long-term observational, prospective study to collect in a

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Non-Interventional Study Protocol

CAIN457A3403

Long-term observational, prospective study to collect in a real life setting data on the retention, effectiveness, safety, treatment pattern, quality of life, and efficiency

of secukinumab in adult patients with moderate to severe plaque psoriasis, psoriatic arthritis or ankylosing spondylitis

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Non-interventional study protocol

03 (incorporating amendment 03) (clean)

No

25-Jun-2018

Property of NovartisConfidential

May not be used, divulged, published or otherwise disclosedwithout the consent of Novartis

NIS Protocol Template Primary Data Collection Version 2.0 dated 15-Sep-2015

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Novartis Confidential

Amended NIS Protocol v03 (clean) CAIN457/secukinumab/CAIN457A3403

Table of contentsTable of contents .................................................................................................................2

List of figures ......................................................................................................................4

List of tables ........................................................................................................................4

List of abbreviations ............................................................................................................5

1 Responsible parties ..............................................................................................................7

2 Abstract................................................................................................................................7

3 Amendments and updates..................................................................................................13

Amendment 1 (local amendment for Germany)................................................................13

Amendment 2 (global amendment) ...................................................................................13

4 Milestones..........................................................................................................................15

5 Rationale and background .................................................................................................16

5.1 Disease background ...............................................................................................16

5.2 Secukinumab..........................................................................................................17

5.3 Rationale ................................................................................................................18

6 Research question and objectives......................................................................................19

6.1 Primary objective...................................................................................................19

6.2 Additional objectives .............................................................................................20

6.2.1 All indications .......................................................................................20

6.2.2 Psoriasis.................................................................................................20

6.2.3 Psoriatic arthritis ...................................................................................20

6.2.4 Ankylosing spondylitis..........................................................................20

7 Research methods..............................................................................................................21

7.1 Study design...........................................................................................................21

7.1.1 Study duration .......................................................................................22

7.1.2 Study completion and discontinuation ..................................................23

7.1.3 Withdrawal of informed consent...........................................................23

7.2 Study endpoints .....................................................................................................23

7.2.1 Primary endpoint ...................................................................................23

7.2.2 Additional endpoints .............................................................................23

7.3 Setting ....................................................................................................................27

7.3.1 Inclusion criteria....................................................................................27

7.3.2 Exclusion criteria ..................................................................................27

7.4 Variables ................................................................................................................28

7.4.1 Patient demographic and other baseline characteristics........................28

7.4.2 Retention ...............................................................................................29



7.4.3 Effectiveness assessments for psoriasis ................................................29

7.4.4 Effectiveness assessments for psoriatic arthritis ...................................32

7.4.5 Effectiveness assessments for ankylosing spondylitis ..........................34

7.4.6 Assessment of tolerability .....................................................................37

7.4.7 Assessment of treatment pattern ...........................................................37

7.4.8 Assessment of quality of life.................................................................37

7.4.9 Assessment of efficiency.......................................................................38

7.4.10 Physical examination and vital signs ....................................................39

7.5 Data sources...........................................................................................................39

7.5.1 Data collection schedule .......................................................................39

7.6 Study size...............................................................................................................43

7.7 Steering Committee ...............................................................................................44

7.8 Data management ..................................................................................................44

7.9 Data analysis ..........................................................................................................44

7.10 Quality control .......................................................................................................46

7.10.1 Data quality management......................................................................46

7.10.2 Data recording and document retention ................................................46

7.10.3 Site monitoring......................................................................................46

7.11 Limitations of the research methods......................................................................47

7.12 Other aspects..........................................................................................................47

8 Protection of human subjects.............................................................................................47

8.1 Regulatory and ethical compliance........................................................................48

8.2 Informed consent procedures.................................................................................48

9 Management and reporting of adverse events/adverse reactions ......................................48

9.1 Adverse event reporting.........................................................................................49

9.2 Serious adverse event reporting.............................................................................51

9.3 Follow-up information...........................................................................................52

9.4 Causality assessment .............................................................................................52

9.5 Disease progression ...............................................................................................53

9.6 Abnormal laboratory values and test results..........................................................53

9.7 Pregnancies ............................................................................................................53

10 Plans of disseminating and communicating study results .................................................53

11 References .........................................................................................................................54

12 Annexes .............................................................................................................................59

12.1 Annex 1 – List of stand-alone documents .............................................................59

12.2 Annex 2 – ENCePP checklist for study protocols .................................................59



12.3 Annex 3 – Additional information.........................................................................59

List of figuresFigure 7-1 Overall study duration including time points for analysis ....................22

Figure 7-2 Study observation period for a single patient........................................22

List of tablesTable 7-1 The PASI scoring system......................................................................31

Table 7-2 Description of a physician’s global assessment of psoriasis.................32

Table 7-3 Assessment of psoriatic nail involvement.............................................32

Table 7-4 MASES and additional expanded assessments .....................................36

Table 7-5 Data collection schedule for patients with psoriasis .............................40

Table 7-6 Data collection schedule for patients with psoriatic arthritis ................41

Table 7-7 Data collection schedule for patients with ankylosing spondylitis .......42



List of abbreviationsADR Adverse Drug Reaction

AE Adverse Event

AP Anterior-Posterior

AS Ankylosing Spondylitis

ASDAS AS Disease Activity Score

BASDAI Bath AS Disease Activity Index

BME Bone Marrow Edema

BMI Body Mass Index

BSA Body Surface Area

CI Confidence Interval

(e)CRF (electronic) Case Report/Record Form

CRO Contract Research Organization

CRP C-Reactive Protein

DIP Distal Interphalangeal

DLQI Dermatology Life Quality Index

DMARD(s) Disease Modifying Anti-Rheumatic Drug(s)

DS&E Drug Safety and Epidemiology

EDC Electronic Data Capture

ENCePP European Network of Centres for Pharmacoepidemiology and Pharmacovigilance

EOS End of Study

EQ-5D QoL questionnaire (developed by EuroQol group) – 5 dimensions

EU European Union

FACIT-Fatigue© Functional Assessment of Chronic Illness Therapy - Fatigue

FPFV First Patient First Visit

GPP Guidelines for Good Pharmacoepidemiology Practices

HAQ-DI© Health Assessment Questionnaire – Disability Index

HCP Healthcare Professional

HLA-B27 Human Leukocyte Antigen B27

hsCRP High Sensitivity C-Reactive Protein

IBD Inflammatory Bowel Disease

ICF Informed Consent Form

ICMJE International Committee of Medical Journal Editors

IEC Independent Ethic Committee

IL-17 Interleukin-17

IL-17A Interleukin-17A

IL-23R Interleukin-23R

IRB Institutional Review Board

ISPE International Society for Pharmacoepidemiology

JSN Joint Space Narrowing

LEI Leeds Enthesitis Index

LOCF Last-Observation-Carried-Forward

LPFV Last Patient First Visit



LPLV Last Patient Last Visit

MASES Maastricht AS Enthesitis Score

MCP Metacarpophalangeal

MedDRA Medical Dictionary for Regulatory Activities

MRI Magnetic Resonance Imaging

MTP Metatarsophalangeal

MTX Methotrexate

NIS Non-Interventional Study

NRS Numeric Rating Scale

NSAID(s) Non-Steroidal Anti-Inflammatory Drug(s)

PA Postero-Anterior

PASI Psoriasis Area Severity Index

PASS Post-Authorization Safety Study

PGA Physician’s Global Assessment

PIP Proximal Interphalangeal

PRO Patient-Reported Outcome

PsA Psoriasis Arthritis

QoL Quality of Life

SAE Serious Adverse Event

SAP Statistical Analysis Plan

SJC Swollen Joint Count

SmPC Summary of Product Characteristics

STROBE Strengthening the Reporting of Observational Studies in Epidemiology

TEAE Treatment Emergent Adverse Event

TJC Tender Joint Count

VAS Visual Analog Scale

WHO World Health Organization



1 Responsible parties

N/A

2 Abstract

Title

Long-term observational, prospective study to collect in a real-life setting data on the retention, effectiveness, safety, treatment pattern, quality of life, and efficiency of secukinumab in adult patients with moderate to severe plaque psoriasis, psoriatic arthritis or ankylosing spondylitis.

Version and date

03 (amended protocol), 25-Jun-2018

Name and affiliation of main author xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxRationale and background

Psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are chronic inflammatory diseases affecting up to 3%, 0.35% and 0.3% of the European population, respectively. Plaque type psoriasis, the most common form of psoriasis, is characterized by thickening, scaling and itching of affected skin areas, most commonly the scalp, the sacral region as well as extensor surfaces of the major joints. In addition to skin involvement, a certain proportion of patients may develop an inflammatory arthritis, known as PsA affecting peripheral joints, entheses and the spine. Ankylosing spondylitis (AS) is an inflammatory disease primarily affecting the axial skeleton with concomitant structural changes which may lead, over the years, to deformity and disability. Both PsA and AS are part of the spondyloarthritis (SpA) group of diseases and are classified according to the predominant but not exclusive involvement of the peripheral (PsA) and axial (AS) skeleton. Psoriasis, PsA and AS have a profound impact on patients’ quality of life (QoL) and have been shown to be associated with affective (e.g. depression) as well as cardiometabolic disorders.

Secukinumab (AIN457, registered as Cosentyx®), a recombinant high-affinity fully human monoclonal antibody targeting interleukin-17A (IL-17A), a major immune-modulating agent involved in the pathogenesis of autoimmune diseases, has been approved for the treatment of moderate to severe plaque type psoriasis, PsA, and AS in adults. The anti-inflammatory mode of action of secukinumab is the same for spondyloarthritis disease (such as PsA and AS) and plaque psoriasis being based on inhibition of IL-17A induced and maintained inflammation of the joints and skin, respectively. In the pivotal clinical studies, secukinumab showed good efficacy and tolerability profiles for psoriasis, PsA and AS; however, information on its use under real-life conditions is sparse. This European observational study aims to evaluate the retention, effectiveness, safety, tolerability, treatment pattern and effects on QoL of secukinumab in patients with moderate to severe plaque psoriasis, active PsA and active AS. It will also facilitate observation of the progression of newly diagnosed PsA in patients with plaque type psoriasis.

Research question and objectives

Primary objective

To assess the long-term retention of secukinumab treatment in routine clinical practice for thetreatment of moderate to severe plaque-type psoriasis, active PsA and active AS (overall) based onthe first dose of secukinumab administered since the start of the study, and to identify factorsaffecting the retention of secukinumab treatment for the overall study population.

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Additional objectives

All indications

To assess the long-term retention of secukinumab treatment in routine clinical practice for the treatment of each individual disease (i.e. moderate to severe plaque-type psoriasis, active PsA, or active AS) based on the first dose of secukinumab administered since the start of the study, and to identify factors affecting the retention of secukinumab treatment in each disease.

To assess the long-term retention of secukinumab treatment in routine clinical practice for the treatment of moderate to severe plaque psoriasis, active PsA and active AS (individually and overall) based on the first dose of secukinumab administered prior to the start of the study (i.e. the patient’s very first dose of secukinumab).

To describe the long-term tolerability of secukinumab in routine clinical practice for the treatment of moderate to severe plaque psoriasis, active PsA and active AS (individually and overall) as observed over the study duration and assessed by the type, frequency, severity and relationship of adverse events (AEs) and serious adverse events (SAEs) and comorbidities.

To describe the treatment pattern with secukinumab for the treatment of moderate to severe plaque psoriasis, active PsA and active AS in terms of dosing, administration intervals and preferred device based on the reported therapy changes.

Psoriasis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of moderate to severe plaque psoriasis as observed over the study duration and assessed by the proportion of patients maintaining clear/almost clear skin over time.

To describe the long-term QoL, which will be evaluated based on patient-reported outcomes (PROs) routinely used for patients with psoriasis, such as the Dermatology Life Quality Index (DLQI) and the Euro-QoL-5 dimension questionnaire (EQ-5D).

To collect data that will be used for conducting efficiency and pharmacoeconomic evaluations. Details on the analysis will be described in separate documents. This objective applies only to the German population in the study.

To explore potential risk factors for developing PsA by assessing anamnestic, demographic and clinical data.

Psoriatic arthritis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of active PsA as observed over the study duration.

To describe the long-term QoL, which will be evaluated based on PROs routinely used for patients with PsA, such as the health assessment questionnaire-disability index (HAQ-DI©) and functional assessment of chronic illness therapy – fatigue (FACIT-Fatigue©).

Ankylosing spondylitis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of active AS as observed over the study duration.

To describe the long-term QoL, which will be evaluated based on PROs routinely used for patients with AS, such as FACIT-Fatigue©.

Study design

This is an international, non-interventional (observational), prospective study that was planned, as per 2nd

protocol amendment, to enroll up to 5000 adult patients in total (approximately 2500 with chronic plaque-type psoriasis and 1250 each with PsA and AS). With the 3rd protocol amendement, the total number of patients has been adjusted to 2700 (approximately 1700, 500, and 500 patients with chronic plaque-type psoriasis, PsA, and AS, respectively). Up to 500 hospital- or office-based physicians experienced in the diagnosis and treatment of conditions for which secukinumab (registered as Cosentyx®) is indicated across Europe are planned to be involved in the study. After the Baseline visit, data will be collected for each patient prospectively every 6 months for up to 5 years. At each visit, effectiveness and tolerability parameters, as well as the patients’ QoL (according to the sites’ clinical routine) will be documented. The



primary endpoint is the retention rate for pooled indications (i.e. psoriasis, PsA and AS) at 2 years after start of participation in this study. Additional endpoints include annualized retention rates after start of participation, effectiveness assessed using disease-specific measures for psoriasis, PsA and AS as used in routine clinical practice, tolerability assessed by means of AE reporting, and secukinumab treatment patterns. Further additional endpoints include QoL via QoL tools used in routine clinical practice, efficiency parameters, as well as risk factors for PsA (in patients with plaque psoriasis).

Population

Inclusion criteria

1. Written informed consent of the patient or legal proxy to participate in the study (according to country specifications).

2. Age: ≥ 18 years.

3. Patients with an assured diagnosis by the Treating Physician of active moderate to severe plaque psoriasis, or active PsA, or active AS who take secukinumab according to the approved product information.

4. Patients must have received at least 16 weeks of commercial secukinumab treatment before study registration.

5. Patients diagnosed as having active moderate to severe plaque-psoriasis must have an available PASI assessment at the day of or up to 1 week prior to initial secukinumab treatment with commercial drug. In countries other than Germany this inclusion criterion is not mandatory.

6. Patients for whom the decision for a therapy with secukinumab was made by the attending Treating Physician, regardless of this non-interventional study.

Exclusion criteria

1. Any medical or psychological condition in the Treating Physician’s opinion which may prevent the patient from study participation for the initial 2 years.

2. Patients participating in parallel in an interventional clinical trial.

3. Patients participating in parallel in any other Novartis-sponsored NIS generating primary data for secukinumab.

4. Patients within the safety follow-up phase of a previous interventional or non-interventional trial using secukinumab as drug of interest or comparator.

5. Patients who received secukinumab as an investigational medical product during a secukinumab interventional trial any time in the past.

Cosentyx® was approved in the European Union (EU) for the treatment of moderate to severe plaque psoriasis in Jan-2015 and subsequently for the treatment of both active AS and active PsA in Nov-2015. Patients with moderate to severe plaque psoriasis, active AS and active PsA who are receiving commercial secukinumab treatment and whose Treating Physician expects them to benefit from continuing secukinumab treatment, will be allowed to participate in the present observational study provided they have been treated using commercially available secukinumab according to the approved product information for at least 16 weeks before study registration.

Endpoints

Primary endpoint

Retention rate of secukinumab at 2 years after start of participation in the study by pooled indications, where retention rate is defined as percentage of patients who have not discontinued the medication.

Additional endpoints

All indications

Retention:

Retention rate of secukinumab therapy by individual and pooled indications at 1, 3, 4, and 5 years after start of participation in the study (i.e. since first dose of secukinumab



administered in this study), and additionally by individual indication at 2 years, where retention rate is defined as percentage of patients who have not discontinued the medication.

Retention rate of secukinumab therapy by individual and pooled indications at 1, 2, 3, 4, and 5 years prior to the start of the study (i.e. since the patient’s very first dose of secukinumab) where retention rate is defined as percentage of patients who have not discontinued the medication.

Tolerability

Incidence rate, relationship with secukinumab and severity of treatment-emergent AEs, SAEs and co-morbidities at 1, 2, 3, 4 or 5 years after start of participation in the study by individual and pooled indications.

Treatment pattern:

Proportion of patients for each indication with alterations of secukinumab treatment regimen (classified according to types of alterations), reasons for, and duration of altered treatment regimens at 1, 2, 3, 4 or 5 years after start of participation in the study.

Proportion of patients for each indication using different drug-delivery products (prefilled syringe, prefilled pen/ autoinjector device), changes between application devices and reasons for changes.

Psoriasis

Effectiveness:

Proportion of patients achieving a PASI 75 response at 1, 2, 3, 4 and 5 years after start of participation in the study.

Proportion of patients achieving a PASI 90 and PASI 100 response at 1, 2, 3, 4 and 5 years after start of participation in the study.

Changes between PASI response categories over time after starting participation in the study.

Absolute PASI scores at 1, 2, 3, 4 and 5 years after start of participation in the study.

Changes in absolute and relative PASI scores over time after inclusion into the study.

Proportion of patients achieving a PGA 0/1 response (clear/almost clear skin) at 1, 2, 3, 4 and 5 years after start of participation in the study.

Note: All effectiveness variables listed above will be assessed 1, 2, 3, 4 or 5 years after start of participation in the study.

In addition, effectiveness endpoints will be assessed after 1, 2, 3, 4 and 5 years prior to the start of the study (i.e. since the patient’s very first dose of secukinumab).

Quality of life:

Proportion of patients achieving a DLQI 0/1 response (0=not at all, 1=a little) at 1, 2, 3, 4 and 5 years after start of participation in the study (only at sites, where DLQI is part of clinical routine)

Change from Baseline of EQ-5D, individual and aggregated scores (only at sites, where EQ-5D is part of the clinical routine in the treatment of psoriasis)

Correlation between QoL and effectiveness measures will be assessed as described in the Statistical Analysis Plan (SAP).

Efficiency: Pharmacoeconomic evaluations will be conducted using the data on days of inability to work and type of health insurance collected in the present non-interventional study (NIS). Details will be described in a separate health economic SAP. This endpoint applies only to the German population in this study.

Risk factors for PsA; proportion of patients reporting joint symptoms or signs (e.g. swollen joints, tender to pressure, joint pain, rheumatoid nodules, morning stiffness) as measured using PsA



disease assessments (as listed under PsA endpoints), at 1, 2, 3, 4 and 5 years after start of participation in the study; time from start of therapy with biologics until onset of PsA.

Psoriatic arthritis

Effectiveness:

78 tender joint count (TJC) and 76 swollen joint count (SJC) at 1, 2, 3, 4 or 5 years.

Physician’s global assessment (PGA) at 1, 2, 3, 4 or 5 years.

Total patient pain assessed by visual analog scale (VAS) at 1, 2, 3, 4 or 5 years.

Presence of any dactylitic digit at 1, 2, 3, 4 or 5 years.

Presence of any enthesitis in the following sites: lateral epicondyle humerus left and right, Achilles left and right and medial condyle femur left and right. Data from entheseal site assessments may be used to calculate the Leeds enthesitis index (LEI) at 1, 2, 3, 4 or 5 years.

Appearance of new bone erosions or worsening of pre-existing erosions in the hands and feet by X-ray assessment, according to the Treating Physician’s opinion, at 1, 2, 3, 4 or 5 years (if available).

The following PASI-specific endpoints will also be assessed if applicable:







In addition, the effectiveness variables will be assessed 1, 2, 3, 4 and 5 years prior to the start of the study (i.e. since the patient’s very first dose of secukinumab).

Quality of life

PsA: HAQ-DI© score and FACIT-Fatigue© at 1, 2, 3, 4 or 5 years after start of participation in the study (only at sites where HAQ-DI© and FACIT-Fatigue© are part of clinical routine).

Correlation between QoL and effectiveness measures will be assessed as described in the SAP.

Ankylosing spondylitis

Effectiveness:

Bath AS disease activity index (BASDAI) response at 1, 2, 3, 4 or 5 years.

Patient’s global assessment of disease activity (numeric rating scale (NRS)) at 1, 2, 3, 4 or 5 years.

C-reactive protein (CRP) or high-sensitivity CRP (hsCRP) (mg/L) at 1, 2, 3, 4 or 5 years (according to clinical practice).

Note: Data from BASDAI, patient’s global assessment (NRS) and CRP/hsCRP can be used to calculate the AS disease activity score (ASDAS).

Total spinal pain assessed using VAS scale at 1, 2, 3, 4 or 5 years.

Presence of any enthesitis in the following sites:

Costochondral 1 right/left


Spina iliaca anterior superior right/left

Crista iliaca right/left

Spina iliaca posterior right/left



Processus spinosus L5

Achilles tendon, insertion right/left

Note: Data from entheseal site assessments, if available, may be used to calculate the Maastricht AS enthesitis score (MASES) at 1, 2, 3, 4 or 5 years.

Appearance or worsening, according to the Treating Physician’s opinion, of any of the following lesions at anterior sites of the vertebrae assessed by X-ray at 1, 2, 3, 4 or 5 years (when available):

Squaring

Erosions

Sclerosis

Syndesmophytes

Bridging syndesmophytes

Appearance or worsening (according to the Treating Physician’s opinion) of bone marrow edema (BME) in the spine and/or sacro-iliac joints assessed by magnetic resonance imaging (MRI) at 1, 2, 3, 4 or 5 years (when available).



Quality of life

AS: FACIT-Fatigue© at 1, 2, 3, 4 or 5 years after start of participation in the study (only at sites, where FACIT-Fatigue© is part of clinical routine).


Data sources

The present observational study will generate primary data collected prospectively for the purposes of this study. Retrospective data collection at Baseline (e.g. medical and treatment history) will be retrieved from the patient’s file. Therefore the sources of data are derived from the Treating Physicians and the patients. All these data should be documented as well in the individual patient charts at the Treating Physician’s office.

Study size

According to the 2nd protocol amendment, it was planned to include up to 5000 adult patients (approximately 2500 with chronic plaque-type psoriasis and 1250 each with PsA and AS). With the 3rd

amendment, the total number of patients is adjusted to 2700 (approximately 1700, 500, 500 patients with chronic plaque-type psoriasis, PsA, and AS, respectively). Up to 500 sites experienced in the diagnosis and treatment of conditions for which secukinumab (registered as Cosentyx®) is indicated, with suffcient capacity and training in conduct of non-interventional clinical studies across Europe, are planned to be involved in the study.

Data analysis

The data will be analyzed by Novartis and/or by the designated Contract Research Organization (CRO). Any data analysis carried out independently by the Treating Physician(s) should be submitted to Novartis before publication or presentation.

Milestones

Start of data collection: Oct-2016 (first patient first visit, FPFV)

End of data collection: May-2022 (last patient last visit, LPLV)

Final report of study results: Jan-2023



3 Amendments and updates

Amendment 1 (local amendment for Germany)

In Germany patients may roll over into the present study from other non-interventional studies. Initiation of secukinumab treatment may therefore be significantly longer than the minimum requirement of 16 weeks. In order to ensure meaningful relative PASI assessments for all patients in Germany are possible, the protocol was amended.

Inclusion criterion 5 was added making availability of PASI assessments at the initiation of secukinumab treatment with commercial drug or study drug, whichever was earlier, mandatory for inclusion in Germany. In countries other than Germany this inclusion criterion is not mandatory.

Mandatory PASI value documentation was added to Section 7.4.3.

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 font for insertions.

A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described in this amended protocol require IRB/IEC approval prior to implementation.

Amendment 2 (global amendment)

This long-term, observational, prospective study was originally designed to collect data on the retention, effectiveness, safety, treatment pattern, quality of life (QoL), and efficiency of secukinumab in a real-life setting in adult patients with moderate to severe plaque psoriasis. Amendment 2 is being introduced to extend this data collection to patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS). The anti-inflammatory molecular mode of action of secukinumab (inhibition of interleukin-17; IL-17) is the same for chronic inflammatory arthropathies (such as PsA and AS) as well as for plaque psoriasis concerning inflammation ofjoints and skin, respectively.

This study will allow the observation of these closely connected patient populations with chronic inflammatory diseases in one study under the same settings, same time-frame, same standards and data collection pre-requisites during a comparable real-world health environment situation. As the clinical signs and symptoms of patients with psoriasis, PsA and AS may change, can overlap or even progress/worsen during the course of the study (for example, psoriasis patients can develop PsA), this study will also provide an opportunity to explore the onset, characteristics and risk factors for patients treated with secukinumab side by side.

Secukinumab was approved for the treatment of both PsA and AS in Europe (in Nov-2015) approximately 10 months after its approval for plaque-type psoriasis (in Jan-2015). This implies that a substantial number of patients have already been treated in a real-life setting both for PsA and AS in addition to the first endorsed indication psoriasis. Secukinumab is anticipated to be available for prescription for PsA and AS, as well as for plaque-type psoriasis, in the majority of countries in Europe. Therefore there is an unmet need to collect and report real-life data for all of these clinically connected conditions in the long-term.



In addition, Amendment 2 provides further specifics on the efficiency analyses for patients with plaque psoriasis. These changes, which apply only to the German population in the study, were made in order to obtain sufficient data to perform pharmacoeconomic analyses of costs associated with Treatment Physician consultations/hospital admissions and inability to work due to psoriasis.

Furthermore, Amendment 2 will exclude patients from study entry if they were previously included in an interventional clinical trial and received secukinumab as an investigational drug due to the fact that long-term (up to 5 years) clinical trials are already underway for patients with plaque-type psoriasis, PsA and AS as outlined in Section 5.3. Exclusion criterion no. 5, i.e. “patients who received secukinumab as an investigational medical product during a secukinumab interventional trial any time in the past” has been added accordingly. As of 24-Feb-2017, 76 patients were enrolled in this study (in accordance with the original protocol) who had previously been exposed to secukinumab during an interventional study; these patients may continue in this study. Regarding the applied methodology for data analysis and sample size selection in this non-interventional study, data from these patients will still be included in the total pool of patients treated with secukinumab given their data will not significantly affect the analysis of the total pool of patients due to the low number of patients involved. The following change to the wording of Inclusion Criterion no. 5 (please also refer to the rationale of amendment 01) has also been introduced:

From:

Patients must have an available PASI assessment at the day of or up to 1 week prior to initial secukinumab treatment with commercial drug or study drug, whichever was earlier. In countries other than Germany this inclusion criterion is not mandatory.

To:

Patients diagnosed as having active moderate to severe plaque-psoriasis must have an available PASI assessment at the day of or up to 1 week prior to initial secukinumab treatment with commercial drug or study drug. In countries other than Germany this inclusion criterion is not mandatory.

Changes to specific sections of the protocol, and newly added sections, are shown in the track changes version of the protocol using strike through red font for deletions and red font for insertions. A summary of the main sections that have been amended to reflect the rationale given above is provided below.

“Abstract (Section 2)”, “Disease background (Section 5.1)”, “Secukinumab (Section 5.2)”, “Rationale (Section 5.3)”, “Research questions and objectives (Section 6)”, “Primary objective (Section 6.1)”, “Additional objectives (Section 6.2)”, “Study design (Section 7.1)”, “Study duration (Section 7.1.1)”, “Study completion and discontinuation (Section 7.1.2)”, “Withdrawal of informed consent (Section 7.1.3)”, “Primary endpoint (Section 7.2.1)”, “Additional endpoints (Section 7.2.2)”, “Inclusion criteria (Section 7.3.1)”, “Exclusion criteria (Section 7.3.2)”, “Patient demographics, baseline characteristics (Section 7.4.1)”, “Retention (Section 7.4.2)”, “Effectiveness assessments for psoriasis (Section 7.4.3)”, “Effectiveness assessments for psoriatic arthritis (Section 7.4.4)”, “Effectiveness assessments for ankylosing spondylitis (Section 7.4.5)”, “Assessment of tolerability (Section 7.4.6)”, “ Assessment of treatment pattern (Section 7.4.7)”, “Assessment of quality of life (Section 7.4.8)”, “Assessment of efficiency



(Section 7.4.9)”, “Physical examination and vital signs (Section 7.4.10)”, “Data collection schedule (Section 7.5.1)”, “Study size “(Section 7.6)”, “Steering Committee (Section 7.7)”, “Data management (Section 7.8)”, “Data analysis (Section 7.9)”, “Limitations of the research methods (Section 7.11)”, “Informed consent procedures (Section 8.2)”, “Adverse event reporting (Section 9.1)”, “References (Section 11)”.

A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities. The changes described in this amended protocol require IRB/IEC and/or Health Authority approval prior to implementation according to country regulations.

Amendment 3 (global amendment)

This amendment addresses the reduction of the study population size. Due to lower than initially anticipated recruitment rates, it is not feasible to achieve the planned study size of 5000 patients in a timeframe that would allow timely analysis and communication of the collected data. Furthermore, the original distribution of study patients between the dermatological andrheumatological indications (1:1) does not correspond to the actual distribution of the patients treated with Cosentyx® in Europe. Thus, the number of patients with chronic plaque-type psoriasis, PsA and AS will be reduced to approximately 1700, 500, and 500, respectively.

Changes to specific sections of the protocol, and newly added sections, are shown in the track changes version of the protocol using strike through red font for deletions and red font for insertions. A summary of the main sections that were amended to reflect the rationale given above is provided below.

“Abstract (Section 2)”, “Secukinumab (Section 5.2)”, “Study design (Section 7.1)”, “Setting (Section 7.3.2)”, “Study size (Section 7.6)”, “Data analysis (Section 7.9)”, “References (Section 11)”.

A copy of this amended protocol will be sent to the IRBs/IECs and Health Authorities. The changes described in this amended protocol are subject to approval by the IRB/IEC and/or Health Authorities prior to implementation as per local regulations applicable for the participating countries.

4 Milestones

N/A



5 Rationale and background

5.1 Disease background

Psoriasis is a chronic, immune-mediated inflammatory disease that affects up to 3% of the population worldwide (Jacobson et al 2011). Psoriasis typically manifests as plaques that occur most commonly on the skin of the elbows and knees (Lebwohl 2003). Plaques can affect any area, including the palms and soles (Pettey et al 2003); fingernails and toenails are also commonly affected (Radtke et al 2011). Chronic plaque psoriasis can have a profound impact on several aspects of patient’s life. Psoriasis affects not only the skin itself, but it has been demonstrated to be closely related to the deterioration of patient’s emotional, social, occupational, and physical functioning (Eskin et al 2014). The impact of chronic psoriasis on quality of life (QoL) has been demonstrated to be similar to the effects of cancer (Bhutani et al 2013). The visible nature of psoriasis can be particularly disabling (Nelson et al 2013) with evidence of psycho-social stigma, lowered self-image, depression, anxiety and suicidal ideation (Fortune et al 1998). Especially on highly visible areas of the skin, psoriasis can be psychologically devastating (Augustin et al 2010a). Psychological impairment has been observed in social settings and in the workplace (de Jong et al 1996, Zachariae et al 2002).

Psoriasis patients report physical discomfort, impaired emotional functioning, a negative body and self-image, and limitations in their daily activities, social contacts and skin-exposing activities, and work (Wahl et al 2014). The systemic inflammation may increase the risk of other chronic diseases, as associations with cardiovascular disorders, type 2 diabetes, obesity and metabolic syndrome have been established. Growing literature on comorbidity risks in psoriasis (Augustin et al 2010b) and increased understanding of the immunopathology of psoriatic inflammation has moreover redefined psoriasis as a chronic systemic inflammation, especially in patients with moderate-to-severe course of the disease (Montaudié et al 2014, Reich 2012). Another medically and socioeconomically important fact is that psoriasis patients live with their disease for periods of up to several decades.

In addition to skin involvement, patients with psoriasis may also present with an inflammatory arthritis, known as psoriatic arthritis (PsA). PsA and ankylosing spondylitis (AS) both belong to a broader family of inflammatory rheumatic diseases known as spondyloarthritis (SpA). SpA are classified according to the predominant, but not exclusive, disease feature as peripheral SpA with main involvement of the appendicular skeleton, or axial SpA with main involvement of the axial skeleton. PsA represents approximately 50% of peripheral SpA and AS accounts for approximately 50% of axial SpA. In addition to involvement of the joints, both PsA and AS may affect several extra-articular structures and systems (Garg et al 2014). Due to progress identifying affected patients, the prevalence of SpA has increased to 1.4% of the European population worldwide over the last years with a comparable proportion of patients affected by AS and PsA (Dean et al 2014); about 2.5 million people across Europe are affected with either AS or PsA.

While PsA, AS and other SpA are considered separate clinical entities, a certain overlap in terms of disease manifestations, environmental and genetic predisposing factors can be identified(Turkiewicz 2007). This latter notion was corroborated by findings in a large-scale single



nucleotide polymorphism scan study, where interleukin-23R (IL-23R) variants that were previously linked to Crohn’s disease and psoriasis (diseases that may both co-exist with SpA) conferred risk to developing AS (Barrett 2008). Together, a common pathway including the interleukin-23 (IL-23)/interleukin-17 (IL-17) axis is thought to play a key role in seronegative SpAs including PsA and AS.

The prevalence of PsA is approximately 0.35% (Gladman et al 2005a). In the majority of patients, the onset of psoriasis precedes by some years the appearance of inflammation of the joints (Helliwell and Ruderman 2015). The proportion of psoriasis patients suffering from PsA was earlier reported to be approximately 5 to 10%. More recent investigations showed a proportion of more than 20% of psoriasis patients (Radtke et al 2009, Reich et al 2009, Gisondi et al 2005) with a highly variable clinical picture and covering a heterogeneous group of inflammatory changes to joints (arthritis, dactylitis), bones, and tendons and ligaments insertions (enthesitis) thus allowing a PsA diagnosis (Taylor 2002). Comorbidities and malignancies are reported to be increased in patients with PsA compared with non-PsA SpA irrespective of demographic factors and type of treatment (Haque et al 2016).

The prevalence of AS is approximately 0.3% in Europe (Dean et al 2014). AS is mainly characterized by involvement of the axial skeleton (spine and sacro-iliac joints) but also affects peripheral joints, entheses and extra-articular organs (Raychaudhuri et al 2014). A significant proportion of patients may present with associated extra-articular manifestations such as uveitis, psoriasis, inflammatory bowel disease (IBD), cardiovascular and pulmonary abnormalities (Mercieca et al 2014). Generalized osteoporosis as well as regional osteopenia are common in AS patients and predispose them to non-traumatic fractures in spite of young age and male gender (Davey-Ranasinghe et al 2013). The presence of the human leukocyte antigen B27 (HLA-B27) allele is strongly associated with AS; 90 to 95% of patients with AS who have European ancestry carry this marker (Pimentel-Santos et al 2013). AS associated with significant morbidity and disability, and thus constitutes a major socioeconomic burden (Cakar et al 2009).

5.2 Secukinumab

Secukinumab (AIN457, registered as Cosentyx®) is a recombinant high-affinity fully human monoclonal anti-human Interleukin-17A antibody of the 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 Th17 cells which, in animal models, were shown to be pivotal for several autoimmune and inflammatory processes. IL-17A is mainly produced by memory effector CD4+ and CD8+ T lymphocytes (Kagami et al 2010, Lowes et al 2008). IL-17A is being recognized as one of the principal pro-inflammatory cytokines in immune mediated inflammatory diseases, such as psoriasis, AS, PsA and other inflammatory conditions. The neutralization of IL-17A is expected to treat the underlying pathophysiology of immune mediated disease, and as a consequence provide relief of symptoms (Patel et al 2013).

Secukinumab was approved in the European Union (EU) in Jan-2015 for the treatment of moderate to severe plaque psoriasis in patients who are candidates for systemic therapy. Secukinumab proved to be very effective in treating plaque psoriasis, with 300 mg being the dose that delivered the most clinically meaningful benefit to patients with respect to achievement of almost clear to clear skin, improved QoL, speed of onset of action, and sustainability of symptom relief. Secukinumab was subsequently approved in the EU in Nov-2015 for the



treatment of patients with active PsA and active AS. Secukinumab proved to be effective in managing the signs and symptoms of PsA at a dose of 150 mg for TNF-naïve patients and at a dose of 300 mg for TNF-inadequate responders or for any patient with concomitant moderate to severe plaque psoriasis. Secukinumab 150 mg proved to be effective in managing the signs and symptoms of AS for all patients. From a safety perspective, secukinumab has been well tolerated.

As of 25-Jun-2017, over 28000 subjects (which included patients and a small number of healthy volunteers) have been enrolled into the secukinumab clinical development program (including trials where secukinumab has been used as a protocol specified treatment), of which approximately 25000 subjects (comprising of patients and healthy volunteers) have received at least one dose of secukinumab. Important identified risks associated with secukinumab treatment are infections and infestations, especially of the upper respiratory tract, neutropenia and hypersensitivity. Important potential risks include malignant or unspecified tumors, major adverse cardiovascular events, immunogenicity, flare-up of Crohn’s disease in patients with uncontrolled Crohn’s disease, and hepatitis B re-activation. There is also an important potential interaction of secukinumab with live vaccines (Investigator’s Brochure, Edition 17, 19-Aug-2017).

Multiple long-term clinical trials (including pivotal phase 3 clinical trial extension studies) of secukinumab in plaque-type psoriasis (e.g. CAIN457A2308, CAIN457A2309, CAIN457A2302E1, CAIN457A2304E1), PsA (e.g. CAIN457F2306E1, CAIN457F2312, CAIN457F2318) and AS (e.g. CAIN457F2305E1, CAIN457F2310, CAIN457F2314) are collecting data for up to 5 years of secukinumab exposure(Investigator’s Brochure, Edition 17, 19-Aug-2017). However, the longer term effectiveness and safety profiles of secukinumab, under real-life conditions in the EU, remains unknown. Other than collecting post-marketing safety information, there is a need for an observational study that collects and analyzes prospectively the outcomes associated with underlying disease and its comorbidities, in terms of assessing long term retention, sustainability of effectiveness, long term safety, treatment patterns over time and impact on QoL of secukinumab treatment in patients with moderate to severe plaque psoriasis, PsA and AS.

5.3 Rationale

The present non-interventional study aims to collect real-life clinical data on the retention, effectiveness, safety, treatment pattern, QoL, and efficiency of secukinumab in adult patients with moderate to severe chronic plaque-type psoriasis, PsA or AS across Europe. The anti-inflammatory molecular mode of action of secukinumab (inhibition of interleukin-17; IL-17) is the same for chronic inflammatory arthropathies (such as PsA and AS) as well as for plaque psoriasis concerning inflammation of joints and skin, respectively.

This study will allow the observation of these closely connected patient populations with chronic inflammatory diseases in one study under the same settings, same time-frame, same standards and data collection pre-requisites during a comparable real-world health environment situation. As the clinical signs and symptoms of patients with psoriasis, PsA and AS may change, can overlap or even progress/worsen during the course of the study (for example, psoriasis patients can develop PsA), this study will also provide an opportunity to explore the onset, characteristics and risk factors for patients treated with secukinumab side by side.



Secukinumab was approved for the treatment of both PsA and AS in Europe (in Nov-2015) approximately 10 months after its approval for plaque-type psoriasis (in Jan-2015). This implies that a substantial number of patients have already been treated in a real-life setting both for PsA and AS in addition to the first endorsed indication psoriasis. Secukinumab is anticipated to be available for prescription for PsA and AS, as well as for plaque-type psoriasis, in the majority of countries in Europe. Therefore there is an unmet need to collect and report real-life data for all of these clinically connected conditions in the long-term.

This study will exclude patients from study entry if they were previously included in an interventional clinical trial and received secukinumab as an investigational drug due to the fact that long-term (up to 5 years) interventional clinical trials are already underway for patients with plaque-type psoriasis, PsA and AS.

In the present study it is aimed to prospectively collect real-life data for up to 5 years in patients who have previously received secukinumab for at least 16 weeks, thus providing valuable insight into the drug’s long-term effectiveness and tolerability in a real-life setting. The minimum treatment duration with secukinumab of 16 weeks before inclusion into this study was chosen because available data suggest that a clinical response to secukinumab is usually achieved within 16 weeks of treatment and the study is focusing on long-term retention and long-term outcomes.

6 Research question and objectives

This observational longitudinal study does not test a statistical hypothesis but is intended to be descriptive, with a collection of historical data on demographics and patient’s characteristics and a prospective data collection on retention, long-term effectiveness and safety in patients with moderate to severe plaque psoriasis, active PsA and active AS under real-life clinical routine conditions. In addition, as secukinumab is available in different drug-delivery products (i.e. pre-filled syringes or for use with an autoinjector device), collecting data on the actual treatment patterns under routine daily conditions is vital for the critical evaluation of each drug-delivery product. Furthermore, real-life data on PROs, where established in the clinical routine, will be collected.

The results of the study will be used for communication/publication purposes and will also help to answer specific questions in the real world setting raised by the Health Authorities / Payers in regards to the long-term use of secukinumab in the approved indication of moderate to severe plaque-type psoriasis, active PsA and active AS.

6.1 Primary objective

To assess the long-term retention of secukinumab treatment in routine clinical practice for the treatment of moderate to severe plaque-type psoriasis, active PsA and active AS (overall) based on the first dose of secukinumab administered since the start of the study, and to identify factors affecting the retention of secukinumab treatment for the overall study population.



6.2 Additional objectives

6.2.1 All indications

To assess the long-term retention of secukinumab treatment in routine clinical practice for the treatment of each individual disease (i.e. moderate to severe plaque-type psoriasis, active PsA, or active AS) based on the first dose of secukinumab administered since the start of the study, and to identify factors affecting the retention of secukinumab treatment in each disease.

To assess the long-term retention of secukinumab treatment in routine clinical practice for the treatment of moderate to severe plaque-type psoriasis, active PsA and active AS (individually and overall) based on the first dose of secukinumab administered prior to the start of the study (i.e. the patient’s very first dose of secukinumab).

To describe the long-term tolerability of secukinumab in routine clinical practice for the treatment of moderate to severe plaque psoriasis, active PsA and active AS (individually and overall) as observed over the study duration and assessed by the type, frequency, severity and relationship of adverse events (AEs) and serious adverse events (SAEs) and comorbidities.

To describe the treatment pattern with secukinumab for the treatment of moderate to severe plaque psoriasis, active PsA and active AS in terms of dosing, administration intervals and preferred device based on the reported therapy changes.

6.2.2 Psoriasis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of moderate to severe plaque psoriasis as observed over the study duration and assessed by the proportion of patients maintaining clear/almost clear skin over time.

To describe the long-term QoL, which will be evaluated based on PROs routinely used for patients with psoriasis, such as the Dermatology Life Quality Index (DLQI) and the EuroQoL-5 dimension questionnaire (EQ-5D).

To collect data that will be used for conducting efficiency and pharmacoeconomic evaluations. Details on the analysis will be described in separate documents. This objective applies only to the German population in the study.

To explore potential risk factors for developing PsA by assessing anamnestic, demographic and clinical data.

6.2.3 Psoriatic arthritis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of active PsA as observed over the study duration.

To describe the long-term QoL, which will be evaluated based on PROs routinely used for patients with PsA, such as the health assessment questionnaire-disability index (HAQ-DI©) and functional assessment of chronic illness therapy – fatigue (FACIT-Fatigue©).

6.2.4 Ankylosing spondylitis

To describe the long-term effectiveness of secukinumab in routine clinical practice for the treatment of active AS as observed over the study duration.



To describe the long-term QoL, which will be evaluated based on PROs routinely used for patients with AS, such as FACIT-Fatigue©.

7 Research methods

7.1 Study design

This is a longitudinal, non-interventional (observational) study with prospective collection of primary data on the retention, safety and effectiveness of secukinumab in patients with moderate to severe chronic plaque-type psoriasis, active PsA and active AS. The study will be performed in up to 500 sites and was planned, as per 2nd protocol amendment, to involve up to 5000 patients across Europe (approximately 2500 with chronic plaque-type psoriasis and approximately 1250 each with PsA and AS). The total number of patients is adjusted to 2700 (approximately 1700, 500, 500 patients with chronic plaque-type psoriasis, PsA and AS, respectively) by the third protocol amendment. It is planned to involve up to 500 hospital- or office-based physicians experienced in the diagnosis and treatment of conditions for which secukinumab (registered as Cosentyx®) is indicated across Europe. Each site will be asked to involve patients in chronological order, regardless of the sites’ available patient pools. The study design is depicted in Figure 7-1 and Figure 7-2.

Patients with chronic plaque-type psoriasis, PsA and AS who have previously started commercial secukinumab treatment for at least 16 weeks will be invited to participate in this observational study upon providing written informed consent. Each patient will participate in the study for a maximum of 5 years (60 months). During this time, visits are documented every 6 months after the Baseline visit. The study will end either when all patients enrolled have been observed for at least 2 years except for patients who stop the observational period early, or when the 5-year visit has been documented for approximately 1000 patients. The end of study will be determined by the later of these 2 time points, i.e. whichever occurs latest.

A first interim analysis is planned based on data collected for the first 1000 enrolled patients, which is anticipated to occur around 12 months after first patient first visit (FPFV). Further interim analyses (up to 5) are planned every 12 months. Final analyses are planned based on data collected for 2700 enrolled patients, when at least 2-year data are available after the last patient first visit (LPFV) and when the 5-year data of approximately 1000 patients including a representative number of patients for all 3 indications are available.

At Baseline, patients must be assigned to the indication of moderate to severe plaque psoriasis, PsA or AS that is the dominant indication intended for treatment with secukinumab. The indication assigned at Baseline will remain until the end of the study. If the clinical signs and symptoms of patients change during the course of the study, additional assessments to describe the patient’s progress can be performed in accordance with routine clinical practice and recorded in the electronic case report form (eCRF).

If a patient switches his/her Treating Physician, the study site should ask the patient’s new Treating Physician for a regular transfer (e.g. by letter) of relevant assessments and information. As an example the switch for a patient with moderate to severe plaque psoriasis from a dermatology site to a rheumatology site may be required due to development of PsA. If no further follow-up by the study site is possible, the patient should complete the study, i.e. no



further data collection by the study site. It should be noted that patients are not allowed to be enrolled twice in this study; for example, a patient enrolled in the study at a dermatology site cannot be subsequently be re-enrolled in the study at a rheumatology site.

Comparison with other therapies for plaque psoriasis, active PsA or active AS is not part of the scope of the SERENA study.

Figure 7-1 Overall study duration including time points for analysis

Figure 7-2 Study observation period for a single patient

Note: End of observation is achieved either after 60 months of study duration or earlier if the end of study is achieved, i.e. Month 24 is documented for approximately 2700 patients and Month 60 is documented for approximately 1000 patients.

7.1.1 Study duration

The study duration is anticipated to be 5-6 years and will consist of an approximately 3-year recruitment period and 2-3 years of minimal observational time for the last patient recruited. For



each patient, the study will last for a maximum of 5 years (60 months) with no further documentation being required after the Year 5 (Month 60) visit. The end of study is anticipated either when all patients enrolled have been observed for at least 2 years except for patients who stop the observational period early or when the 5-year visit has been documented for approximately 1000 patients, including a representative number of patients of all three indications The end of the study will be determined by the later of these 2 time points, i.e. whichever occurs latest.

7.1.2 Study completion and discontinuation

A patient will be considered to have completed the study when:

The patient has completed the planned overall observation time (i.e. 5 years), or

Treatment with secukinumab is permanently discontinued, or

The end of study is reached.

For all patients, a safety follow-up should be conducted as described in Section 9.

7.1.3 Withdrawal of informed consent

Patients may voluntarily withdraw consent to participate in the study for any reason at any time. Withdrawal of consent from the study is defined as when a patient:

Does not want to participate in the study anymore, or

Does not want any further visits or assessments to be documented

In this situation, the Treating Physician must make every effort (e.g. telephone, e-mail, letter) to determine the primary reason for the patient’s decision to withdraw his/her consent and record this information.

All efforts should be made to completely document the assessments prior to study withdrawal. A final evaluation is recommended at the time of the patient’s study withdrawal as detailed in the assessment tables (Table 7-5, Table 7-6 and Table 7-7).

No further data for capture of routine assessments will be collected and the data that would have been collected at subsequent visits will be considered missing.

Further attempts to contact the patient for this study are not allowed unless safety findings require communicating or follow-up.

7.2 Study endpoints

7.2.1 Primary endpoint

Retention rate of secukinumab at 2 years after start of participation in the study by pooled indications, where retention rate is defined as percentage of patients who have not discontinued the medication.

7.2.2 Additional endpoints

7.2.2.1 All indications

Retention:



Retention rate of secukinumab therapy by individual and pooled indications at 1, 3, 4, and 5 years after start of participation in the study (i.e. since first dose of secukinumab administered in this study) and additionally by individual indication at 2 years, where retention rate is defined as percentage of patients who have not discontinued the medication.

Retention rate of secukinumab therapy by individual and pooled indications at 1, 2, 3, 4, and 5 years prior to the start of the study (i.e. since the patient’s very first dose of secukinumab), where retention rate is defined as percentage of patients who have not discontinued the medication.

Tolerability:

Incidence rate, relationship with secukinumab and severity of treatment emergent AEs and SAEs and co-morbidities at 1, 2, 3, 4 and 5 years after start of participation in the study by individual and pooled indications.

Treatment pattern:

Proportion of patients for each indication with alterations of secukinumab treatment regimen (classified according to types of alterations), reasons for, and duration of altered treatment regimens at 1, 2, 3, 4 and 5 years after start of participation in the study.

Proportion of patients for each indication using different drug-delivery products (prefilled syringes, prefilled pen/ autoinjector device), changes between the application devices and reasons for changes.

7.2.2.2 Psoriasis

Effectiveness:






Proportion of patients achieving a PGA 0/1 response (clear/almost clear skin) at 1, 2, 3, 4 and 5 years after start of participation in the study.


In addition, effectiveness endpoints will be assessed after 1, 2, 3, 4 and 5 years prior to the start of the study (i.e. since the patient’s very first dose of secukinumab). Quality of life:

Proportion of patients achieving a DLQI 0/1 response (0=not at all, 1=a little) at 1, 2, 3, 4 and 5 years after start of participation in the study (only at sites, where DLQI is part of clinical routine)

Change from Baseline of EQ-5D, individual and aggregated scores (only at sites, where EQ-5D is part of the clinical routine in the treatment of psoriasis)



Correlation between QoL and effectiveness measures will be assessed as described in the Statistical Analysis Plan (SAP).

Efficiency: Pharmacoeconomic evaluations will be conducted using the data on days of inability to work and type of health insurance collected in the present non-interventional study (NIS). Details will be described in a separate health economic SAP. This endpoint applies only to the German population in this study.

Risk factors for PsA; proportion of patients reporting joint symptoms or signs (e.g. swollen joints, tender to pressure, joint pain, rheumatoid nodules, morning stiffness) as measured using PsA assessments (as listed under PsA endpoints), at 1, 2, 3, 4 and 5 years after start of participation in the study; time from start of therapy with biologics until onset of PsA.

7.2.2.3 Psoriatic arthritis

Effectiveness:

78 tender joint count (TJC) and 76 swollen joint count (SJC) at 1, 2, 3, 4 or 5 years.

Physician’s global assessment (PGA) at 1, 2, 3, 4 or 5 years.

Total patient pain assessed by visual analog scale (VAS) at 1, 2, 3, 4 or 5 years.

Presence of any dactylitic digit at 1, 2, 3, 4 or 5 years.

Presence of any enthesitis in the following sites: lateral epicondyle humerus left and right, Achilles left and right and medial condyle femur left and right. Data from entheseal site assessments may be used to calculate the Leeds enthesitis index (LEI) at 1, 2, 3, 4 or 5 years.

Appearance of new bone erosions or worsening of pre-existing erosions in the hands and feet by X-ray assessment, according to the Treating Physician’s opinion, at 1, 2, 3, 4 or 5 years (if available).

The following PASI-specific endpoints will also be assessed if applicable:








Quality of life

PsA: HAQ-DI© score and FACIT-Fatigue© at 1, 2, 3, 4 or 5 years after start of participation in the study (only at sites where HAQ-DI© and FACIT-Fatigue© are part of clinical routine).




7.2.2.4 Ankylosing spondylitis

Effectiveness:

Bath AS disease activity index (BASDAI) response at 1, 2, 3, 4 or 5 years.

Patient’s global assessment of disease activity (numeric rating scale (NRS)) at 1, 2, 3, 4 or 5 years.

C-reactive protein (CRP) or high-sensitivity CRP (hsCRP) (mg/L) at 1, 2, 3, 4 or 5 years (according to clinical practice).

Note: Data from BASDAI, patient’s global assessment (NRS) and CRP/hsCRP can be used to calculate the AS disease activity score (ASDAS).

Total spinal pain assessed using VAS scale at 1, 2, 3, 4 or 5 years.

Presence of any enthesitis in the following sites:



Spina iliaca anterior superior right/left

Crista iliaca right/left

Spina iliaca posterior right/left

Processus spinosus L5

Achilles tendon, proximal insertion right/left

Note: Data from entheseal site assessments, if available, may be used to calculate the Maastricht AS enthesitis score (MASES) score at 1, 2, 3, 4 or 5 years.

Appearance or worsening, according to the Treating Physician’s opinion, of any of the following lesions at anterior sites of the vertebrae assessed by X-ray at 1, 2, 3, 4 or 5 years (when available):

Squaring

Erosions

Sclerosis

Syndesmophytes

Bridging syndesmophytes

Appearance or worsening (according to the Treating Physician’s opinion) of bone marrow edema (BME) in the spine and/or sacro-iliac joints assessed by magnetic resonance imaging (MRI) at 1, 2, 3, 4 or 5 years (when available).



Quality of life



AS: FACIT-Fatigue© at 1, 2, 3, 4 or 5 years after start of participation in the study (only at sites, where FACIT-Fatigue© is part of clinical routine).


7.3 Setting

This observational study will be performed at up to 500 hospital- or office-based physicians experienced in the diagnosis and treatment of conditions for which secukinumab (registered as Cosentyx®) is indicated across Europe. The study population will consist of a representative group of adults with moderate to severe plaque type psoriasis, active PsA or active AS for whom routine treatment with secukinumab was already initiated. As per 3rd protocol amendment, the goal is to recruit a total of approximately 2700 patients across Europe.

7.3.1 Inclusion criteria

1. Written informed consent of the patient or legal proxy to participate in the study (according to country specifications).

2. Age: ≥ 18 years.

3. Patients with an assured diagnosis by the Treating Physician of active moderate to severe plaque psoriasis, active PsA or active AS who take secukinumab according to the approved product information.

4. Patients must have received at least 16 weeks of commercial secukinumab treatment before study registration.

5. Patients diagnosed as having active moderate to severe plaque psoriasis must have an available PASI assessment at the day of or up to 1 week prior to initial secukinumab treatment with commercial drug. In countries other than Germany this inclusion criterion is not mandatory.

6. Patients for whom the decision for a therapy with secukinumab was made by the attending Treating Physician, regardless of this non-interventional study.

7.3.2 Exclusion criteria

1. Any medical or psychological condition in the Treating Physician’s opinion which may prevent the patient from study participation for the initial 2 years.

2. Patients participating in parallel in an interventional clinical trial.

3. Patients participating in parallel in any other Novartis-sponsored NIS generating primary data for secukinumab.

4. Patients within the safety follow-up phase of a previous interventional or non-interventional trial using secukinumab as drug of interest or comparator.

5. Patients who received secukinumab as an investigational medical product during a secukinumab interventional trial any time in the past.

Cosentyx® was approved in the EU for the treatment of moderate to severe plaque psoriasis in Jan-2015 and subsequently for the treatment of both active AS and active PsA in Nov-2015. Patients with moderate to severe plaque psoriasis, active AS and active PsA who are receiving commercial secukinumab treatment and whose Treating Physician expects them to benefit from



continuing secukinumab treatment, will be allowed to participate in the present observational study provided they have been treated using commercially available secukinumab according to the approved product information for at least 16 weeks before study registration.

7.4 Variables

The variables collected for this study will be those documented at site during routine practice. Assessment and corresponding documentation practice are susceptible to variations between countries and sites and thus are part of the observational character of the study and its methodology. To generate a common understanding on which assessment data should be collected, a set of explanations are given reflecting a summary of a common understanding in the field, to a degree possible, for each individual assessment.

7.4.1 Patient demographic and other baseline characteristics

Patient demographics and Baseline characteristics data (as outlined below) will be collected if available according to clinical routine.

Demography

Age, sex, occupational status, relationship status, education, height, weight, calculated body mass index (BMI), race and ethnicity.

Medical and treatment history

Time since first diagnosis of psoriasis, PsA or AS.

Relevant medical history (including nail involvement), smoking habits and concomitant diseases.

Medical specialization of the Treating Physician at Baseline.

Start date and presence of concomitant co-morbidities.

Family history of psoriasis, arthritis and other inflammatory diseases.

Relevant prior medication up to 6 months before Baseline visit.

Relevant concomitant medication.

Prior treatment for psoriasis, PsA or AS up to 6 months before Baseline visit (including reason for discontinuation, i.e. at least failure to respond, contraindication, intolerance); prior treatment for psoriasis, PsA or AS with biologics should be documented without time limit, i.e. any time prior to the Baseline visit.

Severity of plaque psoriasis (moderate or severe).

Start of treatment with commercial secukinumab.

Potential risk factors for PsA: BMI, body surface area (BSA) affected, nail involvement, family history of arthritis, psoriasis localization.

Concomitant medications

Prior treatments are defined as treatments taken and stopped prior to date of signing the ICF. Any treatment given at least once between the day of signing the ICF and the end of observation will be a concomitant treatment, including those which were started pre-Baseline and continued into the treatment period. Administration and dose of secukinumab will be captured by individual administration records.



Prior and concomitant psoriasis, PsA, and AS treatments will be documented including the start date, end date, dose and reason for discontinuation (with a distinction between at least failure to respond, contraindication or intolerance). Administration and dose of secukinumab will be captured by individual administration records with no time limit (i.e. prior secukinumab administration and dose details taken at any time prior to Baseline including first dose will be recorded). Any intermediary treatment breaks of secukinumab will also be recorded as individual secukinumab administration records. Similarly, administration and dose of any other prior biologics will be captured with no time limit. Other significant prior and concomitant treatments including non-biologic psoriasis, PsA and AS treatments will be documented up to 6 months before the Baseline visit.

7.4.2 Retention

The primary variable in this study is the retention rate of secukinumab at 2 years after start of participation in the study by pooled indications, where retention rate is defined as percentage of patients who have not discontinued the medication.

Retention will be assessed at each visit. A patient is considered to have retained treatment at a given time when he/she has not permanently discontinued the treatment for any reason at that time.

If a patient discontinues treatment with secukinumab, the reasons should be documented, indicating the primary reason. Possible reasons for discontinuation include:

Complete remission of clinical signs and symptoms

Lack of efficacy

Adverse events

Lack of patient’s adherence

Patient wish (any reasons)

Other

7.4.3 Effectiveness assessments for psoriasis

PASI (see Section 7.4.3.1)

PGA of psoriasis (see Section 7.4.3.2)

Psoriatic nail involvement (see Section 7.4.3.3)

78 TJC and 76 SJC including dactylitis (see Section 7.4.4.1)

7.4.3.1 Psoriasis area severity index (PASI)

PASI, according to guidelines definitions, is recommended for both, assessment of disease severity and treatment goals, for patients with plaque psoriasis (Nast et al 2015). Therefore it is expected that PASI might be assessed for all patients with plaque-type psoriasis, and those patients with active PsA showing signs or symptoms of psoriasis, as part of the clinical routine.

PASI can be collected at each visit if it is part of the clinical routine of the site; in addition, and if available, the PASI score from the start of secukinumab treatment will be documented. For all patients in Germany, collection of the PASI score at the initiation of secukinumab therapy with commercial drug is mandatory. The Treating Physician will assess whether deteriorations of



PASI score occurred prior to study start and during the study period. If any deterioration occurs between start of secukinumab treatment and signing of informed consent a spontaneous report should be sent to the local Novartis Drug Safety and Epidemiology (DS&E). The Treating Physician will assess whether deteriorations occurring during the course of the study constitute AEs or SAEs and report them accordingly.

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 results will be added up to estimate the total BSA affected by plaque-type psoriasis.

A PASI score will be derived as indicated in Table 7-1. The head, trunk, upper limbs and lower limbs are assessed separately for erythema, thickening (plaque elevation, induration), and scaling (desquamation).

The average degree of severity of each sign in each of the four body regions is assigned a score of 0-4. The area covered by lesions on each body region is estimated as a percentage of the total area of that particular body region. Further practical details to help with the assessment are provided below:

1. The neck is assessed as part of the head

2. The axillae and groin are assessed as part of the trunk

3. The buttocks are assessed as part of the lower limbs

4. When scoring the severity of erythema, scales should not be removed.

Because the head and neck, upper limbs, trunk and lower limbs correspond to approx. 10%, 20%, 30% and 40% of the BSA, 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

H – Head, U – upper limb, T – trunk, L- lower limb, E – erythema, I – induration, D – desquamation, A - area

Absolute PASI scores can range from a lower value of 0, corresponding to no signs of psoriasis, up to a theoretic maximum of 72.0.

If basic PASI scores for head, trunk, upper limbs and lower limbs described in Table 7-1 are not available in clinical practice the Treating Physician will be asked to record the total PASI score and BSA affected in the eCRF, if available. Relative PASI responses are defined as follows:

PASI 75 response: patients achieving ≥ 75% improvement (reduction) in PASI score, compared to start of treatment, are defined as PASI 75 responders

PASI 90 response: patients achieving ≥ 90% improvement (reduction) in PASI score, compared to start of treatment, are defined as PASI 90 responders

PASI 100 response / remission: complete clearing of psoriasis (PASI=0)



Table 7-1 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 CRF†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



7.4.3.2 Physician’s global assessment

The PGA can be performed for all patients with plaque-type psoriasis, and those patients with active PsA showing signs or symptoms of psoriasis, as part of routine clinical practice.

The physician’s global assessment (PGA) is sometimes called the investigator’s global assessment. For the PGA, the Treating Physician assigns a single estimate of the patient’s overall severity of plaque psoriasis. A 7-point scale (from clear to severe) is typically used (Table 7-2) although many variations have been employed. In most versions of the PGA, the individual elements of psoriasis plaque morphology or degree of body surface area involvement are not quantified. The PGA is collected at each visit.

Table 7-2 Description of a physician’s global assessment of psoriasis

Severe 6 Very marked plaque elevation, scaling and/or erythema

Moderate to severe 5 Marked plaque elevation, scaling and/or erythema

Moderate 4 Moderate plaque elevation, scaling, and/or erythema

Mild to moderate 3 Intermediate between moderate and mild

Mild 2 Slight plaque elevation, scaling and/or erythema

Almost clear 1 Intermediate between mild and clear

Clear 0 No signs of psoriasis (post inflammatory hyperpigmentation may be present)

7.4.3.3 Assessment of nail psoriatic involvement

Nail involvement (nails of the fingers and toes) may be recorded at each study visit (Table 7-5and Table 7-6) based on the total % affected (see Table 7-3) as part of routine clinical practice.

Table 7-3 Assessment of psoriatic nail involvement

Involvement of nails (% affected)

Completely (>90% affected)

50-90% affected

Less than 50% affected

7.4.4 Effectiveness assessments for psoriatic arthritis

78 TJC and 76 SJC including dactylitis (see Section 7.4.4.1)

PGA (see Section 7.4.3.2)

Total pain VAS (see Section 7.4.4.2)

Enthesitis assessment (see Section 7.4.4.3)

X-ray assessment (see Section 7.4.4.4)

PASI (see Section 7.4.3.1)

Psoriatic nail involvement (Section 7.4.3.3)

7.4.4.1 Tender joint 78 count (78 TJC) and swollen joint 76 count (76 SJC)

Joint symptoms and signs of PsA joint involvement (e.g. swollen joints, tender to pressure, joint pain, rheumatoid nodules, morning stiffness) can be collected at each visit.



Data for 78 TJC and 76 SJC can be collected if performed according to daily routine at the study site. Joint count assessment can be performed by the Treating Physician or other involved healthcare professional (HCP) according to daily routine and generally (whenever possible) it is good practice for the same evaluator to perform these assessments at all visits.

As guidance, the following 78 joints are usually assessed for tenderness: 2 temporomandibular, 2 sternoclavicular, 2 acromioclavicular joints, 2 shoulders, 2 elbows, 2 wrists, 2 first carpometacarpal, 10 metacarpophalangeal (MCP), 10 proximal interphalangeal (PIP), 8 distal interphalangeal (DIP) joints of the hands, the 2 hip, 2 knee, 2 talo-tibial, 2 mid-tarsal, 10 metatarsophalangeal (MTP), 10 PIP, and 8 DIP joints of the feet (Gladman et al 2005b).

In medical practice, the 76 joints that are usually examined for swelling are the same as those examined for tenderness with the exception of the hip joints.

Joint tenderness and swelling are graded present (1) or absent (0). Synovial fluid and/or soft tissue swelling but not bony overgrowth represents a positive result for SJC.

Data is recorded for tender and swollen joints (right or left side), i.e. a box (no, yes or not applicable) is ticked for all joints. The total number of tender and swollen joints (right and left) will be automatically calculated in the eCRF.

Dactylitis

Data on presence of dactylitis can be collected as assessed by the Treating Physician or other involved HCP according to routine practice. Dactylitis of a digit in the foot or hand counts as 1 tender and swollen joint (Coates et al 2015).

7.4.4.2 Total pain visual analog scale

The total pain experienced by the patient will be assessed using a 100 mm VAS ranging from ‘no pain’ to ‘unbearable pain’ (Coates et al 2010).

7.4.4.3 Enthesitis assessment

Data on the presence of any enthesitis in the following sites will be assessed by the Treating Physician or other involved HCP according to daily routine: lateral epicondyle humerus (left and right), Achilles (left and right) and medial condyle femur (left and right). Besides a general enthesitis assessment, data collected may be used to calculate the LEI (Orbai et al 2014).

The LEI is a validated enthesitis index that uses 6 sites for the evaluation of enthesitis. For the LEI (in case such data is available), tenderness on examination is recorded as either present (1) or absent (0) for each of the 6 sites, for an overall score range of 0–6. Higher count represents greater enthesitis burden (Mease 2011).

The LEI has demonstrated substantial to excellent agreement with other scores in the indication of PsA (Healy and Helliwell 2008) and axial SpA (Landewe and van Tubergen 2015).



7.4.4.4 X-ray assessment

In this study, X-ray data (when available) can be collected for patients with PsA. Data can be collected from separate radiographs of each hand/wrist (postero-anterior (PA)) and each foot (anterior-posterior (AP)) performed at approximately Baseline, each study visit and at the end of study (EOS)/early discontinuation. New onset of bone erosion or worsening of pre-existing occurrences of bone erosion will be recorded according to the Treating Physician’s judgment. Erosions in wrist joints, all MCPs, PIPs, and DIP joints of each hand, and the first interphalangeal joint and all MTP joints for each foot will be assessed. Details of data analysis are presented in the SAP.

The scores will be calculated by the Treating Physician or other involved HCP according to daily routine. Total erosion score, total joint space narrowing (JSN) score and total radiographic score (calculated) will be captured in eCRF. At each visit, the X-ray performed most closely to that visit should be assessed.

7.4.5 Effectiveness assessments for ankylosing spondylitis

BASDAI (see Section 7.4.5.2)

Patient’s global assessment of disease activity (see Section 7.4.5.3)

CRP and or hsCRP (see Section 7.4.5.4)

ASDAS (see Section 7.4.5.1)

Total spinal pain VAS (see Section 7.4.5.5)

Enthesitis assessment (see Section 7.4.5.6)

X-ray assessment (see Section7.4.5.7)

MRI assessment (see Section 7.4.5.8)

7.4.5.1 Ankylosing spondylitis disease activity score

The ASDAS is a composite index to assess disease activity in AS (Sieper 2009, Lukas 2009).

If available, data on the ASDAS-CRP or ASDAS-hsCRP can be collected and data will be used in medical practice to assess the disease activity status.

Parameters used for the ASDAS include:

Total back pain (BASDAI question 2) (Section 7.4.5.2)

Patient’s global assessment of disease activity (Section 7.4.5.3)

Peripheral pain/swelling (BASDAI question 3) (Section 7.4.5.2)

Duration of morning stiffness (BASDAI question 6) (Section 7.4.5.2)

CRP or hsCRP for example in mg/L (Section 7.4.5.4)

Disease activity states are defined as follows: inactive disease, moderate disease activity, high disease activity, and very high disease activity. The 3 values selected to separate these states are< 1.3 between inactive disease and moderate disease activity, < 2.1 between moderate disease activity and high disease activity, and > 3.5 between high disease activity and very high disease activity. Selected cut-offs for improvement scores are a change ≥ 1.1 unit for “minimal clinically important improvement” and a change ≥ 2.0 units for “major improvement” (Machado 2011).



The ASDAS-CRP or ASDAS-hsCRP score will be calculated in the eCRF if all required parameters are entered correctly. Details of the ASDAS-CRP and ASDAS-hsCRP calculation (Machado et al 2014) are described in the SAP.

7.4.5.2 Bath ankylosing spondylitis disease activity index

The BASDAI is the gold standard for measuring and evaluating disease activity in AS (Sieper et al 2009). The BASDAI is a PRO completed by the patient consisting of a 0 through 10 cm visual analogue scale (0 being no problem and 10 being the worst problem), which is used to answer 6 questions pertaining to the 5 major symptoms of AS:

1. Fatigue

2. Spinal pain

3. Joint pain/swelling

4. Areas of localized tenderness (called enthesitis, or inflammation of tendons and ligaments)

5. Morning stiffness severity

6. Morning stiffness duration

The 6 questions to be answered by the patient are as follows:

1. How would you describe the overall level of fatigue/tiredness you have experienced?

2. How would you describe the overall level of AS neck, back or hip pain you have had?

3. How would you describe the overall level of pain/swelling in joints other than neck, back, hips you have had?

4. How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure?

5. How would you describe the overall level of morning stiffness you have had from the time you wake up?

6. How long does your morning stiffness last from the time you wake up?

To give each symptom equal weighting, the mean (average) of the 2 scores relating to morning stiffness is taken. The resulting 0 to 50 score is divided by 5 to give a final 0 – 10 BASDAI score. It is an accepted practice that BASDAI is a quick and simple index taking between 30 seconds and 2 minutes to complete (Sieper et al 2009).

7.4.5.3 Patient’s global assessment of disease activity

The patient’s global assessment of AS disease activity may be performed using a NRS ranging from 0 (not active) to 10 (very active) (Sieper et al 2009).

7.4.5.4 C-reactive protein and or/ high sensitivity C-reactive protein

No blood collection for this assessment is stipulated by this non-interventional study protocol. Data from daily practice can be collected if available in order to identify the presence of inflammation, to determine its severity, and to monitor response to treatment (Machado et al 2015).

The CRP results and/or hsCRP results as available should be recorded in the eCRF using the local laboratory units. For data analysis purposes, all values will be converted to mg/L (if not already in mg/L per the local laboratory).



7.4.5.5 Total spinal pain visual analog scale

Patient’s assessment of spinal pain due to AS represented by total pain scores (i.e. overall spinal pain, and spinal pain at night) measured on a VAS (Lindstrom et al 2016).

7.4.5.6 Enthesitis assessment

The presence of any enthesitis in the following sites will be recorded as assessed by the Treating Physician or other involved HCP according to daily routine: first costochondral, seventh costochondral, posterior superior iliac spine, anterior superior iliac spine, iliac crest (all above will be assessed bilaterally), fifth lumbar spinous process, Achilles (bilateral). In addition, the lateral epicondyle humerus and the lateral condyle femur will be assessed (Table 7-4). When possible, the MASES score will be then calculated (Heuft-Dorenbosch 2003, Gladman 2007). If data on signs and symptoms of enthesitis are available at the site, these data should be collected in the eCRF.

Table 7-4 MASES and additional expanded assessments

Descriptor MASES Additional assessments (expanded)

First costochondral R L -

Seventh costochondral R L -

Lateral epicondyle humerus - R L

Posterior superior iliac spine R L -

Anterior superior iliac spine R L -

Iliac crest R L -

Fifth lumbar spinous process X -

Achilles R L

Lateral condyle femur - R L

7.4.5.7 X-ray assessment

If available, data for X-rays of the cervical, thoracic and lumbar spine can be collected for patients with AS according to routine practice. The new onset or worsening of pre-existingsquaring, erosions, sclerosis, syndesmophytes and bridging syndesmophytes will be recorded.

7.4.5.8 Magnetic resonance imaging assessment

If available, MRI data can be collected in the eCRF as a means of assessing sacro-iliac inflammation in AS patients. The new onset or worsening of BME in the spine and/or sacro-iliac joints, according to Treatment Physician’s judgment, will be recorded. It is possible that a scoring system for quantification of AS-related pathologies is used in a site’s medical practice, which can be used to get more granularity to assess whether these changes are affected by treatment with secukinumab.

MRIs will be acquired by the Treatment Physician or other involved HCP according to routine practice. MRI scans should be collected using scanning techniques appropriate for the measurement of inflammation, BME and erosion (Baraliakos 2011).



7.4.6 Assessment of tolerability

The management and reporting of AEs / adverse reactions is described in Section 9. The incidence rate, relationship with secukinumab and severity of treatment emergent AEs (TEAEs) and SAEs will be assessed in this study. TEAE is defined as any event not present prior to the initiation of the treatment or any event already present that worsens in either intensity or frequency following exposure to the treatment.

7.4.7 Assessment of treatment pattern

This assessment involves documentation of the kind of drug-delivery product used (prefilled syringe, prefilled pen / autoinjector device), reasons for choosing a particular product, reasons for switching between drug-delivery products, actual dosing and dosing frequency and reasons for alterations. Any intermediary treatment break of secukinumab will also be recorded as an individual secukinumab administration record.

7.4.8 Assessment of quality of life

7.4.8.1 Quality of life data collection

Data on QoL can be collected only at sites where these questionnaires are part of the clinical routine in the treatment of psoriasis, active PsA and active AS. The questionnaires are filled in by the patient and are collected at each visit. The site team should perform a check for completeness, a check for AEs and transcribe the data on QoL into the eCRF. The Treating Physician or other involved HCP will check the data and assess whether the criteria for AEs/SAEs are fulfilled and document as an AE or SAE, as applicable.

Examples of routinely used questionnaires are the DLQI (Section 7.4.8.2) and EQ-5D (Section 7.4.8.3) for patients with psoriasis; the HAQ-DI© (Section 7.4.8.4) and FACIT-Fatigue©

(Section 7.4.8.5) for patients with PsA; and the FACIT-Fatigue© (Section 7.4.8.5) for patients with AS as described below.

7.4.8.2 Dermatology Life Quality Index (DLQI)

The DLQI is a simple, validated questionnaire containing 10 questions that are answered by the patient. It assesses how the skin disorder has affected different domains of the patients’ daily life and its quality over the last week prior to filling out the questionnaire. For each question a score between 0 (not at all) to 3 (very much) is provided; thus, a maximal score of 30 is possible –where scores between 21 and 30 indicate “extremely large effects on patient’s life”. A total DLQI score of 0 or 1 indicates “no effect on patient’s life”.

7.4.8.3 EuroQol-5 Dimensions (EQ-5D)

The EQ-5D is a standardized instrument to measure health outcomes in a variety of health conditions and treatments. The EQ-5D provides a simple descriptive profile and a single index value for health status. The questionnaire consists of a descriptive system, comprising the dimensions mobility, self-care, usual activities, pain/discomfort and anxiety/depression and the EQ visual analogue scale where the patient self-rates his/her health state (ranging from worst to best imaginable health state).



7.4.8.4 Health assessment questionnaire – disability index

The HAQ-DI© is one of the most widely used measures to assess the long-term influence of chronic disease on a patient’s level of functional ability and activity restriction. The disability assessment component of the HAQ, the HAQ-DI©, assesses a patient’s level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The “stem” of each item asks over the past week “Are you able to …” perform a particular task. Each item is scored on a 4-point scale from 0 to 3, representing normal (normal, no difficulty (0)), some difficulty (1), much difficulty (2), and unable to do (3).

The purpose of collecting available HAQ-DI© data according to clinical routine of the Treating Physician in the eCRF is to assess the functional ability of patients with PsA (Kwok et al 2010).

7.4.8.5 Functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue©)

The FACIT-Fatigue© is a 13-item questionnaire (Cella 1993 and Yellen 1997) that assesses self-reported fatigue and its impact upon daily activities and function.

The purpose of collecting available FACIT-Fatigue© data according to clinical routine of the Treating Physician in the eCRF is to assess the impact of fatigue on patients with PsA and AS.

7.4.9 Assessment of efficiency

Pharmacoeconomic analyses can be performed for patients with a primary diagnosis of moderate to severe plaque-type psoriasis using the below listed variables or variables derived from them. Details of the analysis will be described separately in a health economic SAP. Due to country-specific conditions that play a role in pharmacoeconomic evaluations (e.g. type of national health care system) these analyses can be individually performed by participating countries.

In Germany pharmacoeconomic analyses will be performed and will contain but are not restricted to the following analyses:

Evaluation of medication- or therapy-related costs.

Evaluation of costs caused by physician consultations or hospital admissions.

Evaluation of costs caused by inability to work due to psoriasis.

Cost-effectiveness analyses.

The following specifically pharmacoeconomic variables can be collected only at study sites in Germany in order to enable the analyses:

Type of health insurance (statutory with/without private supplementary insurance, private, none).

Current inability to work because of psoriasis (no/ yes, since xxx days).

Days with inability to work because of psoriasis during the last 12 months.

Number of physician consultations and specialization of the consulted physician (dermatologist, rheumatologist, primary care physician, internist, others) during the last 3 months



7.4.10 Physical examination and vital signs

It is recommended as per good practice that a complete physical examination including general appearance and vital signs (blood pressure, heart rate) can be performed at each visit. If indicated based on medical history and/or symptoms, additional examinations are usually performed at the discretion of the Treating Physician. Information for all physical examinations should be included in the source documentation at the study site. Significant findings that are present prior to signing the ICF should be included in the Medical History part of the Case Report Form (CRF). Significant findings made after the signing of the ICF, which meet the definition of an AE should be recorded on the AE section of the eCRF.

7.5 Data sources

Within this study, primary data will be collected prospectively by means of an eCRF. Data on patient’s characteristics will be collected retrospectively.

Data on demography, medical and treatment history may be derived from the patient’s file. Data on primary and additional outcome variables will be collected prospectively in the eCRF. Records from routine clinical documentation are used as data source. These include but are not limited to electronical and paper-based patient charts, hospital discharge files, prescription drug files and doctor’s letters.

QoL assessments should be collected on the respective questionnaire forms (completed by the patient), if this corresponds to daily practice, and entered into the eCRF by the site staff.

Effectiveness values should be collected and entered in the eCRF, if this corresponds to daily practice; for PASI the basic values will be entered in the eCRF and the total score will be calculated within the eCRF.

Concomitant or prior medications entered into the database will be coded using the World Health Organization (WHO) Drug Reference List. Medical history/current medical conditions and AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.

Safety data will be transferred to Novartis at a frequency as defined in Section 9 of this protocol. Clinical data will be transferred to Novartis on an ongoing basis.

7.5.1 Data collection schedule

This is a non-interventional (observational) study which does not impose a therapy protocol, diagnostic/therapeutic procedure, or a visit schedule. Patients will be treated according to the local prescribing information, and routine medical practice in terms of visit frequency and types of assessments performed, and only these data will be collected as part of the study. The treating physician is asked to complete at every patient visit the appropriate CRF, if possible.

However, below is the recommended data collection schedule that most likely mirrors the patterns of routine clinical care of patients being treated with secukinumab in the EU. It is expected that most patients are likely to be seen at regular visits. A visit window does not apply; however it is recommended that data is collected ± 60 days from the anticipated visit recommended in Table 7-5, Table 7-6 and Table 7-7.



Data collection time points (visits) are scheduled every 6 months after Baseline. For sites where patients are seen at different intervals, the visit and assessment closest to the 6-month intervals shall be documented. The 6-month interval is anchored to the date of the Baseline visit.

If a period has elapsed by missing 2 consecutive study visits without the collection of data at site for a single patient and all reasonable attempts have been made by the site to establish contact with the patient, the Sponsor can ask the Treating Physician to discontinue the patient from the study. Once a patient has been discontinued from the study that patient is not allowed to re-enroll or to be reactivated at a later date. In general, a patient ID will not be reused.

Table 7-5 Data collection schedule for patients with psoriasis

Visit number 0 1 to X Final Visit

Time of visit Baseline At each visit EOO/ Discontinuation1

Recommended visit schedule 6 m ± 60 days

Information & informed consent X

Inclusion/exclusion criteria X

Patient demographics, baseline characteristics, medical history

X X2 X2

Prior3 and concomitant medication X X X

Physical examination (vital signs) X X X

Effectiveness variables:

PASI X X X

BSA affected X X X

PGA X X X

78 total joint count and 76 swollen joint count X X X

Presence of dactylitis X X X

Psoriatic nail involvement (hands and feet) X X X

Tolerability: AEs/SAEs X X

Secukinumab:

Treatment pattern X X X

Retention X X

QoL questionnaires

DLQI X X X

EQ-5D X X X

Pharmacoeconomic variables4 X X X

Study completion form X

AE=adverse event, BSA=body surface area, DLQI=dermatology life quality index, EOO=end of observation, EQ-5D=EuroQol 5-dimension questionnaire, m=month, PASI=psoriasis area and severity index, PGA=physician’s global assessment, QoL=quality of life, SAE=serious adverse event1 For patients who discontinue prematurely, the reason for discontinuation should be determined2 Only if relevant changes to certain aspects occur3 Relevant prior medication up to 6 months before Baseline, prior biologics without time-limit 4 Pharmacoeconomic variables will be collected for Germany only.



Table 7-6 Data collection schedule for patients with psoriatic arthritis


Time of visit At Baseline At each visit EOO/ Discontinuation1

Recommended visit schedule 6 m ± 60 d




X X2 X2




78 total joint count and 76 swollen joint count

X X X

PGA X X X

Total pain VAS X X X

Presence of dactylitis X X X

Presence of enthesitis X X X

X-ray assessment X X X

PASI X X X

BSA affected X X X

Psoriatic nail involvement (hands and feet)

X X X


Secukinumab


Retention X X

QoL questionnaires

HAQ-DI© X X X

FACIT-Fatigue© X X X


AE=adverse event, EOO=end of observation, FACIT-Fatigue©=Functional Assessment of Chronic Illness Therapy – Fatigue, HAQ-DI©=Health Assessment Questionnaire-Disability Index, m=month, PGA=physician’s global assessment, PsA=psoriatic arthritis, QoL=quality of life, SAE=serious adverse event, VAS=visual analog scale1 For patients who discontinue prematurely, the reason for discontinuation should be determined2 Only if relevant changes to certain aspects occur3 Relevant prior medication up to 6 months before Baseline, prior biologics without time-limit



Table 7-7 Data collection schedule for patients with ankylosing spondylitis


Time of visit At Baseline At each visit EOO/ Discontinuation1

Recommended visit schedule 6 m ± 60 d




X X2 X2




BASDAI X X X

Patient’s global assessment X X X

CRP/hsCRP X X X

Patient’s assessment of spinal pain X X X

Presence of enthesitis X X X

X-ray assessment X X X

Magnetic resonance imaging X X X


Secukinumab


Retention X X

QoL questionnaire

FACIT-Fatigue© X X X


AE=adverse event, AS=ankylosing spondylitis, BASDAI=Bath AS disease activity index, CRP=C-reactive protein, EOO=end of observation, FACIT-Fatigue©=Functional Assessment of Chronic Illness Therapy – Fatigue, hsCRP=high-sensitivity CRP, m=month, SAE=serious adverse event1 For patients who discontinue prematurely, the reason for discontinuation should be determined2 Only if relevant changes to certain aspects occur3 Relevant prior medication up to 6 months before Baseline, prior biologics without time-limit



7.6 Study size

For non-interventional studies, although considerations regarding sample size are based on statistical principles, a strict methodology with respect to controlling alpha errors and statistical power is not applied. Therefore, the estimation of the study population size is based on considerations of the incidence of the disease, market situation in participating countries, and expected recruitment rate over the duration of the study.

In Europe, the prevalence of plaque psoriasis is estimated to be approximately 0.8 percent. Thismeans that the disease affects about 3.7 million Europeans, with about 2.4 million people considered to have moderate to severe disease (EFPIA website). Data from registries show that roughly 30-40% of patients with moderate to severe psoriasis may be on treatment with biologics (Augustin et al 2014, Garcia-Doval et al 2013) but registries might overestimate the percentages of such patients. Considering the survival rate of biologics it is estimated that roughly 20% of those receiving a biologic treatment may be in a need for a change of therapy (Levin et al 2014a, Levin et al 2014b).

Similarly, the prevalence of AS and PsA is estimated to be approximately 0.3% (Dean et al 2014) and 0.35% (Gladman et al 2005a), respectively. This means that about 2.5 million people across Europe are affected with either AS or PsA. Data from registries show that roughly 25% to 30% of patients with active SpA lose their response to anti-TNF treatment over the first year, while up to 40% don’t respond in the first 2 years of treatment (Glintborg et al 2013).

The density of dermatologists varies across EU ranging from 1 per 100,000 of the population in the UK to 1 per 20,000 in Italy and France (Barker and Forum 2010). Similarly, the number of rheumatologists also varies across the EU ranging from 1 per 100,000 in Cyprus, Latvia and Ireland to 4 per 100,000 in France (Summary Report on Musculoskeletal Health in Europe).

The initially planned sample size of 5000 patients is representative for the population included in this study and ensures that the outcome has sufficient generalizability. However, due to slow recruitment in the rheumatologic indications, the planned study size of 5000 patients (2500 in indication psoriasis and 1250 in each rheumatologic indication; ankylosing spondylitis and psoriatic arthritis) cannot be achieved during a timeframe that would allow timely analysis and communication of the collected data. Furthermore, the originally anticipated distribution of study patients between dermatologic and rheumatologic indications does not correspond to the distribution of patients treated with Cosentyx® in Europe. To avoid such mismatch and to ensure that the study results are available within a timeframe that allows contemporaneous, clinically meaningful interpretation, it has been decided to reduce the sample size to approximately 1700:500:500 patients with active psoriasis, active psoriatic arthritis, and active ankylosing spondylitis, respectively.

With these sample sizes, the calculation of the retention rate can still be ensured with high statistical precision. Assuming a true retention rate within each indication of 50%, these ratescould be estimated with a precision (radius of the 95% confidence interval (CI)) of 2.4% (moderate to severe plaque-type psoriasis) and 4.4% (PsA and AS) respectively.



7.7 Steering Committee

Between 3 and 9 external experts and between 2 and 3 Novartis associates will be appointed to the steering committee. The scope of the steering committee’s mandate is:

Make recommendations for the non-interventional study protocol and amendments

Make recommendations for operational questions of study conduct including but not limited to site selection, local study meetings and newsletters

Review recruitment data, data from the interim analysis and final study data

Make recommendations for the publication of the data

7.8 Data management

Novartis will supply the study site with access to an online eCRF that has been fully validated. Novartis personnel will train designated study site staff on the eCRF system. Alternatively, self-administered online trainings may be applied. Study site staff will not be given access to the eCRF until they have been trained. Designated Treating Physician staff will enter the data required by the protocol into the eCRFs using a computer at the site. Automatic validation programs check for data discrepancies and plausibility in the eCRF and generate appropriate error messages or queries. If entered data is modified to a plausible value, error messages will disappear or queries will be resolved automatically by the eCRF system, respectively. Values that do not meet the plausible ranges must be commented by the study site staff by answering the respective query. The Treating Physician must approve that the data are complete and accurate and that all AEs were documented by signing the eCRF.

The Treating Physicians and site staff will be responsible for primary data collection by capturing the data in eCRFs. The primary data captured in the eCRF must be based on site files and documents, i.e. source data. Please refer to the non-interventional study Monitoring Plan and Section 7.5 and Section 7.8 for further specifications.

The sponsor or the designated contract research organization (CRO) or a third party on behalf of the sponsor can raise manual queries in order to resolve discrepancies resulting from clinical/medical data review. Concomitant medications entered into the database will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification system. Medical history/current medical conditions and AEs will be coded using the MedDRA terminology.

At the end of data collection, data entry should be completed by the site and responses to open queries through the site staff should be shared, and data should be signed by a treating site physician. After these actions have been completed, the database will be locked for data analysis. Local laws, regulations and data privacy policies apply.

7.9 Data analysis

All analyses will be performed by Novartis and/or a designated CRO such as TFS, S.L., Barcelona, Spain, or a third party and the details are included in the Data Validation Plan.

One final analysis and around 5 interim analyses (depending on the recruitment speed) are planned. A first interim analysis is scheduled after data collected for the first 1000 enrolled patients. Each subsequent interim analysis is planned to occur around 12 months after the



previous interim analysis. Final analyses are planned for 2-year data collected after the last patient first visit (LPFV) when all study data is collected. The 5-year data for approximately 1000 patients should also be available for another final analysis. All documented data will be used for interim analysis regardless of implausibilities/ discrepancies (i.e. open queries at data base lock) and signature status. During data analysis, it will be verified if further follow-up of implausibilities/discrepancies is needed. In that case, further queries will be sent to the study sites to resolve these implausibilities/discrepancies. At the time of the final database lock, any identified implausibilities/discrepancies will be resolved.

The data collected will be provided cumulatively and on a country basis to allow meta-analyses to be conducted by combining evidence on the use, in a real-life setting, of secukinumab and other treatments for the populations in scope, such as (but not limited to) non-steroidal anti-inflammatory drugs (NSAIDs), conventional systemic disease-modifying anti-rheumatic drugs (DMARDs) and biologic DMARDs (e.g. TNFα inhibitors, ustekinumab). Details of such analyses are described in a separate document or protocol. Furthermore, the data collected in this study could contribute to the identification of disease-associated risk factors by conducting ananalysis with other observational studies (Miller et al 2013, Haque et al 2016, Stolwijk et al 2015).

The study variables, described in Section 7.4, will also be analyzed according to pre-defined Baseline characteristics of the study population, such as: age, gender, race, country (or country cluster), smoking habit, body weight (or BMI), presence of comorbidities at Baseline or prior to start of secukinumab therapy (e.g. cardiovascular and cerebrovascular diseases, diabetes mellitus) and previous exposure to DMARDs.

The analysis is mainly based on descriptive statistical methods:

Quantitative data (e.g. age) will be analyzed by the statistical parameters valid N, missing N, mean, standard deviation, and selected quantiles: minimum (0%), lower quartile (25%), median (50%), upper quartile (75%), and maximum (100%). If indicated by the data, an additional frequency distribution will be supplied after appropriate grouping of data.

Qualitative (e.g. binary response data) variables (e.g. rating of treatment response) will be presented by (absolute and relative) frequency distributions.

Two-sided 95% CIs will be provided for all binary response rates. The impact of potential prognostic factors on the primary endpoint and on the development of PsA will be investigated by logistic regression methods and subgroup analyses.

The following subgroups are defined a priori:

Stratification according to treatment history (biologicals vs. non-biologicals)

Stratification according to body weight (< 90 kg vs. ≥ 90 kg)

Stratification according to Baseline characteristics, such as family history of PsA, body surface area (BSA) affected, BMI, nail involvement.

Two approaches will be applied to analyze effectiveness variables assessed over time. The first approach is based on an analysis by visit (i.e. for 1, 2, 3, 4 and 5 years after start of study participation). The second approach, as sensitivity analyses for the PASI endpoints, the



regression imputation principle will be used to reduce the risk of bias. The variables to be included in the regression model will be specified in the SAP

Details of statistical analysis and methods will be described in a separate SAP.

7.10 Quality control

7.10.1 Data quality management

All data will be entered via a validated, internet-based electronic data capture (EDC) system. Site personnel will be provided with unique usernames and secured passwords in order to use the EDC system. All sites will be fully trained in using the EDC system. CRF completion guidelines will be shared with every site.

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 Treating Physician site staff.

The Sponsor, designated CRO or a third party on behalf of the Sponsor can raise manual queries in order to resolve discrepancies resulting from clinical/medical data review. To assure database quality, edit checks will be programmed in accordance with the data validation plan. The data entered into the eCRF will be checked automatically for completeness and accuracy. In case of missing relevant data or discrepancies, error messages or queries will be generated automatically by the system.

The Sponsor, designated CRO or a third party on behalf of the Sponsor will assure database quality processes are followed including review of the data entered into the CRFs by investigational staff for completeness and accuracy, and in accordance with the data validation plan.

Local laws, regulations and data privacy policies apply.

7.10.2 Data recording and document retention

In all scenarios, the Treating Physician must maintain source documents for each patient in the study, consisting of case and visit notes (hospital or clinic medical records) containing demographic and medical information, and the results of any other tests or assessments. All information entered in the eCRF must be traceable to these source documents in the patient’s file.

The Treating Physician must give Novartis (or designee) access to all relevant source documents to confirm their consistency with the eCRF entries. No information in source documents about the identity of the patients will be disclosed.

The Treating Physician must keep the original ICF signed by the patient (a signed copy is given to the patient and the patient’s legal proxy, if applicable).

Informed consent forms must not be shared with the sponsor and local data privacy policies apply.

7.10.3 Site monitoring



Formal site monitoring will be performed as described in the Monitoring Plan for this study. Novartis study team, data management and/or designated CRO will assure compliance monitoring.

7.11 Limitations of the research methods

Potential limitations of the present study are due to its non-interventional character. Especially, QoL data from non-blinded patients need to be interpreted carefully. However, the non-interventional character of the study is a preferred way to obtain real-life data. The large number of patients to be observed and the full safety reporting are further assets to this study andminimize its limitations.

A potential bias is expected due to the fact that patients will only be involved in this study if they have already been treated for at least 16 weeks with secukinumab. However, as the main objective of the present study is to collect long-term data on safety and retention and effectiveness, the effects of this bias on these long-term measures is expected to be minimal.

Site specific preferences may bias towards misrepresentation of prior and concomitant treatment types and concomitant treatments if the site selection process or the recruitment is imbalanced. To limit this bias, a balanced selection of sites and a balanced recruitment will be sought. Specifically, it is intended to include a significant proportion of study sites who were not involved in secukinumab clinical trials. Other limitations such as information bias, selection bias, and limitations of feasibility are expected to be similar to other multicenter prospective non-interventional trials.

7.12 Other aspects

Not applicable.

8 Protection of human subjects

The Treating Physician must ensure anonymity of the patients; patients must not be identified by names in any documents submitted to Novartis. Signed ICFs and the patient enrollment log must be kept strictly confidential to enable patient identification at the site.

For audits, inspections or routine monitoring, source data and signed ICFs as well as the patient enrollment log must be available to Novartis representative or Health Authorities.

Patient data will be entered by the Treating Physician into the eCRF in a pseudonymized manner according to legal, compliance and regulatory requirements (unique Patient Number). Only the Treating Physician will be able to allocate the Patient Number to the patient’s identity. The Treating Physician must maintain the patient identification list and source documents for each participating patient. No information in source documents about the identity of the patient will be disclosed.

For analysis and publication purposes, data will be only presented in an anonymized manner, i.e. at population and not individual patient level.

The study may be reviewed while it is in progress. This review may be conducted by the authorities or Novartis to ensure that the rules are followed and quality is maintained. All



persons involved in the study must respect the strictest confidentiality. The name of the patients will never be published in any reports or publications, neither in print nor on the internet, nor in any other place.

8.1 Regulatory and ethical compliance

Compliance with Novartis and regulatory standards provides assurance that the rights, safety, and well-being of patients participating in non-interventional studies are protected (consistent with the principles that have their origin in the Declaration of Helsinki) and that the study data are credible and responsibly reported.

This study was designed and shall be implemented and reported in accordance with the Guidelines for Good Pharmacoepidemiology Practices (GPP) of the International Society for Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (Von Elm et al 2008) and with the ethical principles laid down in the Declaration of Helsinki.

The protocol and the proposed ICF must be reviewed and approved by a properly constituted Institutional Review Board / Independent Ethics Committee (IRB/IEC) before study start according to local regulations. Approval letters concerning protocol and informed consent will be filed by Novartis.

8.2 Informed consent procedures

The Treating Physician must keep the original ICF signed by the patient (a signed copy is given to the patient).

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 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 assent by personally signing and dating the written informed consent document or a separate assent form. Informed consent must be obtained before any data are collected. The process of obtaining informed consent should be documented in the patient source documents.

Novartis will provide to treating physicians or other involved medical professionals in a separate document a proposed ICF that complies with the Declaration of Helsinki principle and regulatory requirements and is considered appropriate for this study.

9 Management and reporting of adverse events/adverse reactions

All AEs – including SAEs and safety endpoints (where relevant) – must be collected and recorded in the study database, irrespective of causal association. All AEs, including SAEs occurring in association with exposure to the Novartis drug of interest, also have to be recordedin the Novartis safety database.



Adverse drug reactions (ADRs) occurring in association with exposure to Novartis drug other than the Novartis drug of interest during the study period, can be reported to the local Health Authority in accordance with national regulatory requirements for individual case safety reporting or Novartis DS&E as a spontaneous report. Adverse drug reactions, like cases of failure to respond or intolerance, under a Novartis drug of interest and other Novartis drugs prior to the study period should be reported to local Novartis DS&E as spontaneous reports.

All adverse reactions identified for non-Novartis products should be reported to the local Health Authority in accordance with national regulatory requirements for individual case safety reporting or the Marketing Authorization Holder as these will not be recorded in the Novartis safety database.

9.1 Adverse event reporting

An AE is any untoward medical occurrence in a patient participating in this study (after signing the ICF) that does not necessarily have a causal relationship with the treatment (secukinumab, drug of interest).

An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug of interest, whether or not related to the medicinal product(s).

Adverse event reporting starts after the patient has signed the ICF. Any relevant medical condition before study start should be recorded in the medical history page of the eCRF.

Secukinumab is the drug under evaluation given at any time during the study. Medical conditions/diseases present before the Baseline visit are only considered AEs if they worsen after start of study (informed consent).

The occurrence of AEs should be sought by non-directive questioning of the patient at each visit during the study. AEs may also be detected when they are volunteered by the patient during or between visits or through physical examination, laboratory test, or other assessments. All AEs must be recorded on the AE form of the eCRF with the following information:

1. The severity grade (mild, moderate, severe)

2. Its relationship to the drug of interest (suspected/not suspected)

3. Its duration (start and end dates or if continuing at final examination)

4. Whether it constitutes a SAE

5. The batch number of the drug used at the time of the occurrence of the event (necessary, because the drug under evaluation is a biological drug (monoclonal antibody))

In addition, all reports of the following special scenarios are also considered an AE irrespective if a clinical event has occurred:

Drug-drug or drug-food interaction

Drug exposure during pregnancy

Drug use during lactation

Lack of efficacy

Note: Reports of lack of efficacy without an associated clinical event must be recorded on the AE form even if lack of efficacy parameters are being recorded elsewhere in the CRF.



Overdose

Intentional drug abuse and misuse

Medication errors including drug maladministration

Dispensing or prescribing errors

Drug dependence or addiction

Withdrawal reaction/syndrome or rebound symptoms

Unexpected beneficial effect

Treatment non-compliance (with clinical symptoms)

Administration of secukinumab not in accordance with the approved labeling (for example administration of like 150 mg dose every 4 weeks to patients with moderate to severe plaque psoriasis; or administration of 300 mg dose every 4 weeks to either patients with AS or to TNF-naïve PsA patients without concomitant moderate to severe psoriasis), will be captured in the eCRF on the drug administration page and does not need to be reported as AE if not associated with any clinical signs and symptoms or worsening of any medical condition.

Note: Occupational or accidental exposure, for example of study personnel or family members of the patient should be reported to the local Health Authority in accordance with national regulatory requirements for individual case safety reporting or Novartis DS&E as a spontaneous report.

Any treatment of any AE should be recorded on the AE CRF. Some examples of treatment to be recorded are: no action taken (i.e., further observation only); drug of interest dosage adjusted/temporarily interrupted; drug of interest permanently discontinued due to this AE; treatment medication introduced or adjusted; non-drug therapy given; patient hospitalized/patient’s hospitalization prolonged.

Once an AE is detected, it should be followed until its resolution or until it is judged to be permanent, and assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to the drug of interest, the interventions required to treat it, and the outcome.

Information about common adverse effects already known about the medicinal product can be found in the locally available labeling document for the approved indication under evaluation in this study. This information will be included in the patient informed consent and should be discussed with the patient prior to study start and during the study as needed.

Non-serious AEs associated with the Novartis drug of interest must also be recorded in the safety database:

Information on all AEs should be entered in the eCRF on a periodic basis but not less frequently than once a month. Information on non-serious AEs is then transferred from the study database to Novartis DS&E by Novartis data management group or designated CRO on a periodic basis but not less frequently than once a month. If local regulations require more frequent periodic reporting than once a month, then the periodic reporting interval set by local regulations should be followed.



9.2 Serious adverse event reporting

A SAE is defined as an event which:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition (not applicable for routine psoriasis treatment)

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since the start of the drug of interest

Social reasons and respite care in the absence of any deterioration in the patient’s general condition

Is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above e.g. may require treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission

Note: Transmission of infectious disease via medication is considered to be a serious adverse reaction and should be reported and assessed as medically significant in the absence of other seriousness criteria.

To ensure patient safety, every SAE, regardless of causality assessment, occurring after the patient has provided informed consent and until 12 weeks (84 days) after the patient has stopped study participation (defined as time of last dose of secukinumab taken or last visit whichever is later) must be reported to Novartis within 24 hours of learning of its occurrence.

Any SAEs experienced after this 84-day period should only be reported to Novartis if the treating physician or other involved HCP suspects a causal relationship to the Novartis drug of interest.

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 treating physician or other involved HCP 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.

Information about all SAEs is collected and recorded on the SAE eCRF; the information needs to be entered into the eCRF within 24 hours of awareness. Depending on local reporting requirements, there may be two ways of submitting the SAE information to Novartis DS&E:

Paper SAE Form: Information about all SAEs is collected and recorded on the SAE Report Form. The Treating Physician or other involved HCP must assess the relationship to the Novartis drug of interest, complete the SAE Report Form and send the completed, signed form by fax within 24 hours to the local Novartis DS&E Department. The telephone and telefax number of the contact persons in the local department of DS&E, specific to the site, are listed in the Treating Physician or other involved HCP folder provided to each site. The



original copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report form documentation at the study site.

Via eCRF: The SAE information is submitted electronically to DS&E after entering into the eCRF. The Treating Physician or other involved HCP must assess the relationship to the Novartis drug of interest, complete the SAE eCRF within, electronically sign it and initiate the report transmission to the local Novartis DS&E Department within 24 hours after becoming aware of the SAE. In case of technical problems, a transmission of the report via fax or telephone is possible (see above).

9.3 Follow-up information

Note that follow-up information on SAE is to be provided within 24 hours of awareness of new information on an existing SAE.

Follow-up information on SAE can be provided by two different ways, depending on the local reporting requirements in your country:

Paper SAE Form: A follow-up is sent to the same person to whom the original SAE Report Form was sent, using a new SAE Report Form stating that this is a follow-up to the previously reported SAE and giving the date of the original report. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, whether the patient continued or withdrew from study participation.

Via eCRF: Follow-up information on SAE is provided by updating the respective section in the eCRF and initiation transmission of the SAE report again; note that follow-up information on SAE also needs to be verified by electronic signature of the Treating Physician. Note that follow-up information on SAE is to be provided within 24 hours of awareness of new information on an existing SAE.

If the SAE is not previously documented in the labeling document for the study (i.e. EU Summary of Product Characteristics, SmPC) a local DS&E Department associate may urgently require further information from the treating physician or other involved HCP for Health Authority reporting.

9.4 Causality assessment

For the assessment of causality between the drug and the event there exist the options “no causal relationship” and “causal relationship suspected”. A medical causality assessment is absolutely necessary and has to be documented in any case. It should be taken into account that many different aspects should be considered for causality assessment. These aspects can concern the individual patient, the underlying disease, comorbidities, concomitant medication (if applicable) or also non-medicinal factors.

No causal relationship: there exists no reasonable possibility of a causal relationship between drug and AE.

Causal relationship suspected: there exists a reasonable possibility of a causal relationship between drug and AE.



9.5 Disease progression

A progression of the underlying disease during treatment with the drug under evaluation (secukinumab) only has to be documented as AE if a causal relationship with the drug under evaluation has been suspected or if as a result of the disease progression one or more of the formal criteria for an SAE apply.

9.6 Abnormal laboratory values and test results

Laboratory values are only taken according to clinical routine and according to Treating Physicians discretion.

Abnormal laboratory values or test results only should be documented as AE if they fulfill the following criteria:

Constitute a change in terms of a worsening of the respective parameter in comparison to the Baseline value (Baseline visit). This term becomes invalid if there is no Baseline value

AND the changed laboratory parameters

Are assessed as clinically relevant OR

Are accompanied by clinical signs or symptoms OR

Require therapeutic intervention OR

Lead to a dosage reduction and/or temporary interruption or permanent discontinuation of the drug under evaluation.

In these cases, they have to be documented on the AE form of the eCRF.

Changes of quantifiable parameters have to be documented as SAEs if formal criteria for an SAE apply (see SAE definition in Section 9.2).

9.7 Pregnancies

To ensure patient safety, any occurrence of a pregnancy in a patient on the Novartis drug of interest 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 a Pharmacovigilance Pregnancy Form and reported by the treating physician or other involved HCP to the local Novartis DS&E Department. In case of any congenital abnormality, birth defect or maternal and newborn complications, the possible relationship to the Novartis drug of interest should be reported.

Additionally, any SAE experienced during pregnancy must be reported on the SAE Report Form.

10 Plans of disseminating and communicating study results

Upon study completion and finalization of the study report, the results of this non-interventional study may be either submitted for publication and/or posted in a publicly accessible database of results. Publications will comply with internal Novartis standards and the International Committee of Medical Journal Editors (ICMJE) guidelines.



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12 Annexes

12.1 Annex 1 – List of stand-alone documents

N/A

12.2 Annex 2 – ENCePP checklist for study protocols

N/A

12.3 Annex 3 – Additional information

N/A

long-term observational, prospective study to collect in a

Documents