH12 
Misrandomized subject 
Subjects who did not take any 
study treatment 
INCL01: ICF missing or not signed; in the case where ICF was obtained after initiating study 
procedures, subjects will be included in all analysis sets 
OTH12: Severe ICH-GCP non-compliance of study site 
 


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6 
Reference 
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of the binomial. Biometrika, 26; 404–413 
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