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PSARTROS II

Observational Study Protocol

Long term follow up of the Psoriasis-Arthritis & Program (PSARTROS study) - Evaluation of inflammatory and structural damage in patients with psoriasis and treated with secukinumab (PSARTROS II)

Version 2.0

Date 08.05.2020

Study type Non-interventional Study (NIS)

Study short title PSARTROS II

Study code CAIN457F2301TE1

Indication Psoriasis Arthritis (PsA), Psoriasis (Pso)

Planned study period 36 months

Medicinal product(s) Secukinumab (Cosentyx)

Investigator

Initiator Universitätsklinikum Erlangen Medizinische Klinik 3

Ulmenweg 18 90154 Erlangen

CONFIDENTIAL AND PROPRIETARY The contents of this document are confidential and proprietary to the institution. Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not be disclosed to parties not associated with the clinical investigation without the prior written consent of the institution.

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

AE Adverse event ACR American College of ALT Alanine aminotransferase Anti CCP Anti-cyclic citrullinated peptide ANOVA Analysis of variance ALT Alanine aminotransferase AST Aspartate aminotransferase BP Blood pressure

BSA Body surface area CASPAR Classification criteria for psoriatic arthritis CCP-AB Anti- cyclic citrullinated peptide CRP C-reactive protein / high sensitivity C-reactive protein DAPSA Disease Activity in Psoriatic Arthritis Score DAS Disease Activity Score DCF Data clarification form DCS Data Collection Sheet DLQI Dermatology Life Quality Index DMARD Disease Modifying Anti-Rheumatic Drug ESR Erythrocyte Sedimentation Rate EULAR European League Against Rheumatism µFEA Micro Finite element analysis GCP Good clinical practice GGT Gamma Glutamyl Transpeptidase GH Global Health HAQ-DI Health Assessment Questionnaire – Disability Index hsCRP high sensitivity C-reactive protein HR Heart rate HR-pQCT High-resolution peripheral quantitative computed tomography ICH International Conference on Harmonization IEC Independent ethics committee IL Interleukin LDH Lactate Dehydrogenase

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LEI Leeds Enthesitis Index Ln Natural logarithm IUD Intrauterine device MASES Maastricht Ankylosing Spondylitis Enthesitis Score MedDRA Medical Dictionary for Regulatory Activities MRI Magnetic resonance imaging µCT Micro-Computer tomomgraphy MSUS Musculoskeletal ultrasound MTX Methotrexate n Number of non-missing observations NSAID Non-steroidal anti-inflammatory drug OSP Observational Study Protocol PASI Psoriasis Area and Severity Index PsA Psoriatic Arthritis PsAiD Psoriatic Arthritis Impact of Disease (questionnaire) PsAMRIS Psoriatic Arthritis Magnetic Resonance Imaging Scoring System PsAQoL Psoriatic Arthritis Quality of Life Questionnaire Pso Psoriasis QoL Quality of Life PT Prothrombin time PTT Partial thromboplastin time RBC Red blood cell count RF Rheumatoid factor SAE Serious adverse event SAP Statistical analysis plan s.c. subcutaneously SD Standard deviation SEL Structural entheseal lesions SF 36 Medical Outcome Short Form (36) Health Survey SJC Swollen joint count SmPC Summary of product characteristics SOC System organ class SOP Standard operating procedure SPARCC Spondyloarthritis Consortium of Canada Score sqrt Square root TJC Tender joint count

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TNF Tumor necrosis factor VAS Visual analogue scale vBMD volumetric bone mineral density WBC White blood cell count

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Table of Contents

SIGNATURE PAGE ...... 2 List of Abbreviations and Definitions of Terms ...... 3 1 STUDY ADMINISTRATIVE STRUCTURE ...... 10 1.1 Responsibilities ...... 10 2 INTRODUCTION ...... 11 2.1 Study background ...... 11 2.2 Study rationale ...... 11 2.3 Benefit-risk assessment ...... 12 3 STUDY OBJECTIVES...... 12 3.1 Primary objective ...... 12 3.2 Secondary objectives ...... 12 4 STUDY DESIGN ...... 12 4.1 Type of Study ...... 12 4.1.1 Study site ...... 13 4.1.2 Time schedule ...... 13 4.1.3 Duration of observation per patient ...... 13 5 STUDY POPULATION ...... 13 5.1 Selection of study population ...... 13 5.2 Inclusion criteria ...... 13 5.3 Exclusion criteria ...... 14 5.4 Removal of patients from assessment ...... 15 5.4.1 Discontinuation of patients...... 15 5.4.2 Premature termination or suspension of the study ...... 15 6 TREATMENT ...... 15 6.1 Drug treatment ...... 15 6.2 Previous and concomitant therapies ...... 16 7 Description of evaluation instruments/ parameters ...... 16 7.1 Clinical Assessments ...... 16 7.1.1 Medical History ...... 16 7.1.2 Physical Examination ...... 16 7.1.3 Disease activity ...... 17 7.1.4 Clinical evaluation by means of patients’ self-assessment ...... 19 7.1.5 Imaging diagnostics ...... 21 7.2 Laboratory evaluations ...... 22 7.2.1 Biomarkers ...... 22 7.2.2 Tissue analysis ...... 23 7.3 Overview of study activities ...... 23 8 Methods ...... 24 8.1 Data collection for evaluation ...... 24 8.2 Statistical Analysis ...... 25 8.2.1 Sample size ...... 25 8.2.2 Analysis sets ...... 25 8.2.3 Variables for analysis ...... 25 8.2.4 Statistical analysis methods...... 26

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8.2.5 Time points of analysis ...... 27 8.2.6 Examination of subgroups ...... 27 9 Adverse Event Reporting ...... 27 9.1 Definition of adverse events/serious adverse events ...... 27 9.1.1 Severity Criteria ...... 28 9.1.2 Causality Assessment ...... 29 9.2 Procedures for safety reporting ...... 29 9.2.1 Procedures for SAE reporting ...... 29 9.2.2 Follow up of serious adverse events ...... 29 9.2.3 Procedures for recording and reporting of adverse events ...... 30 9.2.4 Documentation of adverse events ...... 30 9.2.5 Follow up of adverse events ...... 30 9.2.6 Pregnancy reporting ...... 30 10 DATA QUALITY ASSURANCE ...... 31 10.1 Documentation requirements ...... 31 10.1.1 Data recording ...... 31 10.1.2 Corrections to data ...... 31 10.2 Data management ...... 31 10.3 Monitoring ...... 31 10.4 Recordkeeping ...... 32 11 ETHICS AND REGULATORY ...... 32 11.1 Competent authority ...... 32 11.2 Independent Ethics Committee ...... 32 11.3 Patient information and informed consent ...... 32 11.4 Patient privacy ...... 33 11.5 Insurance ...... 33 11.6 Financing ...... 33 11.7 Publication policy ...... 33 12 REFERENCES ...... 34

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SYNOPSIS

Study title Long term follow up of the Psoriasis-Arthritis & Bone Program (PSARTROS study) - Evaluation of inflammatory and structural joint damage in patients with psoriasis and psoriatic arthritis treated with secukinumab (PSARTROS II) Department Universitätsklinikum Erlangen Medizinische Klinik 3 Ulmenweg 18 91054 Erlangen Indication Psoriasis (Pso) and Psoriasis Arthritis (PsA) Study objective To assess the influence of disease and IL-17 blockade by secukinumab on structural bone and inflammatory changes in Pso and PsA patients Study design Prospective, single center non-interventional (observational) study including a retrospective data analysis of the same patients. Planned study period 36 months Total number of patients 29 Study population, diagnosis Adult patients diagnosed with psoriasis or psoriasis arthritis

Key criteria for inclusion 1. Diagnosis of PsA according to CASPAR criteria OR Diagnosis of psoriasis (confirmed by a dermatologist and/or bioptically confirmed) Previous participation in the PSARTROS trial and subsequent treatment with secukinumab in-label (150 mg or 300 mg s.c. every 4 weeks) OR current treatment with secukinumab in-label (150 mg or 300 mg s.c. every 4 weeks) and treatment started at least 12 months ago 2. Age: 18-70 3. Gender: Males and females

Medicinal product(s), dose, secukinumab (Consentyx®) 150 mg or 300 mg s.c. every 4 and route of administration weeks Observation period per 48 months patient Variables for analysis Primary variable (endpoint):

Change of OMERACT psoriatic arthritis magnetic resonance image scoring system (PsAMRIS) assessed by MRI and change of number and extent of SEL, vBMD and bone microstructure assessed by HR-pQCT. Secondary variables: All other variables described in section 7 will be analyzed (the visits and their assessments are described in section 7.3), in

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particular: • Impact of secukinumab treatment on the disease activity in psoriasis patients (e.g. PASI75) over time • Impact of secukinumab on disease activity in PsA patients (e.g. ACR20 response, DAS28) over time • The change in erosions and osteo/enthesiophytes over time • The change of erosions/synovitis and power doppler signal using ultrasound analysis over time • The change in PRO parameters such as HAQ-DI, SF36, PsAQoL1, PSAID and DLQI over time • Overall safety and tolerability of secukinumab assessed by vital signs, clinical laboratory values and adverse event monitoring • Target genes of the IL-17 axis by quantitative real-time PCR (skin and joint biopsies) over time • Change in cytokine and bone parameters over time

Statistical analysis methods Descriptive statistics are applied according to the scale of measurement of the variable: Nominal and ordinal variables are described by counts and percentages. Interval scaled variables are described by mean and standard deviation, and robust estimators like quantiles (Min, Max, Median). The number of missing and valid values are counted for every variable; Missing values are not imputed. Longitudinal data will be described by their change from baseline and by their raw values. Inference statistics is based on a frequentist approach with hypothesis tests, p-values, and confidence intervals. Applicable tests for this longitudinal study are the ANOVA, Kruskal-Wallis-Test and, χ²-tests, according to the scale of measurement of the variable. The significance level is set to 5%; confidence intervals are two- sided with a length of 95%. The null hypothesis for these tests and all variables is: no change over time of the variable. The alternative hypothesis is the negation of the null hypothesis. As this is an exploratory observational study the intention of p- values and confidence is to detect trends and patterns in the data; they are not intended as a confirmatory analysis and no multiple testing adjustment of the significance level is performed. Patient dispositions, demographic data, and baseline characteristics will be presented using standard descriptive statistics; no homogeneity tests will be performed.

Safety variables: All safety and tolerability parameters (AE, vital signs and clinical laboratory parameters) will be listed by subject/treatment group as well as analyzed according to general procedures. For selected variables and/or subjects, individual tables and/or graphs that track a given subject will be supplied.

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1 STUDY ADMINISTRATIVE STRUCTURE

1.1 Responsibilities

Function Name Address Initiator Universitätsklinikum Erlangen Ulmenweg 18 Medizinische Klinik 3 91054 Erlangen Germany

Investigator Universitätsklinikum Erlangen Medizinische Klinik 3 Ulmenweg 18 91054 Erlangen Germany Tel.: .de Safety Universitätsklinikum Erlangen Management Center for Clinical Studies Krankenhausstr. 12 Tel: Fax: Email: Monitoring Universitätsklinikum Erlangen Center for Clinical Studies Krankenhausstr. 12 91054 Erlangen Tel: Fax:+ Email: @uk-erlangen.de Analysis Universitätsklinikum Erlangen Medizinische Klinik 3 Ulmenweg 18 91054 Erlangen Germany Tel.: + .de-

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2 INTRODUCTION

2.1 Study background

Psoriasis (Pso) and psoriatic arthritis (PsA) are chronic inflammatory diseases affecting the skin, articular and entheseal structures. PsA is a very heterogeneous disease in which the hallmark is articular, periarticular and entheseal inflammation, which leads to structural bone changes within the and at entheses, ultimately resulting in loss of physical function [1]. PsA patients furthermore have a reduced trabecular bone mineral density and an altered bone microstructure [2]. Not only PsA patients with a longstanding disease present these changes of the musculoskeletal system, but already psoriasis patients. Interestingly, psoriasis patients with inflammatory changes of the joints (detected by MRI), bone proliferation at entheseal sides (structural entheseal lesions, SEL) and reduced volumetric bone mineral density (vBMD) at the entheses have a higher risk of developing clinical apparent PsA during their lifetime [3, 4].

In the PSARTROS study – a psoriasis and psoriatic arthritis bone imaging program studying the effect of IL-17 blockade, we observed the effect of IL-17 blockade on disease outcomes for both musculoskeletal and skin disease. In PSARTROS high-end imaging modalities such as magnetic resonance (MRI), high-resolution peripheral computed tomography (HR-pQCT) and musculoskeletal ultrasound (MSUS) were used to understand the impact of IL-17 blockade in detail. In this study a significant improvement of disease activity scores such as DAS-28, DAPSA and ACR response at week 24 were observed. Furthermore, inflammation detected by MRI and MSUS significantly decreased [5, 6]. In PSARTROS, the combined application of MRI, MSUS and HR- pQCT has led to a better understanding of the positive effect of IL-17 blockade in Pso and PsA patients on microstructural bone changes as well as articular and periarticular inflammation. These findings demonstrated the importance for the regular evaluation of structural bone changes and intra- and periarticular inflammation in routine clinical practice in this patient population.

These interesting results of PSARTROS were the first to describe in high-resolution detail the positive effect of IL-17 blockade on bone and the musculoskeletal system. However, it remains unclear which factors can serve as clinical, imaging or serological biomarkers to most accurately measure structural bone changes that are essential for the disease impact of PsA [1] and what the role of IL-17 as a mediator for these changes might be in detail.

2.2 Study rationale

For the long-term structural changes a robust follow up of the PsA and Pso patients is mandatory to understand influencing factors on inflammation and inflammation related bone changes. Moreover, the influence of IL-17 blockade in regards to imaging as well as serum markers will be studied. Thus, these longitudinal data will impact the knowledge of the disease in perspective on the IL-17 – inflammation – bone axis. This observational study will focus on the participants of the PSARTROS study. Additional patients who fulfil the inclusion criteria will be observed as well. Patients who finished the 24 weeks and are still on drug will be assessed under routine clinical practice as outlined below. Therefore, data in regard to inflammation (ultrasound, MRI) and bone structure (HR-pQCT), but also an intense closer focus on most of the patients should be retrospectively analyzed.

Thus, for patients with secukinumab from the PSARTROS trial, a routine follow up in regards to disease activity, patient reported outcomes and more importantly the influence of disease and therapy on structural bone and inflammation changes will be performed. For this purpose, clinical,

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laboratory and imaging (assessed by MSUS, MRI, HR-pQCT) routine parameters, obtained exclusively on the basis of a clinical indication of the joints and entheses will be analyzed up to 48 months.

2.3 Benefit-risk assessment

Since this is a non-interventional study and all assessments comply with standard control examinations of patients treated with secukinumab +/- DMARDs, no additional study-related risk or benefit for study participants exist.

3 STUDY OBJECTIVES

3.1 Primary objective To assess the influence of disease and IL-17 blockade by secukinumab on structural bone and inflammatory changes in Pso and PsA patients.

3.2 Secondary objectives The secondary objectives of this study are to assess:

• The impact of secukinumab treatment on disease activity in psoriasis (PASI75) and PsA patients (ACR20 response, DAS28) over time • The change in erosions and osteo/enthesiophytes over time • The change of erosions/synovitis and power doppler signal using ultrasound analysis over time • The change in PRO parameters such as HAQ-DI, SF36, PsAQoL1, PSAID and DLQI over time • Overall safety and tolerability of secukinumab assessed by vital signs, clinical laboratory values and adverse event monitoring over time • Target genes of the IL-17 axis by quantitative real-time PCR (skin and joint biopsies) over time • The change in cytokine and bone parameters over time

4 STUDY DESIGN

4.1 Type of Study

Prospective single center non-interventional (observational) study including a retrospective data analysis of the same patients.

For the retrospective analysis data continuously collected in the biobank database during routine outpatient consultations at the Medizinische Klinik 3 (“TARDA, Translational Arthritis Research Database”) will be used. As a prerequisite for the routine data collection in the biobank data base the ethic approval was obtained and informed consent of the patients will be requested.

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4.1.1 Study site

The study will be performed at the Universitätsklinikum Erlangen, Medizinische Klinik 3.

4.1.2 Time schedule

The planned study duration will be 36 months.

The start of data collection is defined as the point in time from which information about the first study participant is recorded in the case record forms of the study for the first time.

The end of study will be defined as the last visit of the last patient.

4.1.3 Duration of observation per patient

Patients will be retrospectively and prospectively observed for a maximum of 48 months, counted from the start of treatment with secukinumab.

5 STUDY POPULATION

5.1 Selection of study population

Patients diagnosed with PsA or Pso and who are currently treated with secukinumab, and fulfil the following criteria:

5.2 Inclusion criteria

Only patients meeting all of the following inclusion criteria will be considered for study enrollment:

Inclusion Criteria

1. Written informed consent obtained from the patient

2. Male or female

3. Age 18 -70 years

Diagnosis of PsA according to CASPAR criteria OR Diagnosis of psoriasis (confirmed by a dermatologist and/or bioptically confirmed)

4. Previous participation in the PSARTROS trial and subsequent treatment with secukinumab in-label (150 mg or 300 mg s.c. every 4 weeks) OR Current treatment with secukinumab in-label (150 mg or 300 mg s.c. every 4 weeks) and treatment started at least 12 months ago

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5.3 Exclusion criteria

Patients having any of the following criteria at the start visit will not be included in the study:

Exclusion Criteria

1. Active inflammatory disease other than PsA or Pso that might impair the evaluation of the secukinumab effects

5. Underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions impair the evaluation of the secukinumab effects

6. No MRI and/or HR-pQCT results available and/or presence of known contraindications for MRI* or HR-pQCT**

7. Employee or direct relative of an employee of the study site

8. Previous participation in this study

*List of common conditions that may preclude patients from having a hand MRI:

• History of claustrophobia. • Physical limitation related to fitting in the bore of the magnet. • Presence of tattooed eye-liner or tattoos in the area of interest (hand to be imaged). • History of allergic reaction to contrast agents. • Patients who had exposure to a radiological contrast agent within the 72 hours prior to the MRI examination. • Patients who have a fused joint (i.e. completely destroyed) are being evaluated by the MRI examination. • Patients with a pacemaker, epicardial pacemaker wires, MRI-incompatible cardiac valve prostheses, MRI-incompatible vascular clips implanted less than two-months ago. • MRI-incompatible aneurysm clips of any age. • MRI-incompatible cochlear implants. • Spinal nerve stimulators. • Patients with an infusion pump. • Patients with metallic fragments in the eyes/orbits or in the vicinity of the brain or major neurovascular structures of the body, patients with an employment history which involves exposure to welding, or patients who have shrapnel any place in their body. • Patients with renal insufficiency (i.e., eGFR < 60 mL/min/1.73m2), as they are at increased risk of Nephrogenic Systemic Fibrosis following administration of gadolinium-based MRI contrast agents.

**List of common conditions that may preclude patients from having an HR-pQCT scan:

• Pregnancy • Inability to keep the hand motionless for at least 10 minutes

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5.4 Removal of patients from assessment

5.4.1 Discontinuation of patients

In accordance with the Declaration of Helsinki and the informed consent form, the patient may discontinue the study at any time without any penalty or loss of benefits. Both the discontinuation of study and the reason(s) why the study was prematurely discontinued must be recorded in the patient file and the DCS.

Patients must be discontinued from the study by the investigator at any time for any of the following reasons: • Withdrawal of informed consent. • Discontinuation of secukinumab treatment for any reason (e.g. unacceptable AR)

5.4.2 Premature termination or suspension of the study

The study can be prematurely terminated or suspended by the initiator of the study. Reasons for termination of the study may include, but are not limited to, the following: • Patient enrolment is unsatisfactory. • New scientific data do not justify a continuation of the study. • Unpredictable circumstances in the hospital conducting the study that do not allow the observation study to be continued • The study initiator decides to terminate the study at any time for any other reason.

Furthermore, the study may be prematurely ended if the regulatory authority or the IEC has decided to terminate or suspend approval for the study.

If the study is prematurely terminated or suspended for any reason, the investigator must inform the patients and assure appropriate follow-up treatment.

6 TREATMENT

All study participants are diagnosed with PsA or Pso and have already been treated with secukinumab over the long term in the past. They could have started secukinumab treatment as a participant of the PSARTROS-1 study or more recently on the basis of the clinical indication at the physician’s discretion independent of the participation in this observational study.

6.1 Drug treatment

Secukinumab (Cosentyx) is approved for the treatment of moderate to severe plaque psoriasis or Psoriasis arthritis. Cosentyx is commonly used in these clinical indications as a monotherapy or in combination with other DMARD, such as MTX in accordance with common treatment guidelines of the relevant medical societies (EULAR [7]) and the SmPC.

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The commercial product Cosentyx is provided as a ready-to-fill syringe or a pen for self- administration by the patient. The 300 mg dose is administered given as two consecutive subcutaneous injections of 150 mg.

In psoriasis the recommended standard maintenance dose is 300 mg administered by s.c. injections every 4 weeks.

In PsA the recommended standard maintenance dose is either 150 mg or 300 mg administered s.c. every 4 weeks according to standard treatment guidelines (EULAR).

If clinically indicated any dose reduction or increase is possible at the investigator’s discretion.

6.2 Previous and concomitant therapies

Prior to enrollment, the patient’s medical history should include a detailed list of all medications (including rescue medication) the patient was taking for a period of at least 3 months previous to the start visit. The record should include the drug name (trade or generic), total daily dose/unit (expressed in mg, mL, or IU), indication, the start and stop date (month, and year) for each medication, and if the medication is ongoing at the end of the study.

Therapy changes (including changes of regimen) during the study are to be documented in the patient file and in the DCSs.

7 DESCRIPTION OF EVALUATION INSTRUMENTS/ PARAMETERS

In accordance with the legal regulations, this observational study is limited to recording the course of the disease and the side effects of the drug.

All of the following assessments are routinely performed for standard treatment monitoring of patients with PsA or Pso in the outpatient section of the Medizinische Klinik 3, Universitätsklinikum Erlangen and will be used as evaluation instruments.

7.1 Clinical Assessments

7.1.1 Medical History

Patients will be asked to provide their relevant medical history (focused on PsA or Pso) such as date of diagnosis of PsA/Pso, previous PsA/Pso therapies, duration and dose of secukinumab treatment, cardiovascular medical history, and smoking history. Data will be recorded in the patient’s file.

7.1.2 Physical Examination

A specific physical examination should cover the evaluation of the skin of the whole body, respiratory, cardiovascular, lymphatic, and musculoskeletal system including blood pressure and pulse rate.

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7.1.3 Disease activity

7.1.3.1 Swollen and tender joint counts (SJC/TJC)

An assessment of 66 joints for swelling and 68 joints for tenderness will be made (including the DIP joints of the hands and excluding hips for swelling). Joints will be assessed and classified as swollen/not swollen and tender/not tender by pressure and joint manipulation on physical examination. A rule of thumb is to apply 4 kg/cm2 of pressure. Joints assessed include the distal interphalangeal (DIP), proximal interphalangeal (PIP), and metacarpophalangeal joints of the hands; ∼ the wrist, elbow, shoulder, acromioclavicular, sternoclavicular, temporomandibular, hip, knee, ankle, and midtarsal joints; and the metatarsophalangeal and PIP joints of the feet. Joints which have been replaced, fused or undergone synovectomy at any time prior to, or at any time during the study should be documented as non-evaluable (NE) for the duration of the study [8, 9].

7.1.3.2 Evaluation of Entheses

The presence or absence of entheseal inflammation (enthesitis) will be evaluated by entheseal point count using the 3 following scores:

a. The SPARCC (Spondyloarthritis Consortium of Canada) Score

SPARCC enthesitis score is based on the counting of the presence or absence of tenderness on 16 entheseal sites (eight sites bilaterally): lateral epicondyle, medial epicondyle, supraspinatus insertion into greater tuberosity of humerus, greater trochanter, quadriceps insertion into superior borders of patella, patellar ligament insertion into inferior pole of patella or tibial tubercle, Achilles tendon insertion into calcaneum, and plantar fascia insertion into calcaneum. Tenderness on examination is recorded as either present (1) or absent (0) for each of the 16 sites, summarized in an overall score range of 0–16. A higher count represents a greater enthesitis burden. [10]

b. The Leeds Enthesitis Index (LEI)

The LEI includes 3 entheseal sites bilaterally: lateral epicondyles, medial condyles of the femur, and Achilles tendons. Tenderness on examination is recorded as either present (1) or absent (0) for each of the 6 sites, summarized in an overall score range of 0–6. [11]

c. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES)

The MASES includes 6 bilateral entheseal sites (the bilateral first costochondral joints, seventh costochondral joints, posterior superior iliac spines, anterior superior iliac spines, iliac crests, proximal insertion of Achilles tendons) and the fifth lumbar spinous process. Tenderness on examination is recorded as either present (1) or absent (0) for each of the 13 sites, for an overall score range of 0–13. A higher count represents a greater enthesitis burden. [12]

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7.1.3.3 Dactylitis count

The presence of dactylitis will be assessed by counting the fingers/toes with dactylitis.

7.1.3.4 Skin involvement by PASI (Psoriasis Area and Severity Index)

PASI is the most widely used tool for the measurement of psoriasis severity. PASI combines the assessment of the severity of lesions and the area affected into a single score in the range 0 (no disease) to 72 (maximal disease).

The body is divided into four sections (head (H) (10% of a person's skin); arms (A) (20%); trunk (T) (30%); legs (L) (40%)). Each of these areas is scored by itself, and then the four scores are combined into the final PASI. For each section, the percent of area of skin involved, is estimated and then transformed into a grade from 0 to 6: 0) 0% of involved area, 1) < 10% of involved area, 2) 10–29% of involved area, 3) 30–49% of involved area, 4) 50–69% of involved area, 5) 70–89% of involved area and 6) 90–100% of involved area.

Within each area, the severity is estimated by three clinical signs: erythema, induration and desquamation. Severity parameters are measured on a scale of 0 to 4, from none to maximum. The sum of all three severity parameters is then calculated for each section of skin, multiplied by the area score for that area and multiplied by the weight of the respective section (0.1 for head, 0.2 for arms, 0.3 for body and 0.4 for legs). [13]

7.1.3.5 Skin involvement relative to body surface area (BSA)

For the BSA assessment of psoriatic skin involvement the size of the patient’s hand is used as a scale to estimate the size of the skin surface covered by psoriasis. The patient’s palm covers roughly 1% of body’s surface area. An area of < 3% of the skin involved is considered as mild, of 3-10% as moderate , and >10% as severe psoriasis. [14, 15]

7.1.3.6 Physician’s assessment of global status (VAS)

For description please refer to 7.1.4.3.

7.1.3.7 Minimal Disease Activity (MDA)

The MDA [9] status comprises the assessment of different domains of PsA, consisting of the following individual components: • swollen and tender joint count (SJC/TJC; 66 swollen/68 tender joint count) • tender entheseal point count (entheseal point count with a maximum value of 29, representing the maximum score of the commonly used measures in PsA) • skin involvement (PASI)

• patient self-assessment of pain (VAS) • global disease activity status

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• subject’s self-assessment of functional ability using Stanford Health Assessment Questionnaire disability index, HAQ-DI)

7.1.3.8 DAPSA (Disease Activity in PSoriatic Arthritis) Score

The DAPSA score is a tool for the assessment of disease activity in PsA patients, taking into account disease-specific joint counts as well as the subjective assessment of the patient. DAPSA uses swollen and tender joint count, CRP and patient’s assessment of disease activity and pain by simple addition of the values of the described domains [21]. It is a composite score which is calculated from the sum of: number of tender joints (0-68), number of swollen joints (0-66, hips are not taken into account), CRP (mg/dl), patient`s assessment of global status of disease activity using VAS (0-10) and patient`s self-assessment of pain using VAS (0-10). The value of the composite score DAPSA ≤ 4 marks remission, 5-14 marks low disease activity, 15-28 moderate and >28 high disease activity [8]

7.1.3.9 American College of Rheumatology (ACR) 20/50/70 responses

The ACR response criteria [22] evaluate whether the therapy has led to an improvement of predefined symptoms. An ACR20/50/70 efficiency is present, for example, if the patient has experienced at least a 20%/50%/70% improvement of the following parameters compared to the initial value:

• Number of painful joints

• Number of swollen joints

In addition, 3 of the following 5 parameters must show a > 20%/50%/70% improvement compared to the initial value:

• Physician's global assessment of disease activity

• Patient's global assessment of disease activity

• Pain (visual analogue scale (VAS)

• HAQ functional disability index (HAQ)

• CRP value

7.1.4 Clinical evaluation by means of patients’ self-assessment

7.1.4.1 Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)

The Stanford Health Assessment Questionnaire disability index is based on a patient’s self- assessment questionnaire for persons diagnosed with PsA. 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

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are 20 questions in eight categories of functioning which represent a comprehensive set of functional activities – 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. The patient's responses are made on a scale from zero (no disability) to three (completely disabled). Each category contains at least two specific component questions. The questionnaire will be provided in a German translation and will be scored based on the instructions from the Stanford University Medical Center [16, 17].

7.1.4.2 Patient’s self-assessment of pain (VAS)

The VAS for pain will be completed during the visits. The patient will be asked to place a vertical line on a 100-mm scale on which the left-hand boundary represents “no pain,” and the right-hand boundary represents “pain as severe as can be imagined.” The distance from the mark to the left- hand boundary will be recorded [11].

7.1.4.3 Patient’s and physician’s assessment of global status (VAS)

The VAS for patient’s self-assessment of global status (patient’s global assessment of disease activity) and physician’s global assessment of disease activity. The patient and the physician will be independently asked to place a vertical line on a 100-mm scale on which the left-hand boundary represents “no disease activity,” and the right-hand boundary represents “maximum disease activity.” The distance from the mark to the left-hand boundary will be recorded.

7.1.4.4 Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire

The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire is a disease-specific instrument developed to measure the quality of life in patients with PsA. It is a patient’s self-assessment questionnaire containing 20 items that takes about three minutes to complete. The answers are restricted to true or false.[18]

7.1.4.5 Psoriatic Arthritis Impact of Disease (PsAID)

The PsAID is a score, based on a patient’s self-assessment questionnaire, used to measure the impact of Psoriatic Arthritis on a person’s life. The questionnaire comprises 12 numeric rating scale questions covering the following topics: pain, fatigue, skin problems, work/leisure activities, functional capacity, discomfort, sleep disturbance, coping with PsA, anxiety, embarrassment, social participation, depression. Each question receives a score from 0 to 10. For evaluation these are weighted by factors, then summarized and the total is divided by 20. The range of the final PsAID- score will be 0-10 where higher figures indicate worse status. The questionnaire will be provided in German and will be evaluated according to the instructions provided by the developer. [19]

7.1.4.6 Dermatology life Quality Index (DLQI)

The DLQI is a score, based on a patient’s self-assessment questionnaire, used to measure the impact of the skin disease (psoriasis) on the quality of life of an affected person. The questionnaire contains 10 questions, covering the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, treatment. Each

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question refers to the impact of the skin disease on the patient’s life over the previous week. Each question receives a score from 0 to 3. These are summarized to a final score with a possible range from 0 (meaning no impact on quality of life) to 30 (meaning maximum impact on quality of life). The questionnaire will be provided in German and will be evaluated according to the instructions provided by the developer (University of Cardiff, UK, Dept. of Dermatology). [20]

7.1.4.7 Short Form Health (SF36)

SF-36 is a set of generic, coherent, and easily administered quality-of-life measures. These measures rely upon patient self-reporting and are now widely utilized for routine monitoring and assessment of care outcomes in adult patients. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. The eight sections are: vitality, physical functioning, bodily pains, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

7.1.4.8 DAS28

DAS28 is a Disease Activity Score for monitoring the course of disease in and is calculated as follows:

DAS28 = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * Ln(ESR) + 0.014 * GH (global health)

7.1.5 Imaging diagnostics

7.1.5.1 MRI

A MRI of the hand is routinely performed as standard assessment in 12 monthly intervals, if clinically indicated. Results obtained during the observation period will be evaluated. Patient’s results of examinations already available in the biobank database will be retrospectively evaluated.

The respective hand MRI images are evaluated according to the standardized and validated OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS)[23].

7.1.5.2 HR-pQCT

HR-pQCT provides a three-dimensional image of bone microstructure and allows the assessment of volumetric bone mineral density (vBMD) of the peripheral bone [24, 25]. The assessed density parameters (measured in mg hydroxyapatite/mm³) can be displayed for different bone compartments (trabecular and cortical) [24, 26]. Various morphological parameters such as trabecular thickness and separation or the trabecular number can also be precisely quantified [24]. Furthermore, the calculation of biomechanical bone properties allows statements to be made about bone strength and fracture risk. Biomechanical parameters can be assessed by using micro finite element analysis (µFEA) of segmented HR-pQCT images. The calculation of the µFEA of the distal

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radius facilitates the prediction of bone strength and simulates a fall on the outstretched hand [27- 29]. This makes it possible to identify patients who have an increased risk of fracture. The µFEA of the distal radius has been studied in large cohorts of healthy individuals and in postmenopausal women [30, 31]. Using HR-pQCT it is also possible to assess the presence and extent of bone proliferation at entheseal sides (structural entheseal lesions, SEL) [4].

Therefore, in PSARTROS II the peripheral vBMD and bone microstructure of the radius, finger joints (intraarticular bone area and entheseal bone area [4]) and biomechanical properties will be assessed. Furthermore the number and extent of SEL at finger joints will be assessed. All measurements will rely on the HR-pQCT images collected in clinical routine (A HR-pQCT of the periphery is routinely performed as standard assessment in 12 monthly intervals, if clinically indicated).

7.1.5.3 MSUS

Musculoskeletal ultrasound (MSUS) is a routinely available, noninvasive, patient friendly imaging method and is performed as standard assessment in 12 monthly intervals, if clinically indicated. Using MSUS the assessment of joint effusion, synovial hypertrophy, power-doppler activity, erosions and bone proliferation is possible. In PSARTROS II therefore the presence of joint effusion, synovial hypertrophy, power-doppler activity, erosions and bone proliferation in hand/finger joints and entheses will be assessed.

7.2 Laboratory evaluations

Routine blood examinations contain the following parameters and will be performed if clinically indicated at the investigator’s discretion:

o Serum chemistry: total protein, albumin, calcium, phosphorous, glucose, uric acid, total bilirubin, alkaline phosphatase, AST (SGOT), ALT (SGPT), gamma-glutamyl transferase (GGT), sodium, potassium, chloride, carbon dioxide, urea, creatinine, lactate dehydrogenase (LDH), magnesium.

o Hematology: RBC count, hemoglobin, hematocrit, WBC count and differential, absolute WBC counts, platelet count, and fibrinogene.

o High sensitivity C-Reactive Protein (hsCRP) and/or C-Reactive Protein

o Erythrocyte Sedimentation Rate (ESR; Westergren)

o Urinalysis (dipstick)

7.2.1 Biomarkers

Depending on the availability of blood samples collected as part of routine diagnostics levels during the observation period of disease-specific biomarkers will analysed if clinically indicated. Patient’s samples and/or results already stored in the biobank database will be retrospectively evaluated.

o Immunology/inflammation parameters: Serum cytokines, and molecular characterization of periphereal blood cells (e.g. IL-8 (CXCL8), Calprotectin

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(S100A9/S100A9). IL-22, lipocalin-2 (NGAL), beta defensin 2 [32], ILC, PBMC) and bone parameter (e.g. dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]).

o Rheumatoid factor (RF).

o CCP2-antibody (CCP-AB).

7.2.2 Tissue analysis

Depending on availability tissue samples obtained at routine synovial and/or skin biopsies during the observation period will be examined. Patient’s samples and/or results already stored in the biobank database will be retrospectively examined.

7.3 Overview of study activities

On the start visit (Day1) the prospective period of the observation will begin.

During the observation period, patients will be examined in regular intervals following the clinical routine schedule while being treated with secukinumab in-label as monotherapy or in combination with other DMARD.

Regular routine visits for treatment monitoring are scheduled quarterly. Data collection for this observational study will take place at the time of the regular routine visits with an extended time window for each survey date.

Visits should take place at a date freely set within the calendar quarter and the period between two visits should not be less than 8 weeks.

The final observation visit at the end of study (EOS) will occur 48 months after start of treatment with secukinumab at the latest.

Visit Start Visit Quarterly EOS Visit Timepoint Day 1 About every 3 months Informed Consent X In-/Exclusion Criteria X Demographics X Medical history/Concomitant diseases X Previous medication X Concomitant medication X X X MDA X X X 66 SJC/68 TJC X X X Tender entheseal point count (SPARCC, LEI, X X X MASES)

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Dactylitis count (fingers/toes) X X X Psoriasis Area and Severity Index (PASI) X X X Psoriasis Body Surface Area (BSA) X X X ACR 20/50/70 X X X Patient’s self-assessment pain (VAS) X X X Global disease activity (patient, physician) X X X HAQ-DI X X X DAS 28 X X X SF-36 X X X DLQI X X X PsAID X X X DAPSA X X X PsAQoL X X X Physical examination (including HR, BP) X X X Recording of results from routine MRI (1) X X Recording of results from routine HR pQCT (2) X X Recording of results from routine MSUS (3) X X X Blood sampling/recording results of routine lab X X X tests (Clin. chemistry, hematology, hsCRP, ESR); Urinalysis (dipstick) Blood sampling/recording results of routine X tests for RF, CCP-AB Blood sampling/recording results of routine X X tests for serum cytokines measurement, and molecular characterization periphereal blood cells Blood sampling/recording results of routine X tests for testing osteological parameters (optional) Recording results from routine synovial (PsA) or skin biopsies (Pso) AE inquiry X X

(1) MRI of the hand will be performed in 12 monthly intervals, if clinically indicated. (2) HR-pQCT of the periphery will be performed in 12 monthly intervals, if clinically indicated. (3) MSUS of joints and entheses will be performed in 12 monthly intervals, if clinically indicated.

8 METHODS

8.1 Data collection for evaluation

All parameters of the following categories • Demography (age, gender, height, weight) • Medical history

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• History of PsA • Concomitant diseases • Concomitant treatments • Clinical assessments • Patients’ self-assessments • Laboratory parameter/biomarker • Results from imaging diagnostics • AE/SAE described in detail in section 7.1 and 7.2 will be prospectively collected at the timepoints outlined in Section 7.3 by the investigator and recorded in the DCS for evaluation.

Data of the same categories already recorded during the patient’s previous regular visits for treatment monitoring of secukinumab as monotherapy or in combination with other DMARD in the outpatient department of the Medizinische Klinik 3 during the last 48 months will be taken from the biobank database for retrospective evaluation.

8.2 Statistical Analysis

This section describes the statistical analyses foreseen at the time of study planning. Further details on the statistical and analytical aspects may be presented in the SAP, if needed.

8.2.1 Sample size

29 subjects will be evaluated.

8.2.2 Analysis sets

There is only one analysis set in this observational study: all included patients.

8.2.3 Variables for analysis

8.2.3.1 Primary variable (endpoint):

Change of OMERACT psoriatic arthritis magnetic resonance image scoring system (PsAMRIS) assessed by MRI and change of number and extent of SEL, vBMD and bone microstructure assessed by HR-pQCT.

8.2.3.2 Secondary variables

All other variables described in section 7 will be analyzed (the visits and their assessments are described in section 7.3), in particular: • Impact of secukinumab treatment on the disease activity in psoriasis patients (e.g. PASI75) over time • Impact of secukinumab on disease activity in PsA patients (e.g. ACR20 response, DAS28) over time

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• The change in erosions and osteo/enthesiophytes over time • The change of erosions/synovitis and power doppler signal using ultrasound analysis over time • The change in PRO parameters such as HAQ-DI, SF36, PsAQoL1, PSAID and DLQI over time • Overall safety and tolerability of secukinumab assessed by vital signs, clinical laboratory values and adverse event monitoring • Target genes of the IL-17 axis by quantitative real-time PCR (skin and joint biopsies) over time • Change in cytokine and bone parameters over time

8.2.4 Statistical analysis methods

8.2.4.1 Clinical variables

Descriptive statistics are applied according to the scale of measurement of the variable: Nominal and ordinal variables are described by counts and percentages. Interval scaled variables are described by mean and standard deviation, and robust estimators like quantiles (Min, Max, Median). The number of missing and valid values are counted for every variable; Missing values are not imputed. Longitudinal data will be described by their change from baseline and by their raw values.

Inference statistics is based on a frequentist approach with hypothesis tests, p-values, and confidence intervals. Applicable tests for this longitudinal study are the ANOVA, Kruskal-Wallis-Test and, χ²-tests, according to the scale of measurement of the variable. The significance level is set to 5%; confidence intervals are two-sided with a length of 95%. The null hypothesis for these tests and all variables is: no change over time of the variable. The alternative hypothesis is the negation of the null hypothesis.

As this is an exploratory observational study the intention of p-values and confidence is to detect trends and patterns in the data; they are not intended as a confirmatory analysis and no multiple testing adjustment of the significance level is performed.

Patient dispositions, demographic data, and baseline characteristics will be presented using standard descriptive statistics; no homogeneity tests will be performed.

8.2.4.2 Safety variables

All safety and tolerability parameters (AE, vital signs and clinical laboratory parameters) will be listed by subject/treatment group as well as analyzed according to general procedures. For selected variables and/or subjects, individual tables and/or graphs that track a given subject will be supplied.

The incidence of subjects with AEs will be determined by gender, where applicable. Furthermore, the absolute and relative frequencies for the subjects with a given AE with respect to the preferred term according to the latest available version if the MedDRA dictionary, as well as the absolute and relative frequencies of the individual AEs that have occurred will be determined within each system organ class (SOC)

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Additional tables will summarizes AEs by maximum event intensity and causal relationship with secukinumab, by gender and overall. The countermeasures taken for each AE, the time of onset of AE after dosing and AE duration will be listed, Additional tables with respect to all categories of AE will also include the numbers is subjects who experienced the respective AE.

8.2.5 Time points of analysis

Analysis of the study data will be performed at end of the study when all patients have completed their last follow up (or dropped out) and after the data base is cleaned and closed.

Furthermore two interim analyses are planned:

1. when 5 patients have completed their 12 month observational visit

2. when 15 patients have completed their 12 month observational visit

These interim analysis will analyze all collected data up to the 12 month observational visit.

8.2.6 Examination of subgroups

None planned.

9 ADVERSE EVENT REPORTING

9.1 Definition of adverse events/serious adverse events

An AE is any untoward medical occurrence in a patient administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. Thus, an AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

In order to ensure complete safety data collection, all AEs occurring during the study (i.e., after signing the ICF), must be reported in the DCS. This includes all AEs not present prior to the initial visit and all AEs which recurred or worsened after the initial visit.

Signs or symptoms of the condition/disease for which the focus drug is being studied should be recorded as AEs only if their nature changes considerably or their frequency or intensity increases in a clinically significant manner as compared to the clinical profile known to the Investigator from the subject’s history or the Baseline Period.

An SAE is any adverse event with the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria: • Death

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• Life-threatening Life-threatening does not include a reaction that might have caused death had it occurred in a more severe form. • Significant or persistent disability/incapacity • Congenital anomaly/birth defect (including that occurring in a fetus) • Important medical event that, based upon appropriate medical judgment, may jeopardize the patient or subject and may require medical or surgical intervention to prevent 1 of the other outcomes listed in the definition of serious.

Important medical events may include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. • Initial inpatient hospitalization or prolongation of hospitalization

A patient admitted to a hospital, even if released on the same day, meets the criterion for the initial inpatient hospitalization. An emergency room visit that results in admission to the hospital would also qualify for the initial inpatient hospitalization criterion. However, emergency room visits that do not result in admission to the hospital would not qualify for this criterion and, instead, should be evaluated for 1 of the other criteria in the definition of serious (e.g. life- threatening adverse experience, important medical event).

Hospitalizations for reasons not associated with the occurrence of an AE (e.g. pre-planned surgery or elective surgery for a pre-existing condition that has not worsened or manifested in an unusual or uncharacteristic manner) do not qualify for reporting. For example, if a subject has a condition recorded on his/her medical history and later has a pre-planned surgery for this condition, it is not appropriate to record the surgery or hospitalization as an SAE since there is no AE upon which to assess the serious criterion.

Please note that if the pre-existing condition has worsened or manifested in an unusual or uncharacteristic manner, this would then qualify as an AE and, if necessary, the seriousness of the event would need to be determined.

9.1.1 Severity Criteria

Part of the safety reporting process is also a severity categorization of the respective event. For (S)AEs the following definitions are used to describe the severity of events as part of the (S)AE documentation process. • Mild – defined as event of transient or mild discomfort which requires minimal or no treatment • Moderate – defined as event which results in mild to moderate limitations in activity with applied therapeutic measures. • Severe – defined as events which interrupt a participant’s usual daily activity with possible requirement of assistance. Medical intervention/therapy is required. Hospitalization is possible

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9.1.2 Causality Assessment

The treating physician’s assessment of a possible AE relationship to an applied treatment is part of the documentation process. However it is not a factor in determining what is or is not reported in the study. All occuring AEs should have a relationship assessed to concomitant treatments by a study physician. For relationship assessment, the following terms are applied.

• Related – An AE which is known to occur with a medication or for which a study physician sees a causal relationship between the event and the treatment. • Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a reasonable time after administration of a medication). • Not Related – There is no reasonable possibility by the judgement of a study physician that a medication caused the AE

9.2 Procedures for safety reporting Since this is an observational study, any adverse event/serious adverse event will be reported in accordance to the routine medical care guidelines and according to German regulations. This includes compliance with current data privacy regulations (i.e. anonymous reporting to public health authority in case of a causal relationship to any concomitant treatment).

In addition, all non-serious adverse events suspected to be causally related to secukinumab will anonymously be reported to the marketing authorization holder on a monthly basis. Every serious adverse event as well as events of ‘drug exposure during pregnancy’ or ‘drug misuse and abuse’ are to be anonymously reported to the marketing authorization holder within 15 days.

9.2.1 Procedures for SAE reporting

If an SAE is reported, the initiator must be informed within 24 hours of receipt of this information by the site. The site must document a duly completed SAE report form, even if the data are incomplete, or if it is obvious that more data will be needed in order to draw any conclusions.

Additional information (e.g. autopsy or laboratory reports) received by the Investigator must be provided within 24 hours of receipt of the information. The site is specifically requested to report any SAE (even if the Investigator is certain that they are in no way associated with the focus drug) up to 30 days from the end of the study for each subject, and to also inform participating subjects of the need to inform the Investigator of any AE within this period. Serious adverse events that the Investigator thinks may be associated with the focus drug must be reported regardless of the time between the event and the end of the study.

9.2.2 Follow up of serious adverse events

An SAE should be followed until it has resolved, has a stable sequelae, the leading treating physician determines that it is no longer clinically significant, or the subject is lost to follow-up.

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9.2.3 Procedures for recording and reporting of adverse events

The subject will be given the opportunity to report AEs spontaneously. A general prompt will also be given at each study visit to detect AEs, for example: “Did you notice anything unusual about your health (since your last visit)?”

9.2.4 Documentation of adverse events

When recording an AE, the Investigator should use overall diagnosis or syndrome using standard medical terminology, rather than recording individual symptoms or signs. The CRF and source documents should be consistent. Any discrepancies between the subject’s own words on his/her own records (e.g., diary card) and the corresponding medical terminology should be clarified in the source documentation.

9.2.5 Follow up of adverse events

An AE should be followed until it has resolved, has a stable sequelae, the Investigator determines that it is no longer clinically significant, or the subject is lost to follow-up. If an AE is still ongoing at the end of the study for a subject, follow-up should be provided until resolution/stable level of sequelae, the Investigator no longer deems that it is clinically significant, or until the subject is lost to follow-up. If no follow-up is provided, the Investigator must provide a justification. The follow-up will usually be continued for 30 days after the subject has completed the study.

9.2.6 Pregnancy reporting

Should a subject become pregnant after the intake of the focus drug the treating physician has to be informed immediately and the subject should be withdrawn from the study. The treating physician must inform the subject of information currently known about potential risks and about available treatment alternatives.

In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, the treating physician will contact the subject and his partner to request consent. If the partner agrees to provide additional information, the pregnancy will be documented. The progression of the pregnancy and the eventual birth (if applicable) must be followed-up in which the treating physician has to report on the health of the mother and of the child. The health of the child must be followed for at least 12 months after birth for any significant medical issues. After 1, 3 and 12 months the initiator must provide a Follow up report to the marketing authorization holder.

A pregnancy becomes an SAE in the following circumstances: miscarriage, abortion, or anomaly/birth defect of the child. Those serious events must be additionally reported using the SAE report form.

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10 DATA QUALITY ASSURANCE

10.1 Documentation requirements

All data collected from a patient during the course of a observational study should be entered and/or filed in the respective patient file. The patient file must also contain a copy of the informed consent (see Section 11.3)

10.1.1 Data recording

All data required by this OSP are to be recorded on paper DCS (Data collection sheets) designed for this study as soon as possible. Entries on the DSC must be legible and made with a blue or black ballpoint pen: pencils are not permitted. The monitor is not allowed to make data entries in the DSC.

10.1.2 Corrections to data

It is not permitted to erase, overwrite, or use correction fluid or tape on the DCS. If corrections are necessary, an authorized member of the investigator’s staff will enter them in the following manner: the wrong entry will be crossed out (although it must remain legible) and the correct entry will be placed next to it. Corrections will be initialed, dated, and (if necessary) explained (e.g., corrections concerning AEs or the primary variable). Corrections that become necessary after collection of original DSC data sheets have to be documented on DCFs.

10.2 Data management

Completed DCS by the investigator will be forwarded to the Clinical Data Management. All data from the DCS will be entered into the study database for evaluation. An independent second data entry of key values (e.g. primary variable, inclusion/exclusion criteria) will be performed in order to ensure the quality of data entry.

Plausibility checks will be performed and inconsistencies in the data will be queried to the investigator; changes to the data will be documented on data clarification forms.

Laboratory, antibodies etc. data will be received electronically and uploaded into the study database. Plausibility checks will be performed to ensure correctness and completeness of these data.

After all data are entered and all queries are solved, the database will be closed.

10.3 Monitoring

This study will be monitored regularly by a qualified monitor commissioned from the initiator according to GCP guidelines and the respective SOPs. Interim monitoring visits will take place on a regular basis according to a mutually agreed schedule. During these visits, the monitor will check for completion of the entries on the DCS; for compliance with the OSP, ICH-GCP principles, the Declaration of Helsinki, and regulatory authority requirements; for the integrity of the patient file with the entries on the DCS; and for patient eligibility. Monitoring also will be aimed at detecting any misconduct or fraud.

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In addition, the monitor will check whether all AEs and SAEs have been reported appropriately within the time periods required.

The investigator and all staff will be expected to cooperate with the monitor by providing any missing information whenever possible. The investigator must be available to answer questions arising during regular monitoring visits. Further details of monitoring activities will be set forth in the monitoring manual.

10.4 Recordkeeping

Essential documents should be retained for at least 10 years or according to current regulatory requirements, whichever is longer.

11 ETHICS AND REGULATORY

This investigation will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and applicable regulatory requirements of the country concerned.

11.1 Competent authority

The NIS will be notified to the German Competent Authority prior to the beginning of the study according to German Drug Act. The Competent Authority will then be notified and consulted as required during and after the conduct of the investigation.

11.2 Independent Ethics Committee

The favourable opinion of the responsible Ethic committee will be obtained prior to the beginning of the NIS. The Ethic committee will then be notified and consulted as required during and after the conduct of the investigation.

11.3 Patient information and informed consent

The patient must be informed of the nature of the study, agree to its provisions, and sign and be provided an “Informed Consent/Assent Form” approved by the appropriate Ethics Committee. Each patient will have the opportunity to question the physician about the study prior to giving consent. Informed consent will be obtained in writing directly from the patient.

The consent must be confirmed by the physician who conducted the informed consent briefings. The informed consent process must be traceable from the available documentation. The patient will be given a copy of the signed and dated written informed consent form as well as all consent form updates (if applicable).

During the course of the study, the patient will be informed in a timely manner if information becomes available that may be relevant to the patient’s willingness to continue participation in the study. In case of AEs, or poor tolerability to secukinumab, the patient should inform the physician who then will make a judgment whether continuing in the observation study serves the patient’s best interests. The patient, however, is free to withdraw consent at any time and for any reason, whether expressed or not.

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11.4 Patient privacy

The patient will be informed of procedures to protect patient privacy. Although recorded data will be passed on in a coded version only to authorized individuals, re-identification by the investigator (e.g., in case of emergencies) will be possible by the study number assigned to the patient. Access to non-coded data will be allowed solely to check validity, and such access will be limited strictly to authorized individuals (e.g., the initiator of the NIS or individuals authorized by him, auditors, regulatory authorities, or members of EC) who have been bound to confidentiality. If the results of the study are published, the patient’s identity will remain confidential. Photographs allowing identification of the patient will be published only if the patient has given permission.

11.5 Insurance

Not applicable.

11.6 Financing

The NIS has been initiated by the Medizinische Klinik 3, Universitätsklinikum Erlangen and will be financed by a grant from Novartis GmbH. The financial aspects of the study will be documented in an agreement between Novartis GmbH and the study-initiating institution. Since all investigators are employees of the institution the usual case-by-case payment is not planned.

11.7 Publication policy

The study results will be published in an appropriate journal, and publishing details will be given in the observational study agreement. Publications concerning study results must be approved in advance by initiator of the study in writing.

The results of this study and any discoveries related to this study, regardless of whether they have technical or medical character, are the property of the initiator of the study.

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12 REFERENCES

1. Simon D, Kleyer A, Faustini F, Englbrecht M, Haschka J, Berlin A, et al. Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration. Arthritis Res Ther. 2018; 20(1):203.

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