Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 33
Healthy volunteers: no

Brief summary:
To investigate the safety and tolerability of repeated subcutaneous (s.c.) doses of MOR106 administered concomitantly with topical corticosteroids (TCS) in participants with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Detailed description:

Arms:
arm 1: Participants will receive MOR106 matching placebo via s.c. injection every other week on Day 1, 15, 29 and 43 given concomitantly with a medium potency TCS once daily until Day 57. arm 2: Participants will receive MOR106 320 milligrams (mg) via s.c. injection every other week on Day 15, 29 and 43 given concomitantly with a medium potency topical TCS once daily until Day 57. A loading dose of MOR106 2 x 320 mg via s.c. injection will be administered on Day 1.

Interventions: intervention 1: MOR106 intervention 2: Placebo
Intervention descriptions: intervention 1: MOR106 liquid formulation for s.c. injection administered concomitantly with TCS (medium potency). intervention 2: Placebo liquid formulation for s.c. injection administered concomitantly with TCS (medium potency).

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos NV and 
may not be used, disclosed, reproduced or otherwise disseminated within your organization or communicated to 
any third parties without the express written authorization of Galapagos NV. 
 
MOR106 
CLINICAL STUDY PROTOCOL 
Project 
number: 
MOR106 
CSP Version:  
4.0 
Study Number: MOR106-CL-204 
Date: 
25-Jun-2019 
Study Title 
A randomized, double-blind, placebo-controlled, multicenter 
Phase 2 study to evaluate the safety and tolerability of 
subcutaneous MOR106 administered concomitantly with topical 
corticosteroids for eight weeks, in adult subjects with moderate 
to severe atopic dermatitis. 
Status 
Final 
Development Phase: 
2 
 
 
EudraCT No: 
Not applicable 
CT.gov No: 
NCT03864627 
IND No: 
 
 
 
Sponsor: 
Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, 
Belgium 
 
Study 
Physician: 
 
 
 
General 
Protocol / 
Applicable 
Country(ies) 
 
General Protocol 
 
 
 
 


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EMERGENCY CONTACT INFORMATION 
In case of a serious adverse event (SAE) or a special situation (see Section 9.1.6) during 
the clinical study, or in case of pregnancy within 24 weeks after after last dose of study 
medication, the investigator must report this immediately, and under no circumstances later 
than 24 hours following the knowledge of the SAE, special situation, or pregnancy, as 
follows: 
<
 SAE Fax #: 
> 
<or> 
<E-mail: 
 
 
In case of medical questions during the course of the study, the investigator must contact 
the contract research organization (CRO) Medical Monitor or, if unavailable, his/her back 
up. 
 
Sponsor Back-up contact: 
  
CRO Medical Monitor: 
 
Mobile Phone: 
 
Office Phone: 
 
Email address: 
 


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Table of Contents 
EMERGENCY CONTACT INFORMATION .......................................................... 2 
CLINICAL STUDY PROTOCOL (CSP) HISTORY ................................................ 7 
LIST OF TABLES ................................................................................................. 8 
LIST OF FIGURES ............................................................................................... 8 
LIST OF APPENDICES ........................................................................................ 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................. 9 
1. 
SUMMARY .................................................................................................. 12 
2. 
INTRODUCTION ......................................................................................... 15 
2.1. 
Background - Nonclinical Studies ..................................................... 16 
2.1.1. 
Nonclinical Pharmacology ................................................. 16 
2.1.1.1. 
Primary and Secondary Pharmacology ............ 16 
2.1.1.2. 
Safety Pharmacology ....................................... 17 
2.1.2. 
Nonclinical Pharmacokinetics............................................ 17 
2.1.3. 
Toxicology......................................................................... 17 
2.2. 
Background - Clinical Studies .......................................................... 18 
2.2.1. 
Clinical Pharmacokinetics and Immunogenicity ................. 18 
2.2.2. 
Clinical Safety ................................................................... 19 
2.2.3. 
Clinical Efficacy ................................................................. 19 
3. 
CLINICAL STUDY OBJECTIVES ................................................................ 19 
3.1. 
Primary Objective ............................................................................. 19 
3.2. 
Secondary Objectives ...................................................................... 19 
3.3. 
Other Objectives .............................................................................. 19 
4. 
INVESTIGATIONAL PLAN .......................................................................... 20 
4.1. 
Clinical Study Design ....................................................................... 20 
4.2. 
Clinical Study Rationale ................................................................... 21 
4.2.1. 
Dosing Rationale............................................................... 21 
4.2.2. 
Clinical Study Design Rationale ........................................ 23 
4.3. 
Endpoints ......................................................................................... 23 
4.3.1. 
Primary Endpoint .............................................................. 23 
4.3.2. 
Secondary Endpoints ........................................................ 23 
4.3.3. 
Other Endpoints ................................................................ 23 
4.4. 
Potential Risks and Benefits ............................................................ 24 
4.5. 
Clinical Study Population ................................................................. 25 
4.5.1. 
Inclusion Criteria ............................................................... 25 
4.5.2. 
Exclusion Criteria .............................................................. 26 
4.5.3. 
Prohibition and Restrictions .............................................. 28 
4.5.3.1. 
Precautions for Sexual Intercourse .................. 28 
4.5.3.2. 
Prior and Concomitant Medications ................. 30 
4.5.3.3. 
Prohibited Concomitant Medications and 
Procedures ...................................................... 31 


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4.5.3.4. 
Rescreening .................................................... 32 
4.5.3.5. 
Food and Beverage Restrictions ...................... 32 
4.5.4. 
Treatment Discontinuation (Temporarily and Permanently), 
Subject Withdrawal and Study Termination ....................... 32 
4.6. 
Measures to Minimize Bias .............................................................. 34 
4.6.1. 
Randomization .................................................................. 34 
4.6.2. 
Blinding and Unblinding .................................................... 34 
4.6.3. 
Independent Safety Review Committee ............................ 35 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................... 35 
5.1. 
Identity of the Investigational Medicinal Products ............................. 35 
5.2. 
Dosage and Administration .............................................................. 36 
5.3. 
Packaging, Labeling and Distribution ............................................... 36 
5.4. 
Storage ............................................................................................ 37 
5.5. 
Treatment Compliance and Drug Accountability .............................. 37 
6. 
CLINICAL STUDY ASSESSMENTS ............................................................ 37 
6.1. 
Timing of Assessments .................................................................... 37 
6.2. 
Unscheduled Visits .......................................................................... 38 
6.3. 
Initial Subject and Disease Characteristics ...................................... 38 
6.4. 
Efficacy Assessments ...................................................................... 39 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.5. 
Safety Assessments ........................................................................ 41 
6.5.1. 
Adverse Events ................................................................. 41 
6.5.2. 
Clinical Laboratory Evaluations ......................................... 41 
6.5.3. 
Physical Examination ........................................................ 42 
6.5.4. 
Vital Signs ......................................................................... 43 
6.5.5. 
12-lead Electrocardiogram ................................................ 43 
6.5.6. 
Other Safety Assessments ................................................ 44 
6.5.6.1. 
Injection Site Reactions (ISRs) ........................ 44 
6.5.6.2. 
Management of ISRs ....................................... 45 
6.6. 
Pharmacokinetic and Immunogenicity Assessments ........................ 45 
6.7. 
Pharmacodynamic Assessments ..................................................... 45 
6.8. 
Other Assessments .......................................................................... 45 
 
 
6.8.2. 
Skin Swabs ....................................................................... 46 
 
 
 
6.9. 
Sample Management ....................................................................... 46 
6.9.1. 
Blood and Urine Samples for Routine Safety Tests, 
Serology, FSH and Pregnancy Tests ................................ 46 
6.9.2. 
Blood Samples for PK, ADA, and PD ................................ 46 
 
 
6.10. 
Schedule of Activities ....................................................................... 48 


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7. 
STATISTICAL METHODS ........................................................................... 51 
7.1. 
Determination of Sample Size .......................................................... 51 
7.2. 
Population for Analyses ................................................................... 51 
7.2.1. 
All Screened Subjects ....................................................... 51 
7.2.2. 
All Randomized Subjects .................................................. 51 
7.2.3. 
Full Analysis Set ............................................................... 51 
7.2.4. 
Per-Protocol Set ............................................................... 52 
7.2.5. 
Safety and Immunogenicity Analysis Set .......................... 52 
7.2.6. 
Pharmacokinetic Analysis Set ........................................... 52 
7.2.7. 
Pharmacodynamic Analysis Set ........................................ 52 
7.3. 
Statistical Analyses .......................................................................... 52 
7.3.1. 
General Statistical Considerations .................................... 52 
7.3.2. 
Interim Analysis ................................................................ 52 
7.3.3. 
Primary analysis................................................................ 52 
7.3.4. 
Final analysis .................................................................... 53 
7.3.5. 
Analyses of Demographics and Baseline Characteristics .. 53 
7.3.6. 
Analyses of Efficacy Parameters ....................................... 53 
7.3.7. 
Analysis of Immunogenicity Data ...................................... 54 
7.3.8. 
Analyses of Safety Data .................................................... 54 
7.3.8.1. 
Extent of Exposure .......................................... 54 
7.3.8.2. 
Adverse Events ............................................... 54 
7.3.8.3. 
Clinical Laboratory Evaluations ........................ 54 
7.3.8.4. 
Physical Examinations ..................................... 55 
7.3.8.5. 
Vital Signs ....................................................... 55 
7.3.8.6. 
12-Lead Electrocardiogram .............................. 55 
7.3.8.7. 
Other Safety Assessments .............................. 55 
7.3.9. 
Pharmacokinetic Analyses ................................................ 55 
7.3.10. 
Pharmacodynamic Analyses ............................................. 55 
7.3.11. 
Analysis of Other Assessments ......................................... 55 
7.3.12. 
Additional Statistical Considerations ................................. 56 
8. 
DATA MONITORING ................................................................................... 56 
8.1. 
Independent Medical Review ........................................................... 56 
9. 
SAFETY REPORTING ................................................................................ 56 
9.1. 
Definitions of Adverse Events, Serious Adverse Events, and Special 
Situations ......................................................................................... 56 
9.1.1. 
Adverse Events ................................................................. 56 
9.1.2. 
Serious Adverse Events .................................................... 56 
9.1.3. 
Unlisted (Unexpected) Adverse Event/Reference Safety 
Information ........................................................................ 57 
9.1.4. 
Adverse Events of Special Interest ................................... 57 
9.1.4.1. 
Injection Site Reactions (ISRs) ........................ 57 
9.1.4.2. 
Skin Related Adverse Events .......................... 57 
9.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse 
Events ............................................................................... 57 
9.1.6. 
Special Situations ............................................................. 58 
9.2. 
Assessment of Adverse Events and Serious Adverse Events .......... 58 
9.2.1. 
Assessment of Causality ................................................... 58 
9.2.2. 
Assessment of Severity..................................................... 59 
9.2.3. 
Outcome ........................................................................... 60 


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9.3. 
Investigator Requirements and Instructions for Reporting Adverse 
Events / Serious Adverse Events /Pregnancies, and Other Special 
Situations to the Sponsor ................................................................. 60 
9.3.1. 
Adverse Events ................................................................. 60 
9.3.1.1. 
Adverse Events of Special Interest (AESI) ....... 61 
9.3.2. 
Serious Adverse Events .................................................... 61 
9.3.3. 
Pregnancy......................................................................... 62 
9.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events .............................................. 62 
9.4. 
Sponsor Reporting Requirements .................................................... 62 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ....................... 63 
10.1. 
Sponsor’s Responsibilities ............................................................... 63 
10.1.1. 
Regulatory Approval / Notification ..................................... 63 
10.1.2. 
Clinical Study Closure Considerations .............................. 63 
10.1.3. 
Indemnification .................................................................. 64 
10.1.4. 
Insurance .......................................................................... 64 
10.1.5. 
Reporting .......................................................................... 64 
10.1.6. 
Publication ........................................................................ 64 
10.2. 
Investigator’s Responsibilities .......................................................... 65 
10.2.1. 
Financial Disclosure .......................................................... 65 
10.2.2. 
Source Data and Data Capture ......................................... 65 
10.2.3. 
Archiving ........................................................................... 65 
10.2.4. 
Participation Cards ............................................................ 66 
10.3. 
Confidentiality .................................................................................. 66 
10.4. 
Ethical Considerations ..................................................................... 66 
10.4.1. 
Independent Ethics Committee (IEC) / Institutional Review 
Board (IRB) ....................................................................... 66 
10.4.2. 
Informed Consent ............................................................. 67 
10.5. 
Data Quality Control / Assurance ..................................................... 68 
10.5.1. 
Monitoring ......................................................................... 68 
10.5.2. 
Audit and Inspection ......................................................... 68 
11. REFERENCES ............................................................................................ 69 
12. APPENDICES ............................................................................................. 71 
SIGNATURE PAGE – SPONSOR ...................................................................... 72 
SIGNATURE PAGE – INVESTIGATOR ............................................................. 73 
 
 
 


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CLINICAL STUDY PROTOCOL (CSP) HISTORY 
CSP / Amendment # 
Date 
General / Country Specific 
CSP Version 1.0 
15 August 2018 
General, initial protocol. Not 
submitted. 
CSP Version 2.0 
22 August 2018 
General, minor updates of the 
protocol. Not submitted. 
CSP Version 3.0 
15 October 2018 
General, update of protocol before 
submission. 
CSP Version 4.0 (amendment 1) 
25 June 2019 
General, update of exclusion criteria 
 
SUMMARY OF CHANGES 
CSP version 4.0, amendment 1 (25-Jun-2019) 
The overall reason for the amendment:  
The protocol was updated to refine the wording regarding the use of biologics for AD 
(exclusion criterion 4) and related to wording of history of Hepatitis A and B (exclusion 
criterion 5). 
The changes made to the clinical study protocol MOR106-CL-204 Version 3.0, dated 
15-Oct-2018, are listed below, reflecting a brief rationale of each change and the 
applicable sections. 
Rationale: The wording regarding the prior use of biologics for AD has been updated to 
exclude only prior use of dupilumab. There is only one biologic currently approved for 
AD which is dupilumab. To avoid incurring any potential bias by including patients who 
have failed dupilumab treatment and are potentially treatment resistant, dupilumab will 
continue to be excluded. All other prior biologics will be considered as for  prior non AD 
biologics, with a washout period of 5 half lives or 12 weeks. 
Applicable Section: 4.5.2. Exclusion Criterion 4 (i and v) 
Rationale: The wording has been updated in line with sponsors updated template text to 
allow subjects with a history of Hepatitis A and Hepatitis B to be included. 
Applicable Section: 4.5.2. Exclusion Criterion 5 
 
 


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LIST OF TABLES 
Table 1: 
Grading of AE Severity ...................................................................... 60 
 
LIST OF FIGURES 
Figure 1: Schematic overview of the study design. ............................................... 21 
 
LIST OF APPENDICES 
Appendix 1: Normal Ranges ................................................................................. 71 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations 
  
 
 
AD 
atopic dermatitis 
ADA 
anti-drug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
API 
alanine aminotransferase 
active pharmaceutical ingredient 
AUCτ 
area under the serum concentration-time curve for the 
dosing interval 
AST 
aspartate aminotransferase 
BSA 
body surface area 
CD1 
cluster of differentiation 1 
Cmax 
maximum observed serum concentration 
CSP 
clinical study protocol 
CSR 
clinical study report 
CRO 
contract research organization 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
  
  
DNA 
deoxyribonucleic acid 
EASI  
Eczema Area and Severity Index  
EC50 
50% effective concentration 
ECG 
electrocardiogram 
ED 
early discontinuation 
ETD 
early treatment discontinuation 
EU 
European Union 
FIH 
first-in-human 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 


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GGT 
gamma glutamyl transferase 
HBc 
hepatitis B core 
HBs 
hepatitis B surface 
HOME 
Harmonising Outcome Measures in Eczema 
HIV 
human immunodeficiency virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethical Committee 
IGA 
Investigators’ Global Assessment 
IgE 
immunoglobulin E 
IgG1 
immunoglobulin G1 
IL-17C 
interleukin 17C 
IL-17RE 
interleukin 17 receptor E 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
iSRC 
independent Safety Review Committee 
IWRS 
interactive web response system 
LD 
loading dose 
LFT 
 
 
liver function test 
MAD  
 
multiple ascending dose 
NOAEL 
no observed adverse effect level 
 
 
NYHA 
New York Heart Association 
PD 
pharmacodynamics 
PK 
pharmacokinetic 
  
 
 
PUVA 
psoralen and ultraviolet A 
Q2W 
once every 2 weeks 
Q4W 
once every 4 weeks 


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QTcB 
QT interval corrected for the heart rate using Bazett’s 
formula 
QTcF 
QT interval corrected for the heart rate using 
Fridericia’s formula 
RNA 
ribonucleic acid 
SAD  
 
single ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
  
  
SOC 
System Organ Class 
 
 
SUSAR 
suspected unexpected serious adverse reaction 
TARC  
thymus and activation regulated chemokine  
TBL 
total bilirubin level 
TCS 
topical corticosteroid 
TCI 
topical calcineurin inhibitor 
TEAE 
treatment-emergent adverse event 
Th2 
type 2 T helper cell 
TNF-α  
tumor necrosis factor-alpha  
ULN 
upper limit of normal 
UVB 
ultraviolet B 
VAS  
 
visual analogue scale 
WOCBP 
women of childbearing potential 
 
Definition of Terms 
BMI 
weight (kg) / (height [m])2 
QTcB 
QTcB = QT / √RR 
QTcF 
QTcF = QT x (1000/RR)1/3 
 
 


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1. 
SUMMARY 
Objectives: 
Primary Objective 
 
To investigate the safety and tolerability of repeated subcutaneous (s.c.) doses of 
MOR106 administered concomitantly with topical corticosteroids (TCS) in 
subjects with moderate to severe atopic dermatitis (AD) who are candidates for 
systemic therapy. 
 
Secondary Objectives 
 
To evaluate the pharmacokinetics (PK) of repeated s.c. doses of MOR106 
administered concomitantly with TCS. 
 
To monitor the occurrence of anti-drug antibodies (ADA) as a measure of 
immunogenicity after repeated s.c. doses of MOR106 administered concomitantly 
with TCS. 
 
Other Objectives 
 
 
 
 
 
 
 
 
 
 
Design: 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study of 
repeated s.c. doses of 320 mg MOR106 or placebo, administered concomitantly with 
TCS. On Day 1 a loading dose (LD) will be administered (i.e. 2 x 320 mg MOR106, or 
placebo). 
Adult subjects with moderate to severe AD who are candidates for systemic therapy 
will be randomized 2:1 to receive MOR106 or placebo every other week via s.c. 
injections (on Days 1, 15, 29, and 43). The 8-week treatment period, finishing on Day 
57, is followed by a 16-week follow-up period, finishing on Day 169. A total of 60 
subjects (n=40 on MOR106, and n=20 on placebo) will be enrolled in this study. 


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Rationale: 
This study is being conducted to obtain safety and preliminary efficacy information on 
the s.c. administration of MOR106 with concomitant TCS in subjects with moderate to 
severe AD who are candidates for systemic therapy in comparison to placebo with 
TCS. 
 
 
TCS have been the primary treatment option for AD patients for many years and are 
commonly used as the first line of pharmacologic treatment in patients whose 
symptoms cannot be controlled with general measures such as allergen and irritant 
avoidance, skin hydration, and skin moisturization. TCS are also used to treat AD 
exacerbations. Therefore, many patients may use MOR106 in combination with TCS. 
For this reason, it is judicious to assess if MOR106 can be safely co-administered with 
TCS and to assess the added benefit. In order to standardize treatment conditions, the 
concomitant application of TCS and MOR106 or placebo starts on Day 1 for all 
subjects after a washout period for TCS of at least 7 days prior to the baseline visit (i.e. 
Day 1). 
Endpoints: 
Primary Endpoint 
 
The incidence and severity of treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), and adverse events of special interest (AESIs) through 
Day 169/ early discontinuation (ED) visit. 
 
Secondary Endpoints 
 
MOR106 serum concentrations after repeated s.c. administrations from baseline 
through Day 169/ED visit. 
 
Occurrence of ADA from baseline through Day 169/ED visit. 
 
Other Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
INTRODUCTION 
Atopic Dermatitis (AD) is a chronic pruritic inflammatory skin disease that occurs most 
frequently in children, but also affects adults (Garmhausen, Hagemann, & Bieber, 2013). 
The main features of AD are the impairment of the skin barrier and dysfunction of the 
immune system accompanied with dry skin and severe pruritus that is associated with 
cutaneous hyperactivity to various environmental stimuli. 
In AD the main goals of treatment are improving the appearance of the skin and relieving 
symptoms. Topical corticosteroids (TCS) are the most frequently prescribed class of drugs 
but long-term therapy is hampered by risks of skin atrophy, dyspigmentation, acneiform 
eruptions and risks associated with systemic absorption (growth retardation, hypo-
thalamic-pituitary axis effects etc.). Topical calcineurin inhibitors (TCI) are safe and 
effective short-term treatments but are not suitable for use on severely affected skin. 
Repeated application of topical therapies over a long period is both time consuming and 
inconvenient to patients and their families and leads to poor patient adherence with 
treatment. Patients with moderate to severe AD that is not controlled with optimal topical 
therapy may require phototherapy or systemic immunosuppressant treatment to achieve 
adequate disease control. Oral immunosuppressants and glucocorticoids are also effective 
as short-term or intermittent therapies. However, long-term use is again restricted by 
concerns over toxicity and side effects. Dupilumab, a monoclonal antibody directed against 
IL-4 receptor alpha has been recently approved for the treatment of moderate to severe AD 
in adults by the Food and Drug Administration (Dupixent, 2016), by the European 
Medicines Agency and Health Canada (Dupixent Product Monograph, 2017/2018). 
In inflammatory skin disorders, evidence has accumulated implicating interleukin 17C 
(IL-17C) as a potential important pro-inflammatory agent. IL-17C expression is induced in 
cultured keratinocytes by pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-
α] and IL-1β) or bacteria (Ramirez-Carrozzi, Sambandam, & Luis, 2011) (Johansen, Riis, 
& Gedebjerg, 2011). IL-17C itself induces the expression of cytokines, pro-inflammatory 
mediators, and antimicrobial peptides in epidermal keratinocytes. Increased IL-17C levels 
were observed in AD subjects leading to an approximately 3-fold upregulation in a one 
week production rate compared to healthy subjects (Timmis, 2015). In skin biopsies, IL-
17C was mainly expressed by the keratinocytes and to some extent in endothelial cells and 
infiltrating immune cells (Johansen, Riis, & Gedebjerg, 2011) (Johnston, Fritz, & Dawes, 
2013). In animal models, intradermal injections of IL-17C, or keratinocytes overexpressing 
IL-17C, induced skin inflammation or spontaneous psoriatic-like lesions (Ramirez-
Carrozzi, Sambandam, & Luis, 2011) (Johnston, Fritz, & Dawes, 2013). In IL-17C or IL-
17RE (i.e. IL17C receptor subunit) knock-out mice, the psoriasiform skin inflammation 
induced by imiquimod, a well-established model, was significantly reduced (Ramirez-
Carrozzi, Sambandam, & Luis, 2011). 
MOR106 is a purified human recombinant Immunoglobulin G1 (IgG1) monoclonal antibody 
that binds with a high affinity to human IL-17C, thereby neutralizing its biological activity. 
It is produced in Chinese Hamster Ovarian cells by recombinant expression technology. 
MOR106 has significant effects in different rodent inflammatory skin models of AD and 
psoriasis. Nonclinical safety studies have demonstrated the absence of any adverse effects 
up to the highest dose tested (see Section 2.1.3) offering beneficial safety margins for 


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testing the proposed clinical doses and schedules of this study (see Section 4.2.1). The 
results of the first-in-human (FIH) Phase 1 study have shown that MOR106 is generally 
well tolerated in healthy male subjects and subjects with moderate to severe AD, with 
supportive data from exploratory efficacy assessments in this AD subject group (Timmis, 
2015). To date, MOR106 is the first known IL-17C antagonist being evaluated in clinical 
studies. 
This study is being conducted to obtain preliminary safety information on the s.c. 
administration of MOR106 with concomitant TCS in subjects with moderate to severe AD 
who are candidates for systemic therapy. Many patients may use MOR106 in combination 
with TCS. For this reason, it is prudent to assess if MOR106 can be safely co-administered 
with TCS. 
The following paragraphs summarize the results of prior nonclinical (see Section 2.1) and 
clinical (see Section 2.2) studies for MOR106, more details can be found in the latest 
investigator’s brochure (IB; Edition 3, 29 May 2018). 
This clinical study will be conducted in accordance with the current International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good 
Clinical Practice (ICH-GCP) Guideline E6 (see also Section 10). 
2.1. 
Background - Nonclinical Studies 
2.1.1. 
Nonclinical Pharmacology 
2.1.1.1. 
Primary and Secondary Pharmacology 
MOR106 binds with a high apparent affinity to human IL-17C (50% effective 
concentration [EC50] of 19 ± 6.9 pM). Binding of MOR106 to human IL-17C is 
approximately 14- to 20-fold stronger compared to binding to cynomolgus monkeys and 
mice IL-17C, respectively. Binding of MOR106 is specific for IL-17C. 
In vitro, MOR106 potently inhibits the binding of human IL-17C to its specific receptor 
IL-17RE and inhibits the biological activity of IL-17C. MOR106 inhibits the activity of 
cynomolgus monkeys and mice IL-17C with similar potencies as human IL-17C in contrast 
to the biochemical binding assay. 
MOR106 prevented the occurrence of an AD-like skin inflammation in two different 
mouse models of AD. MOR106 reduced symptoms of the AD-like syndrome in the MC903 
(calcipotriol) mouse model, with a significant impact on epidermal and dermal thickening, 
inflammation and type 2 T helper cell (Th2)-like gene expression. MOR106 also reduced 
the development of atopy and overt dermatitis in the skin barrier defective flaky tail model, 
with effects on gross clinical appearance, acanthosis, mast cell infiltration and serum levels 
of IgE and Th2-related cytokines IL-4 and thymus and activation regulated chemokine 
(TARC). 


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2.1.1.2. 
Safety Pharmacology 
 
 
 
2.1.2. 
Nonclinical Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
2.1.3. 
Toxicology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.2. 
Background - Clinical Studies 
To date, MOR106 has been administered during the single (SAD) and multiple ascending 
dose (MAD) parts of the FIH Phase 1 study MOR106-CL-101 (Timmis, 2015), as well as 
in an ongoing Phase 2 study (MOR106-CL-201, 2017) and an ongoing Phase 1 (MOR106-
CL-102, 2018). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
2.2.1. 
Clinical Pharmacokinetics and Immunogenicity 
 
 
 
 
 
 
 


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2.2.2. 
Clinical Safety 
 
 
 
 
 
2.2.3. 
Clinical Efficacy 
 
 
 
3. 
CLINICAL STUDY OBJECTIVES 
3.1. 
Primary Objective 
 
To investigate the safety and tolerability of repeated subcutaneous (s.c.) doses of 
MOR106 administered concomitantly with topical corticosteroids (TCS) in subjects 
with moderate to severe atopic dermatitis (AD) who are candidates for systemic 
therapy. 
3.2. 
Secondary Objectives 
 To evaluate the PK of repeated s.c. doses of MOR106 administered concomitantly with 
TCS. 
 To monitor the occurrence of anti-drug antibodies (ADA) as a measure of 
immunogenicity after repeated s.c. doses of MOR106 administered concomitantly with 
TCS. 
3.3. 
Other Objectives 
 
 
 
 
 
 


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 
 
 
 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Clinical Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study of 
repeated s.c. doses of 320 mg MOR106 or placebo, administered concomitantly with TCS. 
On Day 1 a loading dose (LD) will be administered (2 x 320mg MOR106, or placebo). 
Adult subjects with moderate to severe AD who are candidates for systemic therapy will be 
randomized 2:1 to receive MOR106 or placebo every other week via s.c. injections (on 
Days 1, 15, 29, and 43). The 8-week treatment period, finishing on Day 57, is followed by 
a 16-week follow-up period, finishing on Day 169. A total of 60 subjects (n=40 on 
MOR106 and n=20 on placebo) will be enrolled in this study. 
The screening visit will take place 7 to 28 days before baseline visit on Day 1. From 
screening onwards, subjects will apply a bland emollient at least twice daily, for at least 7 
days prior to the baseline visit (i.e. Day 1). Emollient use must continue at least twice daily 
throughout the study (once daily in areas of TCS application).  
TCS will not be permitted within 7 days prior to the baseline (Day 1) visit. 
From Day 1 onwards, all subjects will apply concomitant open-label, once daily treatment 
with a medium potency TCS product. Other topical medications, such as a lower potency 
TCS or topical calcineurin inhibitors (TCI), may be used in addition to treat AD lesions 
located on the face, flexural, and genital areas. Once control has been achieved (i.e. lesions 
have cleared or almost cleared), TCS or TCI application to areas from which lesions have 
cleared will be limited to 2 days every week, in an interval of 3 or 4 days, until the end of 
the treatment period. TCS or TCI use will be reviewed at every visit by the investigator. 
During the 16-week follow-up period, topical treatment of residual active AD lesions may 
continue as needed at the investigator’s discretion. 
Eligible subjects will undergo baseline evaluations and randomization, receiving first 
investigational medicinal product (IMP) dosing on Day 1. Following the completion of the 
first IMP administration, subjects will remain on site for a minimum of 2 hours after the 
injections. After the second (i.e. Day 15) and subsequent administrations subjects will 
remain on site for a minimum of 1 hour after each injection. 
An interim analysis (after approximately 50% of the subjects having reached the end of 
treatment period) and a primary analysis (after the end of the treatment period for all 
subjects) are planned (please refer to Section 7.3.2). At the end of the study the final 
analysis will be conducted. 
For the in- and exclusion criteria please refer to Section 4.5.1, “Inclusion Criteria” and 
Section 4.5.2, “Exclusion Criteria”. A schematic diagram of clinical study design is 
provided in Figure 1. 
 


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Figure 1: Schematic overview of the study design. 
For detailed info regarding dosage form, packaging and labeling of the IMP please refer to 
Section 5.2, “Dosage and Administration” and Section 5.3, “Packaging, Labeling and 
Distribution”. 
The end of the study is reached when the last follow-up visit or contact as planned 
according the Schedule of Activities (see Section 6.10) of the last subject is performed. 
4.2. 
Clinical Study Rationale 
This study is being conducted to obtain safety and preliminary efficacy information on the 
s.c. administration of MOR106 with concomitant TCS in subjects with moderate to severe 
AD who are candidates for systemic therapy in comparison to placebo with TCS. 
TCS have been the primary treatment option for AD patients for many years and are 
commonly used as the first line of pharmacologic treatment in patients whose symptoms 
cannot be controlled with general measures such as allergen and irritant avoidance, skin 
hydration, and skin moisturization. TCS are also used to treat AD exacerbations. Therefore, 
many patients may use MOR106 in combination with TCS. For this reason, it is prudent to 
assess if MOR106 can be safely co-administered with TCS and what added benefit this 
may have. In order to standardize treatment conditions, the concomitant application of TCS 
and MOR106 or placebo starts on Day 1 for all subjects after a washout period for TCS of 
at least 7 days prior to the baseline visit (i.e. Day 1). 
4.2.1. 
Dosing Rationale 
For this study a MOR106 dose of 320 mg s.c. is selected. This dose is the anticipated 
highest targeted dose for Phase 3 and is supported by safety data obtained in the FIH with 
i.v. dosing. It provides safety information that would cover potential lower doses as well. 


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Based on the PK results of the FIH study MOR106-CL-101 in AD subjects (Timmis, 
2015), MOR106 serum levels were simulated for the s.c. dose planned for the current study 
(i.e. 320 mg Q2W including a LD at Day 1 over a 8-week treatment period). The following 
conservative assumptions were taken into consideration: 
 Bioavailability following s.c. dosing in AD subjects was assumed at a maximum of 
100%. 
 Cmax will be identical between s.c. and i.v. dosing. 
 The proposed fixed LD of 640 mg s.c. on Day 1 (i.e. 2 x 320 mg) would translate into 
for example a 16 mg/kg dose in a 40 kg person (i.e. reflecting a body weight at the low 
end of the possible range considering study inclusion and exclusion criteria). The fixed 
dose of 320 mg administered every two weeks would translate into 8 mg/kg in a 40 kg 
person. 
Following these simulations, the expected Cmax and exposure (AUC) values for MOR106 in 
this study are covered by the results of the FIH MOR106-CL-101 (Timmis, 2015). In 
addition, AD subjects in study MOR106-CL-101 were dosed once weekly with i.v. doses 
of 1, 4 and 10 mg/kg.
 
 
 
The addition of a loading dose on Day 1 (i.e. doubling the initial dose on Day 1) leads to 
steady-state-like trough or average drug levels directly after start of treatment. With regard 
to drug exposure vs. clinical efficacy, it is expected that clinical effects following MOR106 
treatment/dosing are most likely linked to such stable drug levels as commonly reported for 
this compound class. (BLA761061, 2017). 
Preclinically, the proposed dosing design is supported by the results of the 13-week i.v. 
repeat-dose toxicity study in mice (Perron, 2017) as well as the 4-week s.c. repeat-dose 
toxicity study in cynomolgus monkeys (Grote-Wessels, 2018). Further details are available 
in the IB. 
The total treatment duration of a maximum of 8 weeks in this study is covered by the 
duration and results of the 13-week i.v. toxicity study in mice. In this preclinical study, 
systemic toxicity was evaluated by administering MOR106 i.v. once weekly (5-min bolus) 
for 13 weeks, followed by a 13-week recovery period. MOR106 was well tolerated up to 
the highest dose studied at 200 mg/kg (NOAEL). A safety margin of approximately 18-fold 
in Cmax and 8-fold in exposure (i.e. AUC) is expected based on the observed NOAEL (i.e. 
observed animal values exceeding expected human values). In addition, results of the 4-
week s.c. toxicity study in cynomolgus monkeys demonstrated that MOR106 was well 
tolerated not only systemically but also locally at the injection site after repeated s.c. dosing 
once weekly up to the highest dose tested at 300 mg/kg (NOAEL). 
In summary, the available nonclinical and clinical safety package are considered sufficient 
to support the s.c. administration of MOR106 at a loading dose of 640 mg (i.e. 2 x 320 mg 
on Day 1) followed by 320 mg Q2W for 8 weeks in adult subjects with moderate to severe 
AD in study MOR106 CL-204. 


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4.2.2. 
Clinical Study Design Rationale 
A placebo-controlled design is used to account for the high placebo effect that can be 
observed in the given population. The overall treatment period of 8 weeks is proposed to 
allow for a thorough investigation of the safety profile over a time period where already 
significant clinical treatment effects of both antibodies can be expected. A follow-up period 
of 16 weeks is selected to further monitor any MOR106 induced clinical effects and to 
observe any potential ADA development after treatment stop. 
The clinician and subject-rated scales selected for this study are based on recommendations 
made by the Harmonising Outcome Measures for Eczema (HOME) trials group (Spuls, 
Gerbens, & Simpson, 2017) (Schmitt, Spuls, & Thomas, 2014). They are established scales 
recognized in this field. 
 
 
 
 
 
 
4.3. 
Endpoints 
4.3.1. 
Primary Endpoint 
 
The incidence and severity of treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), and adverse events of special interest (AESIs) through Day 
169/ED visit. 
4.3.2. 
Secondary Endpoints 
 
MOR106 serum concentrations after repeated s.c. administrations from baseline 
through Day 169/ED visit. 
 
Occurrence of ADA from baseline through Day 169/ED visit. 
4.3.3. 
Other Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4. 
Potential Risks and Benefits 
No risk factors for clinical use of MOR106 were identified based on the mode of action of 
the antibody (i.e. IL-17C antagonism). Two relevant nonclinical species were identified 
(mouse and cynomolgus monkey). Toxicity studies in these species applied a multiple of 
the doses anticipated for human use whereas no systemic drug-related AEs were observed 
(i.e. NOAEL in each nonclinical safety study defined at the highest dose studied) 
(Manciaux, 2016a), (Manciaux, 2016b), (Perron, 2017), and (Grote-Wessels, 2018). S.c. 
administration of MOR106 in cynomolgus monkeys did also not reveal any relevant 
observations of local intolerance during a 4-week period of time, up to 300 mg/kg. No sign 
for treatment-related immunotoxicity and no risk for a cytokine release syndrome became 
apparent during the study. Nevertheless, potential reactions will be monitored in this 
clinical study. 
Data on the biology of the target IL-17C (a member of the IL-17 cytokine family) indicates 
a role of IL-17C as a regulatory cytokine for innate immune function in epithelial cells. 
By neutralizing the biological activity of human IL-17C, MOR106 may have the potential 
of providing benefit as an effective and safe long-term treatment. This is in comparison to 
current oral immunosuppressants and glucocorticoids that are only approved as short-term 
or intermittent therapies, because their long-term use is restricted by concerns over toxicity 
and side effects. 
The FIH study, MOR106-CL-101, has not identified any safety risks for i.v. administered 
MOR106 up to 20 mg/kg single doses. One healthy subject exhibited transient ADA 
development without any effect on PK and without impact on clinical safety findings. 


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In the FIH study MAD part i.v. administered MOR106 was well tolerated with no 
identified safety risks at doses up to four weekly doses of 10 mg/kg. One subject with 
moderate to severe AD developed a positive ADA titer during the follow-up period 
exhibiting clearing effects on the PK. There was no impact of the ADA formation on safety 
of this subject. The results from the exploratory objectives in the FIH study in terms of 
efficacy support the potential of MOR106 in the treatment of moderate to severe AD. The 
risk of immunogenicity will be thoroughly monitored throughout the trial. 
Overall, it is considered that MOR106 does not pose a significant safety risk for the study 
subjects. In addition a beneficial effect of MOR106 on top of topical steroids may be 
experienced by the subjects with AD. 
4.5. 
Clinical Study Population 
4.5.1. 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation in 
this study. 
1. Able and willing to comply with the protocol requirements, and signing the informed 
consent form (ICF) as approved by the IEC/IRB, prior to any screening evaluations. 
2. Male or female between 18-65 years of age (extremes included), on the day of signing 
the ICF. 
3. A BMI between 18-40 kg/m², inclusive. 
4. Diagnosis of AD for at least one year since first diagnosis as per the Hanifin and Rajka 
Criteria. 
5. EASI ≥16 at the screening and ≥16 at the baseline visit (Day 1 predose). 
6. IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 is moderate and 4 is severe) at the 
screening and baseline visits. 
7. Greater than or equal to 10% body surface area (BSA) of AD involvement at the 
screening and baseline visits. 
8. Willingness to use a non-medicated, simple bland emollient twice daily for at least 7 
days before the baseline visit and throughout the study. 
9. Subject is a candidate for systemic therapy and has a history of inadequate response to 
TCS or TCI before screening visit, as per investigator’s opinion. 
10. Subject has at least one AD lesion for which treatment with medium potency TCS is 
indicated. 
11. Female subjects must have a negative serum pregnancy test at screening and a negative 
urine pregnancy test at baseline. The exception are women who are surgically sterile 
(hysterectomy, bilateral salpingectomy and bilateral oophorectomy), or 
postmenopausal (i.e. at least 12 consecutive months without menstruation, without an 
alternative medical cause [including hormone replacement therapy]). A determination 
of follicle stimulating hormone (FSH) can be performed with FSH >35 mIU/mL 
confirming postmenopausal status without menstruation for ≥24 months. 


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12. Female subjects of childbearing potential must use a highly effective method of 
contraception from 28 days prior to the first dose of IMP, throughout the study, and for 
at least 24 weeks after the last dose of IMP. 
13. Non-vasectomized male subjects with a female partner of childbearing potential must 
agree to use a condom, in addition to another highly effective form of contraception 
used by the female partner, from prior to the first dose, throughout the study, and for at 
least 24 weeks after the last dose of IMP. 
4.5.2. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not eligible for participation in 
this study: 
1. Prior treatment with MOR106. 
2. Known hypersensitivity to any IMP ingredients as determined by the investigator (such 
as, but not limited to, anaphylaxis requiring hospitalization). 
3. AD lesions located predominantly (≥50% of the cumulative lesional area) on face and 
genital areas. 
4. Having used any of the following treatments: 
i. 
Original criterion (CSP Version 3.0, dated 15-Oct-2018):  
Prior exposure to a biologic therapy for AD. 
    i.1   Change of the original criterion (CSP Version 4.0, dated 25-Jun-2019): 
Prior exposure to Dupilumab. 
ii. 
Immunosuppressive/immunomodulating drugs (e.g. systemic corticosteroids, 
cyclosporine, mycophenolate-mofetil, IFN-γ, azathioprine, methotrexate) within 4 
weeks of baseline (Day 1) visit. 
iii. 
Phototherapy (ultraviolet B [UVB] or Psoralen Ultraviolet A [PUVA]) for AD 
within four weeks of baseline (Day 1) visit. 
iv. 
Treatment with TCS or TCI within 7 days before the baseline (Day 1) visit. 
v. 
Original criterion (CSP Version 3.0, dated 15-Oct-2018):  
Treatment with biologics (for non-AD indications) within five half-lives (if 
known) or 12 weeks prior to baseline visit, whichever is longer. 
      v.1    Change of the original criterion (CSP Version 4.0, dated 25-Jun-2019): 
Treatment with biologics within five half-lives (if known) or 12 weeks prior to 
baseline visit, whichever is longer. 
vi. 
Regular use (more than two visits per week) of a tanning booth/parlor within 
4 weeks of the baseline visit. 
5. Original criterion (CSP Version 3.0, dated 15-Oct-2018): 
Positive serology for hepatitis B (positive hepatitis B surface [HBs] antigen and/or 
positive hepatitis core antibody [HBc]) or hepatitis C (anti-HCV) or any history of 


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hepatitis from any cause with the exception of hepatitis A. Subjects who are immune to 
hepatitis B because of vaccination can be included. 
5.1 Change of the original criterion (CSP Version 4.0, dated 25-Jun-2019): 
Positive serology for hepatitis B (positive hepatitis B surface [HBs] antigen and/or 
positive hepatitis core antibody [HBc]) or hepatitis C (anti-HCV) or any history of 
hepatitis from any cause with the exception of hepatitis A and B. Subjects who are 
immune to hepatitis B because of vaccination can be included. 
6. History of or a current immunosuppressive condition (e.g. human immunodeficiency 
virus [HIV] infection, as determined by a positive HIV test at screening). 
7. Subjects with a history of varicella zoster virus who experienced any episode or 
recurrence of herpes zoster infection within 1 year of screening must be excluded. (A 
history of herpes simplex types 1 or 2 or vaginal candidiasis is permitted.) 
8. Any concurrent illness, condition, disability, or clinically significant abnormality 
(including laboratory tests, a New York Heart Association Classification (NYHA) 
greater than or equal to III/IV) or clinically significant illness in the 3 months prior to 
initial IMP administration that, in the investigator’s opinion, represents a safety risk for 
the subject’s participation in the study, may affect the interpretation of clinical safety or 
efficacy data, or may prevent the subject from safely completing the assessments 
required by the protocol. 
9. Any of the following laboratory abnormalities: 
i. 
Hemoglobin (Hb) <12 g/dL (male) or <10 g/dL (female) 
ii. 
White blood cell count <3.0 x 109 cells/L 
iii. 
Neutrophil count <1.5 x 109 cells/L 
iv. 
Platelet count <100 x 109 cells/L 
v. 
Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2x 
upper limit of normal (ULN) 
vi. 
Total bilirubin level >1.5 x ULN 
10. History of malignancy within the past 5 years prior to screening with the exception of 
excised and curatively treated non-metastatic basal cell carcinoma or squamous cell 
carcinoma of the skin. 
11. Clinically significant abnormalities at the discretion of the investigator detected on vital 
signs or physical examination (other than AD) at screening or baseline (Day 1 predose). 
12. Active drug or alcohol abuse. 
13. Subjects who have had or will have an attenuated live vaccination within 4 weeks of the 
first dosing. 
14. Participation in another experimental therapy study within 90 days or five times the 
half-life of the experimental therapy, whichever is longer, prior to dosing for this study. 
15. Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, 
or other staff who is directly involved in the conduct of the study, or relative thereof. 


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16. Active chronic or acute skin infection requiring treatment with systemic (i.e. oral, s.c., 
i.v.) antibiotics, antivirals or antifungals within 4 weeks of baseline, or clinical signs of 
infective eczema within 7 days before baseline (Day 1 predose) (Note: subjects may be 
rescreened after infection resolves). Oral fluconazole for vaginal yeast infection and 
oral antiviral medication for herpes labialis and herpes genitalis is permitted. 
17. Pregnant or breast feeding female subject (or subject is planning to become pregnant). 
18. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (e.g. tuberculosis, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution or 
unusually frequent, recurrent, or prolonged infections, per investigator judgment. 
19. Not able to manage the electronic diary (e-diary) as per assessment of the investigator. 
20. Any condition or circumstances that in the opinion of the investigator may make a 
subject unlikely or unable to complete the study or comply with study procedures and 
requirements. 
4.5.3. 
Prohibition and Restrictions 
4.5.3.1. 
Precautions for Sexual Intercourse 
Highly effective contraceptive measures for both males and females of childbearing 
potential must be documented in the source documents. 
4.5.3.1.1. Female Subjects 
In line with the Heads of Medicines Agencies (HMA)’s Clinical Trial Facilitation Group 
(CTFG) recommendation, female subjects are considered of non-childbearing potential if 
they meet one of the following criteria: 
 
No menses for 12 or more months without an alternative medical cause. A high FSH 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. However 
in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
 
Permanently surgically sterile (bilateral oophorectomy, i.e. surgical removal of 
ovaries, bilateral salpingectomy or hysterectomy, i.e. surgical removal of uterus). 
All other female subjects are considered to be of childbearing potential (WOCBP) and must 
use one of the following highly effective methods of birth control prior to the first dose of 
IMP, during the clinical study and for at least 24 weeks after the last dose of IMP: 
 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation plus a barrier 
method1. 
                                                 
1 As there is no current data available regarding potential interactions between IMP and hormonal 
contraceptives, female subjects who use hormonal contraception should supplement this with a barrier 
method (preferably male condom). 


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 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated 
with inhibition of ovulation plus a barrier method1. 
 
Intrauterine device. 
 
Intrauterine hormone-releasing system. 
 
Bilateral tubal occlusion. 
 
Sexual abstinence defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and 
the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only and lactational 
amenorrhea method are not acceptable as methods of contraception. 
In case a WOCBP has a vasectomized partner, provided that partner is the sole sexual 
partner of the WOCBP clinical study participant and that the vasectomized partner has 
received medical assessment of the surgical success, then she is not required to use an 
additional form of contraception. 
Within these limits, the specific forms of contraception employed are left to the discretion 
of the subject, the investigator, and/or the subject’s physician. 
The safety of MOR106 during breastfeeding is unknown. Women who are nursing are not 
allowed to take part in this clinical study. 
No ova donation is allowed from first dose of IMP during the clinical study until 24 weeks 
after the last dose of IMP. 
4.5.3.1.2. Male Subjects 
Non-vasectomized male subjects with female partners of childbearing potential must be 
willing to use a condom from the time of the first dose of IMP, during the clinical study, 
and for at least 24 weeks after the last dose of IMP, in addition to having their female 
partner use one of the following forms of contraception: 
 
Combined (estrogen and progesterone containing) (oral, intravaginal, transdermal) 
hormonal contraception associated with inhibition of ovulation. 
 
Progesterone-only hormonal (oral, injectable, implantable) contraception associated 
with inhibition of ovulation. 
 
Intrauterine device. 
 
Intrauterine hormone-releasing system. 
Sexual abstinence defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments is considered a highly effective 
contraceptive measure. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 


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Periodic abstinence (e.g. calendar, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a clinical study, withdrawal, spermicides only and lactational 
amenorrhea method are not acceptable methods of contraception. 
In a case where the female partner of a male subject has undergone documented surgical 
sterilization that was performed more than 1 year before screening, then the subject is not 
required to use an additional form of contraception. 
Vasectomized male subjects with female partners of childbearing potential are not required 
to use an additional form of contraception providing that surgical sterilization has been 
successful (documented azoospermia by semen analysis). 
No sperm donation is allowed from first dose of IMP during the clinical study until 24 
weeks after the last dose of IMP. 
4.5.3.2. 
Prior and Concomitant Medications 
All medications in relation to the treatment of AD that are not allowed in accordance with 
the inclusion and exclusion criteria should not be used during the study. All allowed 
standard treatment should remain on a stable dose until completion of the Day 169 (or ED) 
visit, if possible. 
Prior medications (with the exception of medications used for treatment of AD) used in the 
3 months prior to Day 1 will be recorded in the electronic case report form (CRF). 
Medications used for the treatment of AD received during the last 12 months before Day 1 
will be recorded in the CRF. These include any systemic therapy, biologics, or 
phototherapy ever used for the treatment of AD. 
4.5.3.2.1. Topical Corticosteroids (TCS) 
Subjects will not use any TCS for at least 7 days prior to the baseline (Day 1) visit. 
 
From Day 1 onwards, all subjects will apply concomitant open-label, once daily treatment 
with TCS as follows: 
 
Medium potency TCS (e.g. Triamcinolone 0.1% cream or Mometasone furoate 0.1% 
cream or another sponsor approved TCS) to be used as per approved label. 
 Other topical medications, such as a lower potency TCS or TCI, may be used to treat 
AD lesions located on the face, flexural, and genital areas as per approved label. 
 Once control has been achieved (lesions have cleared or almost cleared), TCS or TCI 
application to areas from which lesions have (almost) cleared, will, under the 
supervision of the investigator, be limited to twice weekly in intervals of 3-4 days until 
the end of the treatment period (D57). 
 During the follow-up period (D57 to D169), topical treatment of residual active AD 
lesions may continue as needed at the investigator’s discretion. This treatment can be 
stepped up or stepped down as clinically indicated per investigator’s discretion. 
 During the follow-up period (D57 to D169), in the event of an AD flare, initiation or 
escalation of TCS therapy will be recorded as rescue therapy in the follow-up period. 


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 All TCS (and TCI if used) use will be recorded daily by the subject in a diary from 
screening visit onwards and throughout the study and will be reviewed at each onsite 
visit by the investigator. 
Detailed instructions on TCS management will be described in a separate study reference 
manual. 
4.5.3.2.2. Emollients 
Subjects should apply emollient (moisturizers) at least twice daily for at least 7 consecutive 
days prior to baseline and continue the treatment throughout the study (including follow-up 
period). Emollient use should continue at least twice daily (once daily in areas of TCS 
application) throughout the study, even in the event of eczematous areas improving or 
resolving. Emollient use must be recorded in the CRF as concomitant medication and use 
will be recorded daily by the subject in a diary from screening onwards and will be 
reviewed at each onsite visit by the investigator. 
Subjects should not apply their emollient within 6 hours prior to skin assessments. The 
emollient can be applied after completion of skin assessments. 
There must be no active ingredients which could potentially affect AD in the emollient. 
This includes urea, ceramides, and antimicrobials. 
If subjects at screening are using a non-medicated emollient, and are eligible for the study 
they must continue the use of this throughout the study. If subjects at screening are not 
using a non-medicated emollient and are eligible for the study, they must start using one 
once all screening assessments are completed. 
4.5.3.2.3. Permitted Medications 
Apart from the prohibited medications listed in Section 4.5.3.3 treatment with concomitant 
medications is permitted throughout the study. This includes oral contraceptives, nasal and 
inhaled corticosteroids, and oral antihistamines. All concomitant medicines must be locally 
approved and administered at a dose that is considered standard-of-care for the treated 
indication. It is required that these medications are given at a stable dose prior to study 
entry and preferably continued without variation of dose or regimen during the study. 
In a case where additional concomitant medication need to be administered or dose 
adjustments for pre-existing conditions (except for AD) need to be performed during the 
study, the risk/benefit ratio to the subject must be carefully assessed and consideration 
given to the timing of any necessary introduction of new medications. Continuation of the 
subject should be reviewed and can be discussed with the medical monitor if needed. 
Oral antibiotics to treat atopic dermatitis-associated superficial skin infections are also 
permitted for up to two weeks duration. 
4.5.3.3. 
Prohibited Concomitant Medications and Procedures 
The following medications are prohibited throughout the study participation: 


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 Topical corticosteroids, except as described in Section 4.5.3.2.1 
 Systemic corticosteroids 
 Topical tacrolimus and pimecrolimus 
 Leukotriene inhibitors 
 Allergen immunotherapy 
 Systemic treatment for AD with an immunosuppressive / immunomodulating 
substance (including but not limited to, cyclosporine, mycophenolate-mofetil, 
azathioprine, methotrexate, biologics or interferon gamma or investigational drugs 
other than MOR106) 
 Treatment with a live (attenuated) vaccine 
 Photopheresis, immunoapharesis/-adsorption 
 
The following concomitant procedures are prohibited throughout study participation: 
 Elective major surgical procedures 
 Concomitant ultraviolet (UV) procedures (phototherapy [narrow band UVB, UVB, 
UVA1 or PUVA1]) 
 Tanning in a bed/ booth 
4.5.3.4. 
Rescreening 
Subjects may only be rescreened with the approval of the medical monitor. If a subject is 
rescreened, all screening assessments will be repeated and a new screening number will be 
applied. If a subject is rescreened, the screening window will begin once the first 
rescreening assessment has been initiated. 
4.5.3.5. 
Food and Beverage Restrictions 
Subjects are not allowed to take alcohol 24 hours before screening and each IMP 
administration and should abstain from alcohol for 24 hours after dosing. Subjects must 
limit their alcohol intake during the study to no more than three glasses of wine or beer or 
equivalent per day. 
4.5.4. 
Treatment Discontinuation (Temporarily and Permanently), Subject 
Withdrawal and Study Termination 
A subject may be withdrawn from the clinical study at any time without the subject’s 
consent if the investigator or sponsor determines that it is not in the best interest of the 
subject to continue participation. In such case, the reason for withdrawal will be 
documented in the source documents, and the subject will complete the early 
discontinuation (ED) visit and /or follow-up visits for safety assessments. 
Treatment with IMP should be discontinued by the investigator (preferably after discussion 
with the CRO medical monitor, who may consult and must inform the sponsor’s study 
physician) for any of the following conditions: 
 
Life-threatening AE or a SAE that places the subject at immediate risk. 
 
Serious infections deemed related to study treatment by the investigator, and requiring 
parenteral antimicrobial therapy and/or hospitalization. 


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 
Confirmed pregnancy in a female subject or female partner of a male subject (due to 
likely unblinding of the subject). 
 
Arrhythmia or conduction abnormality, including but not limited to prolonged QT 
interval corrected for the heart rate using Fridericia’s formula (QTcF), where the 
severity is categorized as Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 3 or higher (QTc >500 ms on at least two separate ECGs). 
 
Increase in liver function tests (LFTs): 
 
Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
elevations >8x ULN: IMP treatment should be withheld and the LFTs should be 
repeated. IMP should be discontinued permanently if the results are confirmed. 
 
AST and/or ALT elevations >3x ULN and <8x ULN: IMP treatment should be 
withheld. 
 
If LFTs do not return to normal within 2 weeks then the IMP should be 
discontinued permanently. 
 
If LFTs return to normal within 2 weeks then IMP could be restarted with 
close monitoring (e.g. repeat testing twice per week for the first 2 weeks 
then weekly for the following month). In the event LFTs become 
abnormal at any subsequent point during the trial (i.e. after rechallenge) 
then the IMP should be permanently discontinued. 
 
AST and/or ALT elevations >3x ULN and total bilirubin level (TBL) >2x ULN or 
international normalized ratio (INR) >1.5: IMP treatment should be withheld and 
the LFTs should be repeated. IMP should be discontinued permanently if the 
results were confirmed. 
 
AST and/or ALT elevations >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia 
(>5%): IMP treatment should be withheld, LFT repeated and IMP discontinued if 
LFT confirmed or if symptoms and signs persist. 
When test results need to be confirmed, the subject should return to the investigational site 
and be evaluated as soon as possible, preferably within 48 hours from awareness of the 
abnormal results. This evaluation should include laboratory tests, detailed history and 
physical assessment. In addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl 
transferase (GGT), INR, and alkaline phosphatase. A detailed history, including relevant 
information (e.g. review of ethanol, recreational drug and supplement consumption, family 
history, sexual history, travel history, history of contact with a jaundiced subject, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure) should be 
collected. Further testing for acute hepatitis A, B or C infection and liver imaging (e.g. 
biliary tract) may be warranted. All cases confirmed on repeat testing with no other cause 
for LFT abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs. Such potential Hy’s Law cases should be reported as SAEs. 
Every effort should be made to keep subjects in the study and on treatment. However, the 
investigator can consider stopping the treatment with IMP, preferably after consultation 
with the sponsor’s study physician, in case of concerns about the subject’s safety, major 
protocol noncompliance, serious or severe AEs or worsening of the disease condition, 


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which in the investigator’s opinion needs an alternative treatment approach not being 
covered in the clinical study (e.g. rescue medication). 
When study treatment is discontinued, the subject will be requested to return for Early 
Treatment Discontinuation (ETD) visit and will be asked to continue the follow-up period 
until end of study. 
Subjects will be informed prior to clinical study entry that they are allowed to withdraw 
from the clinical study. At any time and for any reason, a subject’s participation in the 
clinical study may terminate at his/her request without prejudice to his/her future medical 
care. The subject will be encouraged to share the reason(s) for withdrawal so this can be 
documented in the source documents, and to complete the ED/ETD visit and follow-up 
visits for safety assessments, but will not be obliged to do so. 
Subjects who withdraw from the clinical study without contact with the site (lost-to-follow-
up) should be contacted by the site so that their health status can be assessed and 
documented in the source documents. The site should make every effort to understand 
whether the subject is alive, including checking the medical records and contacting general 
practitioner or relatives, if necessary. All attempts must be documented in the source 
documents. 
The sponsor has the right to terminate the clinical study at any time in case of safety 
concerns or if special circumstances concerning the IMP or the company itself occur, 
making further treatment of subjects impossible. In this event, the investigator(s) and 
relevant authorities will be informed of the reason for clinical study termination. 
4.6. 
Measures to Minimize Bias 
4.6.1. 
Randomization 
At screening, subjects will be assigned a subject screening number in ascending order (per 
site level), which should not be skipped. When subjects are confirmed to be eligible for the 
clinical study, they will be assigned a subject randomization number in ascending order. 
Allocation of each subject to a given treatment will be done using a centralized electronic 
system (interactive web response system [IWRS]), according to a pre-specified 
randomization scheme prepared by an independent statistician at the CRO. Subjects will be 
randomized in a 2:1 ratio to MOR106 or placebo. 
4.6.2. 
Blinding and Unblinding 
This is a randomized, double-blind clinical study. The subject and the entire clinical study 
team, including the investigator, clinical study coordinator, and sponsor personnel are 
blinded to treatment assignment. Details on unblinding procedures for the interim and 
primary analysis are in Section 7.3.2). 
The site pharmacist(s) or appropriately qualified member of the clinical study staff, are 
unblinded to treatment and assigned by the investigator to prepare and administer the IMP 
that corresponds to the assigned subject identification number. All staff members not 
involved in IMP preparation and/or administration are blinded to treatment assignment. 


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The blind can be broken via IWRS only if the investigator deems it necessary for the safety 
of a subject. The investigator is encouraged to discuss considerations to break the blind 
with the CRO medical monitor, whenever possible, and where the situation allows. 
However, the responsibility to break the treatment code in emergency situations resides 
solely with the investigator. The investigator is not required to discuss unblinding 
beforehand if he or she feels rapid emergency unblinding is necessary, but is required to 
inform the sponsor in a timely fashion after unblinding has occurred. 
If the blind is broken for any reason during the course of the clinical study, the moment on 
which the blind was broken and all other relevant information will be documented by the 
investigational site. The reason for breaking the blind will be indicated and justified in the 
source documentation, together with the confirmation that the subject discontinued the 
study treatment with unblinding as the reason for discontinuation. 
If an AE leads to unblinding, the AE will be given as the reason for unblinding. All 
subjects who are unblinded should, where possible, complete the ETD visit. Any AEs 
should be followed until resolution. 
Code-break information (via IWRS vendor) will be provided to the bioanalytical laboratory 
responsible for serum drug determination sample analysis, the laboratory responsible for 
biomarker analysis, and to the sponsor pharmacovigilance lead for SAE reporting purposes. 
4.6.3. 
Independent Safety Review Committee 
To safeguard the safety of the subjects, an independent Safety Review Committee 
consisting of independent dermatology and statistical experts will be implemented to 
review accumulating unblinded safety data for the clinical study, specifically the review of 
any skin related AEs and serious adverse reactions. The specific responsibilities, 
composition, meeting formats and details of output provided for the meetings of the 
independent Safety Review Committee will be outlined in detail in an Independent Safety 
Committee Charter. Members of the independent Safety Review Committee will not be 
involved in the day-to-day conduct of the study. 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
5.1. 
Identity of the Investigational Medicinal Products 
MOR106 
The active pharmaceutical ingredient (API) of MOR106 is a human IgG1 monoclonal 
antibody that binds with a high apparent affinity to human IL-17C. 
For s.c. injection the API of MOR106 is formulated as a sterile, stable and highly 
concentrated liquid formulation of 160 mg/mL filled in a 2R clear glass vial with a rubber 
stopper and blue crimp cap with an extractable volume of 1 mL. The formulation buffer for 
s.c. injection consists of L-histidine, L-Arginine, and 0.02% Polysorbate 20, pH 6.0. 
Placebo 
For s.c injections of placebo sterile formulation buffer of MOR106 in 2R clear glass vial 
with a rubber stopper and blue crimp cap with an extractable volume of 1 mL is available. 


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5.2. 
Dosage and Administration 
The IMP will be prepared by an unblinded and adequately trained member of the clinical 
center pharmacy staff as designated by the principal investigator. 
S.c. injections of MOR106 or placebo will be performed by an unblinded administrator 
who is not performing or involved in any of the study assessments. 
Appropriate measures will be taken to keep the subjects blinded from the administered 
IMP. Details will be provided in the study reference manual. 
For the single dose s.c. injection, the following components will be supplied to the clinical 
centers: 
 Vials containing 160 mg/mL MOR106 injectable solution, buffered at a pH 6.0. 
 Vials containing formulation buffer of MOR106, pH 6.0 (Placebo). 
 
The following doses will be used: 
 MOR106 320 mg (2 mL at 160 mg/mL) every 2 weeks (Q2W) s.c. injection, including 
a LD of 2 x 320 mg in total (2 x 2 mL) on Day 1. 
 Corresponding placebo s.c. injection (2 mL formulation buffer) plus an additional s.c. 
injection (2 mL) on Day 1. 
S.c. injection sites should be alternated among the different quadrants of the abdomen 
(avoiding the navel and waist areas) so that the same site is not injected for two consecutive 
visits. The quadrant injected should be documented in the CRF. Full details on the s.c. 
administration will be provided in the pharmacy manual. To allow for adequate assessment 
of the ISRs study treatment should be administered into an area of normal looking skin 
(where possible). Instructions for assessing and recording ISRs will be provided in the 
study reference manual. 
The dose-corresponding-volume of MOR106 drug product for s.c. injection will be 
collected in a syringe and injected with a suitable hypodermic needle for s.c. injection. As 
placebo, the same volume of placebo solution as the dose-corresponding-volume of 
MOR106 drug product, will be collected in a syringe and injected with a suitable 
hypodermic needle for s.c. injection. 
Detailed instructions on IMP management will be provided in the pharmacy manual. 
5.3. 
Packaging, Labeling and Distribution 
IMP packages will be labeled with clinical study-specific details, including storage 
conditions. 
All manufacturing, packaging, and labeling operations will be performed according to 
Good Manufacturing Practice for Medicinal Products and the relevant regulatory 
requirements. 
The distribution of the IMP to the clinical site will only occur after the required local 
documentation is obtained including clinical study approval by Competent Authorities and 


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the IECs/IRBs, documentation on which the assessment of the investigator’s qualifications 
was based (e.g. curriculum vitae) and the signed and dated study agreement and financial 
agreement. 
5.4. 
Storage 
Sites are to store the IMP supplies in a secure area at 2-8°C (i.e. 36-46 °F) until dispensed. 
Sites will be required to monitor the storage temperature by using a suitable temperature-
recording device in order to establish a record of compliance with these storage conditions. 
Details for the appropriate monitoring of the storage temperature and handling of 
temperature excursions will be provided in the pharmacy manual. 
5.5. 
Treatment Compliance and Drug Accountability 
The pharmacist or other designated clinical site personnel should maintain a log of the total 
amount of IMP received at site, date/time of IMP preparation, and administration to the 
subjects. IMP supplies for each subject will be inventoried and accounted for throughout 
the clinical study. At the end of the treatment period these records will be checked against 
the inventory by the study monitor. All IMP supplies will be stored in locked facilities. 
Upon sponsor approval all unused IMP and empty IMP packages will be destroyed at the 
site. If destruction by the site is not possible or the destruction process is found 
unacceptable by the sponsor, the IMP should be returned to the drug supplier/drug depot as 
appropriate. 
Detailed instructions on IMP handling will be provided in the pharmacy manual. 
6. 
CLINICAL STUDY ASSESSMENTS 
Every effort should be made to ensure that CSP-required tests and procedures are 
completed as described in the Schedule of Activities (see Section 6.10). To avoid inter-
observer variability, every effort should be made to ensure that all safety and efficacy 
evaluations are completed by the same individual who made the initial baseline 
determinations. 
6.1. 
Timing of Assessments 
ICF needs to be signed before any study procedure, including screening procedure, is 
carried out. 
The study assessments will be undertaken at time points as specified in the Schedule of 
Activities in Section 6.10. A window of ±1 day is allowed for Visit 4 and a window of 
±2 days is allowed for all visits from Visit Day 15 onwards (Day 15 included). 
Visit dates are always calculated from Day 1 (unless subject discontinues early and attends 
ETD visit). If a subject has an ETD visit, the follow-up visits are performed 14, 28, 42, 56, 
70, 84, 98 and 112 days after the ETD visit. 


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Subjects who are discontinued from treatment during the dosing period will perform 
Day 57/ETD visit (14 days after the last dose) as the last visit in the dosing period before 
entering the follow-up period. 
Subjects reported outcomes (
 
are to be completed 
on site by the subject preferably before any other study-related procedures is performed. 
 
12-Lead ECGs, vital signs, and physical examinations are to be recorded before invasive 
procedures are performed. 
Blood samples should be taken after all noninvasive procedures (including completion of 
questionnaires) have been finished. 
During the treatment period, procedures and assessments are to be performed prior to 
administration of IMP, except where indicated. For predose assessments, those should be 
done within 3 hours predose. 
The following collection time windows apply: 
 
12-Lead ECGs: A window of ±15 minutes is allowed for the Day 1 and Day 43 
postdose assessments. 
 
Blood sampling: For samples < 24h: +/- 10 min; 24h samples: +/- 1 hour; 48, 72 and 
96h samples: +/- 2 hours. 
 
Urine sampling: predose (within 2 hours before IMP dosing). 
Safety assessments should be repeated at other time points and additional assessments 
made if clinically indicated. 
6.2. 
Unscheduled Visits 
Additional visits can be performed at other time points for any safety assessments, if 
clinically indicated. These unscheduled visits and outcomes of additional assessments need 
to be recorded in the source and if performed before the subject’s last visit per CSP, also in 
the CRF. 
In case of an unscheduled visits, the following procedures and assessments should be 
performed: 
 Record the reason for the unscheduled visit. 
 Perform the assessments and procedures related to the reason for the unscheduled visit 
as deemed to be indicated by the investigator. 
 Record AEs. 
 Record concomitant medication and therapies. 
6.3. 
Initial Subject and Disease Characteristics 
Subjects will be asked to attend the clinical center for a screening assessment. After giving 
written informed consent, demographic data (age, sex and ethnicity) and a medical history 


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will be taken, including questions regarding medication intake. A physical examination will 
be performed, including measurement of body weight and height. 
Vital signs (systolic and diastolic blood pressure, heart rate, body temperature) will be 
measured and a 12-lead ECG will be recorded. Subjects should rest for at least 5 minutes in 
the supine position before the ECG recording, blood pressure, and heart rate measurement. 
Fasting blood and urine samples will be collected for clinical laboratory safety tests. 
The inclusion and exclusion criteria will be checked to assess eligibility for the study. All 
screening tests will be reviewed to confirm eligibility before randomization and dosing. 
6.4. 
Efficacy Assessments 
Clinician-reported outcomes will be assessed throughout the study 
 
. Where possible, these assessments should be performed by the 
same investigator, or adequately qualified and trained designee, at each visit. 
Subject-reported outcomes will be assessed 
 
.
 
Samples of these different clinician- and subject-reported outcomes are provided in the 
study reference manual. Subject-reported outcomes will be available in the subject’s local 
language. 
6.4.1. 
 
 
 
 
6.4.2. 
 
 
 
 
 
 
 
6.4.3. 
 
 
 


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6.4.4. 
 
 
 
. 
6.4.5. 
 
 
 
 
6.4.6. 
 
 
 
 
 
 
 
 
 
 
6.4.7. 
 
 
 
 
 
 
 


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6.4.8. 
 
 
 
 
 
 
 
6.4.9. 
 
 
 
 
 
 
 
6.5. 
Safety Assessments 
This section describes methods and timing for all safety assessments and recording. 
Additional assessments (e.g. unscheduled clinical laboratory tests or extra vital signs 
recordings) are allowed to ensure appropriate collection of safety data and to assess any 
perceived safety concerns. 
6.5.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and 
ends at their last follow-up visit. 
Detailed definitions, ratings, and reporting requirements for AEs, SAEs, and AESIs are 
found in Section 9. 
6.5.2. 
Clinical Laboratory Evaluations 
The following clinical laboratory safety tests will be performed: 
 Hematology: hematocrit, hemoglobin, red blood cell count, white blood cell count, 
white blood cell differential count (absolute and relative), and platelets. 


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 Clinical chemistry: glucose, urea, creatinine, uric acid, sodium, potassium, calcium, 
chloride, phosphorus, AST, ALT, GGT, total bilirubin, alkaline phosphatase, albumin, 
total proteins, triglycerides, cholesterol, high density lipoprotein, low density 
lipoprotein, C-reactive protein, and total IgE. 
 Urinalysis: proteins (semi-quantitative) and ketones can be tested via standard test strip; 
microscopic examination of the sediment (cylinders, erythrocytes, leukocytes) if 
indicated (when the test strip was positive for blood and/or proteins). 
 Serology (only at screening): HBs antigen, HBc antibody, and hepatitis C antibody, and 
HIV 1 and 2. Positive hepatitis, and HIV results should be reported by the investigator 
as required by local law. 
 Pregnancy test for females of childbearing potential: serum beta human chorionic 
gonadotropin at screening, urine dipstick before dosing on Day 1 and at all time points 
thereafter. In case of doubt, determination of FSH can be done at the central laboratory 
to confirm menopause. 
The clinical laboratory evaluations will be performed at visits specified in the Schedule of 
Activities in Section 6.10 (see also Section 6.1, “Timing of Assessments”). On dosing days, 
blood and urine samples will be collected prior to dosing. Blood sampling for clinical lab 
should be done in fasting conditions (for at least 8 hours). Results from the screening visit 
will be used for the inclusion/exclusion criteria on the baseline visit (Day 1). 
Reference ranges will be supplied by the central laboratory. Clinical laboratory values 
outside the normal range will be flagged and clinical relevance will be assessed by the 
investigator. Only laboratory test abnormalities judged as clinically significant by the 
principal investigator should be recorded as AEs. 
Retesting of clinical laboratory screening tests is allowed once only for technical reasons 
(e.g. sample hemolyzed, out of stability or late arrival at central laboratory). Retesting of 
laboratory tests for safety or if medically indicated in the opinion of the investigator is 
always allowed. 
The total amount of blood to be taken during the clinical study will not exceed 330 mL. 
This includes all scheduled samples and sampling for PK and/or PD assessments. 
Additional samples for subject safety would be allowed when needed, if relevant. For more 
details, see Section 6.9. 
The details of blood and urine sample handling and shipment instructions will be provided 
in a separate laboratory manual. 
6.5.3. 
Physical Examination 
Physical examinations or targeted physical examination will be conducted by a physician, 
trained physician’s assistant, or nurse practitioner as acceptable according to local 
regulation and as delegated by the principal investigator; at visits specified in the Schedule 
of Activities in Section 6.10 (see also Section 6.1). The person conducting the physical 
examination will document this in the subject’s medical records. Clinically significant 
abnormal findings should be recorded as AEs. 


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The physical examination will include an assessment of the following systems: general, 
cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, head and neck, 
skin (other than AD), thyroid and endocrine and other. 
The targeted physical examination will include an assessment of the cardiovascular, 
respiratory, gastrointestinal systems, and the skin. 
6.5.4. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, heart rate, and body temperature) will be 
recorded in a standardized manner (i.e. after the subject has rested in a supine position for 
5 minutes) at visits specified in the Schedule of Activities in Section 6.10 (see also Section 
6.1, “Timing of Assessments”). Vital sign parameter normal ranges are presented in 
Appendix 1. Clinically significant abnormal values should be recorded as AEs. 
Height will only be assessed at screening. Weight will be assessed at screening, and on a 
monthly basis as per Schedule of Activities (See Section 6.10). 
6.5.5. 
12-lead Electrocardiogram 
At the time points specified in the Schedule of Activities (see Section 6.10 and also 
Section 6.1, “Timing of Assessments”), a 12-lead ECG will be recorded. ECG recordings 
will be performed before blood sampling and after subjects rested for 5 minutes in supine 
position. In case an indwelling catheter is used, ECGs may be recorded after blood 
sampling, provided that there is at least 30 minutes between catheter insertion and the ECG 
recording. When catheter insertion would fail, the 12-lead ECG needs to be taken before 
the venipuncture and at least 30 minutes after the failed attempt. 
Triplicate ECGs will be performed before dosing at baseline only within a time span of 
approximately 6 minutes, with an approximate 3-minute interval between ECGs. 
Parameters to be recorded include the following: heart rate, PR interval, QRS interval, 
uncorrected QT interval, morphology, and rhythm analysis. Central reading will be 
performed for all ECGs at the time points specified in the Schedule of Activities. Central 
reading will be performed on blinded basis by a cardiologist. Details regarding central ECG 
reading will be provided in the study reference manual. 
QT interval corrected for the heart rate using Fridericia’s formula (QTcF) and QT interval 
corrected for the heart rate using Bazett’s formula (QTcB) will be derived during the 
statistical analysis. ECG parameter normal ranges are presented in Appendix 1. QTc will be 
considered as normal if ≤450 ms (male) and ≤460 ms (female), while a prolongation of 
QTc to ≥500 ms or an increase from baseline >60 ms will be considered a threshold of 
concern. Immediately after recording, the ECG will be reviewed by the investigator on 
clinical significant abnormalities. This immediate review during the visit needs to be 
documented in the subject’s source. Clinically significant abnormal values should be 
recorded as AEs. 


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6.5.6. 
Other Safety Assessments 
6.5.6.1. 
Injection Site Reactions (ISRs) 
The incidence, extent, and/or severity of ISRs (erythema, edema, induration, tenderness, 
and itching) will be assessed by the investigator on dosing days (before injection and one 
hour after completion of the injection). Information on ISRs will be collected for all 
subjects. Tenderness (pain/discomfort on palpation) and itching will be assessed by 
subjects using a 0-100 mm visual analogue scale (VAS). The extent (largest diameter in 
mm) of erythema, edema, and induration will be assessed. If present, the diameter of 
induration should be recorded. In addition, erythema and edema will be qualitatively 
assessed one hour post completion of the injection, and at follow-up visits through the end 
of study or until the injection site appears normalized at two consecutive assessments, 
based on all parameters evaluated. 
The following scales will be used to qualitatively describe the grade of erythema and 
edema: 
Erythema: 
0 = no erythema 
1 = very slight erythema (barely perceptible) 
2 = well-defined erythema 
3 = moderate to severe erythema 
4 = severe erythema (beet redness) to slight eschar formation (injuries in depth) 
 
Edema: 
0 = no edema 
1 = very slight edema (barely perceptible) 
2 = slight edema (edges well-defined) 
3 = moderate edema (raised >1 mm) 
4 = severe edema (raised >1 mm and beyond area of exposure) 
ISRs should be recorded as AEs in line with the Adverse Event Reporting requirements 
detailed in Section 9.3.1 and graded using the CTCAE grading scale (v5.0) (CTCAE, 
2017): 
1. Grade 1: Tenderness with or without associated symptoms (e.g. warmth, erythema, 
itching). 
2. Grade 2: Pain; lipodystrophy; edema; phlebitis. 
3. Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated. 
5. Grade 5: Death. 
In case of severe ISRs (CTCAE Grade 3 or higher) subjects should be evaluated by the 
investigator as soon as possible and subsequent dosing should be discussed with the CRO 
medical monitor and sponsor to review whether the subject remains eligible to proceed. 
Subjects withdrawn due to ISRs will not be replaced. 


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Investigator site staff should photograph any severe ISR, if possible. Instructions for the 
photography are provided in the study reference manual. 
6.5.6.2. 
Management of ISRs 
Injections site reactions should be treated by the investigator following local standard 
operating procedures/policies. 
In case of severe ISRs (CTCAE Grade 3 or higher) subjects should be evaluated by the 
investigator as soon as possible and subsequent dosing should be discussed with the CRO 
medical monitor and sponsor to review whether the subject remains eligible to proceed. 
6.6. 
Pharmacokinetic and Immunogenicity Assessments 
Blood samples for PK and Immunogenicity (ADA) assessment will be collected on the 
visits specified in the Schedule of Activities in Section 6.10 (see also Timing of 
Assessments, Section 6.1). In total 17 blood samples will be collected at various time 
points for analysis of MOR106 and 8 blood sample for the assessment of ADA in serum. 
Samples will be obtained by venipuncture (or indwelling cannula), preferably in the 
forearm. 
The details of blood sample collection, handling, storage, and shipment instructions will be 
provided in a separate laboratory manual. 
6.7. 
Pharmacodynamic Assessments 
Blood samples 
 
, will be collected on the visits specified in the Schedule 
of Activities in Section 6.10 (see also Section 6.1). Samples will be collected by 
venipuncture (or indwelling cannula) preferably in the forearm into tubes. 
The details of blood sample handling and shipment instructions will be provided in a 
separate laboratory manual. 
 
 
6.8. 
Other Assessments 
6.8.1. 
 
 
 
 
 
 


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6.8.2. 
Skin Swabs 
Skin culture samples for assessment of the presence of bacteria, yeast and fungi will be 
collected by cotton swab from the lesional surface of the area of worst eczema involvement 
and another swab from a non-lesional area of skin (within 5 cm of the lesional site) will be 
collected. Samples will be collected from the same lesional and non-lesional areas at 
baseline (Day 1 predose), and Days 57/ETD and 169 (end of study) or ED. 
The detailed procedure for collecting skin culture samples is provided in the laboratory 
manual. 
6.8.3. 
 
 
 
 
 
 
 
6.9. 
Sample Management 
6.9.1. 
Blood and Urine Samples for Routine Safety Tests, Serology, FSH 
and Pregnancy Tests 
All blood and urine samples for routine safety tests, serology, FSH and pregnancy tests will 
be analyzed in a central laboratory and will be destroyed after analysis. 
6.9.2. 
Blood Samples for PK, ADA, and PD 
After the end of the study (e.g. last subject last visit), all PK, ADA and PD samples 
obtained during the clinical study may be stored for a period of maximum 5 years, after 
which the samples will be destroyed. The sample storage period will be in accordance with 
the IRB/IEC-approved ICF and applicable laws (e.g. health authority requirements). 
The stored samples shall only be used by the sponsor, sponsor partners, and/or other 
companies contracted by the sponsor, for research related to this clinical study or based on 
regulatory requirements. Any research outside the context described in this CSP may only 


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be conducted after approval by the IRB/IEC and Regulatory Authority and after obtaining 
informed consent from the subject. 
No characterization of human genetic material (genes, DNA, RNA) will be undertaken on 
these samples. If research is performed on genetic material of the samples then this can 
only be performed in context of the described CSP (example: biomarker analysis) and the 
data obtained may in no case be used for the purpose of identification or re-identification of 
subjects. 
6.9.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.10. 
Schedule of Activities 
For detailed instructions on the clinical study procedures, please see referred Sections below and Timing of Assessments (Section 6.1). 
EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Study Day (D)1 
D-28 to D-7 
D1 
D4 
±1 
D15 
±2 
D29 
±2 
D43 
±2 
D57 
±2/ 
ETD2 
D71 
±2 
D85 
±2/ 
D99 
±2 
D113 
±2 
D127 
±2 
D141 
±2 
D155 
±2 
D169 
±2/ ED 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Informed consent (Section 10.4.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria (Section 4.5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history (Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(Targeted) Physical examination (Section 
6.5.3) 
 
 
 
3 
 
3 
 
3 
 
3  
3  
3  
3  
3  
3  
Vital signs (Section 6.5.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (only at screening) and /or weight 
(Section 6.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG (Section 6.5.5) 
 
4 
 
 
 
4  
 
 
 
 
 
 
 
 
 
Pregnancy test5 (Section 6.5.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
1Visit dates are always calculated from Day 1 (unless subject discontinues early and attends an Early Treatment Discontinuation visit (ETD). If a subject has an ETD visit, the follow-up visits are 
performed 14, 28, 42, 56, 70, 84, 98 and 112 days after the ETD visit. 
2 Subject who are discontinued from treatment during the treatment period will perform Day 57/ETD visit (14 days after the last dose) as the last visit in the treatment period before entering the 
follow-up period. 
3 During these study visits, a targeted physical examination, consisting of cardiovascular, respiratory, gastrointestinal, and skin examination will be performed. 
4 At Day 1, ECG to be taken before dosing (triplicate ECGs) and approximately 1 hour after dosing. At Day 43, single ECG before dosing and approximately 1h after dosing. 
5 Females of childbearing potential only. Serum pregnancy test at screening, urine test before dosing on Day 1 and at all indicated time points thereafter. 


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EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Study Day (D)1 
D-28 to D-7 
D1 
D4 
±1 
D15 
±2 
D29 
±2 
D43 
±2 
D57 
±2/ 
ETD2 
D71 
±2 
D85 
±2/ 
D99 
±2 
D113 
±2 
D127 
±2 
D141 
±2 
D155 
±2 
D169 
±2/ ED 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
Clinical laboratory safety tests (incl. 
hematology, biochemistry and urinalysis), 
prior to injection on dosing days  
(Section 6.5.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology (Section 6.5.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Train and check compliance of e-diary use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording twice daily throughout study 
e-diary: TCS use 
Recording daily throughout study 
e-diary: emollient use 
Recording twice daily throughout study 
Provide Subject Participation Card (Section 
10.2.4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Skin swab (lesional and non-lesional) 
(Section 6.8.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
6 
 
 
 
 
 
 
 
 
                                                 
 
 


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EVENT 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
Study Day (D)1 
D-28 to D-7 
D1 
D4 
±1 
D15 
±2 
D29 
±2 
D43 
±2 
D57 
±2/ 
ETD2 
D71 
±2 
D85 
±2/ 
D99 
±2 
D113 
±2 
D127 
±2 
D141 
±2 
D155 
±2 
D169 
±2/ ED 
Study Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity assessment (ADAs; prior to 
injection on dosing days) (Section 6.6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samples (Section 6.5.6.1) 
 
7 
 
7 
7 
7 
 
 
 
 
 
 
 
 
 
PD and biomarker blood samples, (prior to 
injection on dosing days) (Section 6.7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (Section 4.6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP dosing (Section 5.2)8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection site reactions (Section 6.5.6.1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(S)AE assessment (Sections 6.5.1, 9.2) 
Throughout the study 
Prior/Concomitant medications 
(Section 4.5.3.2) 
Throughout the study 
 
 
 
 
 
                                                 
7 PK samples have to be taken before injection and 1 hour after the injection (+/- 10 minutes) on Day 1. Samples have to be taken before injection on Days 15, 29, and 43. 
8 A loading dose, consisting of two consecutive injections will be performed on Day 1. 


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7. 
STATISTICAL METHODS 
All statistical methods will be detailed in a statistical analysis plan (SAP). All relevant data 
collected in this clinical study will be documented using summary tables, figures, and subject 
data listings. 
An interim analysis may be performed when approximately 50% of subjects have reached the 
end of treatment period. The primary analysis includes all subjects that have completed their 
Day 57 visit or discontinued earlier. The final clinical study report (CSR) will be written at 
the end of the trial. 
The SAP will be prepared before the first interim analysis starts. Any deviations from the 
protocol are to be justified in the SAP. 
7.1. 
Determination of Sample Size 
Strict statistical criteria were not used to determine the sample size. A total of 60 subjects (40 
subjects on MOR106 treatment and 20 subjects on placebo) will be enrolled in this study, 
resulting in an estimated 51 evaluable subjects, which should give reasonable precision 
around the estimates derived for safety, PK, PD, and efficacy evaluation. 
With a sample size of 40 subjects on MOR106, there is a 87% probability to observe at least 
one occurrence of an adverse event if the natural incidence of this adverse event is 5%. The 
control group of subjects will serve as internal validation for any potential finding. 
 
 
 
 
7.2. 
Population for Analyses 
7.2.1. 
All Screened Subjects 
All subjects who signed and dated an ICF and underwent screening assessments to check 
whether or not they are eligible to participate in the clinical study. 
7.2.2. 
All Randomized Subjects 
All enrolled subjects who underwent all screening assessments and were found to be eligible 
for the clinical study and who were randomized into the clinical study. 
7.2.3. 
Full Analysis Set 
All randomized subjects who have received/used at least one dose of IMP and have at least 
one post-baseline assessment. 


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7.2.4. 
Per-Protocol Set 
All Full Analysis Set subjects who did not have a major protocol deviation that impacts the 
efficacy results (as defined in a protocol deviation plan). The determination of the per-
protocol population will be finalized and documented prior to database lock and unblinding. 
7.2.5. 
Safety and Immunogenicity Analysis Set 
All randomized subjects who used at least one dose of IMP. 
7.2.6. 
Pharmacokinetic Analysis Set 
Subset of the safety set, selecting all subjects who have available and evaluable serum 
concentration data (e.g. excluding all protocol deviations or AEs that may have an impact on 
the PK analysis). 
7.2.7. 
Pharmacodynamic Analysis Set 
Subset of the safety set, selecting all subjects who have a baseline and at least one post-
baseline evaluable PD value (e.g. excluding all protocol deviations that may have an impact 
on the PD analysis). 
7.3. 
Statistical Analyses 
7.3.1. 
General Statistical Considerations 
Summary tabulations will be presented and will display the number of observations, mean, 
standard deviations and/or standard error, as appropriate, median, minimum, and maximum 
for continuous variables, and the number and percentage per category for categorical data. In 
addition to tabulated descriptive statistics, graphical data displays may be used to summarize 
the data. Unless otherwise noted, inferential statistics will be interpreted at the 2-sided 5% 
significance level. Data may be pooled across centers. 
7.3.2. 
Interim Analysis 
An interim analysis may be performed when approximately 50% of the randomized subjects 
have completed the treatment period. The interim analysis may be conducted in order to 
obtain early information for planning of further studies and regulatory interactions. 
The results of the interim analysis will not be used to amend the current study. Sponsor 
personnel not involved in the day-to-day conduct of the study will be unblinded to perform 
analyses of the data and interpretation of the results. No study subjects or blinded study 
personnel involved in the day-to-day conduct (such the site staff, investigators and the 
operational team) will have access to the unblinded data before the database is locked for the 
final analysis. Details will be provided in the SAP. 
7.3.3. 
Primary analysis 
The  primary analysis will be performed when all subjects have completed their Day 57 visit 
or discontinued earlier.  


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The results of this analysis will not be used to modify or terminate the current study. The team 
performing or interpreting the analyses will be unblinded, but every effort will be made to 
keep the subject and investigator and those close to data entry/cleaning blinded until the 
database will be locked for the final analysis. At the time point of primary endpoint analysis, 
demographics, reason for early discontinuation from the study, all selected efficacy 
assessments, and safety (i.e. AEs, SAEs, AESIs, and laboratory tests) will be summarized. 
Analyses and populations to be used for the primary analysis will be similar to those for the 
final analysis and details wil be described in the SAP. 
7.3.4. 
Final analysis 
The final analysis will be performed when all subjects have completed their last study visit 
(i.e. Day 169), or discontinued earlier. Details will be provided in the SAP. 
7.3.5. 
Analyses of Demographics and Baseline Characteristics 
Subject disposition (including reasons for early discontinuation), protocol deviations, 
demographics, baseline characteristics, medical history, and concomitant therapies, will be 
analyzed descriptively based on the safety analysis set, and the full analysis set if the latter is 
different from the former. 
7.3.6. 
Analyses of Efficacy Parameters 
Efficacy endpoint analyses will be performed using the Full Analysis Set. Efficacy data will 
be summarized using descriptive statistics of actual values, changes from baseline, and 
percent changes from baseline, with 95% confidence intervals. Binary and categorical 
endpoints will be presented by number (percent) of subjects per treatment group and visit. 
Changes and percent changes from baseline for continuous endpoints 
 
 will be analyzed using an mixed-effects model for repeated measures. The 
model will include terms for treatment and visit as fixed effects, country and baseline value 
(continuous) as covariates, and treatment-visit as interaction term. 
Binary parameters 
) will be analyzed using a generalized 
estimating equation model. The model will include treatment and visit as fixed effects, 
country and baseline value (continuous) as covariates, and treatment-visit as an interaction 
term. 
Time to event endpoints will be presented using the Kaplan-Meier estimates and the two 
treatment groups will be compared using a log-rank test. 
More details will be provided in the SAP. 
The primary approach will be the observed case approach without imputation of missing data. 
In case of unexpected high attrition rates, sensitivity analyses including the use of multiple 
imputation methods may be considered. If more than 10% of subjects included in the full 
analysis set population are excluded from the per protocol analysis, a per protocol analysis 
will be performed. 
Additional exploratory analyses and graphical presentations may be performed when deemed 
useful to better understand the data and will be detailed in the SAP. 


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7.3.7. 
Analysis of Immunogenicity Data 
ADA status (positive/negative), titer (when ADA status was positive), and potential drug 
interference in the assay when ADA negative (yes/no) will be summarized descriptively for 
each part of the study, by treatment group, and time point. 
7.3.8. 
Analyses of Safety Data 
All safety analyses will be performed using the Safety Analysis Set (Section 7.2.5). Subjects 
will be analyzed according to the treatment they actually received. All safety data collected on 
or after the first dose of IMP administration up to the last follow-up visit after the last dose of 
IMP, unless specified otherwise, will be summarized by treatment group according to the IMP 
received. Clinical safety will be addressed by assessing AEs, laboratory assessments, physical 
examinations, vital signs, and 12-lead ECGs. Special attention will be paid to ISRs. 
7.3.8.1. 
Extent of Exposure 
A subject’s extent of exposure to IMP will be generated from the IMP administration page of 
the CRF. Extent of exposure data will be summarized by treatment group. Extent of exposure 
to IMP will be expressed as the number of days between the first and last dose of IMP, 
inclusive, regardless of temporary interruptions in IMP administration and summarized by 
treatment group. 
In addition, the number (percentage) of subjects who received all six doses, only five doses, 
four doses, etc. will also be summarized. 
7.3.8.2. 
Adverse Events 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities. System Organ Class (SOC), High Level Group Term, High Level 
Term, Preferred Term, and Lower-Level Term will be attached to the clinical database. 
Treatment-emergent adverse events (TEAEs) are defined as those with an onset date/time on 
or after the start date/time of the first IMP administration (including the follow-up period). 
Additionally, analyses will also be created, restricted to events with an onset date on or after 
the IMP start and up to 30 days after last dose of IMP. 
Summaries (number and percentage of subjects) of TEAEs per subject by SOC and Preferred 
Term will be provided by treatment group. TEAEs will also be summarized by causal 
relationship to IMP and severity. In addition, TEAEs leading to premature discontinuation of 
IMP will be summarized and listed. Also, all SAEs, including the non-treatment-emergent 
SAEs, will be listed. 
Counts tables will also be provided for the ISRs and skin events of special interest. 
Details will be provided in the SAP. 
7.3.8.3. 
Clinical Laboratory Evaluations 
Laboratory assessments will be analyzed descriptively. Changes from baseline (Day 1 
predose) and shifts according to normal ranges will be presented as well. Analyses will be 
done per treatment group. 


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7.3.8.4. 
Physical Examinations 
Only abnormal post-baseline physical examination results will be listed. 
7.3.8.5. 
Vital Signs 
Vital signs will be analyzed descriptively. Changes from baseline (Day 1 predose) and shifts 
according to normal ranges will be presented as well. Analyses will be done per treatment 
group. 
7.3.8.6. 
12-Lead Electrocardiogram 
A descriptive analysis will be done for the 12- lead ECG. Changes from baseline (Day 1 
predose) and shifts according to normal ranges (Appendix 1) will be presented as well. 
Frequency analyses of subjects with a QTc prolongation of more than >60 ms change from 
baseline; ≥501 ms will be presented as well. Analyses will be done per treatment group. 
7.3.8.7. 
Other Safety Assessments 
Counts tables will be provided for the ISRs. 
7.3.9. 
Pharmacokinetic Analyses 
For subjects in the PK analysis set, individual serum concentrations of MOR106 will be 
listed. Descriptive statistics will be calculated by day for the serum concentrations and on the 
listed PK parameter. Mean (± standard error) serum concentrations of MOR106 versus time 
will be plotted using both linear and semi-logarithmic scales. 
Only terminal elimination half-life (t1/2 expressed in h) will be determined for MOR106 serum 
concentrations by non-compartmental analysis using individual concentration-time profiles. 
Time to reach steady-state will be assessed by visual inspection of the trough serum 
concentrations as well as by means of a mixed effect analysis of variance on ln-transformed 
trough serum concentrations, with subject as random effect and day as fixed effect. 
Comparison between days will be performed. 
MOR106 serum levels will be analyzed using population PK analyses, which will be reported 
separately. 
7.3.10. 
Pharmacodynamic Analyses 
PD data will be summarized using descriptive statistics of actual values, changes from 
baseline, and percent changes from baseline. Details will be provided in the SAP. 
7.3.11. 
Analysis of Other Assessments 
Exploratory efficacy, safety/PK or PK/PD analyses may be added when deemed useful to 
better understand the collected data. Individual and/or mean ± standard error efficacy, safety, 
PD, and/or MOR106 serum concentrations may be plotted against one another. Details will be 
provided in the SAP and/or in a separate analysis plan, as appropriate. 


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7.3.12. 
Additional Statistical Considerations 
Not applicable. 
8. 
DATA MONITORING 
8.1. 
Independent Medical Review 
To safeguard the safety of the subjects, an independent Safety Review Committee (iSRC) 
consisting of independent dermatology and statistical experts will be implemented to review 
any accumulating unblinded safety data for the clinical study, specifically the review of any 
skin related AEs and serious adverse reactions. The specific responsibilities, composition, 
meeting formats and details of output provided for the meetings of the iSRC will be outlined 
in detail in an independent Safety Review Committee Charter. 
9. 
SAFETY REPORTING 
9.1. 
Definitions of Adverse Events, Serious Adverse Events, and 
Special Situations 
9.1.1. 
Adverse Events 
An AE is any untoward medical occurrence, new or worsening of any pre-existing condition, 
in a clinical study subject administered a medicinal product and which does not necessarily 
have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (for example, an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related. AEs may also include pre- or post-treatment 
complications that occur as a result of CSP-specified procedures, worsening of the targeted 
disease, overdose, drug abuse/misuse reports, or occupational exposure. Pre-existing 
conditions that increase in severity or change in nature during or as a consequence of 
participation in the clinical study will also be considered AEs. 
9.1.2. 
Serious Adverse Events 
An SAE is defined as an AE that: 
 
Results in death, 
 
Is life-threatening (Note: The term ‘life-threatening’ in the definition of ‘serious’ refers 
to an event in which the subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were more severe.), 
 
Requires in-patient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity, 
 
Is a congenital anomaly/birth defect, 
 
Is medically significant (medical and scientific judgment 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 
hospitalization but might jeopardize the subject or might require intervention to prevent 
one of the other outcomes listed in the definition above). 


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9.1.3. 
Unlisted (Unexpected) Adverse Event/Reference Safety Information 
An AE is considered unlisted if the nature or intensity is not consistent with the applicable 
product reference safety information. For MOR106, the expectedness of an AE will be 
determined by whether or not it is listed in the reference safety information part of the IB 
MOR106. 
9.1.4. 
Adverse Events of Special Interest 
Categories of AESIs are defined as follows: 
 ISRs (Grade 3 or higher). 
 Skin related AEs (except exacerbations and infective exacerbations of AD). 
 
9.1.4.1. 
Injection Site Reactions (ISRs) 
ISRs will be assessed as described in Section 6.5.6.1. The physician in attendance will do 
whatever is medically needed for the safety and well-being of the subject. The subject will 
remain under observation as long as medically indicated. 
All ISRs should be recorded as AEs in line with the Adverse Event Reporting requirements 
detailed in section 9.3.1 and graded using the CTCAE grading scale (v5.0) (CTCAE, 2017). 
Severe ISRs (CTCAE Grade 3 or higher) should be reported as SAEs in accordance with the 
expedited reporting requirements detailed in Section 9.3.2. 
9.1.4.2. 
Skin Related Adverse Events 
Subjects experiencing a skin related AE (except exacerbations and infective exacerbations of 
AD and ISRs) occurring after the first administration with study drug, should be examined by 
a dermatologist as soon as possible. The dermatologist will do whatever is necessary for the 
safety and well-being of the subject. A full narrative description of the skin related AE must 
be provided and the medical monitor and sponsor medical lead should be informed as soon as 
possible. Skin related AEs meeting seriousness criteria will be reported on an SAE report 
form within 24 hours. The sponsor will be supported by an independent dermatologist in the 
medical review of skin related AEs. 
For all skin related AESI, photography of the lesion(s) should be taken and where medically 
relevant, additional testing as required is permitted and may include the following 
recommended assessments: 
 
Skin swab of the lesion. 
 
Biopsy of the lesion. 
 
Additional blood sample for cytokine analysis. 
9.1.5. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
as Adverse Events or Serious Adverse Events 
Laboratory abnormalities without clinical significance based on the investigator’s judgment 
are not considered AEs or SAEs. However, laboratory abnormalities (e.g. clinical chemistry, 
hematology, and urinalysis) or other abnormal (clinical study-specific) assessments (e.g. 


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ECG, radiography, vital signs) that require medical or surgical intervention, are associated 
with signs and/or symptoms, and/or lead to IMP interruption, modification or discontinuation 
must be recorded as an AE or SAE if they meet the definition as described in Sections 9.1. If 
the laboratory abnormality is part of a syndrome, the syndrome or diagnosis is to be reported 
(e.g. anemia instead of decreased hemoglobin). 
9.1.6. 
Special Situations 
Special situations are situations that have a possible impact on the safe use of the IMP. These 
situations might be or might not be associated with AEs. 
 
Pregnancy 
 
Abuse or misuse of IMP 
 
Abuse of IMP is defined as the persistent or sporadic, intentional excessive use of the 
IMP, which is accompanied by harmful physical or psychological effects. 
 
Misuse of IMP is defined as a situation where the IMP is intentionally and 
inappropriately used not in accordance with the product information. 
 
 Drug interaction or food interaction with IMP 
 
A drug interaction with IMP is defined as a situation in which there is evidence or a 
suspicion that the IMP interacts with another drug when both are administered 
together. 
 
A food interaction with IMP is defined as a situation in which there is evidence or a 
suspicion that the IMP interacts with a food when taken together. 
 
 Medication error with IMP 
 
A medication error with IMP is defined as an unintended failure in the drug 
treatment process that leads to, or has the potential to lead to, harm to the subject. 
 
 Occupational exposure to IMP 
 
Occupational exposure to IMP is defined as an exposure to the IMP as a result of 
one’s professional or non-professional occupation. 
 
 Overdose with IMP 
 
An overdose of IMP is defined as the administration of a quantity of the IMP given 
per administration or cumulatively, which is any dose higher than the prescribed 
treatment. 
 
 Product complaint or quality defect of IMP 
 
Product complaint or quality defect of IMP is defined as complaints or defects of the 
IMP arising from potential deviations in the manufacture, packaging or distribution 
of the IMP. 
9.2. 
Assessment of Adverse Events and Serious Adverse Events 
The investigator is responsible for assessing AEs and SAEs for causality and severity. This is 
the basis for the sponsor’s final review and confirmation of accuracy and completeness of 
event information and causality assessments. 
9.2.1. 
Assessment of Causality 
The investigator is responsible for assessing the causal relationship to IMP(s) administration 
or study procedures (e.g. invasive procedures such as venipuncture) based on her/his clinical 


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judgment. The following decision choice will be used by the investigator to describe the 
causality assessment between the reported event or laboratory test abnormality and the IMP. 
When the causality assessment is ‘possible, probable or certain’, the IMP will be considered 
suspected and a ‘unrelated or unlikely’ causality will be considered as not suspected. 
 
Unrelated: 
Time relationship to IMP intake is improbable. Related to other etiologies such as 
concomitant medications or subject's clinical state. 
 
Unlikely: 
Time relationship to IMP intake is improbable (but not impossible). Concomitant disease 
or other drugs provide plausible explanations. 
 
Possible: 
Time relationship to IMP intake is reasonable. Event or laboratory test abnormality, 
could also be explained by disease or other drugs. Information on IMP withdrawal may 
be lacking or unclear. 
 
Probable: 
Time relationship to IMP intake is reasonable. Unlikely to be attributed to concurrent 
disease or other drugs. Response to withdrawal is clinically reasonable and rechallenge 
not required. 
 
Certain: 
Time relationship to IMP intake is plausible. Cannot be explained by concomitant disease 
or other drugs. Response to withdrawal is plausible (pharmacologically, pathologically). 
Event definitive pharmacologically or phenomenologically (i.e. an objective and specific 
medical disorder or a recognized pharmacological phenomenon). Rechallenge 
satisfactory, if ethical and necessary. 
It should be emphasized that ineffective treatment (worsening of the disease) should not be 
considered as causally related in the context of AE reporting. 
9.2.2. 
Assessment of Severity 
The severity of AEs should be graded using the Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 (CTCAE, 2017). If a CTCAE criterion does not exist, the 
investigator should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 
(severe), Grade 4 (life-threatening) or Grade 5 (fatal) to describe the maximum intensity of 
the AE. For purposes of consistency with the CTCAE, these intensity grades are defined in 
Table 1. 
 


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Table 1: 
Grading of AE Severity 
Grade  
Adjective  
Description  
Grade 1  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2  
Moderate 
Local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL*. 
Grade 3  
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**.  
Grade 4  
Life-threatening 
Urgent intervention indicated.  
Grade 5  
Death 
Death-related AE.  
* 
Instrumental activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or clothes, using the 
 
telephone, managing money, etc. 
** 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
 
bedridden. 
 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality. This is upon the investigator’s 
assessment. 
If there is a change in intensity (worsening or improvement) of an AE, it must be recorded. 
9.2.3. 
Outcome 
Each AE must be rated by choosing among: 
 
Recovered/resolved; 
 
Recovered/resolved with sequelae; 
 
Recovering/resolving; 
 
Not recovered/ not resolved; 
 
Fatal; 
 
Unknown. 
9.3. 
Investigator Requirements and Instructions for Reporting 
Adverse Events / Serious Adverse Events /Pregnancies, and 
Other Special Situations to the Sponsor 
9.3.1. 
Adverse Events 
The AE reporting period for safety surveillance begins when the subject signs the ICF and 
ends at the subject’s last follow-up visit (the last follow-up visit after the last dose of IMP). In 
this period, all new AEs, regardless of cause or relationship, derived by spontaneous, 
unsolicited reports of subjects, by observation and by routine open questioning (such as “How 
do you feel?”) need to be recorded in the source and in the CRF. 


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In case an AE is ongoing at the time of the last follow-up visit, the investigator needs to 
follow-up on the subject until AE resolution or reasonable stabilization and to document in 
the subject’s source documentation. No related updates or additional data on the AE should be 
reported in the CRF. 
If a subject is documented as lost-to-follow-up, ongoing/unknown outcome AEs will not be 
followed-up. 
If the AE meets the criteria for seriousness, the SAE form must be completed and sent to the 
sponsor within 24 hours (see Section 9.3.2). 
9.3.1.1. 
Adverse Events of Special Interest (AESI) 
AESIs need to be reported immediately, and AESIs meeting seriousness criteria need to be 
reported immediately as an SAE, and under no circumstances should this exceed 24 hours 
following the knowledge of the SAE. 
Details on events of special interest can be retrieved under Section 9.1.4. Additional 
information as detailed in Section 9.1.4 will be captured in the CRF. 
9.3.2. 
Serious Adverse Events 
Subjects experiencing an SAE or an emergency situation will be examined by a physician as 
soon as possible. The subject will remain under observation as long as medically indicated. 
Appropriate laboratory tests will be performed until all parameters return to normal or are 
otherwise explained or stable. 
All SAEs, whether or not deemed IMP-related, must be recorded in the CRF and on the SAE 
form. The investigator must report each SAE immediately, and under no circumstances 
should this exceed 24 hours following the knowledge of the SAE, as is indicated on Page 2 
under “Emergency Contact Information”. 
The SAE form should at least contain identifiers of the subject and the reporter, SAE term and 
statement of relatedness to the IMP, and at a later stage if not yet available within 24 hours, 
the form needs to be completed with a clearly written narrative describing signs, symptoms, 
and treatment of the event, diagnostic procedures, as well as any relevant laboratory data and 
any sequelae (preferably by the investigator). 
Follow-up and outcomes should be reported and documented in the source documents for all 
subjects that experience an SAE. It is important that the information provided on the SAE 
form matches the information recorded on the CRF for the same event. 
Copies of additional laboratory tests, consultation reports, post-mortem reports, hospital case 
reports, autopsy reports, and other documents should be sent when requested and available. 
Only subject number should appear on the copies, and all names and initials should be 
blackened and rendered illegible. Follow-up reports relative to the subject’s subsequent 
course must be submitted until the event has subsided or, in case of permanent impairment, 
until the condition stabilizes. 
Any SAE that occurs after the post-treatment follow-up visit but within 30 days of the last 
dose of IMP(s), regardless of causality, should also be reported (Emergency Contact 


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Information on Page 2). Investigators are not obligated to actively seek SAEs after the CSP-
defined follow-up period. However, if the investigator is informed about an SAE that occurs 
at any time after the subjects’ post-treatment follow-up visit and the event is deemed relevant 
to the use of IMP, he/she should promptly document and report the event to the sponsor by 
using the SAE form. 
9.3.3. 
Pregnancy 
All initial reports of pregnancy in female subjects and pregnancies in partners of male 
subjects included in the clinical study must be recorded and documented in the source 
documents and on the pregnancy form. The investigator must report each pregnancy 
immediately, and under no circumstances should this exceed 24 hours following the 
knowledge of the pregnancy, as is indicated on Page 2 under “Emergency Contact 
Information”. 
All pregnancies should be followed-up until delivery or pregnancy interruption. The 
investigator will contact the subject or partner of the subject after giving consent, at the 
expected time of delivery for follow-up and for information regarding the outcome of the 
newborn. Abnormal pregnancy and/or abnormal newborn outcomes are considered SAEs and 
must be reported using the SAE form. 
9.3.4. 
Reporting of Special Situations (Other Than Pregnancy) and 
Associated Adverse Events 
In case a special situation is not associated with an AE, the special situation should be 
reported within 24 hours by using the special situations form as is indicated on Page 2 under 
“Emergency Contact Information” 
In case a special situation is associated with an AE, the special situation should be reported 
within 24 hours by using the special situations form and the associated AE should be reported 
as specified in Section 9.3.1. 
In case a special situation is associated with an SAE, the special situation should be reported 
within 24 hours by using the SAE form (and not the special situations form) and the 
associated SAE should be reported as specified in Section 9.3.2. 
9.4. 
Sponsor Reporting Requirements 
Depending on relevant local legislation or regulations, including the applicable United States 
Federal Drug Administration Code of Federal Regulations, the European Union (EU) Clinical 
Trials Directive (2001/20/EC) and relevant updates, and other country specific legislation or 
regulations, the sponsor may be required to expedite to worldwide regulatory agencies reports 
of SAEs, serious adverse drug reactions, or suspected unexpected serious adverse reactions 
(SUSARs). The sponsor or a specified designee will notify worldwide regulatory agencies and 
the relevant IEC/IRB in concerned Member States of applicable SUSARs as outlined in 
current regulations. 
Assessment of expectedness for SAEs will be determined using reference safety information 
section in the IB or relevant local label as applicable. 


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All concerned investigators will receive a safety letter notifying them of relevant SUSAR 
reports associated with any IMP(s). The investigator should notify the IEC/IRB of SUSAR 
reports as soon as is practical, where this is required by local regulatory agencies, and in 
accordance with the local institutional policy. 
10. 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This clinical study is conducted in accordance with the current applicable regulations, ICH-
GCP Guideline E6, and local regulations. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety and well-being 
of clinical study subjects are protected, consistent with the principles that have their origin in 
the Declaration of Helsinki, and that the clinical study data are credible. 
The name and address of each third-party vendor (e.g. CRO) used in this study and the 
sponsor’s study team members will be maintained in the investigator’s and sponsor’s files as 
appropriate. 
10.1. 
Sponsor’s Responsibilities 
10.1.1. 
Regulatory Approval / Notification 
Prior to clinical study start, this CSP together with all relevant documentation will be 
submitted to the local regulatory authorities for review and approval and/or notification in 
compliance with local requirements. 
10.1.2. 
Clinical Study Closure Considerations 
The sponsor reserves the right to close the investigational site or end the clinical study at any 
time for any reason. In case of an early termination of the clinical study or temporary halt by 
the sponsor, the IEC/IRB should be notified within 15 calendar days unless otherwise 
specified by the IEC/IRB, including a detailed written explanation of the reasons for the 
termination/halt. 
The end of clinical study declaration will be submitted to the regulatory authorities and 
IEC/IRB after the complete clinical study has ended in all participating centers, in all 
countries. This notification will also be submitted within 90 days of the end of the clinical 
study in a given country/member state or within the timelines required by the local 
regulations. 
Reasons for the closure of an investigational site include but are not limited to: 
 
Successful completion of the clinical study at the center. 
 
The overall required number of subjects for the clinical study has been recruited. 
 
Failure of the investigator to comply with the CSP, ICH-GCP Guidelines or local 
regulations. 
 
Inadequate recruitment of subjects by the investigator. 


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Reasons for early termination of a clinical study by the sponsor may include but are not 
limited to: 
 
Safety concerns. 
 
Sufficient data suggesting lack of efficacy. 
10.1.3. 
Indemnification 
Under the conditions of a contract concluded between investigator, site, and sponsor or 
designee, which shall prevail, sponsor shall, except in case of gross negligence or willful 
misconduct, indemnify and hold harmless the investigator and his/her medical staff from any 
claim arising from the clinical study activities carried out in compliance with the CSP, 
sponsor’s instructions, and applicable local regulations. 
The investigator must notify the sponsor immediately upon notice of any claims or lawsuits. 
10.1.4. 
Insurance 
Sponsor shall maintain insurance coverage that is sufficient to cover its obligations and that is 
consistent with human clinical study local regulations. Save in case of gross negligence or 
willful misconduct of the investigator, and provided that the subject has been treated 
according to the CSP and sponsor’s instructions, any injury caused to a subject which is the 
direct result of his/her participation to the clinical study shall be covered by sponsor’s 
insurance. 
10.1.5. 
Reporting 
Where required by IEC/IRB per local requirements, at least once a year the investigator will 
provide the IEC/IRB with a progress report to allow review of the clinical study (see 
Section 10.4.1). At the end of the clinical study, the results of the clinical study will be 
reported in a single CSR. A summary or full report, depending on the requirements, will be 
provided to the investigators, to the applicable regulatory authorities and IECs/IRBs if 
required by the applicable regulatory requirements. 
10.1.6. 
Publication 
It is understood by the investigator that the sponsor shall be free to use the compound-related 
information which is generated during the clinical study and may disclose it to other clinical 
investigators and to regulatory agencies. As a consequence, the investigator agrees to provide 
all clinical study results and data generated during this clinical study to sponsor. 
The investigator shall not be authorized to submit the results of this clinical study and any 
data for publication or presentation without the prior written approval of the sponsor which 
shall not be unreasonably withheld. 
However, it is understood and agreed by the investigators that their results and/or findings 
shall not be authorized for publication prior to sponsor’s publication of the overall clinical 
study results. The investigator agrees that prior to the publication of any results, he/she shall 
provide sponsor with a draft copy of the intended publication. Sponsor shall have the right to 
review it and to make any comments. In accordance with generally accepted scientific 
collaboration principles, co-authorship with any staff member sponsor involved in the clinical 


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study, will be discussed and mutually agreed upon before submission of any manuscript to a 
publisher. 
10.2. 
Investigator’s Responsibilities 
10.2.1. 
Financial Disclosure 
The disclosed financial interest of the investigators must be collected before screening of the 
first subject, following clinical study completion at the investigator site, and 1 year following 
overall clinical study completion. The investigators should promptly update this information 
if any relevant changes occur during this period. Disclosable financial interests will be 
recorded on the Investigator Financial Disclosure Form. 
Any investigator(s) added as investigational staff directly involved in the treatment or 
evaluation of the subject with direct and significant contribution to the study data must 
complete the Investigator Financial Disclosure Form at the beginning of their participation in 
the clinical study. For any investigator(s) leaving the site prior to clinical study completion, an 
Investigator Financial Disclosure Form should be obtained at the end of their contribution to 
the clinical study. 
10.2.2. 
Source Data and Data Capture 
The nature and location of all source documents need to be identified and documented to 
ensure that all sources of original data required to complete the CRF are known and are 
accessible for verification by the monitor. 
Source data may be directly captured from devices transferred from third partners (e.g. 
laboratory data) or entered manually into the CRF. The CRF completion guidelines will be 
provided to each investigational site. 
It is recommended that the author of an entry in the source documents should be identifiable. 
Following ICH-GCP Guidelines, direct access to source documents must be granted for the 
purpose of verifying that the data recorded on the CRF are consistent with the original source 
data. 
10.2.3. 
Archiving 
The investigator shall maintain the clinical study-specific documents as specified in Section 8 
“Essential Documents for the Conduct of a Clinical Study” of the ICH-GCP Guidelines (ICH-
E6) and as required by the applicable regulatory requirement(s). The investigator should take 
measures to prevent accidental or premature destruction of these documents. 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the IMP. These documents should be retained for a 
longer period however if required by the applicable regulatory requirements or by an 
agreement with the sponsor. 
Under no circumstance shall the investigator relocate or dispose of any clinical study 
documents before having obtained a written approval of the sponsor. 


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If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this clinical study, the investigator must permit access to such 
reports. The subject is granting access to his/her source data by signing the informed consent. 
Any difficulty in storing original documents must be discussed with the monitor prior to the 
initiation of the clinical study. 
10.2.4. 
Participation Cards 
If the subjects are not under 24-hour supervision of the investigator or his/her staff (out-
subjects), they must be provided with a subject participation card indicating the name of the 
IMP, the clinical study number, the investigator's name and a 24-hour emergency contact 
number. The subject should be advised to keep the participation card in his/her wallet at all 
times. 
10.3. 
Confidentiality 
The subject will receive all information as required by the EU General Data Protection 
Regulation, namely the identity and contact details of the controller, the contact details of the 
data protection officer, the clinical research purposes, the legal basis for the processing, the 
recipients of the personal data, the transfer of the personal data to third countries and 
respective safeguards, the retention periods, the fair processing of his data, and all his/her data 
subject’s rights. All details are listed in the ICF. 
All information concerning the product and the sponsor’s operations (such as patent 
applications, formulae, manufacturing processes, basic scientific data or formulation 
information supplied to the investigator by the sponsor and not previously published) is 
considered confidential by the sponsor and should not be disclosed by the investigator to any 
third party without the sponsor’s prior written approval. The investigator agrees to use this 
information only in accomplishing the clinical study and will not use it for other purposes. 
In order to permit easy identification of the individual subject during and after the clinical 
study, the investigator is responsible for keeping an updated Subject Identification Code List. 
The monitor will review this document for completeness. However, the investigator must 
guarantee the subject’s anonymity will be maintained. Therefore, in order to ensure subject 
confidentiality, the Subject Identification Code List will remain at the center and no copy will 
be made. 
10.4. 
Ethical Considerations 
10.4.1. 
Independent Ethics Committee (IEC) / Institutional Review Board 
(IRB) 
This clinical study can only be undertaken after full approval of the CSP, informed consent, 
any other written information given to subjects, and subject recruitment materials has been 
obtained from the IEC/IRB. This approval document must be dated and clearly identify the 
clinical study and the related clinical study documents being approved, including the subject 
compensation programs, if applicable. 
During the course of clinical study at least the following documents will be provided to the 
IEC/IRB per local requirements: 


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 
Changes to the IB 
 
Reports of AEs that are serious, unlisted and associated with the investigational drug (in 
compliance with IEC/IRB, per local requirements) 
 
CSP amendments 
 
Informed consent revision(s) 
CSP amendments and applicable ICF revisions must promptly be submitted to the IEC/IRB 
for review and approval prior to implementation of the change(s), except when necessary to 
eliminate an immediate hazard to the clinical study subjects, or according to local 
requirements. 
The IEC/IRB is responsible for continuous review of the clinical study. Where required by 
IEC/IRB per local requirements, at least once a year the investigator will provide the IEC/IRB 
with a progress report to allow review of the clinical study. Additional progress reports should 
be provided according to local legal requirements. These requests and (re) approvals, if 
applicable, should be documented in writing. 
10.4.2. 
Informed Consent 
The principal investigator or designated personnel must explain the clinical study and the 
implications of participation (e.g. objectives, methods, anticipated benefits, and possible risks) 
to potential subjects according to applicable regulations prior to any clinical study-related 
activity. Subjects will be informed that their participation is voluntary and that they may 
withdraw from the clinical study at any time. They will be informed that choosing not to 
participate or to withdraw from the clinical study will not have an impact on the care the 
subject will receive for the treatment of his/her disease. In case the subject is unable to read 
and write, an impartial witness must confirm the informed consent. 
The subject will be given sufficient time to read the ICF and to ask additional questions. After 
this explanation and before entry in the clinical study, consent should be appropriately 
recorded by means of the subject's personally dated signature (or, if applicable, by the 
signature of an independent witness who certifies the subject's consent in writing) and by the 
investigator’s signature. After having obtained the consent, a copy of the signed and dated 
informed consent must be given to the subject. 
If new information becomes available that may be relevant to the subject’s willingness to 
participate in the clinical study, the subject will be informed in a timely manner by means of 
an updated ICF. This amended ICF will be signed and dated by the subject (or, if applicable, 
by an independent witness) and the investigator to document the willingness of the subject to 
continue with the clinical study. 
This signed and dated amended version will be filed together with the initial signed and dated 
ICF. 
The skin biopsy sub-study and eczema area photography are optional and separate ICFs need 
to be obtained from the subjects. Subjects can participate in the main clinical study without 
having to participate in one of the sub-studies. Subjects will also be informed that their 
participation for the sub-studies is voluntary and that they may withdraw their consent at any 
time. If a subject chooses to withdraw consent for a sub-study then the investigator or 
designated personnel must inform the sponsor. 


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A pregnant partner who agrees that information will be gathered about her pregnancy and the 
birth and health of her baby, will sign a specific ICF to participate in the data collection. 
10.5. 
Data Quality Control / Assurance 
10.5.1. 
Monitoring 
This clinical study will be monitored by sponsor representatives according to their current 
Standard Operating Procedure for the monitoring of clinical studies as described in the 
monitoring plan. 
To guarantee adequate protection of the subjects and to guarantee the quality of the data, the 
sponsor will ensure oversight of any clinical study-related duties and functions carried out on 
its behalf, including clinical study-related duties and functions that are subcontracted to 
another party by the sponsor’s contracted CRO(s). 
10.5.2. 
Audit and Inspection 
To ensure compliance with relevant regulations, an independent quality assurance 
representative, regulatory authorities and/or IECs/IRBs may review this clinical study. This 
implies that auditors/inspectors will have the right to inspect the clinical study center(s) at any 
time during and/or after completion of the clinical study and will have access to the data 
generated during the clinical study, source documents, and subject's files. By participating in 
this clinical study, investigators agree to this requirement. 
 


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11. 
REFERENCES 
 
BLA761061. (2017). Tremfva - FDA Multi-disciplanary Review and Evaluation.  
 
 
CTCAE. (2017). Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
Dupixent. (2016). FDA CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS 
REVIEW(S). \\CDSESUB1\evsprod\BLA761055\761055.enx. 
Dupixent Product Monograph. (2017/2018). Health Canada Regulatory Decision Summary 
for Dupixent 2017. //hpr-rps.hres.ca/reg-content/regulatory-decision-summary-
detail.php?lang=en&linkID=RDS00309. 
 
 
Garmhausen, D., Hagemann, T., & Bieber, T. (2013). Characterization of different courses of 
atopic dermatitis in adolescent and adult patients. Allergy, 68(4): 498-506. 
Grote-Wessels, S. (2018). MOR106-P013. 4-week subcutaneous toxicity study in the 
cynomolgus monkey with a 4-week recovery period. MorphoSys. 
 
 
Johansen, C., Riis, J., & Gedebjerg, A. (2011). Tumor necrosis factor alpha-mediated 
induction of interleukin 17C in human keratinocytes is controlled by nuclear factor 
kappaB. J Biol Chem, 286(29): 25487-94. 
Johnston, A., Fritz, Y., & Dawes, S. (2013). Keratinocyte overexpression of IL-17C promotes 
psoriasiform skin inflammation. J Immunol, 190(5): 2252-62. 
 
 
 
Manciaux, D. (2016a). MOR106-P003. MorphoSys. 
Manciaux, D. (2016b). MOR106-P004. Y010218 - 4-week intravenous toxicity study in the 
cynomolgus monkey followed by a 4-week treatment-free period. MorphoSys. 
MOR106-CL-102. (2018). A parallel-design Phase 1 study to assess safety, tolerability and 
pharmacokinetics/exposure following different single dose levels of MOR106 


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(administered subcutaneously or intravenously) in healthy male subjects (randomized, 
open-label), and in subjects. EudraCT: 2018-000357-44. 
MOR106-CL-201. (2017). A Phase II, randomized, double-blind, placebo-controlled 
repeated-dose study to evaluate the efficacy, safety, tolerability, and PK/PD of 
intravenously administered MOR106 in adult subjects with moderate to severe atopic 
dermatitis. EudraCT 2017-001142-10. 
Perron, J. (2017). MOR106-P007. 13-week toxicity study by slow bolus intravenous 
administration in CD1 mice with a 13-week recovery period.  
 
 
 
Ramirez-Carrozzi, V., Sambandam, A., & Luis, E. (2011). IL-17C regulates the innate 
immune function of epithelial cells in an autocrine manner. Nat Immunol., 
12(12):1159-66. 
 
Schmitt, J., Spuls, P., & Thomas, K. (2014). HOME. initiative collaborators. The 
Harmonising Outcome Measures for Eczema (HOME) statement to assess clinical 
signs of atopic eczema in trials. J Allergy Clin Immunol, pp. 134(4):800-7. 
 
 
Timmis, H. (2015). MOR106-CL-101. Randomized, double-blind, placebo-controlled, dose-
escalation, phase I study for the assessment of safety, tolerability and PK of single 
ascending doses of MOR106 in healthy male subjects and multiple ascending doses in 
subjects with moderate. EudraCT: 2015-005434-22. 
 
 
 


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12. 
APPENDICES 
Appendix 1: Normal Ranges 
 
NORMAL RANGES FOR VITAL SIGNS 
Normal ranges applicable in supine position (after 5 minutes): 
Systolic blood 
pressure (mmHg) 
Diastolic blood 
pressure (mmHg) 
Heart rate 
(bpm) 
90≤ BSP ≤140 
45≤ DBP ≤90 
40≤ HR ≤100 
 
NORMAL RANGES FOR ECG PARAMETERS 
Normal ranges applicable in supine position (after 5 minutes): 
PR 
(ms) 
QRS 
(ms) 
QTc 
(ms) 
Heart rate 
(bpm) 
110≤ PR ≤220 
QRS ≤120 
QTc ≤450 (male) 
QTc ≤460 (female)  
40≤ HR ≤100 
 
 
 


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SIGNATURE PAGE – SPONSOR 
 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter Phase 2 
study to evaluate the safety and tolerability of subcutaneous MOR106 
administered concomitantly with topical corticosteroids for eight weeks, 
in adult subjects with moderate to severe atopic dermatitis. 
 
 
 
 
 
This clinical study protocol has been reviewed and approved by the sponsor to ensure 
compliance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practices (GCP) and 
applicable regulatory requirements. 
 
 
 
CSP Version: 
4.0 
 
Date: 
25-Jun-2019 
 
 
 
  
  
Medical Leader 
 Signature 
 Date 
 
 
 


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SIGNATURE PAGE – INVESTIGATOR 
 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter Phase 2 
study to evaluate the safety and tolerability of subcutaneous MOR106 
administered concomitantly with topical corticosteroids for eight weeks, 
in adult subjects with moderate to severe atopic dermatitis. 
 
 
 
 
 
 
I, the undersigned, have read this clinical study protocol and will conduct the study as 
described in compliance with the clinical study protocol, in accordance with International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) guidelines for Good Clinical Practices (GCP) and applicable regulatory requirements. 
 
 
 
 
CSP Version: 
4.0 
 
 
 
 
 
Date: 
 
 
 
 
25-Jun-2019 
 
 
 
  
  
Investigator 
 Signature 
 Date 
 
 

SAP_001.pdf: 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos 
NV or Galapagos SASU and may not be used, disclosed, reproduced or otherwise disseminated within your 
organization or communicated to any third parties without the express written authorization of Galapagos 
NV or Galapagos SASU. 
 
 
STATISTICAL ANALYSIS PLAN 
 
Project Number: 
MOR106 
Study Number: 
MOR106-CL-204 
Study Title: 
A randomized, double-blind, placebo-controlled, multicenter 
Phase 2 study to evaluate the safety and tolerability of 
subcutaneous MOR106 administered concomitantly with topical 
corticosteroids for eight weeks, in adult subjects with moderate to 
severe atopic dermatitis. 
 
Development Phase: 
II 
Status: 
Final 
Version: 
1.0 
Date: 12-Mar-2020 
EudraCT: 
Not applicable 
IND: 
Not applicable 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan L11 A3, 2800 
Mechelen, Belgium 
 
Document Author: 
 
Biostatistician: 
 
Clinical Study Lead: 
 


 
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TABLE OF CONTENTS 
Statistical Analysis Plan ........................................................................................................... 1 
Table of Contents ..................................................................................................................... 2 
List of Tables ............................................................................................................................. 7 
List of Figures ......................................................................................................................... 10 
List of Listings ........................................................................................................................ 11 
Abbreviations Commonly Used ............................................................................................ 13 
Definitions of Terms Commonly Used ................................................................................. 15 
1. Introduction ...................................................................................................................... 16 
1.1. 
Clinical Study Protocol (CSP) and CSP Amendments Version Overview .............. 16 
1.2. 
Statistical Analysis Plan (SAP) Version Overview.................................................. 17 
2. Study Objectives and Design ........................................................................................... 18 
2.1. 
Study Objectives ...................................................................................................... 18 
2.1.1. 
Primary Objective ....................................................................................... 18 
2.1.2. 
Secondary Objectives .................................................................................. 18 
2.1.3. 
Other Objectives ......................................................................................... 18 
2.2. 
Study Design ............................................................................................................ 18 
2.3. 
Study Endpoints ....................................................................................................... 19 
2.3.1. 
Primary Endpoints....................................................................................... 19 
2.3.2. 
Secondary Endpoints................................................................................... 19 
2.3.3. 
Other Endpoints .......................................................................................... 19 
2.4. 
Schematic Diagram of the Study .............................................................................. 20 
2.5. 
Schedule of Activities .............................................................................................. 21 
3. Definition of Analysis Populations .................................................................................. 24 
3.1. 
All Screened Subjects............................................................................................... 24 
3.2. 
All Randomized Subjects ......................................................................................... 24 
3.3. 
Safety and Immunogenicity Analysis Set ................................................................ 24 
3.4. 
Full Analysis Set ...................................................................................................... 24 
3.5. 
Pharmacokinetic Analysis Set .................................................................................. 24 
4. Treatment Groups ............................................................................................................ 25 
4.1. 
Consideration of the Planned versus the Actual Treatment ..................................... 25 
4.2. 
Definition of Treatment Group Labels ..................................................................... 25 
4.3. 
Totals Over Treatment Groups ................................................................................. 25 
5. Definition of Analysis Periods, of Analysis Time Points, and of Baseline ................... 26 
5.1. 
Analysis Periods for Non-visit Data......................................................................... 26 
5.2. 
Algorithm of Allocating Visits to Time Windows ................................................... 26 
5.3. 
Selection of Visits .................................................................................................... 31 
5.4. 
Calculation of Relative Days and Durations ............................................................ 31 
5.5. 
Definition of Baseline .............................................................................................. 32 
6. Selection of Data Records for Analysis ........................................................................... 33 
6.1. 
Records having Extreme Values .............................................................................. 33 
6.2. 
Repeated Analysis Visits and Analysis Time Points ............................................... 33 


 
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6.3. 
Unscheduled Analysis Visits .................................................................................... 33 
6.4. 
Selection of Values Provided in Different Units ...................................................... 33 
7. Handling of Data ............................................................................................................... 33 
7.1. 
Handling of Missing Data ........................................................................................ 33 
7.1.1. 
Missing Records or Missing Values ........................................................... 33 
7.1.2. 
Missing Dates or Times or Partially Known Dates or Times ..................... 33 
7.2. 
Handling of Seconds in Time Fields ........................................................................ 34 
7.3. 
Calculation and Presentation of Descriptive Statistics ............................................. 34 
7.4. 
Presentation of Inferential Statistical Analysis ........................................................ 35 
7.5. 
Calculation and Presentation of Frequencies ........................................................... 35 
7.6. 
Calculation and Presentation of Percentages ........................................................... 35 
7.7. 
Categorization of Results of Continuous Parameters ............................................... 35 
7.8. 
Handling of Values Below or Above a Threshold ................................................... 35 
7.9. 
Software, Procedures and Standards ........................................................................ 36 
7.9.1. 
Software ...................................................................................................... 36 
7.9.2. 
Procedures ................................................................................................... 36 
7.9.3. 
Standards for Data Storage and for Analysis Layout .................................. 37 
8. Statistical Methods ........................................................................................................... 38 
8.1. 
Planned Analyses, Protocol Amendments Included ................................................ 38 
8.1.1. 
Final Analysis ............................................................................................. 38 
8.1.2. 
Sample Size ................................................................................................. 38 
8.1.3. 
General Statistical Considerations .............................................................. 38 
8.1.4. 
Analyses of Demographics and Baseline Characteristics ........................... 38 
8.1.5. 
Analysis of Efficacy Parameters ................................................................. 38 
8.1.6. 
Analysis of Immunogenicity Data .............................................................. 39 
8.1.7. 
Analyses of Safety Data .............................................................................. 39 
8.1.7.1. 
Extent of Exposure ................................................................... 39 
8.1.7.2. 
Adverse Events (AEs) .............................................................. 39 
8.1.7.3. 
Clinical Laboratory Evaluations .............................................. 40 
8.1.7.4. 
Physical Examinations ............................................................. 40 
8.1.7.5. 
Vital Signs ................................................................................ 40 
8.1.7.6. 
12-Lead Electrocardiogram ...................................................... 40 
8.1.7.7. 
Other Safety Assessments ........................................................ 40 
8.1.8. 
Pharmacokinetic Analyses .......................................................................... 40 
8.1.9. 
Pharmacodynamic Analyses ....................................................................... 41 
8.1.10. Additional Statistical Considerations .......................................................... 41 
8.2. 
Changes to the Planned Analyses, Not Covered by The Protocol or by 
Protocol Amendments .............................................................................................. 41 
8.2.1. 
Changes before Database Lock and Justification ....................................... 41 
8.2.2. 
Changes after Database Lock and Justification .......................................... 42 
9. Analysis of General Subject Information and Definition of Analysis TLFs ............... 43 
9.1. 
Subject Disposition .................................................................................................. 43 
9.2. 
Protocol Deviations and Eligibility .......................................................................... 45 
9.3. 
Subjects Excluded from Analysis Part ..................................................................... 46 
9.4. 
Demographics and Baseline Characteristics ............................................................ 46 
9.4.1. 
Parameters ................................................................................................... 46 


 
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9.4.2. 
Analysis ....................................................................................................... 47 
9.5. 
Baseline disease characteristics ................................................................................ 48 
9.5.1. 
Parameters ................................................................................................... 48 
9.5.2. 
Analysis ....................................................................................................... 48 
9.6. 
Medical History and Concurrent Diseases ............................................................... 49 
9.7. 
Prior and Concomitant therapies .............................................................................. 50 
9.7.1. 
Coding of Reported Terms .......................................................................... 50 
9.7.2. 
Categorization for Timing ........................................................................... 50 
9.7.3. 
Calculation of the Relative Days ................................................................ 50 
9.7.4. 
Analysis ....................................................................................................... 51 
9.8. 
Exposure to Study Medication and Compliance ...................................................... 52 
9.8.1. 
Derivations .................................................................................................. 52 
9.8.2. 
Analysis ....................................................................................................... 52 
10. Analysis of Efficacy and Definition of Analysis TLFs ................................................... 54 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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11. Analysis of Pharmacokinetics and Definition of Analysis TLFs .................................. 67 
11.1. Definitions, Derivation Rules and Presentation of PK Parameters .......................... 67 
11.1.1. Available Data............................................................................................. 67 
11.1.2. PK Parameters and Derivation Rules .......................................................... 67 
11.1.3. PK Derivation Rules ................................................................................... 67 
11.1.4. Tables .......................................................................................................... 67 
11.1.5. Figures ......................................................................................................... 68 
11.1.6. Listings ........................................................................................................ 68 
12. Analysis of Immunogenicity and Definition of Analysis TLFs ..................................... 69 
13. Analysis of Pharmacodynamics and Definition of Analysis TLFs ............................... 70 
13.1.1. Disease Status Definition ............................................................................ 70 
13.1.2. Tables .......................................................................................................... 70 
13.1.3. Figures ......................................................................................................... 70 
13.1.4. Listings ........................................................................................................ 70 
14. Analysis of Safety and Definition of Analysis TLFs ...................................................... 71 
14.1. Adverse Events ......................................................................................................... 71 
14.1.1. Coding of Reported Terms .......................................................................... 71 
14.1.2. Definition of Treatment-emergent Adverse Events .................................... 71 
14.1.2.1. 
Combining of Events to be Able to Count Number of Events . 72 
14.1.3. Allocation of Adverse Events to Analysis Periods ..................................... 72 
14.1.4. Treatment Relatedness ................................................................................ 72 
14.1.5. Worst-case Selections ................................................................................. 73 
14.1.6. Adverse Event Onset Day and Duration ..................................................... 73 
14.1.7. Calculation of Percentages .......................................................................... 74 
14.1.8. Tables .......................................................................................................... 74 
14.1.9. Figures ......................................................................................................... 77 
14.1.10. Listings ........................................................................................................ 77 
14.2. Non-drug Related Therapies .................................................................................... 81 
14.2.1. Coding of Reported Terms .......................................................................... 81 
14.2.2. Calculation of the Relative Days ................................................................ 81 
14.2.3. Analysis ....................................................................................................... 81 
14.3. Laboratory Safety ..................................................................................................... 82 
14.3.1. Available Data............................................................................................. 82 


 
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14.3.2. Number of Significant Digits ...................................................................... 82 
14.3.3. Categorization of Laboratory Parameters ................................................... 82 
14.3.4. Derivation of Laboratory Parameters .......................................................... 82 
14.3.5. Baseline and Change from Baseline ........................................................... 82 
14.3.6. Scoring of Laboratory Values ..................................................................... 82 
14.3.6.1. 
Scoring According to Normal Ranges ..................................... 82 
14.3.6.2. 
According to CTCAE Grades .................................................. 83 
14.3.7. Treatment-emergent Principle ..................................................................... 84 
14.3.7.1. 
Toxicity Grades ........................................................................ 84 
14.3.7.2. 
Non-graded Abnormalities ....................................................... 84 
14.3.8. Determination of Worst-case Abnormality ................................................. 85 
14.3.8.1. 
According to Normal Range .................................................... 85 
14.3.8.2. 
According to CTCAE Grades .................................................. 85 
14.3.9. Handling of Categorical Laboratory Parameters ........................................ 85 
14.3.10. Tables .......................................................................................................... 85 
14.3.11. Figures ......................................................................................................... 87 
14.3.12. Listings ........................................................................................................ 87 
14.4. ECG .......................................................................................................................... 88 
14.4.1. Available Data............................................................................................. 88 
14.4.2. Number of Significant Digits ...................................................................... 88 
14.4.3. Derivation of ECG Parameters ................................................................... 88 
14.4.4. Handling of ECGs Measured in Triplicate ................................................. 88 
14.4.5. Definition of Normal Ranges and Abnormalities ....................................... 88 
14.4.6. Definition of Treatment-emergent ECG Abnormalities ............................. 89 
14.4.1. Determination of Worst-case Abnormality ................................................. 89 
14.4.2. Tables .......................................................................................................... 89 
14.4.3. Listings ........................................................................................................ 90 
14.5. Vital Signs ................................................................................................................ 91 
14.5.1. Available Data............................................................................................. 91 
14.5.2. Number of Significant Digits ...................................................................... 91 
14.5.3. Derivation of Vital Signs Parameters .......................................................... 91 
14.5.4. Definition of Normal Ranges and of Abnormalities ................................... 91 
14.5.5. Definition of Treatment-emergent Vital Signs Abnormalities ................... 92 
14.5.6. Determination of the Worst-case Abnormality ........................................... 92 
14.5.7. Tables .......................................................................................................... 92 
14.5.8. Listings ........................................................................................................ 93 
14.6. Physical Examinations ............................................................................................. 93 
15. References .......................................................................................................................... 94 
16. Appendix ............................................................................................................................ 95 
16.1. PK Data Review ....................................................................................................... 95 
 
 
 


 
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LIST OF TABLES 
Table 14.1.1.1:  
Subject disposition: Analysis populations ............................................... 43 
Table 14.1.1.2:  
Subject disposition: Tabulation by country and site ................................ 43 
Table 14.1.1.3:  
Subject disposition: Tabulation of the number of subjects at each 
time interval ............................................................................................. 43 
Table 14.1.1.4:  
Subject disposition: Study and treatment completion and 
discontinuation ......................................................................................... 43 
Table 14.1.1.5:  
Subject disposition: First and last dates in the study ................................ 44 
Table 14.1.4.1:  
Protocol deviations: Summary of major protocol deviations ................... 45 
Table 14.1.3.1:  
Demographic data: Descriptive statistics and tabulation ......................... 47 
Table 14.1.3.2:  
Screening and baseline disease characteristics ........................................ 48 
Table 14.1.3.3:  
Medical history: Tabulation ..................................................................... 49 
Table 14.1.3.4:  
Concurrent diseases: Tabulation .............................................................. 49 
Table 14.1.3.5:  
Prior therapies: Tabulation ....................................................................... 51 
Table 14.1.3.6:  
Concomitant therapies: Tabulation .......................................................... 51 
Table 14.1.5.1:  
Use of study medication: Descriptive statistics ....................................... 52 
Table 14.1.5.2:  
Use of study medication: Tabulation of the number of injections 
received .................................................................................................... 52 
Table 14.2.1.1:  
 
 .............. 54 
Table 14.2.1.4:  
 ........... 55 
Table 14.2.1.5:  
 ......................................................................... 55 
Table 14.2.1.6:  
 ................... 56 
Table 14.2.1.8:  
 ................................................................. 57 
Table 14.2.1.9:  
 
 .............. 58 
Table 14.2.1.11:  
 
 ..................................................................................................... 58 
Table 14.2.1.19:  
 
 
 .......................................................................................................... 63 
Table 14.2.2.1: 
MOR106 serum concentrations (µg/mL): Individual data and 
descriptive statistics and time point ......................................................... 67 
Table 14.2.3.1:  
Anti-MOR106 antibodies (ADA): Tabulation per treatment and 
time point ................................................................................................. 69 
Table 14.3.1.1:  
Treatment-emergent adverse events: Summary table .............................. 74 
Table 14.3.1.2:  
Treatment-emergent adverse events up to 30 days after last dose: 
Summary table ......................................................................................... 74 
Table 14.3.1.3:  
Treatment-emergent adverse events: Tabulation of all adverse 
events ........................................................................................................ 74 


 
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Table 14.3.1.4:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events ............................................................... 75 
Table 14.3.1.5:  
Treatment-emergent adverse events: Tabulation of all adverse 
events by preferred term ........................................................................... 75 
Table 14.3.1.6:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events by preferred term .................................. 75 
Table 14.3.1.7:  
Treatment-emergent adverse events: Tabulation of all adverse 
events – Alphabetic order ......................................................................... 75 
Table 14.3.1.8:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events – Alphabetic order ................................ 75 
Table 14.3.1.9:  
Treatment-emergent adverse events: Tabulation per worst intensity ...... 75 
Table 14.3.1.10:  
Treatment-emergent adverse events: Tabulation of all treatment-
related events ............................................................................................ 76 
Table 14.3.1.11:  
Treatment-emergent adverse events: Tabulation of treatment-
related events per worst intensity ............................................................. 76 
Table 14.3.1.12:  
Treatment-emergent adverse events: Tabulation of all injection site 
reaction events .......................................................................................... 76 
Table 14.3.1.13:  
Treatment-emergent adverse events: Tabulation of all injection site 
reaction events per worst intensity ........................................................... 76 
Table 14.3.1.14:  
Treatment-emergent adverse events: Tabulation of all skin related 
events ........................................................................................................ 76 
Table 14.3.1.15:  
Treatment-emergent adverse events: Tabulation of all skin related 
events per worst intensity ......................................................................... 76 
Table 14.3.1.16:  
Treatment-emergent adverse events: Tabulation of all events for 
which the study or study treatment were discontinued ............................ 76 
Table 14.3.1.17:  
Serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting ................................................................................... 77 
Table 14.3.1.18:  
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting ................................................................................... 77 
Table 14.3.1.19:  
Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting of TEAEs occurring in at least 5% of the 
overall subjects ......................................................................................... 77 
Table 14.3.1.20: 
Non-drug related therapies ....................................................................... 81 
Table 14.3.2.1:  
Laboratory data: Descriptive statistics of the actual values and 
change from baseline per time point ........................................................ 85 
Table 14.3.2.2:  
Laboratory data: Worst-case shift table according to the normal 
range ......................................................................................................... 86 
Table 14.3.2.3:  
Laboratory data: Worst-case treatment-emergent laboratory 
abnormalities ............................................................................................ 86 
Table 14.3.2.4: 
Laboratory data: Worst-case CTCAE toxicity grades ............................. 86 
Table 14.3.2.5: 
Laboratory data: Worst-case shift table of the CTCAE toxicity 
grades ....................................................................................................... 86 


 
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Table 14.3.2.6: 
Laboratory data: Worst-case treatment-emergent CTCAE toxicity 
grades ....................................................................................................... 87 
Table 14.3.3.1:  
ECG: Descriptive statistics of the actual values and change from 
baseline per time point ............................................................................. 89 
Table 14.3.3.2:  
ECG: Worst-case shift table of the categorized actual values ................. 89 
Table 14.3.3.3:  
ECG: Worst-case treatment-emergent categorized QT and QTc 
actual value abnormalities ........................................................................ 90 
Table 14.3.3.4:  
ECG: Worst case treatment-emergent HR and PR actual values 
abnormalities ............................................................................................ 90 
Table 14.3.3.5:  
ECG: Worst-case treatment-emergent categorized abnormal 
changes from baseline in QT and QTc ..................................................... 90 
Table 14.3.3.6: 
ECG: Frequency table of the eCRF ECG interpretation per time 
point .......................................................................................................... 90 
Table 14.3.4.1:  
Vital signs: Descriptive statistics of the actual values and change 
from baseline per time point .................................................................... 92 
Table 14.3.4.2:  
Vital signs: Worst-case shift table according to the normal range ........... 92 
Table 14.3.4.3:  
Vital signs: Worst-case treatment-emergent abnormalities ..................... 92 
 
 
 


 
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LIST OF FIGURES 
Figure 14.2.1.5:  
 
 ........................................................................................................... 56 
Figure 14.2.1.7:  
 
 ............................................................................ 57 
Figure 14.2.1.15:  
 
 ................................................................................................... 59 
Figure 14.2.1.17:  
 
 ............................................................................ 59 
Figure 14.2.1.37:  
 
.................................................................................... 64 
Figure 14.2.2.5:  
MOR106 trough serum concentrations (µg/mL): Subject profile 
plots (linear-linear scale) .......................................................................... 68 
Figure 14.2.2.6:  
MOR106 trough serum concentrations (µg/mL): Mean (+/- SE) 
concentration over time (linear-linear scale) ............................................ 68 
Figure 14.3.1.1:  
Treatment-emergent adverse events sorted by risk difference ................. 77 
Figure 14.3.2.1:  
Laboratory data: Mean (+/- SE) of the actual values over time ............... 87 
Figure 14.3.2.2:  
Laboratory data: Mean (+/- SE) of the changes from baseline over 
time ........................................................................................................... 87 
 
 
 


 
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LIST OF LISTINGS 
Listing 16.2.1.1:  
Subject disposition: Randomization ......................................................... 44 
Listing 16.2.1.2:  
Subject disposition: Listing by country and site ...................................... 44 
Listing 16.2.1.3:  
Subject disposition: Number of days in study .......................................... 44 
Listing 16.2.1.4:  
Subject disposition: Study and treatment completion and 
discontinuation ......................................................................................... 45 
Listing 16.2.1.5:  
Subject disposition: Study analysis periods ............................................. 45 
Listing 16.2.2.1:  
Major protocol deviations ........................................................................ 45 
Listing 16.2.2.2:  
Eligibility criteria: Violations .................................................................. 45 
Listing 16.2.2.3:  
Eligibility: Final statements ..................................................................... 46 
Listing 16.2.3.1:  
Subjects excluded from safety and full analysis sets ............................... 46 
Listing 16.2.4.1:  
Demographic data and baseline characteristics ........................................ 47 
Listing 16.2.4.2:  
Substance use ........................................................................................... 47 
Listing 16.2.4.3:  
Screening and baseline disease characteristics ........................................ 49 
Listing 16.2.4.4:  
Medical history ......................................................................................... 49 
Listing 16.2.4.5:  
Concurrent diseases .................................................................................. 49 
Listing 16.2.4.6:  
Prior and concomitant therapies ............................................................... 51 
Listing 16.2.4.7:  
Prior and concomitant TCS/TCI therapies against atopic dermatitis ....... 51 
Listing 16.2.4.8:  
Concomitant intake of rescue atopic dermatitis medications ................... 51 
Listing 16.2.5.1:  
Study drug administration ........................................................................ 52 
Listing 16.2.5.2: 
Cross-treated subjects ............................................................................... 52 
Listing 16.2.5.3: 
Subjects for whom the injections were not administered per 
protocol .................................................................................................... 53 
Listing 16.2.6.1:  
 ............................................................................................... 57 
Listing 16.2.6.2:  
 ................................................................................................. 58 
Listing 16.2.6.3:  
 ........................................................................................ 60 
Listing 16.2.6.4:  
 ................................................................................................. 61 
Listing 16.2.6.5:  
 ............................................................................................. 61 
Listing 16.2.6.6:  
 ............................................................................................... 62 
Listing 16.2.6.7:  
  
 ................................................................ 64 
Listing 16.2.6.8:  
 .................................................... 64 
Listing 16.2.6.9:  
 ......................................................................................... 65 
Listing 16.2.6.10:  
 ................................................................................. 66 
Listing 16.2.7.1:  
PK data handling ...................................................................................... 68 
Listing 16.2.7.2:  
Actual PK blood sampling times (h) ........................................................ 68 
Listing 16.2.7.3:  
MOR106 serum concentrations (µg/mL): Individual data ....................... 68 
Listing 16.2.8.1:  
Anti-MOR106 antibodies (ADA): Full listing ......................................... 69 
Listing 16.2.9.3:  
 ...................... 70 
Listing 16.2.10.1: Treatment-emergent adverse events: Summary listing ............................ 77 
Listing 16.2.10.2: Treatment-emergent adverse events: Full listing ..................................... 78 


 
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Listing 16.2.10.3: Treatment-emergent adverse events: Summary listing of the grade 
3 or higher adverse events ........................................................................ 78 
Listing 16.2.10.4: Treatment-emergent adverse events: Full listing of the grade 3 or 
higher adverse events ............................................................................... 79 
Listing 16.2.10.5: Adverse events: Full listing of the serious adverse events ....................... 79 
Listing 16.2.10.6: Pre-treatment adverse events: Full listing ................................................ 79 
Listing 16.2.10.7: Adverse events: Summary listing of the injection site reactions 
events ........................................................................................................ 79 
Listing 16.2.10.8: Adverse events: Full listing of the injection site reactions events ........... 79 
Listing 16.2.10.9: Adverse events: Summary listing of the skin related adverse events ...... 80 
Listing 16.2.10.10: Adverse events: Full listing of the skin related adverse events ............... 80 
Listing 16.2.10.11: Adverse events: Full listing of adverse events with temporarily 
discontinued as action .............................................................................. 80 
Listing 16.2.10.12: Adverse events: Full listing of adverse events with permanently 
discontinued as action .............................................................................. 80 
Listing 16.2.10.13: Adverse events: Coding information ....................................................... 80 
Listing 16.2.10.14: Non-drug related therapies ....................................................................... 81 
Listing 16.2.11.1: Laboratory data: Full listing ..................................................................... 87 
Listing 16.2.11.2: Laboratory data: Listing of treatment-emergent abnormalities ............... 88 
Listing 16.2.12.1: ECG: Full listing ...................................................................................... 90 
Listing 16.2.12.2: ECG: Listing of treatment-emergent abnormalities ................................. 91 
Listing 16.2.13.1: Vital signs: Full listing ............................................................................. 93 
Listing 16.2.13.2: Vital signs: Listing of treatment-emergent abnormalities ........................ 93 
Listing 16.2.14.1: Physical examinations: Abnormalities ..................................................... 93 
 
 


 
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ABBREVIATIONS COMMONLY USED  
 
 
AD 
Atopic Dermatitis 
ADA 
Anti-drug Antibody 
ADaM 
Analysis Data Model 
ADY 
Analysis relative day count 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the serum concentration-time curve 
BLOQ 
Below Limit of Quantification 
BMI 
Body Mass Index 
 
 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSP(A) 
Clinical Study Protocol (Amendment) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
 
 
ECG 
Electrocardiogram 
ED 
Early Discontinuation 
FAS 
Full Analysis Set 
GEE 
Generalized Estimating Equations  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
 
 
 
IMP 
Investigational Medicinal Product 
ISR 
Injection Site Reaction 
ISRC 
Independent Safety Review Committee 
LD 
Loading Dose 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Model for Repeated Measurement 
NA 
Not Available 
NAP 
Not Applicable 
NC 
Not Calculated 
 
 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
 
 
Q2W 
Every two weeks 
Q4W 
Every four weeks 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected for the heart rate using Bazett’s formula 


 
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QTcF 
QT interval corrected for the heart rate using Fridericia’s formula 
s.c. 
Subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 
 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
 
 
SOP 
Standard Operation Procedure 
 
 
TCS 
Topical Corticosteroid 
TCI 
Topical Calcineurin Inhibitor 
TEAE 
Treatment-emergent Adverse Event 
TLF 
Tables, Listings, Figures 
VAS 
Visual Analogue Scale 


 
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DEFINITIONS OF TERMS COMMONLY USED 
Analysis part 
Section of the statistical analysis confining the analysis of a specific 
aspect in general terms, like safety, pharmacokinetics, etc.  
Analysis period 
Period of time during a study representing the time of exposure to a 
unique study drug or a unique combination of study drugs.  
Analysis time point 
Point in time within an analysis visit, usually obtained after a specific 
mapping and expressed in hours and/or minutes. It can also be 
expressed as a urine collection interval. Refers to the ATPT ADaM 
variable.  
Analysis value 
Result once established for analysis. Refers to the value stored in the 
AVAL or AVALC ADaM variables. 
Analysis visit 
Visit once established for analysis, usually obtained after a specific 
mapping and expressed in days. Refers to the AVISIT ADaM 
variable. 
Study drug 
administration 
Administration of study drug for the first time in the framework of 
the study.  
Study drug 
Investigational compound, or placebo, or positive control being tested 
or used as a reference in the study.  
Treatment-emergent 
Any (abnormal) condition appearing in a period of time under 
treatment which was not present at a referential point in time before, 
like an abnormality which was not present at baseline or an AE 
occurring after first study drug administration.  
Additional elements can apply to this definition in specific analysis 
sections and for specific purposes. 
 
 


 
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1. 
INTRODUCTION 
This is a Phase II study to assess safety, tolerability and pharmacokinetics/exposure of 
MOR106. 
The statistical analysis described by this analysis plan will be composed by tables, listings and 
figures (TLFs) presented in the following analysis parts: 
- 
General subject information. 
- 
 
 
 
- 
Pharmacokinetics (PK). 
- 
Immunogenicity (ADA). 
- 
Pharmacodynamics (PD) (
 
. 
- 
Safety (adverse events, laboratory, electrocardiogram (ECG), vital signs and physical 
examination sections). 
As a consequence of early termination of the development of MOR106 in atopic dermatitis 
for futility at the time point of MOR106-CL-201 interim analysis, this SAP constitutes an 
accordingly adapted version in terms of statistical evaluations of efficacy and 
pharmacodynamics endpoints. 
1.1. 
CLINICAL STUDY PROTOCOL (CSP) AND CSP 
AMENDMENTS VERSION OVERVIEW 
Final CSP Version 
Date 
CSP V3.0 
15OCT2018 
  
Final CSP Amendments 
Date 
CSP V4.0 
25JUN2019 
CSP Version 1.0 LVA GEO 
24SEP2019 (first country-specific CSP (version 1.0), created for Latvia 
and Georgia, based on version 4.0 of the general CSP) 
This SAP is based on the last version of the protocol. 


 
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1.2. 
STATISTICAL ANALYSIS PLAN (SAP) VERSION 
OVERVIEW 
Final SAP Version 
Date 
V1.0 
12 Mar 2020 
  
 
 
 


 
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2. 
STUDY OBJECTIVES AND DESIGN  
2.1. 
STUDY OBJECTIVES 
2.1.1. Primary Objective 
The primary objective is to investigate the safety and tolerability of repeated subcutaneous 
(s.c.) doses of MOR106 administered concomitantly with topical corticosteroids (TCS) in 
subjects with moderate to severe atopic dermatitis (AD) who are candidates for systemic 
therapy. 
2.1.2. Secondary Objectives 
The secondary objectives are: 
- 
To evaluate the PK of repeated s.c. doses of MOR106 administered concomitantly 
with TCS. 
- 
To monitor the occurrence of anti-drug antibodies (ADA) as a measure of 
immunogenicity after repeated s.c. doses of MOR106 administered concomitantly 
with TCS. 
2.1.3. Other Objectives 
The other study objectives are: 
- 
 
 
 
 
 
 
 
 
 
2.2. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 2 study of repeated 
s.c. doses of 320 mg MOR106 or placebo, administered concomitantly with TCS. On Day 1, a 
loading dose (LD) will be administered (2 x 320mg MOR106, or placebo). 
Adult subjects with moderate to severe AD who are candidates for systemic therapy will 
receive MOR106 or placebo every other week via s.c. injections (on Days 1, 15, 29, and 43). 
The 8-week treatment period, finishing on Day 57, is followed by a 16-week follow-up 


 
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period, finishing on Day 169. A total of 60 subjects (n=40 on MOR106 and n=20 on placebo) 
will be enrolled in this study.  
Subjects will be randomized in a 2:1 ratio to receive one of the following treatments: 
- 
MOR106 320 mg (2 mL at 160 mg/mL) every 2 weeks (Q2W) s.c. injection, with a 
loading dose (LD) of 640 mg (2 x 2mL at 160 mg/mL) s.c. injection on Day 1 
(40 subjects). 
- 
Corresponding placebo s.c. injections (20 subjects). 
A total of 4 treatment days will be administered per subject. The end of the study is reached 
when the last follow-up visit or contact as planned according to the schedule of activities (see 
Section 6.10 of the protocol) of the last subject is performed. 
2.3. 
STUDY ENDPOINTS 
2.3.1. Primary Endpoints 
The primary endpoints are the incidence and severity of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) 
through Day 169/early discontinuation (ED) visit. 
2.3.2. Secondary Endpoints 
The secondary endpoints are: 
- 
MOR106 serum concentrations after repeated s.c. administrations from baseline 
through Day 169/ED visit. 
- 
Occurrence of ADA from baseline through Day 169/ED visit. 
2.3.3. Other Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.4. 
SCHEMATIC DIAGRAM OF THE STUDY 
 
 
 


 
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2.5. 
SCHEDULE OF ACTIVITIES 
The study scheduled of assessments is as follows (the sections mentioned refer the protocol):
 


 
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3. 
DEFINITION OF ANALYSIS POPULATIONS 
The following subject populations will be determined for this statistical analysis. 
The analysis population featuring in each TLF will be printed in a subtitle. 
3.1. 
ALL SCREENED SUBJECTS 
All subjects who signed and dated an ICF and underwent screening assessments to check 
whether or not they are eligible to participate in the clinical study. 
3.2. 
ALL RANDOMIZED SUBJECTS 
All enrolled subjects who underwent all screening assessments and were found to be eligible 
for the clinical study and who were randomized into the clinical study. 
3.3. 
SAFETY AND IMMUNOGENICITY ANALYSIS SET 
All randomized subjects who received at least one dose of investigational medicinal product 
(IMP). This population will be named safety analysis set in the TLFs. 
3.4. 
FULL ANALYSIS SET 
All randomized subjects who received at least one dose of IMP. 
3.5. 
PHARMACOKINETIC ANALYSIS SET 
Subset of the safety set, selecting all subjects who have available and evaluable MOR106 
serum concentration data (e.g. excluding all protocol deviations or AEs that may have an 
impact on the PK analysis). 
 
 
 


 
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4. 
TREATMENT GROUPS 
Subjects being assigned to or actually receiving a common treatment during a period of time 
in this study, constitute a treatment group for analysis. 
4.1. 
CONSIDERATION OF THE PLANNED VERSUS THE 
ACTUAL TREATMENT 
The treatment group as assigned by the randomization will be used in all analyses (i.e., as-
randomized analysis) except the PK analyses where the actual treatment will be used. Cross-
treated subjects will be listed separately. 
4.2. 
DEFINITION OF TREATMENT GROUP LABELS 
Treatment groups will be labeled as follows over the whole statistical analysis: 
- 
Placebo Q2W s.c.  
- 
MOR106 320 mg Q2W s.c. 
4.3. 
TOTALS OVER TREATMENT GROUPS 
Calculation of totals over all treatment groups will be presented only in tables and only in the 
general subject information (e.g. baseline, prior medication, accounting) of the analysis.  
 
 


 
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5. 
DEFINITION OF ANALYSIS PERIODS, OF ANALYSIS 
TIME POINTS, AND OF BASELINE 
5.1. 
ANALYSIS PERIODS FOR NON-VISIT DATA 
These analysis periods are to be used for allocation of events into periods (e.g., adverse 
events). 
Analyses Periods for Non-Visit Data  
Analysis period 
Start period 
End Period 
Screening 
Date of signing the ICF, with 
00:00 added as time part. 
1 minute before the date/time of 
first dose of study medication* 
Treatment 
First dose of study medication 
date/time* 
Last dose of study medication date 
+ 30 days, with 23:59 added as 
time part.# 
Follow-up 
Last dose of study medication date 
+ 31 days, with 00:00 added as 
time part# 
Study discontinuation date, with 
23:59 added as time part. 
* For endpoints without time collected, all assessments done on the day of the first dose will be assigned  to 
the treatment period. 
# Time midnight is used as switch point to conservatively assign endpoints to the treatment period if on the date 
of last dose of study medication + 30 days. 
Note that the last analysis period in case of early discontinuation will always be ended by the 
study discontinuation date (date of last contact in the study).  
5.2. 
ALGORITHM OF ALLOCATING VISITS TO TIME 
WINDOWS 
For the efficacy, PK, PD and safety assessments, all data (including data obtained at 
unscheduled visits) will be placed into time windows based on the relative day (ADY) of the 
assessment, according to the following allocation tables: 
Time windows for study drug administration: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Day 1 
1 
1 
1 
Day 15 
15 
2 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day > 43[1] 
NA 
51 
+INF 
 [1] This time point will be only listed. 
 
 


 
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Time windows for PK: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 1 (1h post-dose)[2] 
1 
1 
1 
Day 4 
4 
2 
10 
Day 15 
15 
11 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day 57 
57 
51 
64 
Day 71 
71 
65 
78 
Day 85 
85 
79 
92 
Day 99 
99 
93 
106 
Day 113 
113 
107 
120 
Day 127 
127 
121 
134 
Day 141 
141 
135 
148 
Day 155 
155 
149 
162 
Day 169 
169 
163 
176 
Day > 169[3] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] For Day 1 (1h post-dose), no time window is defined. The visit as recorded in the CRF will be used, time of the 
assessment will be used to ensure that it was done post-dose.  
[3] This time point will be only listed. 
Time windows for 
 vital signs and physical examination: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 15 
15 
2 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day 57 
57 
51 
64 
Day 71 
71 
65 
78 
Day 85 
85 
79 
92 
Day 99 
99 
93 
106 
Day 113 
113 
107 
120 
Day 127 
127 
121 
134 
Day 141 
141 
135 
148 
Day 155 
155 
149 
162 
Day 169 
169 
163 
176 


 
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Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Day > 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for weight: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 29 
29 
2 
43 
Day 57 
57 
 
 44 
71 
> Day 57[2] 
NA 
72 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for ECG: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 1 (1h post-dose) [2] 
1 
1 
1 
Day 43 (pre-dose) [3] 
43 
2 
50 
Day 43 (1h post-dose) [2] 
43 
2 
50 
Day 57 
 
57 
51 
71 
Day 85 
85 
72 
99 
Day 113 
113 
100 
 
141 
Day 169 
169 
142 
176 
> Day 169[4] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] 1h post-dose assessment, no time window is defined. The visit as recorded in the CRF will be used, time of the 
assessment will be used to ensure that it was done post-dose.  
[3] Pre-dose assessment, no time window is defined. The visit as recorded in the CRF will be used, time of the assessment 
will be used to ensure that it was done pre-dose.  
[4] This time point will be only listed. 
Time windows for safety laboratory tests: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 15 
15 
2 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day 57 
57 
51 
71 
Day 85 
85 
72 
106 


 
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Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Day 127 
127 
107 
141 
Day 155 
155 
142 
162 
Day 169 
169 
163 
176 
> Day 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for 
 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 15 
15 
2 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day 57 
57 
51 
64 
Day 71 
71 
65 
85 
Day 99 
99 
86 
113 
Day 127 
127 
114 
141 
Day 155 
155 
142 
162 
Day 169 
169 
163 
176 
> Day 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for pregnancy test: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 29 
29 
2 
43 
Day 57 
57 
44 
85 
Day 113 
113 
86 
141 
Day 169 
169 
141 
176 
> Day 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
 
 
 


 
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Time windows for
 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 57 
57 
2 
64 
> Day 57[2] 
NA 
65 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for immunogenicity (ADA), PD and biomarkers: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 29 
29 
2 
43 
Day 57 
57 
44 
71 
Day 85 
85 
72 
99 
Day 113 
113 
100 
127 
Day 141 
141 
128 
155 
Day 169 
169 
156 
176 
> Day 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Time windows for injection site reactions: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Day 1 
1 
1 
1 
Day 4 
4 
2 
10 
Day 15 
15 
11 
22 
Day 29 
29 
23 
36 
Day 43 
43 
37 
50 
Day 57 
57 
51 
64 
Day > 57[1] 
NA 
65 
+INF 
[1] This time point will be only listed. 
 
 
 
 
 


 
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Time windows for skin swab: 
Time point label 
Target day 
Interval lower bound 
Interval upper bound 
Baseline[1] 
1 
-INF 
1 
Day 57 
57 
2 
113 
Day 169 
169 
114 
176 
> Day 169[2] 
NA 
177 
+INF 
[1] Baseline will be defined as the last measurement before the start of IMP. 
[2] This time point will be only listed. 
Tables and figures will present the time points, not the visits. Listings will display the time 
points as recorded in CRF and as derived per the above time windows. 
5.3. 
SELECTION OF VISITS 
In case there are multiple measurements within a post-baseline time window, the one closest 
to the target day will be selected for the analyses. If there are multiple measurements at the 
same distance of the target day (meaning: equal ABS[ADY – target day]), then the one latest 
in time will be selected. If multiple measurements are taken on the same day, the mean of 
these values will be used. All data will be presented in listings with a flag if they were used in 
the analysis.  
5.4. 
CALCULATION OF RELATIVE DAYS AND DURATIONS 
The timing of an assessment or event (start or stop) relative to a referential date will be 
calculated as follows:  
ADY (day) = concerned date – reference date (+ 1 day only when the concerned date is the 
same or later than the reference date)  
Where: 
- 
ADY is the analysis relative day count;  
- 
Concerned date is an assessment visit date, or the start or stop date of an event;  
- 
Date implies a complete date (day, month and year available);  
- 
Reference date default is the date of first administration of study drug, unless 
otherwise specified. 
Provided the resolution of the inputs (and respective unit) are adapted, the general terms of 
this formula also apply when similar relative timings are required in another time resolution, 
like in minutes. 
Durations will be calculated in a similar way as:  
Duration (days) = end date – start date + 1.  


 
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5.5. 
DEFINITION OF BASELINE 
For each individual parameter, the last available result before the date and time of first study 
drug administration, whichever this assessment is, constitutes the reference assessment, i.e. 
baseline. 
For electrocardiogram (ECG), the baseline is defined as the mean of the last recorded 
triplicate before the first study drug administration. If no triplicate is available before the first 
dose of study medication intake, the last ECG value will be considered as baseline. 
 
 


 
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6. 
SELECTION OF DATA RECORDS FOR ANALYSIS 
All reported events, and all assessments without missing results will be used in the statistical 
analysis. However, the next specific exclusions will be done in some specific applications. 
6.1. 
RECORDS HAVING EXTREME VALUES 
Records yielding extreme results will be used for analysis in the general subject information, 
efficacy and safety parts of the analysis, even when these results are unusual or seemingly 
impossible. 
In the PK/ part of the analysis, exclusion of abnormal PK concentration results/ will be 
formally discussed and determined after data base lock and before running the PK analysis, 
and documented in the PK/ Data Review Report.  
6.2. 
REPEATED ANALYSIS VISITS AND ANALYSIS TIME 
POINTS 
After baseline and except if unscheduled or being part of a specific profile, no replications of 
analysis visits or analysis time points should exist. Specifications for unscheduled analysis 
visits are described in the next section. 
6.3. 
UNSCHEDULED ANALYSIS VISITS 
Refer to sections 5.2 and 5.3. 
6.4. 
SELECTION OF VALUES PROVIDED IN DIFFERENT UNITS 
When values like results or normal limits are provided in conventional original units as well 
as in standardized units, only the expressions in standardized units will be considered for all 
analysis purposes. Data stored in original, conventional units will be disregarded. 
7. 
HANDLING OF DATA 
7.1. 
HANDLING OF MISSING DATA 
7.1.1. Missing Records or Missing Values 
No imputations will be done in case of missing records (visits) or missing values like results, 
normal limits etc. 
7.1.2. Missing Dates or Times or Partially Known Dates or Times 
No imputations will be done in case of missing date(time) fields, nor for the missing parts of 
partially known date(time) fields. If this causes imprecisions, a worst-case consideration will 
be done, like assuming persistence if an end date is missing, or replicating records over 
different analysis periods. 


 
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7.2. 
HANDLING OF SECONDS IN TIME FIELDS 
The analysis will consider times only in hours and minutes. Seconds in the time of a record, if 
any, will be cut-off before analysis and disregarded.  
7.3. 
CALCULATION AND PRESENTATION OF DESCRIPTIVE 
STATISTICS 
Any descriptive statistics (and summary graphics) for continuous parameters will be printed 
only when the number of observations is two or more, except for PK analysis where specific 
rules are described below.Single observations will only be listed. 
In the general subject information, efficacy and safety parts of the analysis, descriptive 
statistics will include:  
 
the number of non-missing observations (n);  
 
the arithmetic mean; 
 
the standard error (SE); 
 
the standard deviation (SD); 
 
the median; 
 
the minimum and maximum values; 
 
95% confidence interval of the mean (only when requested). 
For each parameter concerned, the number of decimal places printed for all descriptive 
statistics will be the same maximum number of decimals of the actual analysis values of the 
parameter, except:  
 
mean, median, confidence interval of the mean: one more decimal place; 
 
SD, SE: two more decimal places. 
For PK part of the analysis, descriptive statistics will include: 
 
the number of non-missing observations (n);  
 
the number of data points above the limit of quantification (only applicable for 
concentrations); 
 
the arithmetic mean; 
 
the standard error (SE)  
 
the standard deviation (SD)  
 
the median; 
 
the minimum and maximum values; 
 
the coefficient of variation (CV%) 
= 100 x (standard deviation/arithmetic mean); 
 
the geometric mean  
= exp(arithmetic mean of ln-transformed data); 
 
the geometric coefficient of variation (geometric CV%) 
= 100 x ඥ݁ሺ௦௧௔௡ௗ௔௥ௗ ௗ௘௩௜௔௧௜௢௡ ௢௙ ௟௡ି௧௥௔௡௦௙௢௥௠௘ௗ ௗ௔௧௔ሻ² െ1 


 
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If less than 50% of the subjects have quantifiable values, only the number of subjects with 
data, number of data points above the lower limit of quantification (LLOQ), the arithmetic 
mean, median, minimum, and maximum will be presented with the original calculated value. 
The other descriptive statistics will be listed as “NC” (not calculated).  
If the calculated mean is below the lower limit of quantification (BLOQ), then it will be 
presented as “BLQ”.  
The concentration levels will be presented in the original unit. Concentrations will be 
presented with: 
 
2 decimals for values < 10 
 
1 decimal for values > 10 and < 1000 
 
No decimals for value > 1000. 
The descriptive statistics should be rounded to the same number of decimals as the individual 
values. 
7.4. 
PRESENTATION OF INFERENTIAL STATISTICAL 
ANALYSIS 
Refer to section 10 for more details. 
7.5. 
CALCULATION AND PRESENTATION OF FREQUENCIES 
Frequencies of categorical parameters will be calculated only for the actually observed cases. 
All observed frequencies from n = 1 on will be printed.  
7.6. 
CALCULATION AND PRESENTATION OF PERCENTAGES 
Frequencies and percentages will be generated for categorical parameters. Only non-missing 
values will contribute to the denominator when computing percentages. 
The default denominator is the number of subjects in a treatment group, but can be further 
restricted as applicable. The denominator used should always be described in footnotes. 
7.7. 
CATEGORIZATION OF RESULTS OF CONTINUOUS 
PARAMETERS 
Categorization of the results of continuous parameters may apply in different sections of the 
analysis. Categorizations will always be determined after the analysis values of the parameters 
concerned have been established. Rounding of analysis values will not be done. 
7.8. 
HANDLING OF VALUES BELOW OR ABOVE A 
THRESHOLD 
- 
In the general subject information and in the safety part of the analysis: when results 
or normal limits of continuous parameters are expressed in the database as being 
below or above a detection limit (e.g. “<4”, “>1000”) and not available in pure 


 
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numerical form, the analysis value will be the value of the detection limit itself plus 
or minus one precision unit (e.g. 3, 1001, respectively). The values before this 
imputation will only be shown in listings. 
- 
In the PK and PD 
 parts of the analysis:  
o Values below the quantification limit will be imputed by 0 for the calculation 
of descriptive statistics, PK analyses and graphical presentation except for the 
geometric mean and the geometric CV, where it will be imputed as LLOQ/2. 
o Values below the quantification limit will be listed as “BLQ”. 
7.9. 
SOFTWARE, PROCEDURES AND STANDARDS 
7.9.1. Software 
SAS version 9.4 (or higher) will be used for programming. 
Phoenix WinNonLin version 6.4 (or higher) will be used for PK derivations. 
7.9.2. Procedures 
This statistical analysis will comply with ICH regulations, in particular: (ICH-E3), (ICH-E6) 
and (ICH-E9). 
The following Galapagos statistics, programming and pharmacokinetics SOPs will be 
followed: 
 
SOP-CLI-001: Developing Clinical Study Documents (version 2.0) 
 
SOP-BIOM-002: Managing Biostatistics Activities and Programming (version 1.0) 
The following
 statistics and pharmacokinetics SOPs will be followed: 
 
Statistics: 
 
BST002-SOP Version 2.0 
 
BST004-SOP Version 2.0 
 
BST005-SOP Version 2.0 
 
BST007-SOP Version 1.0 
 
PRG001-SOP Version 2.0 
 
PK:  
 
PK003-SOP Version 3.0 
 
PK004-SOP Version 2.0 
 
PK006-SOP Version 2.0 
 
 


 
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7.9.3. Standards for Data Storage and for Analysis Layout 
The database source for this analysis is expected to follow the CDISC SDTM model. 
The analysis derived datasets will follow the CDISC ADaM 2.1 model, based on the 
ADAMIG version 1.1. 
The general layout of the tables, listings and figures of this analysis will follow the Sponsor 
Mock TLFs document (separate document).  
 
 


 
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8. 
STATISTICAL METHODS 
8.1. 
PLANNED ANALYSES, PROTOCOL AMENDMENTS 
INCLUDED 
The SAP will be finalized before the final analysis. All relevant data collected in this clinical 
study will be documented using summary tables, figures, and subject data listings. 
8.1.1. Final Analysis 
The full results will be summarized in a clinical study report (CSR) after all subjects have 
completed their study participation (i.e. Day 169 or discontinued earlier). 
8.1.2. Sample Size 
Refer to section 7.1 of the protocol. 
8.1.3. General Statistical Considerations 
In addition to tabulated descriptive statistics, graphical data displays may be used to 
summarize the data. Unless otherwise noted, inferential statistics will be interpreted at the 2-
sided 5% significance level.  
No analysis by center or country will be performed, unless otherwise specified. 
8.1.4. Analyses of Demographics and Baseline Characteristics 
Subject disposition (including reasons for early discontinuation), protocol deviations, 
demographics, baseline characteristics, medical history, concomitant therapies will be 
analyzed descriptively based on the safety analysis set. 
8.1.5. Analysis of Efficacy Parameters 
Efficacy endpoint analyses will be performed using the FAS. For subjects who use rescue 
medication, all data collected after administration of the rescue medication will be excluded 
from efficacy analysis (this means that data collected on the day of rescue medication 
administration will be used for efficacy analysis). Subject data will be handled as if the 
subject left the study at the moment the rescue medication started. Efficacy assessment 
performed after the start of the rescue medication will only be listed. 
Efficacy data 
) will be summarized using descriptive statistics of actual 
values, changes from baseline, and percent changes from baseline, with 95% confidence 
intervals. Binary and categorical endpoints (
) will be 
presented by number (percent) of subjects per treatment group and visit.  
Percent changes from baseline for continuous endpoints (
) will be 
analyzed using an mixed-effects model for repeated measures. The model will include  


 
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treatment and visit as fixed effects, country and baseline value (continuous) as covariates, and 
treatment-visit as interaction term. 
Binary parameters (
) will be analyzed using a generalized 
estimating equation model. The model will include treatment and visit as fixed effects, 
country and baseline value (continuous) as covariates, and treatment-visit as an interaction 
term. Pairwise comparisons to placebo will be explored as well, without multiplicity 
correction. 
The primary approach will be the observed case approach without imputation of missing data.  
Additional exploratory analyses and graphical presentations may be performed when deemed 
useful to better understand the data. 
All other efficacy endpoints will only be listed 
8.1.6. Analysis of Immunogenicity Data 
ADA status (positive/negative), ADA titer when ADA positive and potential drug interference 
in the assay when ADA negative (yes/no) will be listed by treatment group and time point. 
ADA status and potential drug interference will be also summarized. 
8.1.7. Analyses of Safety Data 
All safety analyses will be performed using the safety analysis set. Subjects will be analyzed 
according to the randomized treatment. All safety data collected on or after the first dose of 
IMP administration up to the last follow-up visit after the last dose of IMP, unless specified 
otherwise, will be summarized by treatment group according to the planned IMP. Clinical 
safety will be addressed by assessing AEs, laboratory assessments, physical examinations, 
vital signs, and 12-lead ECGs. Special attention will be paid to ISRs.  
8.1.7.1. 
Extent of Exposure 
A subject’s extent of exposure to IMP will be generated from the IMP administration page of 
the CRF. Extent of exposure data will be summarized by treatment group. Extent of exposure 
to IMP will be expressed as the number of days between the first and last dose of IMP, 
inclusive, regardless of temporary interruptions in IMP administration and summarized by 
treatment group.  
In addition, the number (percentage) of subjects who received all four treatment days, only 
three treatment days, etc. will also be summarized.  
8.1.7.2. 
Adverse Events (AEs) 
Clinical and laboratory AEs will be coded using the latest version of the Medical Dictionary 
for Regulatory Activities. System Organ Class (SOC), High Level Group Term, High Level 
Term, Preferred Term, and Lower-Level Term will be attached to the clinical database. 
The following AEs will be considered as TEAEs: 


 
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 All events during the complete study, with an onset on or after the IMP start will be 
counted. 
Summaries (number and percentage of subjects and the number of events) of TEAEs by SOC 
and Preferred Term will be provided by treatment group. Subjects with TEAEs will also be 
summarized by causal relationship to IMP and severity. In addition, ISRs, skin related AEs, 
TEAEs leading to premature discontinuation of IMP and SAEs (including the non-treatment-
emergent SAEs) will be summarized and listed. 
Additionally, selected tables will also be created restricted to events with an onset date on or 
after the IMP start date and up to 30 days after last dose of IMP. 
8.1.7.3. 
Clinical Laboratory Evaluations 
Laboratory assessments will be analyzed descriptively. Changes from baseline (Day 1 pre-
dose) and shifts according to normal ranges and CTCAE grades will be presented as well. 
Analyses will be done per treatment group. 
8.1.7.4. 
Physical Examinations 
Only abnormal post-baseline physical examination results will be listed. 
8.1.7.5. 
Vital Signs 
Vital signs will be analyzed descriptively. Changes from baseline (Day 1 pre-dose) and shifts 
according to normal ranges will be presented as well. Analyses will be done per treatment 
group. 
8.1.7.6. 
12-Lead Electrocardiogram 
12-lead ECG will be analyzed descriptively. Changes from baseline (Day 1 pre-dose) and 
shifts according to normal ranges will be presented as well. Frequency analyses of subjects 
with a prolongation of more than > 60 ms change from baseline; > 500 ms for  QT, QTcF and 
QTcB will be presented as well (for each parameter separately). Analyses will be done per 
treatment group. 
8.1.7.7. 
Other Safety Assessments 
Summary statistics for ISRs and skin related AEs are described in section 8.1.10.2. 
8.1.8. Pharmacokinetic Analyses 
For subjects in the PK analysis set, individual serum concentrations of MOR106 will be 
listed. Descriptive statistics will be calculated by day for the serum concentrations. Mean (± 
standard error) serum concentrations of MOR106 versus time will be plotted using both linear 
and semi-logarithmic scales. 
MOR106 serum levels will be analyzed using population PK analyses, which will be 
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8.1.9. Pharmacodynamic Analyses 
PD data will only be listed using the subjects in the safety analysis set. 
8.1.10. Additional Statistical Considerations 
NAP. 
8.2. 
CHANGES TO THE PLANNED ANALYSES, NOT COVERED 
BY THE PROTOCOL OR BY PROTOCOL AMENDMENTS 
8.2.1. Changes before Database Lock and Justification 
Per Sponsor’s decision: 
- 
ECG parameters normal ranges will be different to the ones mentioned in protocol to 
be consistent with other Sponsor’s studies. 
- 
For laboratory statistical analyses, CTCAE version 4.03 will be used instead of 
version 5.0 to be consistent with other Sponsor’s studies. 
- 
FAS population definition will be updated to be the same as the safety analysis set 
(due to the type of subjects and disease, it is not anticipated to have a difference 
between these populations). 
- 
The safety analyses will be based on the randomized treatment and not on the actual 
treatment (cf. section 7.3.8 of the protocol). 
 As a consequence of early termination of MOR106 development in atopic dermatitis: 
- 
Per Protocol analysis set will not be defined as no analyses will be performed on this 
set.  
- 
The Primary Analysis will not be conducted as mentioned in the protocol. 
- 
 
- 
 
- 
 
. 
- 
Time-to-event analysis will not be performed 
- 
 
- 
 
 
 


 
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- 
 
- 
Terminal half-life t1/2 will not be derived as mentioned in the protocol.  
- 
 
 
8.2.2. Changes after Database Lock and Justification 
Any planned analyses made after database lock will be documented in the CSR with a 
justification. 
 


 
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9. 
ANALYSIS OF GENERAL SUBJECT INFORMATION AND 
DEFINITION OF ANALYSIS TLFS 
The analysis of general subject information will be descriptive. No inferential statistics will be 
computed. 
9.1. 
SUBJECT DISPOSITION 
Table 14.1.1.1:  
Subject disposition: Analysis populations 
Tabulation per treatment group (and over all subjects) of the number of subjects in each of the 
analysis populations (screened, randomized, safety/immunogenicity, FAS and PK) defined for 
the study. 
Population: all screened subjects. 
Table 14.1.1.2:  
Subject disposition: Tabulation by country and site 
Tabulation per treatment group (and overall) of the number of subjects in each of the 
countries and sites. 
Population: all randomized subjects. 
Table 14.1.1.3:  
Subject disposition: Tabulation of the number of subjects at each 
time interval 
Tabulation per treatment group (and over all subjects) of the number of subjects in each 
visit/time interval. 
Population: safety analysis set. 
Table 14.1.1.4:  
Subject disposition: Study and treatment completion and 
discontinuation 
Table per treatment group (and overall) of  completion/discontinuation from study and from 
study medication and the reason for discontinuation. 
Population: safety analysis set. 
 
 


 
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Table 14.1.1.5:  
Subject disposition: First and last dates in the study 
Summary showing these key dates (regardless of treatment assignment): 
 
Date of the earliest ICF signed for this study;  
 
Date of first and of last screening visit (visits as reported in the database); 
 
Date of first study drug administration; 
 
Date of last physical visit performed in this study;  
 
Last date of contact with any subject in this study. 
Population: all screened subjects. 
Listing 16.2.1.1:  Subject disposition: Randomization 
Listing per subject showing subject number, ICF date, randomization number, randomization 
groups, randomization date and time and any information on code breaking:  
 the reason for blind broken  
 the number of days since first study dose of study medication at the time the subject is 
unblinded  
 the AE preferred term (in case the unblind was due to an AE)  
  (verbatim) explanation on the unblinding reason. 
Discrepancies between planned and actual randomization groups will be flagged.  
Population: all randomized subjects. 
Listing 16.2.1.2:  Subject disposition: Listing by country and site 
Listing per treatment arm showing the country name, the site number and the list of subjects 
screened at this site. 
Population: all randomized subjects. 
Listing 16.2.1.3:  Subject disposition: Number of days in study 
Listing per treatment group, per subject and per time point showing subject number, the 
analysis populations inclusions, the actual study day of each visit and the whole study 
duration. 
The whole study duration is derived as last date of contact – date of ICF + 1 day. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.1.4:  Subject disposition: Study and treatment completion and 
discontinuation 
Listing per treatment group and per subject showing the study completion or discontinuation 
status, the number of days since first study treatment administration at study termination and 
the subject’s date of last contact in study. In case of discontinuation, the related reason and 
any available specifications will also be printed (i.e. the AE reported terms if the 
discontinuation was due to an AE, etc.).  
The treatment completion or discontinuation status will be listed in a similar way.  
Population: safety analysis set. 
Listing 16.2.1.5:  Subject disposition: Study analysis periods  
Listing per treatment group and per subject showing the analysis periods, including the start 
and end dates of each analysis period and the date of first and last study drug administration.  
Population: safety analysis set. 
9.2. 
PROTOCOL DEVIATIONS AND ELIGIBILITY 
Table 14.1.4.1:  
Protocol deviations: Summary of major protocol deviations 
Frequency tabulation per treatment group (including the overall total) of major protocol 
deviations. 
Population: safety analysis set 
Listing 16.2.2.1:  Major protocol deviations  
Listing per treatment group and per subject showing all major protocol deviations that 
occurred during the study. 
Population: safety analysis set. 
Listing 16.2.2.2:  Eligibility criteria: Violations 
Listing per treatment group and per subject showing only the violated selection criteria for 
subjects treated (inclusion criteria not met, and exclusion criteria met), if any. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.2.3:  Eligibility: Final statements  
Listing per treatment group and per subject showing the eligibility statements at Screening 
and Day 1 (answers to the question  “Did the subject meet all inclusion criteria and did not 
meet any exclusion criteria?”). 
Population: safety analysis set  
9.3. 
SUBJECTS EXCLUDED FROM ANALYSIS PART 
Note that for the PK data there is a specific PK data handling listing. PK is therefore not 
included in this section. 
Listing 16.2.3.1:  Subjects excluded from safety and full analysis sets  
Listing of all subjects who were not treated due to any reason, showing them categorized as 
not treated subjects who were not randomized at all, and not treated subjects who were 
randomized (if randomization applies). 
The study completion or discontinuation status, and any available reasons or specifications 
will also be printed next to each subject. 
In the exceptional case a same subject participated more than once in this study due to any 
reasons (like first as a reserve subject not treated, and then again as a treated subject), the 
multiple participations of such a subject will be flagged and mentioned in this listing.    
Population: all screened subjects (only subjects excluded from safety analysis set will be 
listed). 
9.4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
9.4.1. Parameters 
The following parameters will be presented: 
 
Gender; 
 
Age (years) at the date of ICF signature; 
 
Year of birth: only listed; 
 
Date of study participation ICF signature: only listed; 
 
 
 
 
 
; 
 
Race; 
 
Ethnicity; 
 
Height (cm) at baseline; 
 
Weight (kg) at baseline; 
 
Body mass index (BMI) at baseline; 
 
BMI categories at baseline: 
≤ 18.5 kg/m² 


 
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]18.5, 25.0] kg/m² 
]25.0, 30.0] kg/m² 
> 30.0 kg/m²; 
 
Systolic blood pressure (mmHg) at baseline: only listed; 
 
Diastolic blood pressure (mmHg) at baseline: only listed; 
 
Heart rate (bpm) at baseline: only listed; 
 
Temperature (°C) at baseline: only listed; 
 
Childbearing potential for females: yes, no; 
 
Alcohol consumption: never, current, former; 
 
Nicotine consumption: never, current, former; 
 
Caffeine consumption: never, current, former. 
Parameters mentioning ‘at baseline’ imply the selection of the last available result before the 
first study drug administration.  
9.4.2. Analysis 
Table 14.1.3.1:  
Demographic data: Descriptive statistics and tabulation 
Continuous parameters: descriptive statistics per treatment group (including the overall total). 
Categorical parameters: frequency tabulation per treatment group (including the overall total). 
Population: safety analysis set. 
Listing 16.2.4.1:  Demographic data and baseline characteristics 
Listing per treatment group and per subject of all demographic and baseline characteristic 
parameters. 
Population: safety analysis set. 
Listing 16.2.4.2:  Substance use 
Listing per treatment group and per subject of alcohol, nicotine and caffeine consumptions. 
Population: safety analysis set. 
 
 


 
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9.5. 
BASELINE DISEASE CHARACTERISTICS 
9.5.1. Parameters 
 
Duration of AD (years) = 
ሺୢୟ୲ୣ ୭୤ ୱ୧୥୬୧୬୥ ୍େ୊ሻିሺୢୟ୲ୣ ୭୤ ୧୬୧୲୧ୟ୪ ୢ୧ୟ୥୬୭ୱ୧ୱሻାଵ 
ଷ଺ହ.ଶହ
. 
If the date of initial diagnosis is incomplete, then the following rules will be applied: 
Missing day: use the first of the month.  
Missing month: use January; 
 
Duration of AD, categorized as: 
< 1 year, 
[1, 2[ year, 
[2, 5[ year, 
[5, 10[ year, 
[10, 20[ year, 
≥ 20 year; 
 
Date of initial diagnosis: only listed; 
 
Age at time of initial diagnosis = 
ሺୢୟ୲ୣ ୭୤ ୧୬୧୲୧ୟ୪ ୢ୧ୟ୥୬୭ୱ୧ୱሻିሺୢୟ୲ୣ ୭୤ ୠ୧୰୲୦ሻାଵ 
ଷ଺ହ.ଶହ
 (as day and month 
of the date of birth are not recorded in the database, this will be imputed to the 1st of 
July), categorized as: 
< 18 years, 
[18, 50[ years, 
≥ 50 years; 
 
; 
 
; 
 
; 
 
; 
 
Use of the following therapy (Yes/No): 
o 
Biologics therapy; 
o 
Non-biologic systemic therapy; 
o 
Phototherapy; 
o 
Topical treatment for AD; 
 
Any other AD: only listed. 
9.5.2. Analysis 
Table 14.1.3.2:  
Screening and baseline disease characteristics 
Continuous parameters: descriptive statistics per treatment group (and overall).  
Categorical parameters: frequency tabulation per treatment group (and overall).  
Population: safety analysis set. 
 
 


 
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Listing 16.2.4.3:  Screening and baseline disease characteristics 
Listing per treatment group and per subject of all baseline disease characteristic parameters 
(date of initial diagnosis, duration of AD (flag the imputed durations), previous treatments for 
AD, other atopic disease), 
 
 
Population: safety analysis set. 
9.6. 
MEDICAL HISTORY AND CONCURRENT DISEASES 
Table 14.1.3.3:  
Medical history: Tabulation 
Frequency tabulation per treatment group (and overall) of the system organ classes and 
preferred terms, selecting only medical conditions no longer present at the start of the study 
i.e. start of screening period. 
Population: safety analysis set. 
Table 14.1.3.4:  
Concurrent diseases: Tabulation 
Frequency tabulation per treatment group (and overall) of the system organ classes and 
preferred terms, selecting only medical conditions still present at the start of the study i.e. start 
of screening period. 
Population: safety analysis set. 
Listing 16.2.4.4:  Medical history 
Listing per treatment group and per subject of the reported medical conditions no longer 
present at the start of the study i.e. start of screening period (including system organ class and 
preferred term from MedDRA coding dictionary). 
Population: safety analysis set. 
Listing 16.2.4.5:  Concurrent diseases 
Listing per treatment group and per subject of the reported medical conditions still present at 
the start of the study i.e. start of screening period (including system organ class and preferred 
term from MedDRA coding dictionary). 
Population: safety analysis set. 
 
 


 
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9.7. 
PRIOR AND CONCOMITANT THERAPIES 
9.7.1. Coding of Reported Terms 
All prior and concomitant medications terms are expected to be coded using the WHO-DRUG 
coding dictionary (version March 2018 or later).  
In the tables, the generic term will be used. The ATC classification will be used for analysis. 
Multiple records of the same generic term for the same subject with the same categorization 
will be counted only once. The table will therefore present subjects, not occurrences. 
9.7.2. Categorization for Timing 
All prior and concomitant therapy records will be categorized as follows, considering their 
dates: 
 
Prior only: when the record ended before the first study drug administration date. 
 
Concomitant only: when the record started on the same date or after the first study drug 
administration date until the last study drug administration + 30 days. 
 
Prior and concomitant: when the record started before the date of the first study drug 
administration, and ended on a date after the first study drug administration (or on the 
same date) or continued. 
Records without a start date are assumed to have started before the date of the first study drug 
administration (records without an end date are assumed to be ongoing).  
When the start or end dates of the prior and concomitant therapy records are incomplete, the 
date of the first study drug administration will be considered to the same level of information 
provided by the incomplete dates in order to categorize these records. This means a record 
only having month and year information will be categorized comparing only to the month and 
the year of the first study drug administration. The CRF question “Did the concomitant 
medication start prior to the first dose of study treatment?” will be also used for the 
categorization of the medication, if needed. 
9.7.3. Calculation of the Relative Days 
For both the start and the end dates of  the concomitant therapy records, their day relative to 
the day of the first study drug administration will be calculated as described in section 5.4 of 
this SAP (calculation of relative days).  
The relative day for a missing start date will be set to missing. 
The relative day for an incomplete start or end date will be set to missing. 
The relative day for a missing end date will be calculated up to the subject’s date of last 
contact in study, and will be printed as ‘>X days’.  


 
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9.7.4. Analysis 
Table 14.1.3.5:  
Prior therapies: Tabulation 
Frequency tabulation per treatment group (and overall) of the ATC 4 classes and generic 
terms. Only therapies defined above as ‘prior only’ or as ‘prior and concomitant’ are to be 
included. 
Population: safety analysis set. 
Table 14.1.3.6:  
Concomitant therapies: Tabulation 
Frequency tabulation per treatment group (and overall) of the ATC 4 classes and generic 
terms. All therapies defined above as ‘concomitant only’ or ‘prior and concomitant’ are to be 
included. 
Population: safety analysis set. 
Listing 16.2.4.6:  Prior and concomitant therapies 
Listing per treatment group and per subject of all prior and concomitant therapy records, also 
showing their categorized timing as prior only, concomitant only or prior and concomitant.  
When these records are linked to medical history or adverse events, these additional details 
(reported term of the medical history condition(s) or reported term of the adverse event(s), 
including their record ID numbers) will be printed as well. 
Population: safety analysis set. 
Listing 16.2.4.7:  Prior and concomitant TCS/TCI therapies against atopic dermatitis 
Same as Listing 16.2.4.6, only selecting TCS/TCI medications (i.e., Was this a TCS/TCI 
medication?=”Yes”). 
Population: safety analysis set. 
Listing 16.2.4.8:  Concomitant intake of rescue atopic dermatitis medications 
Same as Listing 16.2.4.6, selecting only rescue medications records (i.e., indication=”Rescue 
AD medication”). 
Population: safety analysis set. 
 
 


 
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9.8. 
EXPOSURE TO STUDY MEDICATION AND COMPLIANCE 
9.8.1. Derivations 
A total of 4 treatment days with s.c. doses (including loading dose on day 1) are to be 
received by the subject.  
Total treatment duration (days) = last dose of study medication date – first dose of study 
medication date + 1 day. 
In addition, the number (%) of subjects who received >4, 4, 3, 2, 1 treatment days with s.c. 
injections will be tabulated. 
9.8.2. Analysis 
Table 14.1.5.1:  
Use of study medication: Descriptive statistics 
Descriptive statistics per treatment group (and overall) of the total treatment duration (days).  
Population: safety analysis set. 
Table 14.1.5.2:  
Use of study medication: Tabulation of the number of injections 
received 
Frequency tabulation per treatment group (and overall) of the number of treatment days with 
s.c. injections received: >4, 4, 3, 2, 1. 
Population: safety analysis set. 
Listing 16.2.5.1:  Study drug administration 
Listing per treatment group and per subject of all records related to the administration of study 
drug. 
Population: safety analysis set. 
Listing 16.2.5.2: 
Cross-treated subjects 
Listing of subjects who took incorrect study medication (from another randomization group) 
for at least part of the treatment period, all prime therapy records are to be included to provide 
an overview of the amount of cross-treatment relative to the total treatment period. Results are 
to be presented by treatment and subject. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.5.3: 
Subjects for whom the injections were not administered per protocol  
Listing of subjects who did not receive injection per-protocol (i.e. loading dose was not 
provided at day 1 or provided at another time point will be listed; reason for not providing the 
dose will be listed as well). Results are to be presented by treatment and subject. 
Population: safety analysis set. 
 
 


 
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10. 
ANALYSIS OF EFFICACY AND DEFINITION OF 
ANALYSIS TLFS 
The efficacy outputs will be generated using FAS. 
10.1. DEFINITIONS, DERIVATION RULES AND PRESENTATION 
OF EFFICACY PARAMETERS 
10.1.1. 
 
10.1.1.1. 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
10.1.1.2. 
Tables 
Table 14.2.1.1:  
 
 
 
 
.  
Population: full analysis set. 


 
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Table 14.2.1.4:  
 
 
 
 
 
 
 
 
 
  
 
 
       
 
       
 
       
 
       
  
       
  
       
 
                
    
 
                
    
 
                
  
 
               
 
       
               
 
  
 
 
Population: full analysis set. 
Table 14.2.1.5:  
 
 
 
 
 
 
 
 
 
 
 


 
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Table 14.2.1.6:  
 
 
 
 
 
  
 
 
       
 
       
 
       
 
       
 
       
               
                
  
 
                
  
               
 
       
      
     
 
  
 
 
 
   
 
Population: full analysis set. 
10.1.1.3. 
Figures 
Figure 14.2.1.5:  
 
 
 
  
Population: full analysis set. 
 
 


 
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Figure 14.2.1.17:  
 
 
 
Population: full analysis set. 
10.1.1.4. 
Listings 
Listing 16.2.6.1:  
 
 
Population: full analysis set. 
10.1.2. 
 
10.1.2.1. 
Derivations 
 
 
 
 
 
10.1.2.2. 
Tables 
Table 14.2.1.8:  
 
 
 
 
Population: full analysis set. 
 
 
10.1.2.3. 
Figures 
No figure will be provided for this parameter. 
 
 


 
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10.1.2.4. 
Listings 
Listing 16.2.6.2:  
 
 
 
 
Population: full analysis set. 
10.1.3. 
 
10.1.3.1. 
Derivations 
 
 
 
 
 
 
 
 
 
 
10.1.3.2. 
Tables 
Table 14.2.1.9:  
 
 
 
 
  
Population: full analysis set. 
Table 14.2.1.11:  
 
 
Population: full analysis set. 


 
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10.1.3.3. 
Figures 
Figure 14.2.1.15:  
 
 
 
Population: full analysis set. 
Figure 14.2.1.17:  
 
Same figure as  
 


 
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. 
Population: full analysis set. 
10.1.3.4. 
Listings 
Listing 16.2.6.3:  
 
 
 
Population: full analysis set. 
10.1.4. 
 
10.1.4.1. 
Derivations 
 
 
 
 
10.1.4.2. 
Tables 
No table will be provided for this parameter. 
10.1.4.3. 
Figures 
No figure will be provided for this parameter. 
 
 


 
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10.1.4.4. 
Listings 
Listing 16.2.6.4:  
 
 
Population: full analysis set. 
10.1.5. 
 
10.1.5.1. 
Derivations 
 
 
 
 
  
 
 
10.1.5.2. 
Tables 
No table will be provided for this parameter. 
10.1.5.3. 
Figures 
No figure will be provided for this parameter. 
10.1.5.4. 
Listings 
Listing 16.2.6.5:  
 
 
 
Population: full analysis set. 


 
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10.1.6. 
 
10.1.6.1. 
Derivations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.1.6.2. 
Tables 
No table will be provided for this parameter. 
10.1.6.3. 
Figures 
No figure will be provided for this parameter. 
10.1.6.4. 
Listings 
Listing 16.2.6.6:  
 
 
 
Population: full analysis set. 
 
 


 
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10.1.7. 
 
10.1.7.1. 
Derivations 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
10.1.7.2. 
Tables 
Table 14.2.1.19:  
 
 
 
 
Population: full analysis set. 
 
 


 
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10.1.7.3. 
Figures 
Figure 14.2.1.37:  
 
 
 
 
Population: full analysis set. 
10.1.7.4. 
Listings 
Listing 16.2.6.7:  
 
 
Population: full analysis set. 
Listing 16.2.6.8:  
 
 
 
Population: full analysis set. 
10.1.8. 
 
10.1.8.1. 
Derivations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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10.1.8.2. 
Tables 
No table will be provided for this parameter. 
10.1.8.3. 
Figures 
No figure will be provided for this parameter. 
10.1.8.4. 
Listings 
  
 
 
 
10.1.9. 
 
10.1.9.1. 
Derivations 
 
 
 
 
 
 
 
 
 
 
 
10.1.9.2. 
Tables 
No table will be provided for this parameter. 
10.1.9.3. 
Figures 
No figure will be provided for this parameter. 
 
 


 
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10.1.9.4. 
Listings 
 
 
 
 
 


 
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11. 
ANALYSIS OF PHARMACOKINETICS AND DEFINITION 
OF ANALYSIS TLFS 
11.1. DEFINITIONS, DERIVATION RULES AND PRESENTATION 
OF PK PARAMETERS 
11.1.1. Available Data 
Compound: MOR106 in serum (free drug levels). 
11.1.2. PK Parameters and Derivation Rules 
No PK parameters will be derived. 
11.1.3. PK Derivation Rules  
 
Time deviation:  
 
The actual sampling time will be used for graphical presentation of the individual 
data. 
 
Handling of BLOQ values: 
 
Concentration BLOQ will be imputed according to the rules mentioned in section 
7.8. 
 
If the concentrations before the first quantifiable concentration time point is BLOQ, 
the concentration will be set to 0. 
 
If the concentrations after the last quantifiable concentration time point is BLOQ, the 
concentration will be set to missing. 
 
If there are embedded BLOQ values between quantifiable concentrations after the 
last dose on Day 43, these BLOQ values will be set to missing. 
 
If there is a quantifiable concentration after 2 consecutive BLOQ values at the end of 
the profile after the last dose on Day 43, this quantifiable concentration will be set to 
missing. 
Excluded data will be discussed in the PK Data Review (Appendix 16.1) and flagged in the 
TLFs. 
11.1.4. Tables 
Table 14.2.2.1: 
MOR106 serum concentrations (µg/mL): Individual data and 
descriptive statistics and time point 
Subject data and descriptive statistics per analysis visit/time point of the serum concentrations 
will be displayed. 
Population: PK analysis set. 


 
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11.1.5. Figures 
Figure 14.2.2.5:  
MOR106 trough serum concentrations (µg/mL): Subject profile plots 
(linear-linear scale) 
Subject profile plots of the MOR106 trough serum concentrations over time with all subjects 
on the same plot (up to Day 57 including only pre-dose timepoints and Day 57 results to be 
displayed on the same plot). 
Population: PK analysis set. 
Figure 14.2.2.6:  
MOR106 trough serum concentrations (µg/mL): Mean (+/- SE) 
concentration over time (linear-linear scale) 
Arithmetic mean with SE of the MOR106 trough serum concentrations over time (up to Day 
57 including only pre-dose timepoints and Day 57 results to be displayed on the same plot). 
Population: PK analysis set. 
11.1.6. Listings 
Listing 16.2.7.1:  PK data handling 
Listing per treatment, subject and analysis visit/time point of any data issue. 
Population: PK analysis set. 
Listing 16.2.7.2:  Actual PK blood sampling times (h) 
Listing per treatment, subject and analysis visit/time point of the PK sampling times relative 
to the actual drug intake. Deviations from the scheduled sampling times of more than 10% 
will be flagged (for post-dose assessments), as well as pre-dose samples that were actually 
taken post-dosing. 
Population: PK analysis set. 
Listing 16.2.7.3:  MOR106 serum concentrations (µg/mL): Individual data  
Listing per treatment, subject and analysis visit/time point of all MOR106 serum 
concentration data. 
Population: PK analysis set. 
 
 


 
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12. 
ANALYSIS OF IMMUNOGENICITY AND DEFINITION OF 
ANALYSIS TLFS 
Table 14.2.3.1:  
Anti-MOR106 antibodies (ADA): Tabulation per treatment and time 
point 
Frequency table of ADA status (positive/negative) and potential drug interference in the assay 
when ADA negative (yes/no) by treatment group at Day 1 and all post-dose time points. 
Population: safety analysis set. 
Listing 16.2.8.1:  Anti-MOR106 antibodies (ADA): Full listing 
Listing per treatment, subject and analysis visit/time point of ADA results, titer and potential 
drug interference. 
Population: safety analysis set. 
 
 


 
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13. 
ANALYSIS OF PHARMACODYNAMICS AND DEFINITION 
OF ANALYSIS TLFS 
13.1.1. Disease Status Definition 
 
 
 
 
 
 
 
 
13.1.2. Tables 
No table will be provided for these parameters. 
13.1.3. Figures 
No figure will be provided for these parameters. 
13.1.4. Listings 
Listing 16.2.9.3:  
 
, 
 
  
Population: safety analysis set. 
 
 


 
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14. 
ANALYSIS OF SAFETY AND DEFINITION OF ANALYSIS 
TLFS 
The analysis of safety data will be descriptive. No inferential statistics will be computed.  
The analysis of safety assessments in this study will include summaries of the following 
categories of safety and tolerability data collected for each subject (safety analysis set): 
- 
Adverse events  
- 
Non-drug related therapies 
- 
Laboratory safety  
- 
Electrocardiogram (ECG) investigations 
- 
Vital signs 
- 
Physical examination 
14.1. ADVERSE EVENTS 
14.1.1. Coding of Reported Terms 
All adverse event terms are expected to be coded using the MedDRA coding dictionary 
(version 21.0 or higher). 
All tables in this section will show the AE terms coded into preferred terms and system organ 
classes. Subject listings will also show the reported terms. All other coding levels will only be 
shown in a listing summarizing coding or when explicitly mentioned.   
14.1.2. Definition of Treatment-emergent Adverse Events 
All adverse events starting as of the point of administration of study drug (i.e. start date of 
dose administration for s.c. dosing) until the last contact of the subject are defined as 
treatment-emergent adverse events (TEAE). 
All adverse events tables will only show TEAEs. 
Adverse events starting before administration of study drug (not TEAEs) will only be listed. 
If an AE starts before administration of study drug but worsens after then: 
 Until the worsening, the AE will be considered as a non-TEAE; 
 From the worsening, the AE will be considered as a TEAE. 
But if an AE starts before administration of study drug and improves after the first dose, the 
AE will not be considered as a TEAE. 


 
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14.1.2.1. 
Combining of Events to be Able to Count Number of Events  
A worsening is defined when one of the attributes of the events worsens (severity, 
seriousness, relationship or action taken). Worsenings observed after first dose of study 
medication of an event will be considered as a new event, improvements will not. 
14.1.3. Allocation of Adverse Events to Analysis Periods 
All adverse events records will be placed into analysis periods considering their start 
date(time), i.e. aiming to report the incidence of these events only in the analysis period 
during which they started. 
The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date(time) ≤ AE start date(time) ≤ analysis period end date(time) 
If the start date(time) of an AE is incomplete and to such a level preventing a clear allocation 
of the AE to one single analysis period, a worst-case consideration will be done aiming to 
allocate the AE record to one single analysis period, if possible. The CRF question “Did the 
adverse event start prior to the first dose of study treatment?” will also be considered for the 
analysis period allocation.  
When a worst-case consideration is needed for allocation to analysis periods, the end date of 
the AE records, if and as available, should also be considered; if such AEs clearly end on a 
given point, this will exclude the possibility to allocate the AE to an analysis period after that 
point. 
- 
An AE which according to the available information of its start date(time) could 
belong to the screening and to the treatment analysis period will only be placed in the 
treatment analysis period. 
- 
An AE which according to the available information of its start date(time) could 
belong to the treatment analysis period and to the Follow-up analysis period will only 
be placed in the treatment analysis period.  
14.1.4. Treatment Relatedness 
Following (ICH-E3), the originally reported relatedness to study drug of an AE will be 
dichotomized as follows: 
- 
Not study drug related: this includes the levels ‘unrelated’, ‘unlikely’ and ‘not 
applicable’.  
- 
Study drug related: this includes the levels ‘possible’, ‘probable’ and ‘certain’ 
(includes, as a worst-case consideration, any missing drug relatedness). 
This dichotomized relatedness will only be used in tables; relatedness as originally reported 
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14.1.5. Worst-case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (e.g., intensity), the worst-
case is always applied within each subject, preferred term and analysis period, i.e., when a 
subject has multiple times the same AE preferred term in the same analysis period, then the 
subject is reported only once: only with the worst intensity. If this happens in two different 
analysis periods, the AE is reported twice: once in each analysis period. 
CRF will collect the changes in AE. If there is a change of intensity, seriousness, drug 
relatedness or action taken, the worst category (by analysis period when applicable) will be 
considered for tables. 
14.1.6. Adverse Event Onset Day and Duration 
See section Calculation of Relative Days and Durations. 
For each AE record, its onset day in study (the day of the AE start date relative to the date of 
administration of study drug), its onset day in the analysis period, and its duration in days will 
be calculated and shown only in listings.  
These relative onset days, and the AE duration will be set to missing if the AE start date is 
incomplete or missing.  
If the AE end date is incomplete, the AE duration will be set to missing. 
If the AE end date is missing, the AE duration will be calculated until the date of last contact 
in the study for the concerned subject, printing such AE duration as ‘>X days’.  
If the outcome of an AE is ‘not resolved’ or equivalent, the AE duration will be calculated 
with either the provided AE end date or until the date of last contact in the study for the 
concerned subject (whichever is earliest/available), also printing such duration as ‘>X days’. 
Since worsenings of intensity, seriousness, drug relatedness or action taken are recorded in the 
CRF, two durations will be computated: 
- 
The duration (days) of the individual event: the duration of the event until worsening 
or until resolution or until the date of last contact (whatever applies). 
- 
The duration (days) of the overall event: the duration of the event until the end of the 
worsening or until resolution or until the date of last contact (whatever applies). 
If there is no worsening, the individual event duration and the overall event duration will be 
equal. In case of worsening, for the event(s) stating for the worsening(s), only the individual 
event duration will be computed. For the initial event, both durations will be computed as for 
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14.1.7. Calculation of Percentages 
The denominator for all percentages will be the total number of subjects in each treatment 
group within the analysis period. 
14.1.8. Tables 
Analysis periods will be replaced by their respective treatment via the randomization list (i.e, 
an as-randomized allocation) in all tables and listings. 
Table 14.3.1.1:  
Treatment-emergent adverse events: Summary table 
Tabulation per treatment group of the incidence of subjects: 
 
With at least one treatment-emergent adverse event (TEAE); 
 
With at least one serious TEAE; 
 
With at least one ISR; 
 
With at least one skin related TEAE; 
 
With at least one ISR (Grade 3 or higher) or skin related TEAE; 
 
With at least one AE leading to death; 
 
With at least one mild TEAE as worst intensity per treatment; 
 
With at least one moderate TEAE as worst intensity per treatment; 
 
With at least one severe TEAE as worst intensity per treatment; 
 
With at least one life threatening TEAE as worst intensity per treatment; 
 
With at least one fatal TEAE as worst intensity per treatment; 
 
With at least one TEAE considered related to study drug; 
 
With at least one TEAE for which the study drug was temporarily stopped; 
 
With at least one TEAE for which the study drug was permanently stopped. 
Population: safety analysis set. 
Table 14.3.1.2:  
Treatment-emergent adverse events up to 30 days after last dose: 
Summary table 
Same as Table 14.3.1.1, but restricted to events that started after start of study medication and 
up to 30 days after last dose. 
Population: safety analysis set. 
Table 14.3.1.3:  
Treatment-emergent adverse events: Tabulation of all adverse events 
Incidence of subjects tabulation per treatment group of TEAE classified per system organ 
class and preferred term. 
Population: safety analysis set. 
 
 


 
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Table 14.3.1.4:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events 
Same as Table 14.3.1.3, but restricted to events that started after start of study medication and 
up to 30 days after last dose. 
Population: safety analysis set. 
Table 14.3.1.5:  
Treatment-emergent adverse events: Tabulation of all adverse events 
by preferred term 
Incidence of subjects tabulation per treatment group of TEAE classified per preferred term. 
Population: safety analysis set. 
Table 14.3.1.6:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events by preferred term 
Same as Table 14.3.1.5, but restricted to events that started after start of study medication and 
up to 30 days after last dose. 
Population: safety analysis set. 
Table 14.3.1.7:  
Treatment-emergent adverse events: Tabulation of all adverse events 
– Alphabetic order 
Same as Table 14.3.1.3 but sorted by alphabetic order. 
Population: safety analysis set. 
Table 14.3.1.8:  
Treatment-emergent adverse events up to 30 days after last dose: 
Tabulation of all adverse events – Alphabetic order 
Same as Table 14.3.1.3, but restricted to events that started after start of study medication and 
up to 30 days after last dose and sorted by alphabetic order. 
Population: safety analysis set. 
Table 14.3.1.9:  
Treatment-emergent adverse events: Tabulation per worst intensity 
Cross-tabulation of incidence of subjects per treatment group of TEAE preferred terms 
classified per system organ class versus their intensity. Considering the worst-case intensity 
per TEAE preferred term and per subject in each treatment group. 
Population: safety analysis set. 
 
 


 
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Table 14.3.1.10:  Treatment-emergent adverse events: Tabulation of all treatment-
related events 
Same as Table 14.3.1.3, but restricted to the AEs categorized as related to study drug.  
Population: safety analysis set. 
Table 14.3.1.11:  Treatment-emergent adverse events: Tabulation of treatment-related 
events per worst intensity 
Same as Table 14.3.1.9, but restricted to the AEs categorized as related to study drug.  
Population: safety analysis set. 
Table 14.3.1.12:  Treatment-emergent adverse events: Tabulation of all injection site 
reaction events 
Same as Table 14.3.1.3, but restricted to the ISR events.  
Population: safety analysis set. 
Table 14.3.1.13:  Treatment-emergent adverse events: Tabulation of all injection site 
reaction events per worst intensity 
Same as Table 14.3.1.9, but restricted to the ISR events.  
Population: safety analysis set. 
Table 14.3.1.14:  Treatment-emergent adverse events: Tabulation of all skin related 
events 
Same as Table 14.3.1.3, but restricted to the skin related events.  
Population: safety analysis set. 
Table 14.3.1.15:  Treatment-emergent adverse events: Tabulation of all skin related 
events per worst intensity 
Same as Table 14.3.1.9, but restricted to the skin related events.  
Population: safety analysis set. 
Table 14.3.1.16:  Treatment-emergent adverse events: Tabulation of all events for 
which the study or study treatment were discontinued 
Same as Table 14.3.1.3, but restricted to the TEAEs for which the study treatment was 
permanently discontinued, or for which the study was discontinued.  
Population: safety analysis set. 
 
 


 
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Table 14.3.1.17:  Serious treatment-emergent adverse events: Tabulation for EudraCT 
reporting 
Frequency tabulation per treatment group of serious TEAEs per system organ class and 
preferred term, showing both the number of subjects and events themselves. 
Population: safety analysis set. 
Table 14.3.1.18:  Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting 
Same as Table 14.3.1.17, but restricted to the non-serious TEAEs. 
Population: safety analysis set. 
Table 14.3.1.19:  Non-serious treatment-emergent adverse events: Tabulation for 
EudraCT reporting of TEAEs occurring in at least 5% of the overall 
subjects 
Same as Table 14.3.1.17, but restricted to the non-serious TEAEs. 
All the lines from the table where there is at least 5% occurrence (of the subjects) of the 
overall subjects either at system organ class or at preferred term level will be displayed. If the 
system organ class line is selected but none of the associated preferred terms, then the system 
organ class will still be presented but without preferred terms. 
Population: safety analysis set. 
14.1.9. Figures 
Figure 14.3.1.1:  
Treatment-emergent adverse events sorted by risk difference 
Graphical presentation ordered by risk difference versus placebo, presenting for each 
preferred term on the left panel the proportion of subjects with at least one TEAE for the 
active and placebo group and in the right panel the treatment difference and its 95% CI. The 
95% CI is to be calculated using the Miettinen-Nurminen  method, available in the FREQ 
procedure of SAS 9.4. 
Population: safety analysis set. 
14.1.10. Listings 
Listing 16.2.10.1: Treatment-emergent adverse events: Summary listing 
Summary listing per treatment group and per subject showing the following: 
 
Treatment start/stop date(time); 
 
AE preferred term (flagging ISR of grade 3 or higher and skin related AEs); 
 
AE start and end date(time); 
 
AE onset day in study; 


 
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 
AE number; 
 
AE duration; 
 
AE intensity (CTCAE version 5.0); 
 
AE seriousness; 
 
AE relatedness to study drug; 
 
AE action taken; 
 
AE outcome. 
This listing will show all information for each TEAE record fitting in one line. Each change in 
seriousness/intensity/relationship/action taken will be displayed each time in another line with 
the AE start date of this change and the AE stop date of this change. 
Population: safety analysis set. 
Listing 16.2.10.2: Treatment-emergent adverse events: Full listing 
Full listing per treatment group and per subject and per analysis period showing the 
following: 
 
Treatment start date(time); 
 
AE system organ class, preferred term, verbatim term; 
 
AE start and end date(time); 
 
AE onset day in study; 
 
AE number; 
 
AE duration; 
 
AE intensity (CTCAE version 5.0); 
 
AE seriousness; 
 
AESI category (ISR and skin related events); 
 
AE relatedness to study drug; 
 
AE outcome; 
 
AE action taken; 
 
Concomitant therapy started (yes/no) because of the AE (and the generic name of the 
medication). 
Each change in seriousness/intensity/relationship/action taken will not be displayed but the 
worst case for each parameter will be provided.  
Population: safety analysis set. 
Listing 16.2.10.3: Treatment-emergent adverse events: Summary listing of the grade 3 
or higher adverse events 
Same as Listing 16.2.10.1, only showing grade 3 or higher TEAEs.  
Population: safety analysis set. 


 
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Listing 16.2.10.4: Treatment-emergent adverse events: Full listing of the grade 3 or 
higher adverse events 
Same as Listing 16.2.10.2, only showing grade 3 or higher TEAEs.  
Population: safety analysis set. 
Listing 16.2.10.5: Adverse events: Full listing of the serious adverse events 
Same as Listing 16.2.10.2, only showing SAEs, whether treatment-emergent or not.  
Population: safety analysis set. 
Listing 16.2.10.6: Pre-treatment adverse events: Full listing 
Same as Listing 16.2.10.2, only showing the AE records reported in the screening period. 
Population: safety analysis set. 
Listing 16.2.10.7: Adverse events: Summary listing of the injection site reactions events 
Same as Listing 16.2.10.1, only showing ISR events.  
Population: safety analysis set. 
Listing 16.2.10.8: Adverse events: Full listing of the injection site reactions events 
Full listing per treatment group, per subject and time point showing the following: 
 
Treatment start date(time); 
 
ISR start and end date(time); 
 
ISR system organ class and preferred term; 
 
ISR anatomical site; 
 
ISR grade; 
 
ISR action taken; 
 
Narrative; 
 
Photography taken (yes/no); 
 
Erythema grade and extent; 
 
Edema grade and extent; 
 
Induration extent; 
 
Tenderness VAS; 
 
Itching VAS. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.10.9: Adverse events: Summary listing of the skin related adverse events 
Same as Listing 16.2.10.1, only showing skin related events.  
Population: safety analysis set. 
Listing 16.2.10.10: Adverse events: Full listing of the skin related adverse events 
Full listing per treatment group, per subject showing the following: 
 
Treatment start date(time); 
 
AE start and end date(time); 
 
AE system organ class and preferred term; 
 
Photography taken (yes/no and the anatomical site of lesion); 
 
Skin swab (yes/no and the anatomical site of lesion); 
 
Biopsy (yes/no and the anatomical site of lesion); 
 
Additional blood sample for cytokine analysis (yes/no); 
 
Tests and results (for cytokine analysis); 
 
Description of results and final diagnosis. 
Population: safety analysis set. 
Listing 16.2.10.11: Adverse events: Full listing of adverse events with temporarily 
discontinued as action 
Same as Listing 16.2.10.2 only showing AEs, with action taken study drug temporarily 
discontinued, whether related to study drug or not. 
Population: safety analysis set. 
Listing 16.2.10.12: Adverse events: Full listing of adverse events with permanently 
discontinued as action 
Same as Listing 16.2.10.2 only showing AEs, with action taken study drug permanently 
discontinued, whether related to study drug or not. 
Population: safety analysis set. 
Listing 16.2.10.13: Adverse events: Coding information 
Overview listing of all distinct MedDRA coding pathways for all AEs reported in this study 
and population, from AE reported term until AE system organ class, also showing the subjects 
associated to each distinct coding pathway. 
Population: safety analysis set. 


 
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14.2. NON-DRUG RELATED THERAPIES 
14.2.1. Coding of Reported Terms 
All therapies are expected to be coded using the MedDRA coding dictionary (version 21.0 or 
higher). 
14.2.2. Calculation of the Relative Days 
For both the start and the end dates of the therapy records, their day relative to the day of the 
first study drug administration will be calculated as described in section 5.4 of this SAP 
(calculation of relative days).  
The relative day for a missing start date will be set to missing. 
The relative day for an incomplete start or end date will be set to missing. 
The relative day for a missing end date will be calculated up to the subject’s date of last 
contact in study, and will be printed as ‘>X days’.  
14.2.3. Analysis 
Table 14.3.1.20: 
Non-drug related therapies 
Number (percent) of subjects per treatment group classified per system organ class and 
preferred term. 
Population: safety analysis set. 
Listing 16.2.10.14: Non-drug related therapies 
Listing per treatment group and per subject of all non-drug therapy records. 
When these records are linked to medical history or adverse events, these additional details 
(reported term of the medical history condition(s) or reported term of the adverse event(s), 
including their record ID numbers) will be printed as well. 
Population: safety analysis set. 
 
 


 
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14.3. LABORATORY SAFETY 
14.3.1. Available Data 
Laboratory parameters expected are described in the protocol (section 6.5.2 of the protocol). 
Only central laboratory data will be included. 
14.3.2. Number of Significant Digits 
The standardized results of continuous laboratory parameters, as well as their standardized 
normal limits, will be mapped to analysis values and analysis normal limits without rounding. 
Only for printing in the analysis TLFs, a maximum of 3 decimal positions will be shown.  
14.3.3. Categorization of Laboratory Parameters 
Laboratory parameters will be presented grouped into three main categories: biochemistry, 
hematology and coagulation. Urinalysis, serology, cytokines and pregnancy test will be only 
listed. All central lab data will be listed even unscheduled lab category/parameter. 
14.3.4. Derivation of Laboratory Parameters 
NAP. 
14.3.5. Baseline and Change from Baseline 
The baseline is defined as the last sample prior to the first dose of study medication. Baseline 
will be determined per lab test individually. It is recognized that baseline tests may thus come 
from more than one lab sample and not just from the “baseline visit” sample.  
The change from baseline will be calculated for all post-baseline time points as: 
Change from baseline at time point t = value at time point t – baseline value. 
14.3.6. Scoring of Laboratory Values 
14.3.6.1. 
Scoring According to Normal Ranges 
The position of the actual analysis values versus their normal ranges will be determined 
directly using the position indicator provided in the database as reported by the laboratory 
(lbnrind), expressing the classes for these analysis values as low (L), normal (N) or high (H).  
 
 


 
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14.3.6.2. 
According to CTCAE Grades 
CTCAE version 4.03 classification is only for the below tests. For other tests, only the 
classification according to normal ranges will be done. 
Chemistry: 
Laboratory test 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin (g/L) 
≥ LLN 
[30,LLN[ 
[20,30[ 
<20 
(NAP) 
ALT (U/L) 
≤ ULN 
]1.0,3.0] x ULN 
]3.0,5.0] x ULN 
]5.0,20.0] x ULN 
> 20.0 x ULN 
AST (U/L) 
≤ ULN 
]1.0,3.0] x ULN 
]3.0,5.0] x ULN 
]5.0,20.0] x ULN 
> 20.0 x ULN 
Alkaline 
phosphatase 
(U/L) 
≤ ULN 
]1.0,2.5] x ULN 
]2.5,5.0] x ULN 
]5.0,20.0] x ULN 
> 20.0 x ULN 
GGT (U/L) 
≤ ULN 
]1.0,2.5] x ULN 
]2.5,5.0] x ULN 
]5.0,20.0] x ULN 
> 20.0 x ULN 
Total bilirubin 
(µmol/L) 
≤ ULN 
]1.0,1.5] x ULN 
]1.5,3.0] x ULN 
]3.0,10.0] x ULN 
> 10.0 x ULN 
Calcium low 
(mmol/L) 
≥ LLN 
[2.00,LLN[ 
[1.75,2.00[ 
[1.50,1.75[ 
<1.50 
Calcium high 
(mmol/L) 
≤ ULN 
]ULN,2.9] 
]2.9,3.1] 
]3.1,3.4] 
>3.4 
Total cholesterol 
(mmol/L) 
≤ ULN 
]ULN,7.75] 
]7.75,10.34] 
]10.34,12.92] 
>12.92 
Creatinine 
(µmol/L) 
≤ ULN 
]1.0,1.5] x ULN 
 
]1.5,3.0] x ULN 
 
]3.0,6.0] x ULN 
 
> 6.0 x ULN 
Creatinine kinase 
≤ ULN 
]1.0,2.5] x ULN 
]2.5,5.0] x ULN 
 
]5.0,10.0] x ULN 
> 10.0 x ULN 
Glucose low 
(mmol/L) 
≥ LLN 
[3.0,LLN[ 
[2.2,3.0[ 
[1.7,2.2[ 
<1.7 
Glucose high 
(mmol/L) 
[fasting] 
≤ ULN 
]ULN,8.9] 
]8.9,13.9] 
]13.9,27.8] 
>27.8 
Phosphate 
(mmol/L) 
≥ LLN 
[0.8,LLN[ 
[0.6,0.8[ 
[0.3,0.6[ 
<0.3 
Potassium low 
(mmol/L) 
≥ LLN 
[3.0,LLN[ 
(NAP) 
[2.5,3.0[ 
<2.5 
Potassium high 
(mmol/L) 
≤ ULN 
]ULN,5.5] 
]5.5,6.0] 
]6.0,7.0] 
>7.0 
Sodium low 
(mmol/L) 
≥ LLN 
[130,LLN[ 
(NAP) 
[120,130[ 
<120 
Sodium high 
(mmol/L) 
≤ ULN 
]ULN,150] 
]150,155] 
]155,160] 
>160 
Triglycerides 
(mmol/L)  
< 1.71 
 [1.71,3.42] 
]3.42,5.7] 
]5.7,11.4] 
> 11.4 


 
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Hematology: 
Laboratory test 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin 
(g/L) 
≥ LLN 
[100,LLN[ 
[80,100[ 
< 80 
(NAP) 
WBC (giga/L) 
≥ LLN 
[3.0,LLN[ 
[2.0,3.0[ 
[1.0,2.0[ 
<1.0 
Lymphocyte 
count decreased 
(giga/L) 
≥ LLN 
[0.8,LLN[ 
[0.5,0.8[ 
[0.2,0.5[ 
< 0.2 
Lymphocyte 
count increased 
(giga/L) 
(NAP) 
(NAP) 
]4,20] 
>20 
(NAP) 
Neutrophils 
(giga/L) 
≥ LLN 
[1.5,LLN[ 
[1.0,1.5[ 
[0.5,1.0[ 
< 0.5 
Platelet count 
(giga/L) 
≥ LLN 
[75,LLN[ 
[50,75[ 
[25,50[ 
< 25 
Coagulation: 
Laboratory test 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Activated Partial 
thromboplastin 
time (s) 
≤ ULN 
]1.0,1.5] x ULN 
]1.5,2.5] x ULN 
> 2.5 x ULN 
(NAP) 
INR 
≤ ULN 
]1.0,1.5] x ULN 
]1.5,2.5] x ULN 
> 2.5 x ULN 
(NAP) 
Laboratory test 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Activated Partial 
thromboplastin 
time (s) 
≤ ULN 
]1.0,1.5] x ULN 
]1.5,2.5] x ULN 
> 2.5 x ULN 
(NAP) 
Note: 
 
LLN = lower normal limit, 
 
ULN = upper normal limit, 
 
(NAP) = grade does not exist. 
14.3.7. Treatment-emergent Principle 
14.3.7.1. 
Toxicity Grades 
A post-baseline toxicity grade 1, 2, 3 or 4 is defined as treatment-emergent when higher than 
the toxicity grade of the baseline result. If the baseline result is missing, a post-baseline 
toxicity grade 1, 2, 3 or 4 will always be considered as treatment-emergent. 
14.3.7.2. 
Non-graded Abnormalities 
A post-baseline non-graded abnormality class L or H is defined as treatment-emergent when it 
differs from the abnormality class of the baseline result. If the baseline result is missing, a 
post-baseline abnormality L or H will always be considered as treatment-emergent. 


 
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14.3.8. Determination of Worst-case Abnormality 
14.3.8.1. 
According to Normal Range 
The worst-case post-baseline result position versus normal range (L/N/H) will be determined 
per subject and per parameter.  
The following worst-cases will be determined, using all non-missing post-baseline records 
(including unscheduled and follow-up visits): 
 
H = high: 
At least one post-baseline result is classified as H, and there are no results classified as L. 
 
L = low: 
At least one post-baseline result is classified as L, and there are no results classified as H. 
 
H+L = high and low: 
At least one post-baseline result is classified as H, and at least another post-baseline result 
is classified as L. 
 
N = normal: All post-baseline results are classified as N.  
14.3.8.2. 
According to CTCAE Grades 
The worst-case post-baseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject and 
per parameter (and direction, if below and above), using all non-missing post-baseline records 
(including unscheduled and follow-up visits). 
14.3.9. Handling of Categorical Laboratory Parameters 
Categorical laboratory parameters (usually urinalysis) will only be listed. No determination of 
toxicity grades nor determination of worst-cases apply to these parameters.   
14.3.10. Tables  
Laboratory parameters with an overall low sample size (<2 observations looking at the whole 
study) will not be presented in tables, but only in listings.  
All tables in this section will be presented per treatment group and analysis visit/time point. 
Table 14.3.2.1:  
Laboratory data: Descriptive statistics of the actual values and 
change from baseline per time point 
Descriptive statistics of the actual values and changes from baseline (including 95% CI of the 
mean for change from baseline values) per laboratory test category, parameter, treatment 
group and analysis visit/time point.  
Population: safety analysis set. 
 
 


 
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Table 14.3.2.2:  
Laboratory data: Worst-case shift table according to the normal 
range 
Shift table per laboratory test category, parameter and treatment group.  
This table will present the shift in abnormality (L/N/H) for the worst-case versus the baseline 
abnormality (L/N/H).  
Table for lab tests with normal ranges. 
Population: safety analysis set. 
Table 14.3.2.3:  
Laboratory data: Worst-case treatment-emergent laboratory 
abnormalities 
Frequency table of the worst-case treatment-emergent abnormalities per laboratory test 
category, parameter and treatment group.  
Table for lab tests with normal ranges. 
Population: safety analysis set. 
Table 14.3.2.4: 
Laboratory data: Worst-case CTCAE toxicity grades 
Frequency table of the worst-case CTCAE toxicity grades (including cumulative percentages) 
per laboratory test category, laboratory test and treatment group. 
Table for lab tests with CTCAE grading. 
Population: safety analysis set. 
Table 14.3.2.5: 
Laboratory data: Worst-case shift table of the CTCAE toxicity 
grades 
This table will present the shift in CTCAE toxicity grade for the worst-case versus the CTCAE 
toxicity grade of the baseline result per laboratory test category, laboratory test and treatment 
group. 
Table for lab tests with CTCAE grading. 
Population: safety analysis set. 
 
 


 
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Table 14.3.2.6: 
Laboratory data: Worst-case treatment-emergent CTCAE toxicity 
grades 
Frequency table of the worst-case treatment-emergent lab CTCAE toxicity grades per lab test 
category, lab test and treatment group. 
Table for lab tests with CTCAE grading. 
Population: safety analysis set. 
14.3.11. Figures 
Figure 14.3.2.1:  
Laboratory data: Mean (+/- SE) of the actual values over time 
Arithmetic mean with SE of the laboratory test results over time, with both treatment groups 
on the same plot (all study days/time points to be displayed on the same plot). Each laboratory 
parameter will be on a new plot. 
Population: safety analysis set. 
Figure 14.3.2.2:  
Laboratory data: Mean (+/- SE) of the changes from baseline over 
time 
Arithmetic mean with SE of the laboratory test change from baseline results over time, with 
both treatment groups on the same plot (all study days/time points to be displayed on the same 
plot). Each laboratory parameter will be on a new plot. 
Population: safety analysis set. 
14.3.12. Listings 
Next to the actual values and the changes from baseline, all listings will present the following 
parameters: 
 
The sample date and time; 
 
The subject’s fasting status for the laboratory sample (Y or N); 
 
The value abnormality (result position versus normal range, L or H); 
 
The CTCAE toxicity grade (where applicable) 
 
The normal range associated to the parameter value; 
 
Any related comments. 
Listing 16.2.11.1: Laboratory data: Full listing 
Listing per treatment group, per subject, parameter and analysis visit/time point of all data. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.11.2: Laboratory data: Listing of treatment-emergent abnormalities 
Listing per treatment group, per subject and per time point of all post-baseline time points 
scored as treatment-emergent (normal ranges and toxicity grades), plus also the baseline 
reference time point. 
Population: safety analysis set. 
14.4. ECG 
14.4.1. Available Data 
The following provided ECG parameters will be analyzed: heart rate, RR interval, PR 
interval, QRS interval, uncorrected QT interval, QT interval corrected for the heart rate using 
Fridericia’s formula (QTcF) and QT interval corrected for the heart rate using Bazett’s 
formula (QTcB). 
14.4.2. Number of Significant Digits 
The standardized results of continuous ECG parameters will be mapped to analysis values 
without rounding. 
Only for printing in the analysis TLFs, a maximum of 3 decimal positions will be shown.  
14.4.3. Derivation of ECG Parameters 
No derivation of ECG parameters will be done. Data as recorded in the CRF/external ECG 
vendor file will be used for analyses. 
14.4.4. Handling of ECGs Measured in Triplicate 
The mean over the triplet will be calculated for each parameter. Mean values will be derived 
during the statistical analysis. Only means will be reported in tables and listings. 
14.4.5. Definition of Normal Ranges and Abnormalities  
For the QT, QTcF and QTcB parameters, the following categorizations will be done: 
 
of the actual values:  
 
<= 450 ms (considered as normal range),  
 
]450,480] ms,  
 
]480,500] ms,  
 
>500 ms; 
 
of the changes from baseline:  
 
<= 30 ms (including all decreases in QT) (considered as normal range),  
 
]30,60] ms,  
 
>60 ms. 
For PR, the following categorizations will be done: 


 
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 
< 120 ms,  
 
[120, 220] ms  (considered as normal range),   
 
>220 ms; 
For heart rate, the following categorizations will be done: 
 
< 50 bpm,  
 
[50, 100] bpm  (considered as normal range),   
 
>100 bpm; 
14.4.6. Definition of Treatment-emergent ECG Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when 
the abnormality is worse compared to the abnormality at baseline. When the baseline value is 
missing, post-baseline abnormalities are always considered as treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
14.4.1. Determination of Worst-case Abnormality 
The worst-case post-baseline categorized actual analysis value and the worst-case categorized 
change from baseline will be determined per subject and per parameter, using all non-missing 
post-baseline records (including unscheduled and follow-up visits). 
The worst-case categorized actual analysis value is the category corresponding to the highest 
post-baseline actual value. 
The worst-case change from baseline is the category corresponding to the largest increase 
(positive change) from baseline. 
14.4.2. Tables 
Table 14.3.3.1:  
ECG: Descriptive statistics of the actual values and change from 
baseline per time point 
Descriptive statistics of the actual values and changes from baseline (including 95% CI of the 
mean for change from baseline values) per parameter, treatment group and analysis visit/time 
point.  
Population: safety analysis set. 
Table 14.3.3.2:  
ECG: Worst-case shift table of the categorized actual values 
This table will present the shift in categorized actual values for the worst-case versus the 
categorized baseline value per parameter (QT, QTcF, QTcB, PR and HR) and treatment 
group. 
Population: safety analysis set. 


 
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Table 14.3.3.3:  
ECG: Worst-case treatment-emergent categorized QT and QTc 
actual value abnormalities 
Frequency table of the treatment-emergent categorized abnormal actual values per parameter 
(QT, QTcF and QTcB), treatment group for the worst-case. 
Population: safety analysis set. 
Table 14.3.3.4:  
ECG: Worst case treatment-emergent HR and PR actual values 
abnormalities 
Frequency table of the treatment-emergent categorized (L, N, H) abnormal actual values per 
parameter (PR and HR), treatment group for the worst-case.  
Population: safety analysis set. 
Table 14.3.3.5:  
ECG: Worst-case treatment-emergent categorized abnormal changes 
from baseline in QT and QTc 
Frequency table of the worst-case treatment-emergent categorized abnormal changes from 
baseline per parameter (QT, QTcF and QTcB) and treatment group.  
Population: safety analysis set. 
Table 14.3.3.6: 
ECG: Frequency table of the eCRF ECG interpretation per time 
point 
Frequency table per treatment group and time point of the ECG interpretation scores. 
Interpretation scores are: Normal/Abnormal. 
Population: safety analysis set. 
14.4.3. Listings 
Next to the actual values and the changes from baseline, all listings will present the following 
parameters: 
 
The abnormality of the actual values and of changes from baseline; 
 
Any input related interpretations of the ECG; 
 
Any related comments. 
Listing 16.2.12.1: ECG: Full listing 
Listing per treatment group, per subject, parameter and analysis visit/time point of all data. 
Population: safety analysis set. 
 
 


 
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Listing 16.2.12.2: ECG: Listing of treatment-emergent abnormalities 
Listing per treatment, subject, parameter and analysis visit/time point showing only analysis 
visits/time points having treatment-emergent abnormal results (on actual value and/or on 
changes from baseline). Next to the selected analysis visits/time points, the baseline record 
will fully be presented at all times.  
Population: safety analysis set. 
14.5. VITAL SIGNS 
14.5.1. Available Data 
The following provided vital signs parameters will be analyzed: weight, heart rate, diastolic 
and systolic blood pressure and temperature. 
14.5.2. Number of Significant Digits 
The standardized results of continuous vital signs parameters will be mapped to analysis 
values without rounding. 
Only for printing in the analysis TLFs, a maximum of 3 decimal positions will be shown.  
14.5.3. Derivation of Vital Signs Parameters 
NAP. 
14.5.4. Definition of Normal Ranges and of Abnormalities  
The actual analysis values for the following vital signs parameters will be categorized into 
abnormality classes according to their position to normal range (table below), defining these 
classes as low (L), normal (N) or high (H).  
Values within or equal to the normal range boundaries are considered normal (N). Values 
below the lower limit of the normal range are categorized as low (L), and values above the 
upper limit of normal range are categorized as high (H). 
Parameter (unit) 
Normal range 
Lower limit 
Upper limit 
Heart rate (bpm) 
40 
100 
DBP (mmHg) 
45 
90 
SBP (mmHg) 
90 
140 
Temperature (°C) 
35.5 
37.5 


 
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14.5.5. Definition of Treatment-emergent Vital Signs Abnormalities 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs 
from the abnormality class at baseline. If the baseline result is missing, a post-baseline 
abnormality L or H will always be considered as treatment-emergent. 
14.5.6. Determination of the Worst-case Abnormality 
The following worst-case post-baseline abnormalities L, N or H will be determined per 
subject and per parameter, using all non-missing post-baseline records (including unscheduled 
and follow-up visits): 
 
H = high: 
At least one post-baseline result is classified as H, and there are no results classified as L. 
 
L = low: 
At least one post-baseline result is classified as L, and there are no results classified as H. 
 
H+L = high and low: 
At least one post-baseline result is classified as H, and at least another post-baseline result 
is classified as L. 
 
N = normal: All post-baseline results are classified as N. 
14.5.7. Tables  
Table 14.3.4.1:  
Vital signs: Descriptive statistics of the actual values and change from 
baseline per time point 
Descriptive statistics of the actual values and changes from baseline (including 95% CI of the 
mean for change from baseline values) per parameter, treatment group and analysis visit/time 
point.  
Table 14.3.4.2:  
Vital signs: Worst-case shift table according to the normal range 
This table will present the shift in abnormality (L/N/H) for the worst-case versus the baseline 
abnormality (L/N/H) per parameter and treatment group. Parameters without normal ranges 
will not be presented. 
Population: safety analysis set. 
Table 14.3.4.3:  
Vital signs: Worst-case treatment-emergent abnormalities 
Frequency table of the treatment-emergent abnormalities per parameter, treatment group for 
the worst-case. Parameters without normal ranges will not be presented. 
 Population: safety analysis set. 
 
 


 
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14.5.8. Listings 
Next to the actual values and the changes from baseline, all listings will present the following 
parameters: 
 
The value abnormality (result position versus normal range, L or H); 
 
The normal range associated to the parameter value; 
 
Position in which the measurement was taken (sitting, standing or supine). 
Listing 16.2.13.1: Vital signs: Full listing 
Listing per treatment group, per subject, parameter and analysis visit/time point of all data. 
Population: safety analysis set. 
Listing 16.2.13.2: Vital signs: Listing of treatment-emergent abnormalities 
Listing per treatment, subject, parameter and analysis visit/time point showing only analysis 
visits/time points having treatment-emergent results. Next to the selected analysis visits/time 
points, the baseline record will fully be presented at all times.  
Population: safety analysis set. 
14.6. PHYSICAL EXAMINATIONS 
Listing 16.2.14.1: Physical examinations: Abnormalities 
Listing per treatment group, per subject and per analysis visit/time point only showing the 
visits having abnormal physical examination findings.  
Population: safety analysis set. 
 
 
 


 
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15. 
REFERENCES 
Bazett, H. (1920 (7)). An analysis of the time-relations of electrocardiograms. Heart, 353–370. 
Fridericia, L. (1920). Die systolendauer im elektrokardiogramm bei normalen menschen und bei 
herzkranken. 53:469-486. 
ICH-E3. (December 1995). Structure and content of clinical study reports. Step 4 Guideline.  
ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline.  
ICH-E9. (5 February 1998). Statistical principles for clincal trials. Step 4 guideline.  
 
 
 


 
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16. 
APPENDIX 
16.1. PK DATA REVIEW 
For the review of PK/ data, following items should be checked: 
I. 
PK 
I.1. 
MISSING PK DATA 
I.1.1. Missing concentrations/measurement 
I.2. 
REVIEW OF PK PROFILES AND CONCENTRATION VALUES 
I.2.1. Abnormal PK concentration/measurement profiles 
I.2.2. Abnormal PK concentration/measurement data point 
II. 
PK ANALYSIS SET 
II. 
PK ANALYSIS SET