LIBERO - Paul Ehrlich Institute

GPP statement: This Non-Interventional Study will be conducted in compliance with

the Clinical Study Protocol, Good Pharmacoepidemiology Practices

and applicable regulatory requirement(s).

Sponsoring LEO entity:

LEO Pharma GmbH

Frankfurter Str. 233

D-63263 Neu-Isenburg

Protocol Code Number

LEO Study ID:

NIS-KYNTHEUM-

1400

Date: 8- NOV-2017

Version: 2.0

KEY STUDY PERSONNEL

STUDY MANAGER

PHARMACOVIGILANCE SCIENTIST

STATISTICIAN

National Coordinating Investigator

Non-Interventional Study Protocol

Management of moderate to severe plaque psoriasis

with Kyntheum® in Daily Practice

Prospective, observational, non-interventionaL, multicenter real-world evIdence (RWE)

study of Brodalumab 210mg (Kyntheum®) to manage patients with modERate-to-severe

plaque psOriasis in daily practice (LIBERO)

LIBERO

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Non-Interventional Study Protocol Page 2 of 45

P-001 - Clinical Study Protocol (template); version 27-Nov-20125

THIS DOCUMENT CONTAINS TRADE SECRETS, AND/OR COMMERCIAL OR FINANCIAL INFORMATION, PRIVILEGED OR CONFIDENTIAL, DELI-

VERED IN CONFIDENCE AND RELIANCE THAT SUCH INFORMATION WILL NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY

WITHOUT THE WRITTEN CONSENT OF LEO PHARMA A/S

APPROVERS

The following persons within LEO Pharma (LEO) have approved this Study Protocol by

signing the Non-Interventional Study Protocol Approval Form adjoined as a separate page to

this document:

The following persons outside LEO have approved this Clinical Study Protocol by signing the

Clinical Study Protocol Approval Form adjoined as a separate page to this document:

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1. Table of Contents

Contents

1. Table of Contents.......................................................................................................... 3

2. List of Abbreviations ......................................................................................................... 5

3. Responsible Parties ............................................................................................................ 7

4. Abstract ............................................................................................................................. 8

5. Amendments and Updates ............................................................................................... 13

6. Milestones ....................................................................................................................... 13

7. Rationale and Background .............................................................................................. 14

8. Research Question and Objectives .................................................................................. 15

9. Research Methods ........................................................................................................... 16

9.1 Study Design ............................................................................................................... 16

9.2 Setting .......................................................................................................................... 18

9.3 Variables ...................................................................................................................... 22

9.4 Data Source ................................................................................................................. 24

9.5 Study Size .................................................................................................................... 24

9.6 Data Management ........................................................................................................ 24

9.7 Data Analysis ............................................................................................................... 25

9.7.1 Interim Analyses .......................................................................................................... 27

9.8 Quality Control ............................................................................................................ 27

9.9 Limitations of Research Methods ................................................................................ 27

9.10 Other Aspects .............................................................................................................. 28

10 Protection of human subjects .............................................................................................. 29

11 Management and Reporting of Adverse Events and Other Experiences ............................. 32

12 Plans for Disseminating and Communicating Study Results .............................................. 36

Annex 1. List of Stand Alone Documents ................................................................................ 38

Annex 2: Signature Page .......................................................................................................... 39

Annex 3: Contact details .......................................................................................................... 40

References ................................................................................................................................ 42

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APPENDICES

1. List of Stand Alone Documents (08. NOV 2017, 1 page)

2. Approver´s Signature Page

3. Contact Details of all key study personell (08. NOV 2017, 2 pages)

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2. List of Abbreviations

ADR Adverse Drug Reaction

AE Adverse Event

AMG Arzneimittelgesetz (German Medicine Law)

ANFOMED Anfomed GmbH (CRO)

BfArM Bundesinstitut für Arzneimittel und Medizinprodukte

BSA Body Surface Area

CHMP Committee for Medicinal Products for Human Use

CI Confidence Interval

CRF Case Report Form

CRO Contract Research Organization

DLQI Dermatology Quality of Life Index

EC Ethics Committee

EEA European Economic Area

EMA European Medicines Agency

FPI First Patient In

Ig Immunglobulin

IL Interleukin

ITT Intention To Treat

LEO LEO Pharma GmbH (Sponsor)

LOCF Last Observation Carried Forward

LPI Last Patient In

LPO Last Patient Out

MedDRA Medical Dictionary for Regulatory Activities

NIS Non Interventional Study

OE Other Event

PaGA Patient Global Assessment

PASI Psoriasis Area and Severity Index

PBI Patient Benefit Index

PEI Paul Ehrlich Institute

PGA Physician Global Assessment

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Q2W Every other week

QA Quality Assurance (Qualitätssicherung)

QW Weekly

RCT Randomized Clinical Trial

RWE Real World Evidence

SAE Serious Adverse Event

SAP Statistical Analysis Plan

SOC System Organ Class

SOP Standard Operating Procedure

sPGA Static Physician Global Assessment

SmPC Summary of Product Characteristics

Tab Table

TSQM Treatment Satisfaction Questionnaire for Medication

V Visit

W Week

WHO World Health Organization

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3. Responsible Parties

LEO Pharma GmbH (LEO) is the sponsor of the NIS and Anfomed GmbH (ANFOMED) is

the Contract Research Organisations (CRO) authorised by LEO to act on behalf of LEO.

LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark will be the Data

Controller.

(LEO) is the study manager and responsible for overall project

coordination.

is the principal investigator of the study and

will provide ongoing expert input into the conduct of the study and evaluation of study

results, including review of safety data to enable early and ongoing risk management during

the conduct of the Study. He will provide guidance on development and review of study

materials, documents (e.g. protocol, Case Report Forms, disease-specific questionnaires) and

procedures, will support the successful roll-out of the Registry and encourage active

participation from the selected investigators and sites.

is responsible for writing the protocol

and the final publication with scientific support and under the supervision of the national

coordinating investigator.

is responsible for statistical analysis and for writing the

biometric clinical study report.

Contact and responsibilities of all parties contributing to the study, including all investigators,

are listed in Annex 3. For key contributors LEO will keep CVs and documentation regarding

Conflicts of Interest and make such documentation available upon request from relevant

parties, e.g. authorities, journals. LEO will keep a record of all relevant sponsor personnel.

The CRO will keep a record of all involved CRO personnel.

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4. Abstract

Title Prospective, observationaL, non-interventional, multicenter, real-world

evIdence (RWE) study with Brodalumab 210mg (Kyntheum®) to manage

patients with modERate-to-severe plaque psOriasis in daily practice

(LIBERO)

Version 2.0, 08. NOV 2017

Rationale

and

background

Kyntheum® is the first IL 17- Receptor A Blocker, which has shown in clinical

trials superior efficacy and a comparable safety profile vs. Ustekinumab

(Lebwohl et al, NEJM 2016). In July 2017 Kyntheum® obtained approval in

the EEA (European Eonomic Area) for the treatment of patients with

moderate-to-severe plaque psoriasis in adult patients, who are candidates for

systemic treatment. To-date there is no evidence, how the management of

moderate-to-severe psoriasis patients with Kyntheum® results in daily practice

and how different patient profiles are managed with Kyntheum® in the

diversity of a real world setting.

Research

questions

and

objectives

This NIS aims

to assess the short and long-term management outcome in patients with

moderate-to-severe psoriasis starting with Kyntheum® under daily

practice conditions

to describe different patient profiles managed with Kyntheum® in the

diversity of a real world setting

The NIS will deliver real world evidence in the German healthcare setting

regarding patient profiles, physician´s decision algorithm (e.g. more biologic

naive, after failure of anti-TNF-biologics or ustekinumab etc.) and brodalumab

effectiveness.

Patient reported outcomes will create substantial insights regarding care with a

modern biologic outside of randomized clinical trials (RCT).

Study

design

Open-label, multicenter, real-world, 12 and 52 weeks, prospective, non-

interventional, non-controlled (single-arm), observational study

Population Inclusion criteria

Adult patients (≥ 18 years)

Patients must be a candidate for systemic therapy with Kyntheum®

according to SmPC and local guidelines.

Decision to start treatment with Kyntheum® in a patient was taken

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before enrolment in the study.

Patients must have understood and voluntarily signed the ICF.

Exclusion criteria

Patients who are enrolled in any interventional clinical trial in parallel.

Patients who are already treated or have been previously treated with

Kyntheum® before enrolment.

Patients, who did not sign the informed consent or incapacitated

patients, who are not able to provide informed consent and/ or are under

institutionalized care.

Variables Primary endpoints

Proportion of patients achieving an absolute PASI value of 3 at week

12

Proportion of patients who continued with Kyntheum® after 12 weeks

of treatment achieving sPGA success (defined as clear = 0 and almost

clear = 1) at week 52

Secondary endpoints

Short term effectiveness as measured by the proportion of patients

achieving

o PASI 75/ 90/ 100 at week 12

o sPGA-success (clear = 0 or almost clear = 1) at week 12

o sPGA = 0 at week 12

o Time to response (absolute PASI ≤ 3, PASI 75/90, PGA 0/1,

PGA 0)

Long term effectiveness of continued Kyntheum® treatment as

measured by the proportion of patients over time on a quarterly basis

and at week 52 measured by

o mean PASI

o Proportion of patients achieving a PASI ≤ 3

o PASI 75/ 90/ 100

o sPGA = 0/1 und sPGA = 0

Description of the frequency of adverse events as per MedDRA

preferred term and systemic organ class (SOC) during induction phase

(week 0-12) and maintenance phase (week 13-52).

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Description of patient profiles with regard to

o demographics (e.g. gender, age, health insurance status,

socioeconomic status, disease duration),

o disease severity (sIGA, sPaGA, BSA, PASI),

o previous treatment regimens,

o satisfaction with previous treatment and

o reasons for choosing Kyntheum®

Patient Reported Outcomes (PROs) at week 12 and week 52 as

measured by

o Mean change in Patient Global Assessment (PaGA) and

proportion of patients with sPaGA of 0 clear or 1 almost clear.

o Mean change in overall PBI and subscales on psoriasis

symptoms, social life and emotional well-being and proportion

of scales/ subscales with a score of 4 or 5

o Mean proportion of patients, who were satisfied/ very satisfied

with treatment (TSQM-9)

o Mean change in DLQI Score and proportion of patients, who

achieved a DLQI Score of 0-1 (= no impact on QoL)

Physician and patient reported outcome variables will be collected in the first

four weeks on a biweekly basis followed by quarterly follow-ups (W12, W24,

W36, W48) and a close-out visit at W52.

Data

sources

Data will be collected by the physicians from the standard medical records of

the participating out-patient clinics and private practices.

At their regular visits patients will be asked to complete a questionnaire on

assessing severity of their psoriasis (PaGA) during the 52 weeks treatment

period. They will be asked to answer a short series of questionnaires about their

quality of life (DLQI), general and emotional well-being (PBI) and their

satisfaction with therapy (TSQM-9).

Study size The study aims to include 500 patients in about 100-150 sites all over

Germany. A participating site should be willing to enrole at least 3-6 patients to

the study.

The primary purpose of this NIS is descriptive and the number of 500 patients

is a representative patient clientele for Germany aspired by epidemiological

data. With this sample size it is expected to see the same or similar outcome

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compared to randomized clinical trials (RCT) with Kyntheum®. The results

could bridge the RCT data with the real-world experience.

With 500 documented cases:

In case of dichotomous variables, a 95% confidence interval for the

underlying binomial probabilities will have a maximum length of 8.94

percentage points.

95% confidence intervals for the underlying mean values of

quantitative variables will have a length of 0.176 standard deviations.

Rare events with an incidence down to 0.006 (1/167) will appear at

least once in the sample with 95% probability.

Patient groups formed by anamnestic or other characteristics will

usually be large enough to allow reliable subgroup analyses.

Data

analysis

Populations to be analyzed:

The ITT (Intention-To-Treat) population being all patients who have given

written informed consent to use of their data for the short and longer term

effectiveness.

The safety population being the subset of the ITT- patients who have either

confirmed in patient reported data that they have administered the initially

prescribed medication at least once, or have confirmed to site staff at a later

contact that they have administered the initially prescribed medication at least

once.

The short-term effectiveness population being the subset of the safety

population who has data on at least one of the effectiveness outcome variables

available until week 12 (LOCF).

The long-term effectiveness population being the subset of the effectiveness

population, who agreed to continue with Kyntheum® after week 12, has

received at least once the study medication in maintenance phase and has at

least one of the effectiveness outcome variables available after week 12.

Statistical analysis

Taking into account the non-interventional character of the study, statistical

analysis will be performed in a descriptive and explorative way after 12 and 52

weeks of treatment. Continuous variables will be described by number of valid

(evaluable) cases, mean, standard deviation, minimum, lower quartile, median,

upper quartile and maximum. Categorical variables will be described by

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number of cases, frequency, and percentage. 95%-confidence intervals will be

computed where suitable.

A statistical analysis plan will provide details of analyses, data tabulation, and

listings (see Annex 4)

Milestones First patient in: Nov 15th

2017

Last patient in: Nov 15th

2018

Last patient out (12 W): Feb 15th

2019

Last patient out (52 W): Nov 15th

2019

Interim Analysis Study Report at Week 12: May 30th

2019

Clinical Study Report at Week 52: April 30th

2020

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5. Amendments and Updates

None

6. Milestones

Milestone Planned Date

Start of data collection November 15th

2017

End of data collection November 15th

2019

Interim report (12 Weeks) May 30th

2019

Final study report (52 Weeks) April 30th

2020

The start of the study is defined as the date on which the first information on a study patient is

recorded in the study dataset. LEO will ensure that End-of-Data Collection (End of Study)

notification is submitted to the concerned authorities and ECs.

Based on upcoming knowledge, LEO might choose to terminate the study prematurely. In

such case the study sites, ECs and authorities will be informed promptly.

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7. Rationale and Background

Psoriasis is a chronic relapsing immunological skin disease characterized by proliferation of

keratinocytes and accumulation of immune cells in the affected skin, that occurs in 2 - 3% of

the Caucasian population.1,2,3 Despite the availability of several therapies, many patients

remain untreated, do not have an adequate response or have treatment- related toxic effects.4

The Interleukin (IL)-17 pathway has shown to play a key role in the immunopathogenesis of

psoriasis.5 Genomewide association studies have linked IL-17 pathway-related genes with

psoriasis6,7 and IL-17 mRNA levels are higher in psoriatic lesions than in normal skin.

8,9

Numbers of T-helper (h) 17 cells are increased in psoriatic lesions and are stimulated by IL-23

to release IL-17 cytokines.10

IL-17 cytokines, which include IL-17A, IL-17C, IL- 17F, and IL-

17A/F, can induce expression of psoriasis-related proinflammatory molecules in

keratinocytes, leading to the recruitment and accumulation of neutrophils, T cells, and

dendritic cells. 11

,12

,13

Kyntheum® (Brodalumab 210mg) is the first human monoclonal IgG2 antibody that

selectively binds to the human IL-17 A receptor and thereby blocks its interactions with a

number of cytokines of the IL-17 family (IL-17-A, - C, -E, -F). 14

,15

,16

In July 2017, the European Medicines Agency's (EMA's) Committee for Medicinal Products

for Human Use (CHMP) recommended the granting of a marketing authorisation for

Kyntheum® for the treatment of moderate to severe plaque psoriasis in adults who are

candidates for systemic therapy.17

The approval of Kyntheum® was based on three randomized, double-blind, placebo-controlled

phase 3 trials including a 12 week induction phase followed by withdrawal/ retreatment or a

maintenance phase.

AMAGINE-1 (n=661) evaluated the efficacy, safety, and withdrawal and retreatment

effect of brodalumab compared with placebo.18

AMAGINE-2 (n=1831) and AMAGINE-3 (n=1881) were 12-week induction trials

followed by re-randomization at week 12 and evaluated the efficacy and safety of

induction and maintenance of brodalumab compared with ustekinumab and placebo.19

Results showed that Kyntheum® 210mg offered more patients complete skin clearance

measured by Improvement of the Psoriasis Area Severity Index by 100% (PASI 100) at 12

weeks compared to patients treated with ustekinumab [AMAGINE-2: 44% (n=272) versus

22% (n=65), p<0.001; AMAGINE-3: 37% (n=229) versus 19% (n=58), p<0.001].18,19

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In AMAGINE-1 83% of patients on Kyntheum® 210mg achieved PASI 75 compared to 3% of

patients treated with placebo at 12 weeks [83.3% (n=185) versus 2.7% (n=6), p<0.001] and

76% of patients achieved static Physcian Global Assessment (PGA) success versus 1% of

patients treated with placebo [75.7% (n=168) versus 1.4% (n=3), p<0.001].18

In the AMAGINE trials more than half (53-56%) of patients on continuous Kyntheum®

treatment achieved PASI 100 at week 52.18,19

Patients also reported experiencing improved health-related quality of life after four weeks of

treatment with Kyntheum®. After 12 weeks of treatment, seven of ten patients (72%, n=29/40,

p<0.0001) reported psoriasis no longer impaired their health-related quality of life, (0/1

DLQI) compared with placebo (5%, n=2/37).20

Data from the three large randomised, controlled AMAGINE clinical trials, found

Kyntheum® to be well tolerated, with an acceptable safety profile.

21 The most common

adverse events were arthralgia, headache, fatigue, diarrhoea and oropharyngeal pain.18

The approval of a new pharmaceutical product is based on data from randomized, controlled

clinical trials in patient populations that are based on stringent inclusion and exclusion

criteria. Even when the studies are designed to be representative of the patients described in

the indication, clinical trials often do not cover the diversity of the real-world setting.

To-date there is no evidence, how the management of moderate-to-severe psoriasis patients

with Kyntheum® results in the daily practice and how different patient profiles are managed

with Kyntheum® in the diversity of a real world setting in Germany.

8. Research Question and Objectives

The primary objective of this non-interventional observational study is to assess the short-

and long-term management outcome of patients with moderate-to-severe psoriasis

starting with Kyntheum® under daily practice conditions by assessing the proportion of

patients achieving an absolute PASI 3 at week 12 and – in patients, who continued

Kyntheum® after 12 weeks of treatment - the proportion of patients achieving sPGA success

(defined as clear/ almost clear) at week 52.

Secondary objective is to describe different patient profiles managed with Kyntheum® in

the diversity of a real world setting with regard to demographics, disease severity, previous

treatment regimen and satisfaction with it. LIBERO will deliver real world evidence on

physician´s decision algorithm (e.g. more biologic naive? After failure of anti-TNF-biologics

or ustekinumab? ) in the German healthcare system and effectiveness in the respective groups.

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Patient reported outcomes will create substantial insights regarding the patient´s benefit as

well as satisfaction with the first IL-17-Receptor A Blocker outside of randomized clinical

trials (RCTs).

9. Research Methods

9.1 Study Design

DESIGN

This study is an open-label, multicenter, real-world, 12 and 52 weeks, prospective, non-

controlled (single-arm) observational study.

The study is a ‘non-interventional study’ as defined for drug studies in AMG §4 (23) and in

Directive 2001/20/EC22

with primary data collection and will follow the guidelines for Good

Pharmacoepidemiology Practices.23

This means that:

The assignment of a patient to Kyntheum® is not decided in advance by the study protocol

but falls within current practice.

The prescription of Kyntheum® is clearly separated from the decision to include the

patient in the study.

Kyntheum® is prescribed in accordance with the terms of the marketing authorization.

17

Kyntheum® is obtained through the usual distribution channels.

No additional diagnostic or monitoring procedures shall be applied to the patients.

Epidemiological methods shall be used for the analysis of collected data.

ENDPOINTS

To meet the primary and secondary objectives of this study the following endpoints have been

defined:

Primary endpoints

Proportion of patients achieving an absolute PASI value of 3 at week 12.

Proportion of patients who continued with Kyntheum® after 12 weeks of treatment.

achieving sPGA success (defined as clear = 0 and almost clear = 1) at week 52.

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Secondary endpoints

Short-term effectiveness as measured by the proportion of patients achieving

o PASI 75/ 90/ 100 at week 12

o sPGA-success (clear = 0 or almost clear = 1) at week 12

o sPGA = 0 at week 12

o Time to response (absolute PASI ≤ 3, PASI 75/90, PGA 0/1, PGA 0)

Long-term effectiveness of continued Kyntheum® treatment as measured by the

proportion of patients (LOCF) over time on a quarterly basis and at week 52 measured

by

o mean PASI

o Proportion of patients achieving a PASI ≤ 3

o PASI 75/ 90/ 100

o sPGA = 0/1 und sPGA = 0

Description of the frequency of adverse events as per MEDRA24

preferred term and

systemic organ class (SOC) during induction phase (week 0-12) and maintenance

phase (week 13-52).

Description of patient profiles with regard to

o demographics (e.g. gender, age, health insurance status, socioeconomic status,

disease duration),

o disease severity (sPGA, sPaGA, BSA, PASI),

o previous treatment regimens,

o satisfaction with previous treatment and

o reasons for choosing Kyntheum®

Patient Reported Outcomes (PROs) at week 12 and week 52 as measured by

o Mean change in Patient Global Assessment (PaGA) and proportion of patients

with a PaGA of 0 = clear or 1 = almost clear.

o Mean change in overall Patient Benefit Index (PBI) and subscales on psoriasis

symptoms, social life and emotional well-being and proportion of scales/

subscales with a score of 4 or 5

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o Mean proportion of patients, who were satisfied/ very satisfied with treatment

(TSQM-9)

o Mean change in DLQI Score and proportion of patients, who achieved a DLQI

Score of 0-1 (= no impact on QoL)

9.2 Setting

POPULATION

The study aims to include 500 moderate-to-severe plaque psoriasis patients in about 100 - 150

dermatological sites (private practices, out-patient clinics) all over Germany over a 12- and

52-weeks period.

Each participating site is expected to include between 3 and 6 patients. Patients should be

included in the study only once.

Inclusion requires that Kyntheum® is prescribed in accordance with the approved terms of the

EU marketing authorization and that none of the stated contraindications apply.

Caution should be taken by the treating physician concerning any precautions, warnings and

potential drug interactions stated in the terms of the marketing authorization (SmPC).

SELECTION CRITERIA

Inclusion criteria

Adult patients (≥ 18 years)

Patients must be a candidate for systemic therapy with Kyntheum® according to

SmPC17

and local guidelines.25,26

Decision to start treatment with Kyntheum® in a patient was taken before enrolment in

the study.

Patients must have understood and voluntarily signed the ICF.

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Exclusion criteria

Patients who are enrolled in any interventional clinical trial in parallel.

Patients who are already treated or have been previously treated with Kyntheum®

before enrolment.

Patients, who did not sign the informed consent or incapacitated patients, who are not

able to provide informed consent and/ or are under institutionalized care.

PARTICIPATING SITES

Office based dermatologists or out-patients clinics, who are experienced for the clinical care

and follow-up of psoriasis patients, are invited to participate in the NIS.

DATA COLLECTION

Prospective data collection from consented patients will be performed by the participating

dermatologists during the course of routine patient care at the time of first injection of

Kyntheum® (Baseline) and at the following time intervals: week (W)2, W4, W12, quarterly in

the subsequent months (W24, W36, W48) until W52 (close-out visit). See further details in

Table 1 and in section 9.3. on variables.

As this is an observational study, participation will not change the patient/physician

relationship, nor influence the physician’s drug prescription or therapy choices or other

management of the patient’s disease.

Data collected by physicians

Data will be collected by the physicians from the standard medical records of the participating

out-patient clinics and private practices.

At baseline physicians will complete a questionnaire on the patient´s demographics, physical

examination, vaccination status, psoriasis and medical history, prior and current psoriasis

treatment and concomitant medication and – in women in childbearing age – pregnancy

status/ pregnancy prevention control method, respectively. If available, relevant lab testing

results are collected.

At all visits the clinical psoriasis status is assessed by describing psoriasis type and

characteristics, affected areas, BSA, PASI and sPGA (6-point scale, ranging from 0 = clear

skin to 5 = very severe disease; a score of 3 indicates moderate disease). Date of

administration of recent Kyntheum® injections and any change in psoriasis or concomitant

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medication, concomitant diseases and – in woman in childbearing age – pregnancy status is

recorded. If available, relevant lab testing results are collected.

Adverse Events and Other Experiences which during the study are brought or come to the

attention of a healthcare professional involved in the study will be documented in separate

forms and processed as described in section 11.

Physician´s satisfaction with efficacy and safety of psoriasis treatment regimen is assessed at

Baseline visit, at the end of the induction phase (W12) and at the close-out visit on W52

during the maintenance phase.

Data collected by patients

At each visit patients are also asked to assess their psoriasis via a static Patient Global

Assessment (PaGA) mirroring the sPGA 6-point scale (0 = clear skin to 5 = very severe

disease; a score of 3 indicates moderate disease).

At Baseline, at the end of the induction phase (W12) and during the close-out visit on W52

they will be asked to answer a short series of questionnaires about their quality of life

(DLQI)27

, general and emotional well-being (PBI)28

and their satisfaction with previous and

current therapy (TSQM-9).29,30

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Data collection overview

Table 1 summarizes the proposed time intervals on data collection and variables in the

LIBERO-NIS.

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PATIENT DISCONTINUATION

Patients will be considered as withdrawals (data until moment of withdrawal included in the

analyses) if they indicate they do not want to provide any further follow-up data after having

completed at least the first visit in its entirety.

Patients will be considered as lost to follow-up (included in the analyses) if they prove to be

non-contactable by a participating physician before the end of the follow-up.

Missing questionnaires at one or several time points, or changing of participating physician, is

not a criterion for patient exclusion from the analyses.

Definition of the analyses datasets will be further detailed in the Statistical Analysis Plan.

Subsequent management of missing data will also be described in the Data Management Plan.

9.3 Variables

VARIABLES COLLECTED BY THE PHYSICIAN

Baseline Visit (at inclusion)

Date of the signed informed consent

Inclusion/ exclusion criteria

Pseudonymous patient ID identifier Log (to ensure alignment of patient IDs if a

patient is enrolled in parallel in PsoBEST)

General patient characteristics (demographics, health insurance status, socio-

economic data, concomitant diseases, height, weight, waist and hip circumference)

Vaccination status (date of last vaccinations and last tuberculosis testing incl.

Quantiferon – TB Gold/ ELISPOT test result)

Pregnancy status/ pregnancy prevention method incl. date and result of last

pregnancy test(s) if available (in women of childbearing age only)

Lab-testings (last available results on clinical chemistry, hematology and urine

dipstick, fasting glucose and lipid panel)

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Psoriasis history (disease duration, psoriasis characteristics e.g. plaque-type, nail-

type, PGA/ BSA highest observed activity in the past, previous psoriasis therapies)

Current psoriasis status (BSA, PASI, sPGA (6-point scale)1 and affected area)

Psoriasis management (reasons for choosing Kyntheum®, date of first Kyntheum

®

administration, other psoriasis medication and other concomitant medication)

At all Follow-up visits:

Date of visit and date of previous Kyntheum® injections since last visit

Current psoriasis status (BSA, PASI, sPGA (6-point scale) and location of lesions)

Any change in psoriasis management

Any change in concomitant disease and medication

Any (S)AE, (S)ADR as defined in section 11

Any change in pregnancy status (in woman of childbearing age only)

At W12 and W52 Follow up in addition:

Any change in Lab – testing results (if of clinical significance, AE form to be

completed)

Height and weight, waist and hip circumference

Overall satisfaction with efficacy and tolerability

VARIABLES COLLECTED BY THE PATIENT

At all Visits

Current psoriasis status assessed by patients via sPGA

1 Scores on the static physician’s global assessment (sPGA) range from 0 (clear skin) to 5 (very severe disease);

a score of 3 indicates moderate disease.

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At Baseline, W12 and W52

Satisfaction questionnaire with previous treatment (Baseline) and abbreviated

Treatment Satisfaction Questionnaire for Medication (TSQM-9) at W12 and W52.

Disease and Life Quality Index (DLQI) – Questionnaire

Patient Benefit Index (PBI)

9.4 Data Source

Study data to be collected from the site will be transcribed from the routine medical records of

the participating patients. In addition, participating patients will be asked to provide data

through patient questionnaires, as described in section 9.3.

9.5 Study Size

The study aims to include 500 patients in about 100-150 sites all over Germany. The primary

purpose of this NIS is descriptive and the number of 500 patients is a representative patient

clientele for Germany aspired by epidemiological data. With this sample size it is expected to

see the same or similar outcome compared to randomized clinical trials (RCT) with

Kyntheum®. The results could bridge the RCT data with the real world experience.

With 500 documented cases:

In case of dichotomous variables a 95% confidence interval for the underlying

binomial probabilities will have a maximum length of 8.94 percentage points,

95% confidence intervals for the underlying mean values of quantitative variables will

have a length of 0.176 standard deviations,

Rare events with an incidence down to 0.006 (1/167) will appear at least once in the

sample with 95% probability.

Patient groups formed by anamnestic or other characteristics will usually be large

enough to allow reliable subgroup analyses.

9.6 Data Management

The Study Site will receive from ANFOMED data collection tools (one or two study binders)

containing paper based CRFs and PRO questionnaires for three patients as well as the

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protocol, Kyntheum®

SmPC, the patient identifier log, patient informed consent forms and

(S)AE-/ pregnancy reporting forms.

Text field entries and any data collected on paper should be made in legible German.

The completed questionnaires need to be sent by the study site to ANFOMED after visit 3

(W12), visit 5 (W36), and visit 7 (W52).

The Study Site Responsible must sign off the complete data set for each patient, confirming

that a signed informed consent of the patient is available and the accuracy and completeness

of the collected data. Only signed data sets will be included in the database.

Any Adverse Events, other experiences or pregnancies should be reported according to

section 11 and should be signed off separately by a physician who may or may not be

involved in the study.

Data Management will be carried out according to a Data Management Plan, which must be

written and approved before the design of the study database is finalized. The data

management provider should approve all data formats before the data collection tools are

made available to the sites.

If the written informed consent of a patient is known not to be available in spite of it being

required, data for this patient is not entered into or is deleted from the database.

If a patient is erroneously included in the study more than once only the data relating to the

first inclusion will be kept in the database and be available for analysis. Data from later

inclusions will be transferred to the first dataset when relevant, i.e. if collected within the time

frame of the first follow-up period.

If a patient is included in the study in spite of not being treated according to the approved

terms of the marketing authorization, data is kept in the database and analyzed separately and

as part of the overall analyses as described in the Statistical Analysis Plan.

Coding of medical history, concomitant illness and adverse events is performed per MedDRA

Codes and concomitant medication per WHO-Drug classification

9.7 Data Analysis

Statistical Methods

This study is observational and epidemiological methods will be employed for data analyses.

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Taking into account the non-interventional character of the study, statistical analysis will be

performed in a descriptive and explorative way after 12 and 52 weeks of treatment.

Descriptive analysis will be performed of all collected data except data collected only for the

purpose of data cleaning, i.e. all data listed in section 9.3. Continuous variables will be

described by number of valid (evaluable) cases, mean, standard deviation, minimum, lower

quartile, median, upper quartile and maximum. Categorical variables will be described by

number of cases, frequency, and percentage. 95%-confidence intervals will be computed

where suitable.

The Statistical Analysis Plan describes the statistical analyses as foreseen at the time of

planning the study. Any known deviations from the planned analyses, the reason for such

deviations and all alternative/additional statistical analyses that may be performed as well as

the final statistical analysis must be described in a revised Statistical Analysis Plan (SAP)

before completion of data collection. All later deviations and/or alterations will be

summarised in the Clinical Study Report.

Populations

The following populations will be analyzed:

The ITT (Intention-To-Treat) population being all patients who have given written

informed consent to use of their data for the short and longer term effectiveness.

The safety population being the subset of the ITT- patients who have either confirmed in

patient reported data that they have administered the initially prescribed medication at least

once, or have confirmed to site staff at a later contact that they have administered the initially

prescribed medication at least once.

The short-term effectiveness population being the subset of the safety population who has

data on at least one of the effectiveness outcome variables available until week 12 (LOCF).

The long-term effectiveness population being the subset of the effectiveness population,

who agreed to continue with Kyntheum® after week 12, has received at least once the study

medication in maintenance phase and has at least one of the effectiveness outcome variables

available after week 12.

Safety analysis

All AEs reported in Kyntheum® treated patients reported to LEO Safety Contact Person or

directly to competent authorities according to section 11 will be all captured in the study

database and listed or tabulated in the final report. AEs will be classified by system organ

class (SOC), preferred terms (PT) in accordance with the current version of the Medical

dictionary for Regulatory Activities (MedDRA), and by causality and seriousness.

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9.7.1 Interim Analyses

To assess short term effectiveness during induction phase with Kyntheum®

an interim analysis

is planned after week 12.

To assess long term effectiveness during maintenance phase final analysis is planned after the

week 52 visit is completed in patients, who agreed to continue with Kyntheum® after week

12.

9.8 Quality Control

Monitoring

For quality control monitoring visits can be performed at the participating sites. During a

monitoring visit it will be verified, if the signed informed patient consent is available and if

the documented data are identical with the source data from the patient charts (source data

verification).

Safety data reconciliation

A monthly reconciliation of the events and experiences received from the sites will be

performed between LEO GmbH and GPV according to standard LEO processes. Before

closure of the LIBERO database for interim- or final analysis after week 12 and week 52,

LEO DE and Anfomed will perform reconciliation of reported events between the LEO Safety

Database and the LIBERO database. Reconciliation is further specified in a separate Safety

Plan.

9.9 Limitations of Research Methods

Generally, two types of bias are distinguished in epidemiology and should be considered:

selection and information bias.

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Selection bias

Selection bias is a entails the selective recruitment into the study of subjects that are not

representative of the exposure or outcome pattern in the source population. The selection bias

in this study may result from selectively prescribing of a medication to more severe patients.

As a result of a higher background risk, the reported event rate may be higher and give the

appearance of an elevated risk related to the use of the primary medication. The collection of

the Baseline information will help to identify the presence of elevated background risk so that

event rates can be compared through sub-group analysis (those with or without prior events)

to determine if the elevated risk is likely to be related to background risk or use of

Kyntheum®

Information bias

Information bias arises when incorrect information about either exposure or outcome or any

covariates is collected in the study. This could occur in this study if physicians do not report

certain types of events of potential interest because they feel they are not related to the safety

of the medication. In order to address this, a data quality audit will be conducted with

physicians by the CRO to determine how well their medical records data matches the

information provided in the NIS.

9.10 Other Aspects

Audits and Inspections

The Quality Assurance (QA) unit at LEO may audit the study to ensure that study procedures

comply with the protocol and LEO standard operating procedures, and that collected data is

correct and complete. Representatives from IEC or Competent Authority may in rare cases

wish to inspect the study on site. Upon receiving notification of such inspection, the Study

Site Responsible must immediately contact LEO and must make the records available as

requested.

Archiving of Study Data and Documentation

During the course of the study the Site Responsible must as a minimum file the essential

documents (Section 3), the protocol (all used versions), the list of participating patients, the

written informed consents, the CRFs and the progress reports in the Study Site File. After

final database lock the Site Responsible must as a minimum store the list of participating

patients and the signed Informed Consent Forms on site for 10 years.

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The Site Responsible should store additional study documentation for a longer period of time

as required by any local regulations and/or hospital/clinic requirement.

10 Protection of human subjects

Ethical conduct of the study

This study is a non-interventional study where the existence of the study has no impact on the

patient. The treatment of the participating patients will not be any different from patients not

participating in the study, except for collection of informed consent to use of the patient’s data

and collection of the following non-standard Patient Reported Outcomes: PaGA, DLQI, PBI,

TSQM-9

This study will be conducted in accordance with the current version of the

Declaration of Helsinki (Fortalza, 2013)31

Good Pharmacoepidemiology Practices23

VFA Empfehlungen zur Verbesserung der Qualität und Transparenz von nicht-

interventionellen Studien (NIS)32

Gemeinsame Empfehlung des BfArM und des PEI zur Planung, Durchführung und

Auswertung von Anwendungsbeobachtungen33

AKG-Kodex 34

Fundamental principles on the lawful processing of personal data provided by the EU

directive on data protection (95/46/EC) must be respected.35

LEO Pharma A/S, Industriparken 55, Ballerup will be the data holder.

Information and Patient Consent/ Assent

The Site Study Responsible must give the patient oral and written information about the study

in a form that the patient can understand, and obtain the patient’s assent written consent

before collection by LEO of identifiable patient information (hereinafter referred to as

personal data).

Before consenting, the patient must be given sufficient time to consider and to pose questions.

Since the study is observational the consent only concerns the data collection per se and is not

consent to any interventional procedure or treatment.

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The patient must agree that his/her pseudononymized, key-coded data will be processed,

stored and may be transferred to third parties, e.g. other companies or authorities, that may be

located in other countries with potentially different regulations for data. Written informed

consent to use of collected data must always be obtained before collection of any personal,

sensitive data.

Data erroneously collected from patients for which written consent is not available, will not

be included in or will be deleted from the database, as feasible.

The patient has the right to withdraw his/her consent at any time without prejudice. In the

Informed Consent Form it is stated, that if consent is withdrawn, any data collected before

withdrawal of consent will be kept. The original, signed Informed Consent Forms must be

kept on the Site.

For details, see the Patient Information Sheet and Informed Consent Form.

Submissions

ANFOMED will ensure that the protocol and any amendments and the Patient Information

Sheet/Informed Consent Form and Questionnaires are submitted to the relevant Independent

Ethics Committees (IECs)/Institutional Review Boards (IRBs) and/or competent authorities

and/or other national or regional authorities according to German requirements. According to

applicable regulations, LEO, the appointed CRO or the Site Study Responsible will submit

required documents to the IEC / IRB, such as:

periodic updates on the progress of the study

notification of the end-of-study

a summary of the study results

LEO will keep a copy of all documents submitted and an updated list of all submission and

approval dates of all documents submitted to the IEC / IRB and/or authorities and will

provide the Site Responsible with a copy of this list. Copies of the documents will be

distributed upon request.

Remuneration of the participating sites is calculated based on the German “Gebührenordnung

für Ärzte (GOÄ)”. The study will be registered in a public accessable database.

According to AMG §67(6) the study will be notified to the “Bundesoberbehörde”, the

“kassenärztliche Bundesvereinigung” and the “Spitzenverbände der Krankenkassen”.

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Data Protection

The patient personal data and treating physician personal data, which may be included in the

NIS database held by ANFOMED during study, but owned by LEO, shall be treated at all

times in compliance with all local applicable privacy laws and regulations

Patient´s personal information will remain pseudonymous and key-coded at all times.

The key-coded data will be stored in a secure database at ANFOMED/ LEO. They will not be

made available to the public. “Key-coded” means that at the time of patient enrolment in the

registry, he/ she will be assigned a code that will be used instead of his/her name to identify

him/her in any NIS-related documentation. The patient´s personal data are therefore

considered as “pseudonymous” as they will be identified by the assigned code rather than the

patient´s name.

A patient identification list will be kept by the Principal Investigator on site during the course

of the NIS and up to 10 years thereafter. The list will be kept confidential and will be

accessible only to the medical personnel at Principal Investigator’s office, monitors who will

visit the site to verify the data that are entered into the registry database, regulatory and health

authorities and ANFOMED or LEO auditors.

Regulatory and health authorities and other study personnel representing ANFOMED/ LEO

or its agents, may be granted direct access to the patient´s medical records to verify the

registry procedures or the accuracy of the data. The information will be treated strictly

confidentially and reviewed with the permission of the Principal Investigator.

LEO may disclose the key-coded data to its affiliated companies and subsidiaries, as well as

to its service providers and contractors, including, but not limited to ANFOMED and its

agents, and regulatory and health authorities. The key-coded data will be used by these parties

for performing the NIS, including review and scientific analysis.

The collected data will be combined with data from other participants in the Study and the

results may be used for scientific reasons including but not limited to research, publications or

presented at congresses. When the study results are published or reported, patient´s identity

will not be disclosed.

When archiving or processing personal data pertaining to the treating physician and/or to the

patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to

this data by any unauthorized (third) party.

The use of key-coded or indirect identifiable data is essential for the following reasons:

Patients are followed up for 52 weeks, with collection of longitudinal information.

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Quality control of the data will be done with the treating physicians in order to guarantee

the data quality, with possible correction requests for missing or inconsistent data as

regards key data.

The patient will be informed of his/her right of access, objection and correction of the data

recorded during this study, and that this right may be exercised at any time through his/her

physician.

11 Management and Reporting of Adverse Events and Other Experiences

DEFINITIONS

Adverse Event (AE)

An adverse event (AE) is any untoward medical occurrence in a patient administered a

medicinal product and which does not necessarily have to have a causal relationship with this

treatment. An AE can therefore be any unfavourable and unintended sign (e.g. an abnormal

laboratory finding), symptom, or disease temporally associated with the use of a medicinal

product, whether or not considered related to the medicinal product.

Adverse Drug Reaction (ADR)

An Adverse Drug Reaction (ADR) is a response to a medicinal product which is noxious and

unintended. Response in this context means that a causal relationship between a medicinal

product and an adverse event is at least a reasonable possibility. ADRs may arise from use of

the product within or outside the terms of the marketing authorisation or from occupational

exposure. Conditions of use outside the marketing authorisation include off-label use,

overdose, misuse, abuse and medication errors.

Other Experiences (OE)

Other Experiences (OE) are considered ‘non events’ which describe the circumstances around

the use of a drug which potentially could cause drug related problems or which could

potentially give positive knowledge of a drug.

These may or may not be associated with adverse events.

These cases include but are not limited to:

unintended beneficial effects,

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drug exposure in utero,

drug exposure before and/or during pregnancy,

drug exposure via breast milk,

paternal drug exposure before and/or during pregnancy,

occupational exposure,

drug overdose or abuse,

drug misuse,

medication error (including potential and intercepted),

off label use/unapproved use,

lack of efficacy,

drug and food interaction,

any suspicion of counterfeit product

any suspected transmission of an infectious agent by a medicinal product

CLASSIFICATION

Seriousness

A serious ADR or Adverse Event is any ADR or Adverse Event which results in death, is life

threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or is a congenital anomaly or birth

defect.

Life-threatening in this context refers to a reaction in which the patient was at risk of death a

the time of the event; it does not refer to an event which hypothetically might have caused

death if it were more severe.

Medical and scientific judgement should be exercised in deciding whether other situations

should be considered serious, such as important medical events that might not be immediately

life-threatening or result in death or hospitalisation but might jeopardise the patient or might

require intervention to prevent one of the other outcomes listed above.

Any suspected transmission of an infectious agent via a medicinal product is considered a

serious ADR.

Severity

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Severity is a clinical observation and describes the intensity of the event.

Mild: Transient symptoms, no interference with the patient’s daily activities

Moderate: Marked symptoms, moderate interference with the patient’s daily activities

Severe: Considerable interference with the patient’s daily activities.

Causality

Related: A reasonable temporal relationship between the medicinal product

administration and the event where there is no other obvious explanation for the

occurrence of the event

Not related: There is evidence for (an) alternative explanation(s) for the event (e.g. the

event is explained by one or more of the following: a) the patient’s medical condition, b) a

concomitant medication for which the event is labelled, or c) the event occurred prior to

the introduction of the medicinal product)

RESPONSIBILITIES

Physician’s responsibility for reporting of Adverse Drug Reactions, Adverse Events and

Other Experiences

Physicians and other healthcare professionals involved in the study should report to LEO any

SAE, AE, OE, ADR or pregnancy in patients who are or were treated with Kyntheum® during

the study within 24 hours after becoming aware of it.

The provided LEO Adverse Event Form – Marketed Products or in case of pregnancies – the

Pregnancy Form (Part 1) should be used for the reports and completed carefully, including the

section on causality. A copy of the completed form must be sent within 24 hours to the LEO

Safety Contact Person by email or fax (contact details below) .

Email: [email protected]

Fax: + 49 6102 201 125

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LEO will notify the competent authorities of all serious and non-serious ADRs related to LEO

product(s) and pregnancies according to the currently applicable pharmacovigilance

guidelines for non-interventional studies.

If the patient is enrolled in parallel in the PsoBest Registry both study IDs (PsoBest ID and

LIBERO ID) must be included in the forms sent to LEO and to PsoBest. In order to reduce

duplicate reporting and as LEO is reporting the cases to the competent authorities the

physician does not need to report to the Paul Ehrlich Institute (PEI) if the patient participates

in LIBERO. If - for one reason or another – the physician has also reported the event to PEI,

this should be clearly marked on the form (please tick in tick box on the form) to facilitate

identification of duplicate reports.

The original “LEO Adverse Events Form - Marketed Products” and any follow-up

documentation submitted by email or fax to [email protected] remain in the

study documentation folder and will be sent together with the other forms to ANFOMED after

visit 3 (week 12), visit 5 (week 36), and visit 7 (week 52).

In addition, the physician should notify local competent authorities (PEI for biological

medicinal products and BfArM for the rest) or the concerning manufacturer/ marketing

authorization holder, but not both, of AEs at least possibly related to non-LEO products

including a reference to the Study ID or study title.

Important additional information obtained later, e.g. a report of diagnostic procedures or a

hospital discharge summary should be provided in pseudonymous, key-coded form to LEO as

follow-up report by the same route as the initial AE/OE report.

The physician should record a precise medical term for an AEs preferably a diagnosis. Please

observe that death or surgery are considered as outcome, not as an event, so it is the event

leading to death or surgery which should be recorded.

Only one AE or OE should be recorded per form. If no diagnosis is available, the physician

should record each sign and symptom in separate form. For each AE or OE the causality,

severity and outcome must be included.

LEO may request further information from the physician in order to fully assess the safety

reports.

LEO responsibilities for reporting of safety-related data

mailto:[email protected]

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LEO will notify the competent authorities of all serious and non-serious ADRs related to LEO

product(s) and pregnancies according to currently applicable pharmacovigilance guidelines

for non-interventional studies.

All safety data collected in the study database or reported to LEO pharmacovigilance will be

summarized in the Non-Interventional Study Report.

12 Plans for Disseminating and Communicating Study Results

LEO will prepare a Non-Interventional Study Report based on the results obtained. The Final

Study Report shall be reviewed and approved by the Coordinating Investigator and be

available within one year from collection of the last data point. In case the Coordinating

Investigator changes during study conduct, all investigators will be informed and asked for

their consent to delegate this responsibility to the new Coordinating Investigator. The sites

that have enrolled patients in the study will be informed about the results when the report is

finalized. Summary results will be posted on a publicly accessible database.

LEO aims to have the results of this study published and acknowledges the right of the

participating sites to publish results from this study.

The principles guiding publications from this NIS dictate that usable scientifically or

medically significant information, hypotheses or analysis are widely disseminated, that good

publication practice is adhered to (and in particular the GPP2 guidelines (http://www.gpp-

guidelines.org), that redundant publication is avoided, that publications are of high scientific

and linguistic standard, that an ethical approach is applied at all times, that the reputations of

the NIS, the (financial) Sponsors and their stakeholders and the participating investigators

should be up held as well as all relevant regulatory requirements.

A primary publication based on all study data and following the STROBE guidelines36

in an

international peer reviewed journal is foreseen with the Coordinating Investigator as the first

or last author. Any manuscripts for secondary publications or abstracts may not be submitted

until after the primary publication manuscript has been accepted for publication. Any

manuscript or abstract must be sent to LEO for commenting at least 30 calendar days prior to

submission.

LEO has the right to use the data and results for regulatory and reimbursement purposes, and

for internal presentation within the company and to partners. In addition, LEO may use the

data for analysis of pooled data from various studies.

http://www.gpp-guidelines.org)/

http://www.gpp-guidelines.org)/

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Annex 1. List of Stand Alone Documents

Date: 8 NOV 2017

Number Document

Reference

number

Date Title

1 V2 8 NOV 2017 Signature page of key study

personell

2 V2 8 NOV 2017 Contact and responsibility details

for all parties contributing to the

study

3 V1 Data Management Plan

4 V1 Statistical Analysis Plan

5 V1 07 NOV 2017 Safety Plan

6 V1 06 NOV 2017 LEO Adverse Event Form –

Marketed Products and Pregnancy

Forms

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Annex 2: Signature Page

The following persons approve the Study Protocol:

“Prospective, observational, non-interventionaL, multicenter real-world evIdence (RWE)

study of Brodalumab 210mg (Kyntheum®) to manage patients with modERate-to-severe

plaque psOriasis in daily practice (LIBERO)”

Version 2.0 – 8 NOV 2017

Place, Date

Place, Date

Place, Date

Place, Date

Place, Date

Place, Date

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Anfomed GmbH

Röttenbacher Str. 17

91096 Möhrendorf

Study Manager

LEO Pharma GmbH



Protocol author

Biostatistics

Anfomed GmbH

Röttenbacher Str. 17

91096 Möhrendorf

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Pharmacovigilance

LEO Pharma GmbH



Ethic committee

Freiburger Ethik-Kommission

GmbH international

Mozartstraße 21

D-79104 Freiburg

(Germany)

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