A Randomised, Double-blind, Placebo-controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Tralokinumab in Combination With Topical Corticosteroids in Subjects With Moderate to Severe Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: LEO Pharma

 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: Tralokinumab in combination with topical corticosteroids for moderate to severe atopic 
dermatitis ECZTRA 3 (ECZema TRAlokinumab trial no. 3) 
LEO Pharma number: LP0162-1339 
NCT number: NCT03363854 
Date: 29-Aug-2018 
 

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 2 of 129 
Clinical trial protocol statements  
Approval statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
, MSc Stat 
Biostatistics Lead, Global Clinical Operations 
, MD, PhD 
Medical Lead, Medical Sciences and Safety 
, RN, PhD 
Clinical Operations Lead, Global Clinical Operations 
Approval statement international coordinating investigator 
The international coordinating investigator approves the clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by manually 
signing the International Coordinating Investigator Clinical Trial Protocol Approval Form, 
which is a separate document adjoined to this document. 
The following person has approved this clinical trial protocol: 
Associate Professor Jonathan Silverberg, MD, 
PhD, MPH 
International coordinating investigator 
Acknowledgement statement investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by signing a 
Clinical Trial Protocol Acknowledgement Form or a similar document. 
TMF-000005673 - Version
4. 0
PPD
PPD
PPD

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 3 of 129 
Protocol amendment summary of changes table 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 3 
(substantial) 
29-Aug-2018
Global 
Amendment 2 
(substantial) 
10-Apr-2018
Global 
Amendment 1 
(non-substantial) 
15-Dec-2017
Global 
Original protocol 
04-Oct-2017
NA 
Amendment 3 (29-Aug-2018) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The main reason for the amendment is to introduce the possibility for eligible subjects in 
selected countries to participate to a long-term extension trial (conducted under a separate 
protocol [LP0162-1337, ECZTEND]) without completing the safety follow-up period in the 
present trial. Indeed, a new anti-drug antibodies (ADA) assay has been developed with 
improved tralokinumab tolerance. This means that the presence or absence of ADA can be 
determined in serum samples with tralokinumab present. Previously, this was not possible and 
therefore ADA sampling at the end of the 14-week off-treatment safety follow-up was 
originally required for the ADA evaluation. Thus, in selected countries, the new ADA assay 
will allow eligible subjects who have completed the treatment periods of the present trial to 
continue into the long-term extension trial without completing the safety follow-up period in 
the present trial. These subjects will have their safety follow-up period after end of treatment 
in the long-term extension trial. 
Additional changes included in the amendment are presented in the table below. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 4 of 129 
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
Section no. and 
name 
Description of change 
Brief rationale 
Clinical trial 
protocol 
statements 
Section 1 
Protocol synopsis 
Appendix 6 
Contact list 
Professor 
 is replaced by 
Associate Professor Jonathan 
Silverberg. 
As a new international coordinating 
investigator was appointed for this 
trial. 
Section 1 
Protocol synopsis 
Section 4 
Schedule of 
procedures 
Panel 3 
(footnote 1) 
Section 7.1 
Overall trial 
design 
Section 7.3 
End of trial 
definition 
Section 9.9 
Provision for 
subject care 
following trial 
completion 
Subjects will have a final safety follow-
up visit 16 weeks after the last dose of 
IMP (which is also considered end of 
trial visit), except subjects who enter 
the long-term extension trial 
(conducted under a separate protocol 
[LP0162-1337, ECZTEND]). The 
subjects may enter ECZTEND at any 
time during the off-treatment safety 
follow-up period. For these subjects, 
the end of trial visit will be the last visit 
in the present trial. 
The subjects entering ECZTEND after 
completion of the end of treatment visit 
(Week 32) will also be considered as 
trial completers. For all subjects 
assigned treatment, an end of treatment 
form and end of trial form will be 
completed in the eCRF. 
To clarify that eligible subjects who 
have completed the treatment periods 
of the present trial may continue into 
the long-term extension trial 
(conducted under a separate protocol 
[LP0162-1337, ECZTEND]) without 
completing the safety follow-up 
period. 
TMF-000005673 - Version
4. 0
PPD

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 5 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 6 
Trial objectives 
and endpoints 
The following endpoints are added in 
Panel 4 under Other endpoints: 

Reduction from baseline to
Week 16 of POEM score ≥4
points in subjects with baseline
POEM score ≥4.

HADS anxiety and HADS
depression subscale scores <8 at
Week 16 in subjects with
baseline HADS anxiety or HADS
depression subscale scores ≥8.
To allow for a further evaluation of 
the efficacy of tralokinumab+topical 
corticosteroids (TCS) on patient 
reported outcomes compared with 
placebo+TCS. 
Section 9.8.2.1 
Storage of IMPs 
The IMP must be stored at 2 to 8°C at 
the site. The temperature during storage 
must be monitored by a calibrated, 
stationary, and continuously 
monitoring recording system. 
Minimum requirement is a calibrated 
min/max thermometer. 
To clarify that the storage 
temperature of IMP will be 
monitored. 
Section 9.8.2.2 
Storage of NIMP 
The NIMP must be stored at room 
temperature at the site according to the 
approved local label for mometasone 
furoate (Canada: 15 30°C; Europe: 
< 25°C; US: at 25°C [excursions to 15
30°C permitted]). The temperature 
during storage must be monitored by a 
calibrated, stationary, and continuously 
monitoring recording system. 
Minimum requirement is a calibrated 
min/max thermometer. 
To ensure that the NIMP will be 
stored at the trial site according to the 
approved local label and clarify that 
the storage temperature of NIMP will 
be monitored. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 6 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 9.8.3.1 
IMP 
accountability 
Used syringes will be destroyed at the 
trial site provided the trial site has 
procedures in place for such IMP 
destruction; this requires that the trial 
site is able to issue a certificate 
documenting the kit number(s) that 
were destroyed. 
Trial sites which do not have such IMP 
destruction procedures in place will 
dispose used syringes in sharps bins 
which will be shipped to the CMO at 
the end of the trial. 
For more information about IMP 
accountability, please refer to the 
IMP handling manual. 
To clarify that a certificate of 
destruction is not required for used 
IMP. 
To also allow shipment of sharps bins 
to the CMO during the trial. 
Section 10.3.2.9 
EQ-5D-5L 
The second section consists of a 
vertical visual analogue scale anchored 
at 0 (‘the worst best health you can 
imagine’) and 100 (‘the best worst 
health you can imagine’). 
To correct the definition of extremes 
in the vertical visual analogue scale. 
Section 11.1 
Collection of 
adverse events 
AEs must be collected from time of 
first trial-related activity after the 
subject has signed the informed consent 
form (ICF) until completion of the 
clinical trial (defined as the safety 
follow-up visit 16 weeks after last 
injection of IMP). For subjects 
entering the long-term extension trial 
(LP0162-1337, ECZTEND), any 
(S)AE with onset before the final
visit in LP0162-1339 should be 
reported in LP0162-1339. If ongoing, 
the (S)AE will also be recorded as 
medical history in ECZTEND. 
To clarify how (S)AEs occurring in 
subjects entering LP0162-1337 
(ECZTEND) will be collected if 
visits in LP0162-1339 overlap with 
visits in ECZTEND. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 7 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 11.5.1 
Adverse events of 
special interest 
Panel 10 
The text in the heading of the right 
column was modified as follows: 
Additional information to be provided 
(if available1) 
A footnote was added: 
1The additional data to be recorded 
in the eCRF are not a requirement, 
but are to be reported by the 
investigator, if available, for example 
as part of standard clinical practice. 
To clarify that additional information 
is to be provided only if available and 
is not requirement. 
Section 12.3.8.2 
Patient-reported 
outcomes 
The following text is added: 
In the subgroup of subjects with 
either HADS anxiety or HADS 
depression subscale score ≥8 at 
baseline, the proportion of subjects 
with both HADS anxiety and HADS 
depression subscale score <8 at 
Week 16 will be summarised by 
treatment group and analysed as 
described for the primary analysis of 
the primary estimand for the 
primary endpoints. 
In the subgroup of subjects with a 
baseline POEM score ≥4, the 
proportion of subjects with a 
reduction in POEM score ≥4 at 
Week 16 will be summarised by 
treatment group and analysed as 
described for the primary analysis of 
the primary estimand for the 
primary endpoints. 
To describe the statistical analyses of 
the new endpoints. 
Section 12.3.9.1 
Adverse events 
SAEs and AESIs will be evaluated 
separately. and aA narrative for each 
SAE will be given. AESIs and AEs 
leading to withdrawal from trial or 
permanent discontinuation of IMP will 
be tabulated and listed. 
Tabulation and listings are considered 
a more practical and informative way 
of presenting AESIs. This will enable 
easier overview of the individual 
cases as well as sorting and pooling 
of data from other trials. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 8 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 12.3.9.5 
Anti-drug 
antibodies 
Evaluations of nAB will be conducted 
on those serum samples that test 
positive for ADA. The test sample is 
deemed positive or negative for the 
presence of nAB to tralokinumab 
relative to a pre-determined (in assay 
validation) statistically derived cut 
point. Samples positive for nAB to 
tralokinumab are then titrated to 
determine relative amounts of nAB 
present in each test sample. 
To reflect that titre information from 
the nAB assay will not be available. 
Appendix 6 
Contact list 
LEO Pharma protocol authors are 
omitted. 
To comply with the European 
General Data Protection Regulation. 
Throughout 
Minor editorial and document 
formatting revisions. 
Minor, have therefore not been 
summarised. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 9 of 129 
Table of contents 
Clinical trial protocol statements ................................................................................................ 2 
Protocol amendment summary of changes table ........................................................................ 3 
Table of contents ........................................................................................................................ 9 
List of panels ............................................................................................................................ 14 
List of abbreviations ................................................................................................................. 15 
1 Protocol synopsis ................................................................................................................. 17 
2 Trial identification ............................................................................................................... 21 
3 Schematic of trial design ..................................................................................................... 21 
4 Schedule of procedures ........................................................................................................ 22 
5 Introduction and rationale .................................................................................................... 26 
5.1 Atopic dermatitis ............................................................................................................. 26 
5.2 Experience with investigational medicinal product ........................................................ 26 
5.3 Trial rationale .................................................................................................................. 27 
5.4 Justification for dose ....................................................................................................... 28 
5.5 Benefit/risk assessment ................................................................................................... 29 
5.6 Ethical considerations ...................................................................................................... 30 
6 Trial objectives and endpoints ............................................................................................. 32 
7 Trial design .......................................................................................................................... 34 
7.1 Overall trial design .......................................................................................................... 34 
7.2 Number of subjects needed ............................................................................................. 37 
7.3 End of trial definition ...................................................................................................... 37 
7.4 Scientific rationale for trial design .................................................................................. 37 
8 Trial population and withdrawal .......................................................................................... 38 
8.1 Subject eligibility ............................................................................................................ 38 
8.2 Inclusion criteria .............................................................................................................. 39 
8.3 Exclusion criteria ............................................................................................................. 40 
8.4 Enrolment ........................................................................................................................ 44 
8.5 Discontinuation ............................................................................................................... 44 
9 Treatments ........................................................................................................................... 47 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 10 of 129 
9.1 Trial product description ................................................................................................. 47 
9.1.1 
Investigational medicinal product ............................................................................... 47 
9.1.2 
Non-investigational medicinal product ....................................................................... 48 
9.1.3 
Administration of trial products .................................................................................. 48 
9.1.3.1 
Administration of IMP ............................................................................................. 48 
9.1.3.2 
Administration of NIMP .......................................................................................... 50 
9.2 Treatment assignment ...................................................................................................... 50 
9.2.1 
Blinding ....................................................................................................................... 51 
9.2.2 
Emergency unblinding of individual subject treatment ............................................... 52 
9.3 Background treatment (emollients) ................................................................................. 52 
9.4 Concomitant medication and procedures ........................................................................ 53 
9.5 Prohibited medication and procedures ............................................................................ 54 
9.6 Rescue treatment ............................................................................................................. 55 
9.7 Dose modification and IMP discontinuation rules .......................................................... 55 
9.7.1 
Reasons for permanent discontinuation of IMP .......................................................... 55 
9.7.2 
Reasons for temporary discontinuation of IMP .......................................................... 56 
9.8 Treatment logistics and accountability ............................................................................ 57 
9.8.1 
Labelling and packaging of trial products ................................................................... 57 
9.8.1.1 
Labelling and packaging of IMPs ............................................................................ 57 
9.8.1.2 
Labelling and packaging of NIMP .......................................................................... 57 
9.8.2 
Storage of trial products .............................................................................................. 57 
9.8.2.1 
Storage of IMPs ....................................................................................................... 57 
9.8.2.2 
Storage of NIMP ...................................................................................................... 58 
9.8.3 
Drug accountability ..................................................................................................... 59 
9.8.3.1 
IMP accountability ................................................................................................... 59 
9.8.3.2 
NIMP accountability ................................................................................................ 59 
9.8.4 
Trial product destruction ............................................................................................. 60 
9.8.5 
Treatment compliance ................................................................................................. 60 
9.9 Provision for subject care following trial completion ..................................................... 60 
9.10 Reporting product complaints ......................................................................................... 60 
10 Trial schedule and assessments ........................................................................................... 62 
10.1 Overview ......................................................................................................................... 62 
10.2 Assessments performed only at screening/baseline ........................................................ 63 
10.2.1 Columbia-Suicide Severity Rating Scale .................................................................... 63 
10.2.2 Demographics .............................................................................................................. 63 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 11 of 129 
10.2.3 Medical history ............................................................................................................ 64 
10.2.4 Height and weight ....................................................................................................... 64 
10.2.5 Body surface area involvement ................................................................................... 64 
10.3 Efficacy assessments ....................................................................................................... 65 
10.3.1 Investigator assessments .............................................................................................. 65 
10.3.1.1 Investigator’s Global Assessment ............................................................................ 65 
10.3.1.2 Eczema Area and Severity Index ............................................................................. 65 
10.3.1.3 Scoring Atopic Dermatitis ....................................................................................... 67 
10.3.1.4 Atopic dermatitis flares ............................................................................................ 68 
10.3.2 Subject assessments ..................................................................................................... 68 
10.3.2.1 Eczema-related Sleep numeric rating scale ............................................................. 69 
10.3.2.2 Worst Daily Pruritus numeric rating scale ............................................................... 69 
10.3.2.3 Average Daily Pruritus numeric rating scale ........................................................... 69 
10.3.2.4 Patient Days of Topical Treatment Use ................................................................... 69 
10.3.2.5 Patient Global Impression of Bother ....................................................................... 69 
10.3.2.6 Patient Global Impression of Severity ..................................................................... 70 
10.3.2.7 Patient-Oriented Eczema Measure .......................................................................... 70 
10.3.2.8 Dermatology Life Quality Index ............................................................................. 70 
10.3.2.9 EQ-5D-5L ................................................................................................................ 70 
10.3.2.10 Hospital Anxiety and Depression Scale ................................................................... 71 
10.4 Safety assessments .......................................................................................................... 71 
10.4.1 Vital signs .................................................................................................................... 71 
10.4.2 Physical examination ................................................................................................... 72 
10.4.3 Digital ECG ................................................................................................................. 72 
10.4.4 Pregnancy test .............................................................................................................. 73 
10.4.5 Laboratory testing ........................................................................................................ 73 
10.4.6 Pharmacokinetic assessments ...................................................................................... 75 
10.4.7 Anti-drug antibodies measurements ............................................................................ 75 
10.5 Estimate of total blood volume collected ........................................................................ 76 
11 Adverse events ..................................................................................................................... 76 
11.1 Collection of adverse events ............................................................................................ 76 
11.2 Reporting of adverse events ............................................................................................ 77 
11.3 Reporting of serious adverse events ................................................................................ 77 
11.3.1 Investigator reporting responsibilities ......................................................................... 77 
11.3.2 LEO reporting responsibilities .................................................................................... 78 
11.4 Other events that require expedited reporting ................................................................. 79 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 12 of 129 
11.4.1 Pregnancy .................................................................................................................... 79 
11.5 Reporting of other events ................................................................................................ 79 
11.5.1 Adverse events of special interest ............................................................................... 79 
11.5.2 Overdose ...................................................................................................................... 81 
11.5.3 Medication error .......................................................................................................... 81 
11.5.4 Misuse ......................................................................................................................... 81 
11.5.5 Abuse ........................................................................................................................... 81 
11.5.6 Aggravation of condition ............................................................................................. 82 
11.6 Follow-up for final outcome of adverse events ............................................................... 82 
11.7 Handling of an urgent safety measure ............................................................................. 82 
12 Statistical methods ............................................................................................................... 83 
12.1 Sample size ...................................................................................................................... 83 
12.2 Trial analysis sets ............................................................................................................ 83 
12.3 Statistical analysis ........................................................................................................... 84 
12.3.1 Disposition of subjects ................................................................................................ 84 
12.3.2 Demographics and other baseline characteristics ........................................................ 85 
12.3.3 Exposure and treatment compliance ............................................................................ 85 
12.3.3.1 Exposure .................................................................................................................. 85 
12.3.3.2 Treatment compliance .............................................................................................. 85 
12.3.4 Multiple testing procedure ........................................................................................... 85 
12.3.5 Analysis of primary endpoints..................................................................................... 86 
12.3.5.1 Primary estimand: ‘composite’ ................................................................................ 87 
12.3.5.2 Secondary estimand: ‘hypothetical’ ........................................................................ 88 
12.3.5.3 Tertiary estimand: ‘treatment policy’ ...................................................................... 91 
12.3.6 Analysis of secondary endpoints ................................................................................. 92 
12.3.6.1 Primary estimand for the continuous secondary endpoints: ‘hypothetical’ ............. 92 
12.3.6.2 Secondary estimand for the continuous secondary endpoints: ‘treatment policy’ .. 94 
12.3.7 Analysis of additional secondary endpoints ................................................................ 96 
12.3.8 Analysis of other endpoints ......................................................................................... 97 
12.3.8.1 Efficacy related other endpoints .............................................................................. 97 
12.3.8.2 Patient-reported outcomes ....................................................................................... 98 
12.3.9 Analysis of safety ........................................................................................................ 99 
12.3.9.1 Adverse events ......................................................................................................... 99 
12.3.9.2 Vital signs .............................................................................................................. 100 
12.3.9.3 Clinical laboratory evaluation ................................................................................ 100 
12.3.9.4 Pharmacokinetics ................................................................................................... 100 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 13 of 129 
12.3.9.5 Anti-drug antibodies .............................................................................................. 101 
12.3.10 Interim analysis ......................................................................................................... 101 
12.3.11 Analysis of data up to Week 32 ................................................................................. 101 
12.3.12 General principles ...................................................................................................... 102 
12.3.13 Handling of missing values ....................................................................................... 102 
13 References ......................................................................................................................... 103 
Appendix 1: Definitions of adverse events and serious adverse events ................................. 107 
Appendix 2: Classification of adverse events ........................................................................ 109 
Appendix 3: Trial governance considerations ........................................................................ 111 
Appendix 3A: Regulatory and ethical considerations ............................................................ 111 
Appendix 3B: Informed consent process ............................................................................... 111 
Appendix 3C: Subject and data confidentiality ...................................................................... 112 
Appendix 3D: Record keeping, quality control, and data handling ....................................... 113 
Appendix 3E: Registration, reporting, and publication policy ............................................... 117 
Appendix 3F: Insurance ......................................................................................................... 118 
Appendix 3G: Financial disclosure ........................................................................................ 118 
Appendix 3H: Trial and site closure ....................................................................................... 119 
Appendix 3I: Responsibilities ................................................................................................ 120 
Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD (21) ................................ 121 
Appendix 5: Guidance for anaphylaxis diagnosis (24) .......................................................... 122 
Appendix 6: Contact list ......................................................................................................... 123 
Appendix 7: Protocol amendment history .............................................................................. 125 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 14 of 129 
List of panels 
Panel 1  Trial design ................................................................................................................. 21 
Panel 2  Schedule of trial procedures: screening and treatment periods .................................. 22 
Panel 3  Schedule of trial procedures: follow-up including early termination ......................... 25 
Panel 4  Objectives and endpoints............................................................................................ 32 
Panel 5  Identification of investigational medicinal products .................................................. 47 
Panel 6  Investigator’s Global Assessment .............................................................................. 65 
Panel 7  Calculation of the Eczema Area and Severity Index .................................................. 66 
Panel 8  EASI severity score scale and area score scale .......................................................... 66 
Panel 9  Central laboratory testing ........................................................................................... 74 
Panel 10  Adverse events of special interest ............................................................................ 80 
Panel 11  Testing procedure for primary and secondary endpoints .......................................... 86 
Panel 12  Transmission of electronic data .............................................................................. 116 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 15 of 129 
List of abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSA 
body surface area 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS
Columbia-Suicide Severity Rating Scale  
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
at least 50% reduction in EASI score 
EASI75 
at least 75% reduction in EASI score 
EASI90 
at least 90% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HCP 
healthcare professional 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification number 
IEC 
independent ethics committee 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 16 of 129 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IgG4 
immunoglobulin G4 
IL 
interleukin 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
LEO 
LEO Pharma A/S 
LOCF 
last observation carried forward  
PK 
pharmacokinetics 
nAB 
neutralising antibodies 
NIMP 
non-investigational medicinal product 
NRS 
numeric rating scale 
PGI-B 
Patient Global Impression of Bother 
PGI-S 
Patient Global Impression of Severity 
POEM 
Patient Oriented Eczema Measure 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
SAE 
serious adverse event 
SC 
subcutaneous 
SCORAD 
Scoring Atopic Dermatitis  
SCORAD50 
at least 50% reduction in SCORAD score 
SCORAD75 
at least 75% reduction in SCORAD score 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
Th2 
T-helper-2
ULN 
upper limit of normal (range) 
UV 
ultraviolet 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 17 of 129 
1 Protocol synopsis 
Trial ID 
EudraCT no. 
NCT no. 
LP0162-1339  
2017-002065-21 
03363854 
Title of trial 
ECZTRA 3 (ECZema TRAlokinumab trial no. 3) 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the 
efficacy and safety of tralokinumab in combination with topical corticosteroids 
(TCS) in subjects with moderate-to-severe atopic dermatitis (AD) who are 
candidates for systemic therapy. 
Short title 
Tralokinumab in combination with TCS for moderate-to-severe AD. 
Main objectives 
Primary objective: 
To demonstrate that tralokinumab in combination with TCS is superior to 
placebo in combination with TCS in treating moderate-to-severe AD. 
Secondary objectives: 
To evaluate the efficacy of tralokinumab in combination with TCS on severity 
and extent of AD, itch, and health-related quality of life compared with placebo 
in combination with TCS.  
To assess safety of tralokinumab in combination with TCS when used to treat 
moderate-to-severe AD for 32 weeks. 
Primary endpoints 

Investigator’s Global Assessment (IGA) score of 0 (clear) or 1 (almost
clear) at Week 16.

At least 75% reduction in Eczema Area and Severity Index (EASI)
score from baseline (EASI75) at Week 16.
Secondary 
endpoints 

Change in Scoring Atopic Dermatitis (SCORAD) from baseline to
Week 16.

Reduction of Worst Daily Pruritus numeric rating scale (NRS) (weekly
average) of at least 4 from baseline to Week 16.

Change in Dermatology Life Quality Index (DLQI) from baseline to
Week 16.
Trial design 
The trial will consist of a screening period of 2 to 6 weeks (Weeks -6/-2 to 0), 
an initial treatment period of 16 weeks (Weeks 0 to 16), a continuation 
treatment period of 16 weeks (Weeks 16 to 32), and a 14-week off-treatment 
follow-up period for the assessment of safety (Weeks 32 to 46).  
Subjects will be randomised in a 2:1 ratio to receive multiple subcutaneous 
(SC) doses of tralokinumab (300 mg) or placebo every 2 weeks (Q2W) 
following a loading dose of 600 mg on Day 0 (or 4 mL placebo). 
Randomisation will be stratified by region and baseline disease severity.  
At Week 16, subjects will continue into continuation treatment until Week 32 
(the last dose of investigational medicinal product [IMP] will be given at 
Week 30). The treatment during the continuation treatment period will depend 
on the regimen received in the initial treatment period and on the subject’s 
clinical response at Week 16 (defined as IGA of 0 or 1 on a 5-point scale 
ranging from 0 [clear] to 4 [severe], or EASI75).  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 18 of 129 
Subjects randomised to tralokinumab in the initial treatment period and with a 
clinical response at Week 16 will be re-randomised 1:1 to one of the following 
Q2W maintenance regimens stratified by region and IGA response at Week 16 
(IGA 0/1 or IGA >1): 

Tralokinumab 300 mg Q2W.

Alternating dose administrations tralokinumab 300 mg and placebo
(tralokinumab Q4W).
Subjects randomised to placebo in the initial treatment period and with a 
clinical response at Week 16 will receive placebo Q2W in the continuation 
treatment period. Non-responders at Week 16 in the tralokinumab and placebo 
groups will receive tralokinumab 300 mg Q2W.  
The primary endpoints are assessed at Week 16, and the final efficacy 
assessment will be conducted at Week 32. 
Starting on Day 0 (baseline), all subjects will be allowed to initiate treatment 
once daily with a supplied TCS on lesional skin and continue as needed 
throughout the treatment period. TCS use will be monitored throughout the 
trial.  
All subjects will use an emollient twice daily (or more, as needed) for at least 
14 days before randomisation and will continue this treatment throughout the 
trial (including safety follow-up). On lesional skin, emollients should only be 
applied at a time where TCS is not applied; on TCS-untreated areas, the 
emollients may be applied at all times. 
Main assessments 
Efficacy: investigator assessments 

IGA.

EASI.

SCORAD.

AD flares.
Efficacy: subject assessments 
Six patient-reported outcomes (PROs) will be assessed daily using an electronic 
diary: Eczema-related Sleep NRS, Worst Daily Pruritus NRS, Average Daily 
Pruritus NRS, Patient Days of Topical Treatment Use, Patient Global 
Impression of Bother (PGI-B), and Patient Global Impression of Severity 
(PGI-S). 
Four PROs will be completed by the subjects at the site during trial visits: 
Patient Oriented Eczema Measure (POEM), DLQI, EuroQoL 5-Dimension 
Health Questionnaire 5 Level (EQ-5D-5L), and Hospital Anxiety and 
Depression Scale (HADS).  
Safety assessments 
Vital signs, physical examination, electrocardiograms, laboratory testing, 
pharmacokinetics, anti-drug antibodies, and adverse event reporting. 
Main criteria for 
inclusion 

Age 18 and above.

Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria
for AD.

History of AD for ≥1 year.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 19 of 129 

Subjects who have a recent history of inadequate response to treatment
with topical medications.

AD involvement of ≥10% body surface area at screening and baseline.

An EASI score of ≥12 at screening and 16 at baseline.

An IGA score of ≥3 at screening and at baseline.

A Worst Daily Pruritus NRS average score of ≥4 during the week prior
to baseline.

Stable dose of emollient twice daily (or more, as needed) for at least
14 days before randomisation.
Main criteria for 
exclusion 

Subjects for whom TCSs are medically inadvisable e.g., due to
important side effects or safety risks in the opinion of the investigator.

Active dermatologic conditions that may confound the diagnosis of
AD.

Use of tanning beds or phototherapy within 6 weeks prior to
randomisation.

Treatment with systemic immunosuppressive/immunomodulating
drugs and/or systemic corticosteroid within 4 weeks prior to
randomisation.

Treatment with TCS, TCI, or topical phosphodiesterase 4 (PDE-4)
inhibitor within 2 weeks prior to randomisation.

Receipt of any marketed biological therapy (i.e. immunoglobulin, anti- 
immunoglobulin E) including dupilumab or investigational biologic
agents.

Active skin infection within 1 week prior to randomisation.

Clinically significant infection within 4 weeks prior to randomisation.

A helminth parasitic infection within 6 months prior to the date
informed consent is obtained.

Tuberculosis requiring treatment within the 12 months prior to
screening.

Known primary immunodeficiency disorder.
Investigational 
medicinal products 
Tralokinumab (human recombinant IL 13 monoclonal antibody) 
150 mg/mL solution for SC injection in an accessorised pre-filled syringe, 
1.0 mL fill volume. Each kit contains 1 syringe. 
Placebo 
Placebo solution for SC injection in an accessorised pre-filled syringe, 1.0 mL 
fill volume. Each kit contains 1 syringe. 
Non-
investigational 
medicinal product 
TCS (Europe: Class 3 [potent]; US: Class 4 [mid-strength]) 
Mometasone furoate, 0.1% cream provided in kit sizes of 180–225 g every 
2 weeks. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 20 of 129 
Duration of 
treatment 
Each subject’s trial participation will be up to approximately 52 weeks: 
screening period (including wash-out, if applicable) up to 6 weeks, treatment 
period of 32 weeks, and follow-up period of 14 weeks (subjects may enter the 
long-term extension trial [LP0162-1337, ECZTEND], at any time during the 
safety follow-up period). 
Number of subjects 
to be enrolled 
A total of 369 subjects will be randomised 2:1 to treatment (246 subjects to 
tralokinumab; 123 subjects to placebo). 
Number and 
distribution of trial 
sites  
Approximately 70 sites in Europe and North America. 
Statistical methods 
Primary endpoints 
The difference in response rates between treatment groups will be analysed 
using the Cochran-Mantel-Haenszel test stratified by region and baseline 
disease severity. Subjects with missing data or subjects who receive rescue 
medication prior to the Week 16 visit will be considered as non-responders in 
the analysis. 
The primary endpoints will be tested sequentially at a 5% significance level. 
First IGA 0/1 and, if significant, EASI75. If both primary null hypotheses are 
rejected, the secondary endpoints will be tested.  
Secondary endpoints 
The change from baseline to Week 16 in SCORAD will be analysed using a 
repeated measurements model on the post baseline responses up to Week 16. 
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 from 
baseline to Week 16 is a binary endpoint, and as such it will be analysed as 
described for the primary endpoints. 
Change from baseline to Week 16 in DLQI will be analysed the same way as 
change in SCORAD. 
The secondary endpoints will be tested using the Holm method for multiplicity 
adjustment hereby controlling the overall type 1 error rate for the trial. 
International 
coordinating 
investigator 
Associate Professor Jonathan Silverberg, MD, PhD, MPH, Departments of 
Dermatology, Preventive Medicine and Medical Social Sciences, Northwestern 
University Feinberg School of Medicine, United States. 
Sponsor’s name/ 
address 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 21 of 129 
2 Trial identification  
EudraCT number: 2017-002065-21 
IND number: 123,797 
ClinicalTrials.gov number: NCT03363854 
3 Schematic of trial design 
Panel 1  Trial design 
Abbreviations: AD, atopic dermatitis; No, number; re-rando, re-randomisation; Q2W, every 2 weeks; 
Q4W, every 4 weeks; TCS, topical corticosteroids; w, week. 
Note: Clinical response is defined as subjects achieving Investigator’s Global Assessment response of 0 (clear) 
or 1 (almost clear) or at least 75% reduction in Eczema Area and Severity Index.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 24 of 129 
3)
The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout of disallowed
medications.
4)
Re-randomisation at Week 16: the treatment during the continuation treatment period will depend on the regimen received in the initial treatment period and on the subject’s
clinical response at Week 16 (see Section 7.1). Subjects will continue their use of TCS.
5)
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before randomisation and must continue this treatment throughout the trial (including
safety follow-up).
6)
For the first 3 IMP dosing visits (visits 3 to 5) and after re-randomisation (visits 11 to 13), subjects will be monitored after IMP administration for immediate drug reactions for a
minimum of 30 minutes with vital signs taken at 30 minutes or until stable, whichever is later (see Section 9.1.3.1).
7)
eDiary includes: Eczema-related Sleep NRS, Worst Daily Pruritus NRS, Average Daily Pruritus NRS, Patient Days of Topical Treatment Use, PGI-B, and PGI-S; subjects will
complete daily from Week -2 to 32, except for Patient Days of Topical Treatment Use which will be completed daily from Week 0 to 32.
8)
IgE not assessed at screening.
Abbreviations: BSA, body surface area; C-SSRS, Columbia-Suicide Severity Rating Scale; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; 
EASI75, at least 75% reduction in EASI score; ECG, electrocardiogram; eDiary , electronic diary; EQ-5D-5L, EuroQoL 5 Dimension Health Questionnaire 5 Level; HADS, Hospital 
Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; NA, not applicable; NIMP, non-
investigational medicinal product; NRS, numeric rating scale; PGI-B, Patient Global Impression of Bother; PGI-S, Patient Global Impression of Severity; POEM, Patient Oriented 
Eczema Measure; SCORAD, Scoring Atopic Dermatitis; TCS, topical corticosteroid. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 26 of 129 
Depression Scale; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; 
NIMP, non-investigational medicinal product; NRS, numeric rating scale; POEM, Patient Oriented Eczema Measure; 
SCORAD, Scoring Atopic Dermatitis; SFU, safety follow-up; TCS, topical corticosteroid.  
5 Introduction and rationale 
5.1 Atopic dermatitis 
Atopic dermatitis (AD) is a chronic inflammatory skin disease that may affect up to 20% of 
children and up to 10% of adults. In its severe form, AD is characterised by widespread skin 
lesions, intractable itch, as well as enhanced susceptibility to bacterial, viral, and fungal skin 
infections (1-4). AD is associated with a substantial patient burden that typically includes poor 
quality of life, sleep disturbance, and reductions in work productivity (5). 
AD is characterised by an activated T-helper-2 (Th2) pathway with increased skin expression 
of key Th2 cytokines including interleukin (IL)-13 (6, 7). The expression of IL-13 is increased 
in lesional skin compared to non-lesional skin, and the proportion of CD4+ and CD8+ cells 
expressing IL-13 is upregulated in AD patients compared to individuals without AD (6, 8).  
IL-13 acts on keratinocytes to release C-C motif chemokine 22 (CCL22) and recruit more 
IL-13 expressing Th2 cells, decrease differentiation, and contribute to decreased barrier 
function (9). IL-13 also drives immunoglobulin E (IgE) production and contributes to mast 
cell activation status and, once allergen cross-links IgE on the cell surface, drives histamine 
release and induces itch (10, 11). Indeed, itch is a key issue in AD, which drives significant 
mechanical damage to the skin and further facilitates allergen and pathogen entry.  
These effects together drive and exacerbate the disease phenotype. A review of the available 
preclinical literature from mouse and human ex vivo models suggests IL-13 as a, if not the, 
central mediator of the AD skin phenotype. Indeed, there is evidence that blocking the IL-4 
receptor (which is part of the receptor complex which also binds IL-13) with the monoclonal 
antibody dupilumab leads to clinical improvement in subjects with AD (12). 
5.2 Experience with investigational medicinal product 
Tralokinumab is a human recombinant monoclonal antibody of the immunoglobulin G4 
(IgG4) subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 
receptors (13-15). A compilation of clinical and nonclinical data on tralokinumab including 
pharmacokinetics (PK) is given in the current version of the Investigator’s Brochure. 
In total, 13 clinical trials with tralokinumab have been completed to date, with phase 3 
development ongoing in AD and asthma. Other clinical trials with tralokinumab have been 
conducted in subjects with ulcerative colitis, idiopathic pulmonary fibrosis, and in healthy 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 27 of 129 
subjects. Further information on these trials can be found in the current version of the 
Investigator’s Brochure.  
In a phase 2b trial (D2213C00001), adults with moderate-to-severe AD on a background of 
mild to moderate topical corticosteroids (TCS) were treated with 3 different regimens of 
tralokinumab (45 mg every second week [Q2W], 150 mg Q2W, or 300 mg Q2W) or placebo 
to evaluate the safety and efficacy over a treatment period of 12 weeks. The primary 
endpoints were change from baseline in Eczema Area and Severity Index (EASI) at Week 12 
and the percentage of subjects achieving Investigator’s Global Assessment (IGA) response of 
0 (clear) or 1 (almost clear) at Week 12. Secondary endpoints included change from baseline 
in EASI and Scoring Atopic Dermatitis (SCORAD) scores, the percentage of subjects 
achieving at least 50% reduction from baseline in EASI and SCORAD scores (EASI50 and 
SCORAD50). In the overall intent-to-treat phase 2b population, an improvement in EASI 
score at Week 12 was seen in the tralokinumab 300 mg Q2W group versus placebo. 26% of 
subjects achieved an IGA of 0 or 1 in the tralokinumab 300 mg Q2W group versus 12% in the 
placebo group. The most commonly reported causally related treatment-emergent adverse 
event (AE) was upper respiratory tract infection (6 subjects [3.9%] in the combined 
tralokinumab group [45 mg, 150 mg, and 300 mg] and 2 subjects [3.9%] in the placebo 
group). 
In total, more than 2,296 subjects have been treated with tralokinumab (cut-off date: 
18-Aug-2016). The safety of all doses studied so far has been with an acceptable benefit-risk
profile and no major safety concerns have been identified. Possible risks associated with use 
of tralokinumab are summarised in Section 5.5.  
5.3 Trial rationale 
Treatment recommendations for AD include topical therapies, the main being TCS. 
Unfortunately, TCS and topical calcineurin inhibitors (TCIs) have limited efficacy in patients 
with moderate-to-severe disease. TCS and non-biologic systemic therapies (e.g. cyclosporine, 
azathioprine) are all associated with toxicities with long-term use (16-18). The recently 
approved biological agent dupilumab exhibits an acceptable benefit-risk ratio in clinical trials 
investigating subjects with moderate-to-severe AD, however there is limited experience with 
long-term dupilumab use in the post marketing setting. 
The purpose of this phase 3 trial is to provide evidence of the efficacy and safety of 
tralokinumab in combination with TCS in the treatment of subjects with moderate-to-severe 
AD inadequately controlled with topical therapies. Such subjects would be candidates for 
systemic therapy.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 28 of 129 
Since TCS represent the mainstay of pharmacological treatment of AD, many patients may 
use tralokinumab in combination with TCS and this trial is intended to inform about treatment 
and maintenance with concomitant use of tralokinumab and TCS. After a 16-week initial 
treatment period, the trial will evaluate 2 different treatment options for additional 16-weeks 
of maintenance therapy in the continuation treatment period (tralokinumab 300 mg Q2W and 
300 mg every 4 weeks [Q4W]).  
The primary objective of this trial is to demonstrate that tralokinumab in combination with 
TCS provides more effective control of the skin manifestations of AD than placebo in 
combination with TCS. The trial will evaluate the percentage of subjects achieving IGA 
response of 0 (clear) or 1 (almost clear) and the percentage of subjects achieving at least 75% 
reduction in EASI score (EASI75) at Week 16, with secondary endpoints addressing symptom 
scores and extent of AD (SCORAD), itch severity, and health-related quality of life (HRQoL) 
measures related to AD.  
Thus, the trial will further contribute to the characterisation of the benefit-risk profile of 
tralokinumab.  
5.4 Justification for dose 
The dose selected for the tralokinumab phase 3 development programme is 300 mg Q2W 
administered subcutaneously. All subjects randomised to treatment with tralokinumab will get 
an initial loading dose of 600 mg on Day 0 (baseline). The administration of the loading dose 
of tralokinumab will allow systemic concentrations to reach steady-state faster, and 
potentially reduce the time to onset of clinical effect. The serum concentrations of 
tralokinumab after the 600 mg loading dose will not exceed the serum tralokinumab 
concentrations at steady state for the 300 mg Q2W. 
The tralokinumab 300 mg Q2W dose was chosen based on the results of the phase 2b trial in 
subjects with moderate-to-severe AD (trial D2213C00001) described in Section 5.2. The 
subjects were treated with 3 different fixed dose regimens of tralokinumab (45, 150, or 
300 mg Q2W) or placebo to evaluate safety and efficacy over a treatment period of 12 weeks. 
In the overall intention-to-treat phase 2b population, a statistically significant improvement in 
EASI change from baseline at Week 12 was observed in the tralokinumab 300 mg group 
versus placebo; however, formal statistical significance was not demonstrated for the 
co-primary endpoint IGA. The key secondary and exploratory endpoint results from 
trial D2213C00001 also supported the selection of the tralokinumab Q2W 300 mg dose for 
phase 3 development; and overall, larger numerical differences were observed for 300 mg 
tralokinumab dose than for 150 mg compared to placebo for most of the trial endpoints. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 29 of 129 
Since the safety profile in trial D2213C00001 was acceptable in all treatment cohorts and no 
clear safety related dose-response pattern was identified, the dose of 300 mg Q2W has been 
selected for evaluation in the phase 3 development programme for tralokinumab in AD.  
In the continuation treatment period, one of the treatment arms will be dosed with 
tralokinumab Q4W. This approach will allow the sponsor of the trial, LEO Pharma A/S 
(hereinafter “LEO”), to evaluate whether less frequent dosing of tralokinumab in combination 
with TCS therapy may be sufficient for maintenance of efficacy. 
5.5 Benefit/risk assessment 
There is an unmet medical need for new therapies for use in subjects with moderate-to-severe 
AD as current immunosuppressive medications, such as cyclosporine, methotrexate, and 
azathioprine, have associated long-term toxicities. Albeit dupilumab exhibits an acceptable 
benefit-risk ratio in clinical trials in AD, the long-term efficacy and safety experience with 
dupilumab is currently limited. 
Tralokinumab has already demonstrated efficacy in both moderate-to-severe AD as well as in 
a severe asthma population in phase 2 trials, and has shown an acceptable safety profile in 
AD, asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in trials with healthy 
subjects. The evidence discussed in Section 5.2 further supports the hypothesis that 
individuals with AD may benefit from treatment with tralokinumab. 
In the clinical trials completed to date, tralokinumab was well tolerated. A number of 
theoretical potential risks have been identified that are described in the current version of the 
Investigator’s Brochure, including hypersensitivity reactions, immune complex disease, 
severe infections, malignancies, and interference with reproductive function; measures are in 
place in this trial to protect participating subjects as follows: 

Close monitoring of subjects during the trial with trial visits every 2 weeks
during the treatment period (see the schedule of procedures in Section 4).

Close monitoring of subjects during the post-dosing period at the first
3 investigational medicinal product (IMP) dosing visits in the initial treatment
period (i.e., Weeks 0, 2, and 4) and after re-randomisation (i.e., Weeks 16, 18,
and 20) as a precautionary measure against hypersensitivity reactions (further
details are given in Section 9.1.3.1).
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 30 of 129 

Monitoring of subjects for clinical manifestations that may be associated with
the development of specific antibodies to tralokinumab (i.e., immune complex
disease).

Exclusion of subjects with untreated systemic helminth infestations or subjects
who have failed to respond to standard of care therapy; neutralisation of IL-13
might theoretically cause a worsening of parasitic infestation, in particular
prevention of expulsion of gastrointestinal worms (helminths) (19).

Exclusion of subjects with a history of tuberculosis requiring treatment within
12 months prior to the screening visit.

Exclusion of subjects with a history of a clinically significant infection
(defined as a systemic or serious skin infection requiring parenteral antibiotics,
antiviral, or anti-fungal medication; see Section 8.3) within 4 weeks prior to
baseline which, in the opinion of the investigator or sponsor’s medical expert,
may compromise the safety of the subject in the trial.
In conclusion, previous clinical experience with tralokinumab shows no major safety or 
tolerability concerns and appropriate measures have been instituted in this trial to protect 
subjects from potential risks that have been previously identified and to closely monitor each 
subject. The current risk/benefit ratio is favourable and supports the administration of 
tralokinumab in combination with TCS therapy for the purposes of achieving the objectives of 
this trial. 
5.6 Ethical considerations 
No children or other vulnerable subjects incapable of giving informed consent will be 
enrolled in this clinical trial. Furthermore, women who are pregnant, breastfeeding, or trying 
to become pregnant will not be enrolled in this clinical trial. Women of child-bearing potential 
must agree to use a highly effective method of contraception to prevent pregnancy during the 
clinical trial and until 16 weeks after discontinuation of treatment with the IMP. In addition, 
all female subjects of child-bearing potential will have a pregnancy test performed before, 
during and at end-of-treatment to ensure that no foetuses are exposed to the IMP.  
In a 13-week repeated-dose nonclinical study in male cynomolgus monkeys, no adverse 
effects on male reproductive endpoints were observed (Investigator’s Brochure). Coupled 
with the negligible exposure risk for drugs and antibodies by way of semen to achieve 
meaningful pharmacological levels in a pregnant woman or in the conceptus (20), it is not 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 31 of 129 
considered necessary to impose restrictions on fathering a child or sperm donation in clinical 
trials with tralokinumab. 
In this trial in adult subjects with moderate-to-severe AD who are otherwise healthy, the 
efficacy of tralokinumab in combination with TCS therapy will be compared with a placebo 
control group on TCS therapy. The choice of placebo (on the background of TCS) as control 
is appropriate for addressing the objectives of this trial and it will provide information 
regarding treatment with tralokinumab in combination with TCS. Subjects will be under 
supervision by a dermatologist or allergist every second week for the duration of the treatment 
period, which is more frequent than standard clinical practice. All subjects will be treated with 
TCS (Europe: Class 3 [potent]; US: Class 4 [mid-strength]) as needed, and rescue treatment 
may be given to the subjects at the investigator’s discretion for the duration of the trial. 
Moreover, 67% of the subjects will be randomised to treatment with tralokinumab in the 
initial treatment period, and except for those with a clinical response in the placebo group at 
Week 16, all subjects will be treated with tralokinumab in the continuation period with a 
potential effect and benefit for the individual subject. This will ensure that the subject’s AD is 
carefully monitored and treated as needed in this trial. If subjects are rescued with systemic 
corticosteroids or nonsteroid immunosuppressants they must discontinue IMP but may be 
eligible to restart IMP after discontinuing such rescue treatment. 
Altogether, the risks associated with participating in this clinical trial are considered very low 
and outweighed by the benefit of a potential future treatment option for moderate-to-severe 
AD.  
In accordance with the current version of the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, qualified medical personnel employed by LEO will 
be readily available to advise on trial-related medical questions. Medical monitoring will be 
performed throughout the trial and safety data will be reviewed regularly by medically 
qualified staff at LEO to ensure that prompt action is taken, if needed, to maximise patient 
safety.  
In conclusion, the trial design chosen for this efficacy and safety trial on tralokinumab in 
combination with TCS therapy is regarded as ethically justified and adherent with ethical 
requirements. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 34 of 129 
To evaluate the efficacy of 
tralokinumab in combination with 
TCS on patient-reported outcomes 
compared with placebo in 
combination with TCS. 

Change in Eczema-related Sleep NRS (weekly
average) from baseline to Week 16.

Reduction of Worst Daily Pruritus NRS (weekly
average) of at least 4 from baseline to Week 2.

Change in Worst Daily Pruritus NRS (weekly
average) from baseline to Week 2.

Reduction of Worst Daily Pruritus NRS (weekly
average) of at least 3 from baseline to Week 16.

Reduction of Worst Daily Pruritus NRS (weekly
average) of at least 3 from baseline to Week 2.

Change in POEM score from baseline to Week 16.

Reduction from baseline to Week 16 of POEM
score ≥4 points in subjects with baseline POEM
score ≥4.

Change in EQ-5D-5L from baseline to Week 16.

Change in HADS from baseline to Week 16.

HADS anxiety and HADS depression subscale
scores <8 at Week 16 in subjects with baseline HADS
anxiety or HADS depression subscale scores ≥8.
Abbreviations: AD, atopic dermatitis; AE, adverse event; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and 
Severity Index; EASI50, at least 50% reduction in EASI score; EASI75, at least 75% reduction in EASI score; EASI90, at 
least 90% reduction in EASI score; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS, Hospital 
Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; NRS, numeric rating scale; POEM, Patient Oriented 
Eczema Measure; SAE, serious adverse event; SCORAD, Scoring Atopic Dermatitis; SCORAD50, at least 50% reduction in 
SCORAD score; SCORAD75, at least 75% reduction in SCORAD score; TCS, topical corticosteroid.  
7 Trial design  
7.1 Overall trial design 
Overview 
This is a randomised, double-blinded, placebo-controlled phase 3 trial to confirm the efficacy 
and safety of tralokinumab administered on a background of TCS therapy in adult subjects 
with moderate-to-severe AD. The trial will consist of a screening period of 2 to 6 weeks 
(Weeks -6/-2 to 0), an initial treatment period of 16 weeks (Weeks 0 to 16), and a continuation 
treatment period of 16 weeks (Weeks 16 to 32). The primary endpoints are assessed at 
Week 16, and the final efficacy assessment will be performed at Week 32. An off-treatment 
follow-up period for the assessment of safety is also included (Weeks 32 to 46). A schematic 
of the trial design is provided in Panel 1. 
Screening period (Week -6 to Week 0) 
The screening period has a minimum duration of 2 weeks and a maximum duration of 
6 weeks and includes 1 or 2 screening visits. The exact duration of the screening period for 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 35 of 129 
the individual subject depends on the length of any washout period needed, as specified in the 
exclusion criteria in Section 8.3 (i.e. 4 weeks prior to randomisation for systemic 
immunosuppressive/immunomodulating drugs, systemic corticosteroid use, or three or more 
bleach baths during any week within the 4 weeks; 2 weeks prior to randomisation for TCSs, 
TCIs, or topical phosphodiesterase 4 [PDE-4] inhibitors). If no washout or a 2-week washout 
period is required, screening will be reduced to 2 weeks and reduced to 1 visit (Week -2; 
visit 2), i.e., the 2 screening visits will be merged. Eligibility will be assessed at the (first) 
screening visit and on Day 0 (hereinafter “baseline”) prior to randomisation. 
All subjects will attend a screening visit 14 days before baseline (Week -2; visit 2) where they 
will receive electronic diary (eDiary) training and start the eDiary. Data entered into the 
eDiary during the 2 weeks before randomisation (including the data collected on the day of 
the baseline visit [visit 3]) will be used to calculate baseline values of the patient-reported 
outcomes (PROs). 
All subjects will use an emollient twice daily (or more, as needed) for at least 14 days before 
randomisation and will continue this treatment throughout the trial (including safety follow-
up). Subjects will initiate emollient treatment no later than the Week -2 visit. On lesional skin, 
emollients should only be applied at times where TCS is not applied (i.e., emollients and TCS 
should not be used on the same areas at the same time of day); on TCS-untreated areas, the 
emollients may be applied at all times.  
Initial treatment period (Week 0 to Week 16) 
Following the screening period, approximately 369 subjects will be randomised 2:1 to one of 
the following groups stratified by region (Europe and North America) and baseline disease 
severity (IGA 3 or 4): 

Tralokinumab 600 mg (4 mL) at baseline, then 300 mg (2 mL) Q2W.

Placebo (4 mL) at baseline, then placebo (2 mL) Q2W.
Doses will be administered at the trial site by subcutaneous (SC) injection. 
Subjects in both treatment groups will apply a thin film of a supplied TCS (Europe: Class 3 
[potent]; US: Class 4 [mid-strength]) once daily to areas with active lesions as needed; lower 
potency TCS or TCI may be prescribed if needed on body areas where the supplied TCS is 
not advisable or on areas where continued treatment with TCS is considered unsafe. Topical 
therapy will be discontinued when control is achieved; discontinuation should preferably be 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 36 of 129 
gradual. The safety and appropriateness of continued or repeated courses of TCS therapy will 
be monitored and supervised by site staff.  
Continuation treatment period (Week 16 to Week 32) 
At Week 16, all subjects will be assigned to continuation treatment that will carry on until 
Week 32 (the last dose of IMP will be administered at Week 30). The treatment during the 
continuation period will depend on the regimen received in the initial treatment period and on 
the subject’s clinical response at Week 16. Clinical response is defined as IGA of 0 or 1 or 
EASI75. 
Subjects randomised to tralokinumab in the initial treatment period and with a clinical 
response at Week 16 will be re-randomised 1:1 to one of the following Q2W maintenance 
regimens stratified by region and IGA response at Week 16 (IGA 0/1 or IGA >1): 

Tralokinumab 300 mg (2 mL) (‘tralokinumab Q2W’).

Alternating dose administrations of tralokinumab 300 mg (2 mL) and placebo
(2 mL) (‘tralokinumab Q4W’).
Subjects randomised to placebo in the initial treatment period and with a clinical response at 
Week 16 will continue to receive placebo Q2W in the continuation treatment period. 
Subjects randomised to tralokinumab or placebo in the initial treatment period who do not 
fulfil either of the criteria for clinical response at Week 16 will receive tralokinumab Q2W in 
the continuation treatment period. 
All subjects will stay on the TCS regimen during the continuation treatment period. 
Safety follow-up period (Week 32 to Week 46) 
Subjects, except those who enter the long-term extension trial (LP0162-1337, ECZTEND, see 
below), will complete a 14-week off-treatment follow-up period for the assessment of safety, 
PK, and anti-drug antibodies (ADA). 
Long-term extension trial (selected countries) 
Eligible subjects may be invited to enter a long-term extension trial conducted under a 
separate protocol (LP0162-1337, ECZTEND). Subjects who transfer to ECZTEND must have 
had their last visit in the treatment period (Week 32 under the current protocol). 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 37 of 129 
7.2 Number of subjects needed 
Assuming a screening failure rate of 25%, approximately 492 subjects will be screened and 
approximately 369 subjects will be randomly assigned to the initial treatment period (2:1; 
246 subjects in the tralokinumab group and 123 subjects in the placebo group). At Week 16, 
approximately 40% of the tralokinumab treated subjects are expected to be re-randomised 
(1:1 to tralokinumab Q2W or tralokinumab Q4W) into the continuation treatment period. 
Randomisation and re-randomisation will be handled in the interactive web response system 
(IWRS) to ensure continued blinding in the trial (see Section 9.2.1). 
The statistical power considerations for this sample size (n=369) are described in 
Section 12.1. 
This trial will be conducted at approximately 70 sites in Europe and North America. The 
anticipated minimum number of subjects per trial site is 4 and the maximum number of 
subjects is 30. 
7.3 End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the safety follow-up visit (Week 46). Subjects entering the long-term extension 
trial (LP0162-1337, ECZTEND) after completion of the end of treatment visit (Week 32) will 
also be considered as trial completers. 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally. 
7.4 Scientific rationale for trial design 
The trial is designed to evaluate the efficacy and safety of tralokinumab in combination with 
TCS therapy versus placebo with TCS in subjects with moderate-to-severe AD. The trial 
endpoints have been selected to evaluate the efficacy of tralokinumab in improving the 
severity and extent of AD including both objective signs of disease and subjective symptoms 
(e.g. itch) as well as HRQoL. The two primary efficacy endpoints IGA score of 0 or 1 and 
EASI75 are recognised as important endpoints in clinical trials in AD by regulators in the US 
and EU, respectively.  
The planned trial design is considered appropriate for evaluating the trial objectives, as the 
double-blind conditions regarding the subject’s treatment (tralokinumab or placebo) are 
maintained and the possible observer bias regarding treatment effects are minimised. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 38 of 129 
Stratification by region (Europe and North America) and baseline disease severity 
(IGA 3 or 4) in this multi-centre trial will provide a strong basis for generalisation of the 
findings to the target patient population. Further, the trial population will comprise male and 
female subjects to explore effects between genders and across the adult age range.  
By using a placebo-controlled parallel group design for the initial treatment period, 
superiority of tralokinumab in combination with TCS versus placebo in combination with 
TCS can be investigated, hereby adding to the knowledge needed for positioning 
tralokinumab in the AD treatment pathway.  
The most important inclusion criterion for entry into the trial is an established diagnosis of 
AD (as defined by the Hanifin and Rajka 1980 criteria for AD)(21) at screening and a history 
of AD for at least one year, to ensure correct diagnosis and rule out differential diagnosis. A 
prerequisite for inclusion into the trial is a documented history of topical AD treatment failure 
(due to inadequate response), to ensure that the subject is candidate for systemic treatment. 
Subjects for whom topical treatment with TCS are medically inadvisable may not be enrolled 
as TCS therapy will be administered in this trial.  
AD is a chronic condition and the 32-week treatment duration has been chosen to evaluate the 
maintenance of effect as well as the safety and tolerability of tralokinumab in combination 
with TCS therapy. Data on antibodies against tralokinumab (i.e., ADAs) and tralokinumab 
drug concentration (i.e., PK) will be collected and the assessment of the potential for 
immunogenicity in the context of continuous treatment will also be evaluated up until 
16 weeks after last dose of trial product to ensure adequate washout (approximately 5 times 
the half-life) of tralokinumab. 
8 Trial population and withdrawal 
8.1 Subject eligibility 
The investigator should only enrol subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial, and can be expected to comply with the protocol.  
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria at visits specified in Section 4. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in the submission documentation to regulatory 
authorities/ethics committees, as applicable.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 39 of 129 
8.2 Inclusion criteria 
1. Written informed consent and any locally required authorisation obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations.
2. Age 18 and above.
3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (21;
Appendix 4).
4. History of AD for ≥1 year.
5. Subjects who have a recent history (within 1 year before the screening visit) of
inadequate response to treatment with topical medications.

Inadequate response is defined as failure to achieve and maintain remission or
a low disease activity state (comparable to IGA 0=clear to 2=mild) despite
treatment with a daily regimen of TCS of medium to higher potency (±TCI as
appropriate), applied for at least 28 days or for the maximum duration
recommended by the product prescribing information (e.g., 14 days for
super-potent TCS), whichever is shorter.

Subjects with documented systemic treatment for AD in the past year are also
considered as inadequate responders to topical treatments and are potentially
eligible for treatment with tralokinumab after appropriate washout.
6. AD involvement of ≥10% body surface area at screening and baseline (visit 3)
according to component A of SCORAD.
7. An EASI score of ≥12 at screening and 16 at baseline.
8. An IGA score of ≥3 at screening and at baseline.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 40 of 129 
9. A Worst Daily Pruritus numeric rating scale (NRS) average score of ≥4 during the
week prior to baseline.

Worst Daily Pruritus NRS at baseline will be calculated from daily assessments
of worst itch severity (Worst Daily Pruritus NRS) during the 7 days
immediately preceding randomisation (Day -6 to 0). A minimum of 4 Worst
Daily Pruritus NRS scores out of the 7 days is required to calculate the
baseline average score. For subjects who do not have at least 4 scores reported
during the 7 days immediately preceding the planned randomisation date,
randomisation should be postponed until this requirement is met, but without
exceeding the 6 weeks’ maximum duration for screening.
10. Subjects must have applied a stable dose of emollient twice daily (or more, as needed)
for at least 14 days before randomisation.
11. Women of child-bearing potential must use a highly effective* form of birth control
(confirmed by the investigator) throughout the trial and at least for 16 weeks
(5 half-lives) after last administration of IMP.
*A highly effective method of birth control is defined as one which results in a low
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), combined (oestrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), sexual 
abstinence (when this is in line with the preferred and usual life style of the subject), 
vasectomised partner (given that the subject is monogamous). The subjects must have 
used the contraceptive method continuously for at least 1 month prior to the pregnancy 
test at baseline. A female is defined as not being of child-bearing potential if she is 
postmenopausal (at least 12 months with no menses without an alternative medical 
cause prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy 
or bilateral oophorectomy).  
8.3 Exclusion criteria 
1. Subjects for whom TCSs are medically inadvisable e.g., due to important side effects
or safety risks (including intolerance to treatment, hypersensitivity reactions,
significant skin atrophy, systemic effects etc.) in the opinion of the investigator.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 41 of 129 
2. Concurrent enrolment in another clinical trial where the subject is receiving an IMP.
3. Previous randomisation in a tralokinumab clinical trial.
4. Active dermatologic conditions that may confound the diagnosis of AD or would
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or
psoriasis.
5. Known active allergic or irritant contact dermatitis that is likely to interfere with the
assessment of severity of AD.
6. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB],
ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), within
6 weeks prior to randomisation.
7. Treatment with the following medications within 4 weeks prior to randomisation:

Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate,
cyclosporine, azathioprine, mycophenolate-mofetil, Janus kinase inhibitors).

Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).

Three or more bleach baths during any week within the 4 weeks.
8. Treatment with the following medications within 2 weeks prior to randomisation

TCS.

TCI.

Topical phosphodiesterase 4 (PDE-4) inhibitor.
9. Receipt of live attenuated vaccines 30 days prior to the date of randomisation and
during the trial including the safety follow-up period.

Receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed,
provided they are not administered within 5 days before/after any trial visit.
10. Receipt of any marketed biological therapy (i.e. immunoglobulin, anti-IgE) including
dupilumab or investigational biologic agents:

Any cell-depleting agents including but not limited to rituximab: within
6 months prior to randomisation, or until lymphocyte count returns to normal,
whichever is longer.

Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to
randomisation.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 42 of 129 
11. Receipt of any investigational non-biologic agent within 5 half-lives prior to
randomisation.
12. Receipt of blood products within 4 weeks prior to screening.
13. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or
hospitalisation during the trial period.
14. Known or suspected allergy or reaction to any component of the IMP formulation.
15. History of any active skin infection within 1 week prior to randomisation.
16. History of a clinically significant infection within 4 weeks prior to randomisation
which, in the opinion of the investigator or sponsor’s medical expert, may compromise
the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the
subject’s ability to participate in the trial. Clinically significant infections are defined
as:

A systemic infection.

A serious skin infection requiring parenteral (intravenous or intramuscular)
antibiotics, antiviral, or antifungal medication.
17. A helminth parasitic infection within 6 months prior to the date informed consent is
obtained that has not been treated with, or has failed to respond to, standard of care
therapy.
18. History of anaphylaxis following any biological therapy.
19. History of immune complex disease.
20. History of cancer:

Subjects who have had basal cell carcinoma, localised squamous cell
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided
that the subject is in remission and curative therapy was completed at least
12 months prior to the date informed consent was obtained.

Subjects who have had other malignancies are eligible provided that the
subject is in remission and curative therapy was completed at least 5 years
prior to the date informed consent was obtained.
21. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation
will be according to local guidelines as per local standard of care.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 43 of 129 
22. History of any known primary immunodeficiency disorder including a positive human
immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral
medications as determined by medical history and/or subject’s verbal report.
23. History of chronic alcohol or drug abuse within 12 months prior to screening, or any
condition associated with poor compliance as judged by the investigator.
24. History of attempted suicide or is at significant risk of suicide (either in the opinion of
the investigator or defined as a “yes” to suicidal ideation questions no. 4 or 5 or
answering “yes” to suicidal behaviour on the Columbia-Suicide Severity Rating Scale
[C-SSRS] Screening version).
25. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic,
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological,
immunological, psychiatric, or major physical impairment that is not stable, in the
opinion of the investigator, and could:

Affect the safety of the subject throughout the trial.

Influence the findings of the trial or their interpretations.

Impede the subject’s ability to complete the entire duration of trial.
26. Any clinically significant abnormal findings in physical examination, vital signs,
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the
screening period, which in the opinion of the investigator, may put the subject at risk
because of his/her participation in the trial, or may influence the results of the trial, or
the subject’s ability to complete entire duration of the trial.
27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times
the ULN (upper limit of normal) at screening.
28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb),
hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serology
at screening. Subjects with positive HBsAb may be randomised provided they are
hepatitis B vaccinated and have negative HBsAg and HBcAb.
29. Subjects who are not willing to abstain from donating blood and/or plasma from the
time of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.
30. Subjects who are legally institutionalised.
31. Pregnant, breastfeeding, or lactating women.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 44 of 129 
32. Employees of the trial site or any other individuals directly involved with the planning
or conduct of the trial or immediate family members of such individuals.
8.4 Enrolment 
Trial participation begins once written informed consent is obtained (see Appendix 3B for 
details on the informed consent process). Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central IWRS and the screening 
evaluations to assess eligibility criteria may begin. The subject ID will be used to identify the 
subject during the screening process and throughout trial participation, if applicable. A master 
log of all consented subjects will be maintained at the trial site. 
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements (22) 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screening failure details, eligibility criteria, and reporting of any AEs and serious 
AEs (SAEs). Follow-up of SAEs must be carried out according to Section 11.6. 
Individuals who do not meet the criteria for participation in this trial (screening failures) may 
not be re-screened. However, if the reason for screening failure is administrative and not due 
to the subject failing to meet the eligibility criteria, re-screening may be permitted (this will 
require approval by the sponsor’s medical expert after thorough review of all data from the 
original screening visit in the electronic case report form [eCRF]). Individuals who are 
re-screened will get a new subject ID. 
The investigator will maintain a list of all randomised subjects at the trial site including each 
subject’s identity, date of informed consent, and corresponding subject ID so that any subject 
may be identified if required for any reason. The list must not be copied or retained by LEO. 
8.5 Discontinuation 
A subject may withdraw from trial or from treatment at any time (prior to first dose or during 
the treatment period) at his/her own request. A subject may be withdrawn at any time at the 
discretion of the investigator. Discontinued subjects will not be replaced.  
Medical reasons for permanent discontinuation of IMP are given in Section 9.7.1. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 45 of 129 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit and return to the trial site for 1 or 2 additional visits as indicated below 
depending on the time of discontinuation of IMP (see the schedule of procedures [Panel 3] for 
data to be collected at these visits). The investigator will review any AEs which will be 
followed-up according to Section 11.6, if the subject agrees. 
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend: 

Early termination visit.

Nominal Week 16 visit (16 weeks after randomisation).

Safety follow-up visit (16 weeks after last administration of IMP).
Subjects who permanently discontinue IMP at Week 16 or after Week 16 will be asked to 
attend:  

Early termination visit.

Safety follow-up visit (16 weeks after last administration of IMP).
If a subject withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site’s trial records.  
Reason(s) for discontinuation from IMP and withdrawal from the trial must be recorded in the 
medical records and the eCRF (lack of efficacy, AE, withdrawal by subject, lost to follow-up, 
death, other). For subjects randomised to IMP but not attending any post-baseline visits, it 
will be recorded whether any safety evaluations were performed after exposure to IMP. 
Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 46 of 129 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 

The trial site must attempt to contact the subject and reschedule the missed
visit as soon as possible and counsel the subject on the importance of
maintaining the assigned visit schedule and ascertain whether the subject
wishes to and/or should continue in the trial.

Before a subject is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the subject (where possible,
3 telephone calls and, if necessary, a certified letter to the subject’s last known
mailing address or local equivalent methods). These contact attempts should be
documented in the subject’s medical record.

Should the subject continue to be unreachable, they will be considered to have
withdrawn from the trial with a primary reason of lost to follow-up.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 47 of 129 
9 Treatments 
9.1 Trial product description 
9.1.1 Investigational medicinal product 
Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that 
specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is 
presented as a liquid formulation for SC administration. 
Tralokinumab and placebo will be packaged in individually numbered kits, each containing 
1 pre-filled syringe. Refer to Panel 5 for further details. 
Panel 5  Identification of investigational medicinal products 
Investigational 
medicinal 
product 
Dosage form 
Concentration and 
formulation 
Manufacturer 
Tralokinumab 
150 mg/mL solution 
for injection in an 
accessorised 
pre-filled syringe, 
1.0 mL fill volume. 
Formulated at a nominal 
concentration of 150 mg/mL in 
50 mM sodium acetate/acetic 
acid buffer, 85 mM sodium 
chloride, 0.01% (w/v) PS-80, 
pH 5.5 solution. 
MedImmune 
Placebo 
Placebo solution for 
injection in an 
accessorised 
pre-filled syringe, 
1.0 mL fill volume. 
Placebo contains the same 
excipients, in the same 
concentration only lacking 
tralokinumab. 
MedImmune 
The accessorised pre-filled syringe is a single-use, disposable system that is designed to 
administer the labelled dose of the system to the subcutaneous space during 1 injection and 
automatically provide a safety mechanism to reduce the occurrence of accidental needle sticks 
during disposal of the system.  
The accessorised pre-filled syringe consists of a pre-filled syringe sub-assembly (1 mL 
pre-filled syringe barrel with a 1/2 inch 27 gauge thin wall staked-in needle, rigid needle 
shield, plunger stopper), and a safety device. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 48 of 129 
9.1.2 Non-investigational medicinal product 
Each subject will be prescribed a non-investigational medicinal product (NIMP) for the 
duration of the trial: the subjects will receive a TCS cream (Europe: Class 3 [potent]; 
US: Class 4 [mid-strength]) from randomisation (Week 0) to Week 32. This will be provided 
as mometasone furoate, 0.1% cream in kit sizes of 180–225 g every 2 weeks. This should be 
the only TCS product applied to the body during this period, excluding areas of the body 
where the supplied TCS is not advisable or where continued use is considered unsafe (see 
Section 9.1.3.2 for further details). 
9.1.3 Administration of trial products 
9.1.3.1 Administration of IMP  
The IWRS will assign the required IMP kit numbers for each subject at each dispensing visit. 
The first day of dosing is considered Day 0 (visit 3). Each subject will receive 4 SC injections 
(each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total loading dose of 
600 mg tralokinumab or placebo. 
At subsequent visits in the initial treatment period, each subject will receive 2 SC injections 
(each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total dose of 300 mg 
tralokinumab or placebo (Q2W).  
Subjects in the continuation treatment period will receive either: 

Tralokinumab Q2W (2 SC injections [each 1.0 mL] of 150 mg tralokinumab).

Tralokinumab Q4W (alternating dose administrations of 2 SC injections [each
1.0 mL] of 150 mg tralokinumab and placebo).

Placebo Q2W (2 SC injections [each 1.0 mL] of placebo)
Dosing visits are shown in the schedule of procedures (Section 4). The last administration of 
IMP will occur at Week 30. 
IMP will be administered by a qualified, unblinded healthcare professional (HCP; see 
Section 9.2.1 for blinding details). A minimum interval of 7 days is required between 2 dosing 
visits.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 49 of 129 
The injections will be administered into the SC tissue of the upper arm, anterior thigh, or 
abdomen, separated by at least 3 cm. The injection site must be recorded in the source 
documents at each treatment visit and recorded in the eCRF.  
Further details on IMP administration are provided in a drug handling manual. 
IMP administration must be carried out according to these instructions. 
After IMP administration 
For the first 3 IMP dosing visits in both the initial treatment period (i.e., Weeks 0, 2, and 4) 
and after re-randomisation (i.e. Weeks 16, 18, and 20), subjects will be monitored after IMP 
administration for immediate drug reactions for a minimum of 30 minutes with vital signs 
taken at 30 minutes or until stable, whichever is later. Vital signs will be documented in the 
eCRF. 
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organization has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) (23). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5 (24). Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be 
immediately available at the trial sites, and trial personnel should be trained to recognise and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge, for 
analysis of serum tryptase at the central laboratory. 
Conditions requiring IMP administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and IMP 
should not be administered until the rescheduled visit: 

The subject has an intercurrent illness that, in the opinion of the investigator,
may compromise the safety of the subject in the trial (e.g., viral illnesses).

The subject is febrile (defined as ≥38°C) within 72 hours prior to IMP
administration.
If the trial visit cannot be rescheduled to maintain minimum of 7 days to subsequent dose, the 
sponsor’s medical expert should be contacted. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 50 of 129 
9.1.3.2 Administration of NIMP 
The IWRS will assign the required NIMP (TCS) kit numbers for each subject at each 
dispensing visit. The NIMP will be provided as mometasone furoate, 0.1% cream in kit sizes 
of 180–225 g every 2 weeks. If needed, additional NIMP kit(s) may be dispensed to the 
subject at a scheduled or unscheduled visit at the investigator’s discretion. The amount of 
additional NIMP dispensed must be recorded in the eCRF. 
Subjects will be instructed to apply a thin film of the dispensed TCS (Europe: Class 3 
[potent]; US: Class 4 [mid-strength]) once daily to active lesions, as needed. The TCS should 
be discontinued when control is achieved; discontinuation should preferably be gradual and 
the maximum duration of treatment should not exceed 3 weeks. The safety and 
appropriateness of continued or repeated courses of TCS therapy will be monitored and 
supervised by site staff.  
From randomisation (Week 0) through Week 30, the TCS will be dispensed and the subject 
must return used and unused TCS tubes at each subsequent trial visit, to assess the amount of 
medication used. The subjects must be instructed by the site staff on the importance of 
returning all used and unused TCS tubes. The site staff will return used and unused TCS tubes 
to the contract manufacturing organisation (CMO). The TCS tubes will be weighed at the 
CMO before shipment to the trial sites and again upon return.  
An additional, lower potency TCS or TCI may be used at the investigator’s discretion on areas 
of the body where use of the supplied TCS is not advisable such as areas of thin skin (face, 
skin fold areas, genital areas, etc.) or on areas where continued treatment is considered unsafe. 
The low potency TCS and TCI will not be provided by LEO and will not be weighed, but 
must be registered in the eCRF as concomitant medications (see Section 9.4).  
Further details on NIMP dispensing are provided in a drug handling manual. 
NIMP administration must be carried out according to these instructions. 
9.2 Treatment assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised at baseline (Day 0) to receive treatment with 
either tralokinumab or placebo. Treatment assignment will be pre-planned according to a 
computer-generated randomisation schedule in a 2:1 ratio (tralokinumab:placebo) stratified by 
region (Europe and North America) and baseline disease severity (IGA of 3 or 4).  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 51 of 129 
Subjects will be re-randomised to continuation treatment at Week 16. The treatment during 
this period will depend on the regimen received in the initial treatment period and the 
subject’s clinical response at Week 16. Subjects randomised to tralokinumab who have a 
clinical response at Week 16 (i.e. IGA 0/1 or EASI75), will be re-randomised to the 
continuation treatment period in a 1:1 ratio (tralokinumab Q2W:tralokinumab Q4W) stratified 
by region and IGA response at Week 16 (IGA 0/1 or IGA >1). Subjects randomised to placebo 
who have a clinical response at Week 16 will continue on placebo. Subjects in either the 
tralokinumab or placebo group who have not achieved a clinical response at Week 16 will 
receive tralokinumab Q2W in the continuation treatment period.  
IWRS will be used to control randomisation, re-randomisation, and stratification factors, 
along with IMP supply chain and expiry tracking, and for dispensing and return of NIMP 
(TCS). 
9.2.1 Blinding 
This is a double-blinded trial in which tralokinumab and placebo are visually distinct from 
each other. Neither the subject nor any of the investigator or LEO staff who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of the 
treatment received.  
The packaging and labelling of the IMPs will contain no evidence of their identity. IMP is 
packed in identical boxes, with non-sequential kit numbers to ensure that unblinding does not 
occur during shipment and handling of the drug. 
Since tralokinumab and placebo are visually distinct and not matched for viscosity, IMP will 
be handled and administered by a qualified, unblinded HCP (trained site staff) at the site who 
will not be involved in the management of trial subjects and who will not perform any of the 
assessments. 
If treatment allocation for a subject becomes known to the investigator or other trial staff 
involved in the management of trial subjects, LEO must be notified immediately.  
Should an issue arise with the IMP (e.g., damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g., a 
malfunction during IMP administration]), the unblinded HCP at the site will contact the 
clinical research associate (CRA) to determine whether any specific actions are required. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 52 of 129 
The trial site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of IMP administration used to maintain the blind. 
To support submission for marketing approval, an analysis of trial data up to and including 
visit 19 (Week 32) will be performed and will require unblinding of data. To perform this 
analysis, an Analysis Group consisting of a Medical Expert, a Statistician, a Statistical 
Programmer and a Medical Writer will be unblinded to individual subject treatment allocation 
following database lock for the 32-week data. All staff involved in the conduct of the trial will 
remain blinded to treatment allocation for the entire duration of the trial. This principle will be 
applied to all investigator staff and to staff employed by the sponsor except for those who are 
directly involved in the execution of the analysis. See Section 12.3.11 for details regarding the 
statistical aspects of the analysis of data up to Week 32. 
9.2.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, other HCPs who are not members of the trial staff, or authorised 
LEO personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
IWRS. For a requester who is not a member of the trial staff and who does not have access to 
IWRS (e.g., a physician at an emergency room), a local contact number for the emergency 
unblinding contract research organisation (CRO) is provided on the subject card (see 
Appendix 3B) to be used if the investigator or delegated site staff cannot be reached. The 
requester will provide the trial ID and subject ID to the emergency unblinding CRO who will 
immediately reveal the individual treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the LEO 24/7 
contact which will be diverted to the medical cover.  
9.3 Background treatment (emollients) 
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before 
randomisation; the background treatment should preferably be an additive free, basic bland 
emollient. On lesional skin, emollients should only be applied at times where TCS is not 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 53 of 129 
applied (i.e., emollients and TCS should not be used on the same areas at the same time of 
day); on TCS-untreated areas, the emollients may be applied at all times. Subjects must 
continue their background emollient treatment throughout the trial (including safety 
follow-up). 
9.4 Concomitant medication and procedures 
Any medication or vaccine that the subject receives from 3 months prior to screening through 
safety follow-up (Week 46) must be recorded in the subject’s medical record and the eCRF 
along with details such as: 

Reason for use.

Dates of administration including start and stop dates.

Dosage information including dose and frequency.
Similarly, concomitant procedures (including body location, diagnosis, and start and stop 
date) must also be recorded in the subject’s medical record and the eCRF. Note: in this trial, 
only surgical procedures will be recorded. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.5. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
Concomitant medication for conditions other than AD may be continued throughout the trial 
without any change in dosage whenever possible. 
All subjects will receive a TCS (Europe: Class 3 [potent]; US: Class 4 [mid-strength]) for 
treatment of their AD from randomisation through the treatment periods (Week 0 to 32) to be 
used as needed based on the subject’s own judgement (see Section 9.1.3.2 for details 
regarding dispensing of TCS [NIMP]). Low potency TCS or TCI may be used at the 
investigator’s discretion on areas of the body where use of the supplied TCS is medically 
inadvisable such as areas of thin skin (face, skin fold areas, genital areas, etc.) or on areas 
where continued treatment is considered unsafe. Low potency TCS or TCI must be reported 
as concomitant medications. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 54 of 129 
In addition, the following concomitant medications related to AD treatment are permitted 
from screening through safety follow-up (Week 46): 

Oral antibiotics, antiviral, or antifungal therapy for skin infections as
appropriate.

Stable doses of an emollient (see Section 9.3; subjects must apply such
emollients twice daily [or more, as needed] for at least 14 days before baseline
and throughout trial participation).

Oral anti-histamines.
9.5 Prohibited medication and procedures 
The following medications are prohibited during the trial from randomisation (Week 0) 
through Week 32: 

Use of ultraviolet A or B (UVA or UVB), psoralen + UVA (PUVA), other
phototherapy, or tanning beds.

Three or more bleach baths per week.
Any prohibited topical treatments must be recorded as concomitant medication. 
The following medications are prohibited during the trial from randomisation through safety 
follow-up (Week 0 to 46): 

Other topical medications used for the treatment of AD other than the supplied
TCS, except lower potency TCS or TCI which may be used at the
investigator’s discretion on areas of the body where use of the supplied TCS is
not advisable.

Investigational agents other than tralokinumab.

Immunoglobulin or blood products.

Systemic corticosteroids (nasal and inhaled corticosteroids are allowed).

Systemic treatment for AD with an immunosuppressive/ immunomodulating
agent (e.g., cyclosporine, mycophenolate mofetil, azathioprine, methotrexate,
Janus kinase inhibitors, interferon-gamma, dupilumab or other biologics).

Allergen immunotherapy.

Live (attenuated) vaccine.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 55 of 129 
The sponsor’s medical expert must be notified if a subject receives any of these medications 
during the trial. 
9.6 Rescue treatment 
If medically necessary (i.e., to control intolerable AD symptoms), rescue treatment for AD 
may be provided to trial subjects at the discretion of the investigator. If possible, investigators 
should attempt to limit the first step of rescue therapy to topical medications, and escalate to 
systemic medications only for subjects who do not respond adequately after at least 14 days 
of topical treatment. The subject will be monitored for signs of local or systemic TCS toxicity 
and the safety and appropriateness of continued use will be supervised by site staff. For 
reporting of AD flares see Section 10.3.1.4. 
Subjects who receive topical rescue treatment (higher potency TCS: Europe Class >3; US 
Class <4) will continue IMP treatment.  
If a subject receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate-mofetil, azathioprine, 
etc.), IMP will be immediately discontinued (see Section 9.7.2, reasons for temporary 
discontinuation of IMP). After the treatment with these medications is completed, IMP may 
be resumed if deemed appropriate by the investigator and sponsor’s medical expert, but not 
sooner than 5 half-lives after the last dose of systemic rescue medication.  
Investigators should make every attempt to conduct efficacy and safety assessments (at least 
disease severity scores [IGA and EASI], concomitant medications/procedures, and AEs) 
immediately before administering any rescue treatment. An unscheduled visit may be used for 
this purpose, if necessary.  
In the primary efficacy analyses, subjects who receive topical or systemic rescue treatment 
during the treatment periods will be considered as non-responders. 
9.7 Dose modification and IMP discontinuation rules 
9.7.1 Reasons for permanent discontinuation of IMP 
Subjects will be permanently discontinued from IMP in the event of: 

Anaphylactic reaction or other severe systemic reaction to IMP injection.

An AE that, in the opinion of the investigator or sponsor’s medical expert,
contraindicates further dosing.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 56 of 129 

Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the
cervix, or localised squamous or basal cell carcinoma of the skin.

Evidence of pregnancy.

Any infection that is opportunistic, such as active tuberculosis and other
infections whose nature or course may suggest an immuno-compromised
status.

Severe laboratory abnormalities:
o
ALT and/or AST values >3×ULN with total bilirubin >2×ULN
(unless elevated bilirubin is related to Gilbert-Meulengracht
Syndrome).
o
Confirmed AST and/or ALT >5×ULN (for more than 2 weeks).
Subjects who in the opinion of the subject or investigator have unacceptable treatment effect 
of IMP in combination with TCS therapy may discontinue treatment permanently and enter 
the safety follow-up period.  
Refer to Section 8.5 for details on the handling of subject discontinuation and Panel 3 for 
assessments to be performed at an early termination visit for subjects who discontinue IMP 
permanently.  
9.7.2 Reasons for temporary discontinuation of IMP 
IMP dosing may be temporarily suspended in the event of: 

Other intercurrent illnesses or major surgery.

An infection that requires parenteral treatment with antibiotic, antifungal,
antiviral, anti-parasitic, or anti-protozoal agents.

Treatment with systemic corticosteroids or non-steroidal
immunosuppressive/immunomodulating medications (e.g., cyclosporine,
methotrexate, azathioprine, mycophenolate-mofetil, Janus kinase inhibitors,
dupilumab or other biologics). IMP dosing may be resumed after the
medication leading to suspension of IMP is discontinued; see Section 9.6 for
details regarding re-initiation of IMP after discontinuation of systemic rescue
treatment.
A decision to discontinue IMP temporarily or to reinstitute IMP treatment must be discussed 
with sponsor’s medical expert. However, the investigator may suspend trial treatment at any 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 57 of 129 
time, even without consultation with sponsor’s medical expert if the urgency of the situation 
requires immediate action and if this is determined to be in the subject’s best interest. In such 
cases, sponsor’s medical expert should be informed as soon as possible.  
9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
9.8.1.1 Labelling and packaging of IMPs 
The IMP will be packaged in individually numbered kits, each containing 1 syringe 
(tralokinumab 150 mg or placebo). 
Primary and secondary packaging materials (syringe and outer carton, respectively) will be 
individually labelled. 
The labelling of IMPs will be in accordance with Annex 13, local regulations, and trial 
requirements. Label text will be translated into local languages, as required. The inner label 
will be in English for kits used at trial sites. 
9.8.1.2 Labelling and packaging of NIMP 
The NIMP (TCS) will be packaged in individually numbered kits that contain tubes of TCS 
cream with a total weight of 180–225 g.  
Primary and secondary packaging materials (tube and outer kit carton, respectively) will be 
individually labelled. 
The labelling of NIMPs will be in accordance with Annex 13, local regulations, and trial 
requirements. Label text will be translated into local languages, as required. The inner label 
will be in English for kits used at trial sites. 
9.8.2 Storage of trial products 
9.8.2.1 Storage of IMPs 
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
The IMP must be stored at 2 to 8°C at the site. The temperature during storage must be 
monitored by a calibrated, stationary, and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 58 of 129 
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately contact their CRA for further guidance: 

Temperature excursion upon receipt or during storage at the trial site.

Damaged kit upon receipt.

Damaged syringe/cartridge.
Damaged IMP should be documented via IWRS (refer to the IWRS instructions for further 
details) and reported as a product complaint to Global Pharmacovigilance, LEO (see 
Section 9.10). Damaged IMP should not be used.  
9.8.2.2 Storage of NIMP 
All LEO supplied NIMP (TCS) must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed. 
The NIMP must be stored at room temperature at the site according to the approved local 
label for mometasone furoate. The temperature during storage must be monitored by a 
calibrated, stationary, and continuously monitoring system. Minimum requirement is a 
calibrated min/max thermometer. 
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of NIMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected NIMP and should 
immediately contact their CRA for further guidance: 

Temperature excursion upon receipt or during storage at the trial site.

Damaged kit upon receipt.
Damaged NIMP should be documented via IWRS (refer to the IWRS instructions for further 
details) and reported as a product complaint to Global Pharmacovigilance, LEO (see 
Section 9.10). Damaged NIMP should not be used.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 59 of 129 
9.8.3 Drug accountability 
9.8.3.1 IMP accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
An inventory (trial medication inventory log) must be kept of the IMP administered to each 
subject randomised in the trial. The trial medication inventory log must be available for 
inspection during monitoring visits and will be checked by the CRA to ensure correct 
dispensing of the IMP. 
Full drug accountability will also be performed in the IWRS. 
Used syringes will be destroyed at the trial site provided the trial site has procedures in place 
for such IMP destruction. 
Trial sites which do not have such IMP destruction procedures in place will dispose used 
syringes in sharps bins which will be shipped to the CMO. 
The trial site will maintain trial kit cartons from used kits until reconciliation. The IMP will be 
fully accounted for by the CRA with the help of the unblinded HCP. Accountability will be 
documented on the trial medication inventory log and in the IWRS. Following reconciliation, 
the trial kit cartons from used kits may be discarded. 
All unused IMP supplied by the CMO on behalf of LEO will be returned to the CMO. IMP 
may be returned from the trial site either to the CMO directly or via the LEO affiliate or CRO 
responsible for the running of the clinical trial. The IMP returned to the CMO will be 
reconciled with the individual drug accountability forms. 
For more information about IMP accountability, please refer to the IMP handling manual. 
9.8.3.2 NIMP accountability 
The investigator is fully responsible for the NIMPs (TCS) at the trial site and for maintaining 
adequate control of the NIMPs and for documenting all transactions with them. 
An inventory (trial medication inventory log) must be kept of the NIMP administered to each 
subject randomised in the trial. The trial medication inventory log must be available for 
inspection during monitoring visits and will be checked by the CRA to ensure correct 
dispensing of the NIMP.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 60 of 129 
Full drug accountability will also be performed in the IWRS. Furthermore, the number of 
TCS tubes returned by the subject must be documented in the eCRF by the trial staff. 
The trial site will maintain trial kit cartons from used kits until reconciliation. The NIMP will 
be fully accounted for by the CRA. Accountability will be documented on the trial medication 
inventory log and in the IWRS. Following reconciliation, the trial kit cartons from used kits 
may be discarded.  
All used and unused NIMP tubes supplied by the CMO on behalf of LEO will be returned to 
the CMO. NIMP may be returned from the trial site either to the CMO directly or via the LEO 
affiliate or CRO responsible for the running of the clinical trial. All returned NIMP tubes will 
be weighed by the CMO to determine the amount of TCS used by the subject and will be 
reconciled with the individual drug accountability forms. The detailed procedure for weighing 
of NIMP tubes and subsequent transfer of tube weight data to the clinical database will be 
documented.  
9.8.4 Trial product destruction 
Unused IMP(s), used and unused NIMP (TCS), as well as used syringes returned to the CMO, 
will be destroyed by the CMO according to approved procedures and/or local requirements.  
9.8.5 Treatment compliance 
IMP injections will be performed by site staff that will also hand-out NIMP (TCS) for self-
administration and keep the accountability records up to date.  
Any non-compliance with IMP administration and dispensing and return of NIMP and the 
reason for it must be recorded in the eCRF. 
9.9 Provision for subject care following trial completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. Subjects who qualify for the long-term extension trial (see 
Section 7.1) may be offered participation (selected countries). 
9.10 Reporting product complaints 
Any defects or issues with the IMP as well as any IMP device deficiency (including 
malfunctions, use errors, and inadequate labelling) must be reported to Global 
Pharmacovigilance at LEO on the trial-specific (paper) Complaint Form within 3 days of first 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 61 of 129 
knowledge. Critical product complaints must be reported to Global Pharmacovigilance at 
LEO within 24 hours. Critical product complaints are defined as issues, defects, or device 
deficiencies that has or potentially could have a serious impact for the subject (e.g., SAE, or 
large particles in the syringe). 
Complaint Forms should contain a detailed description of the defect, issue, or device 
deficiency including whether it led to an AE. (S)AEs which occur due to a defect or issue with 
the IMP or due to a IMP device deficiency will be reported by the investigator as described in 
Sections 11.2 and 11.3. Similarly, any defects or issues with the NIMP (TCS) must also be 
reported to Global Pharmacovigilance at LEO using the same complaint procedure as for the 
IMP and IMP device. 
Refer to the drug handling manual for information on how to update the kit status in the 
IWRS. 
During the investigation of the product complaint, the IMP device must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the IMP device 
needs to be returned for further investigation or may be destroyed. 
Product complaints will be reported to Global Pharmacovigilance at LEO using the fax 
number or email address below: 
Fax number: +45 7226 3287 
E-mail address: drug.safety@leo-pharma.com
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 62 of 129 
10Trial schedule and assessments 
10.1 Overview 
During the trial, there are 20 scheduled site visits at the clinic. The visits and procedures to be 
carried out at each visit, as well as the intervals between visits, are summarised as trial flow 
charts in the schedule of procedures (Section 4). Refer to Panel 2 for assessments during 
screening and treatment, to Panel 3 for assessments during follow-up (including early 
termination, nominal Week 16 visit [for subjects who permanently discontinue IMP prior to 
Week 16] and unscheduled visits), and to Section 7 for further details on the trial design. 
Assessments/procedures at any trial visit should be performed in the following order: 

PROs.

Investigator assessments (performed only by adequately trained investigators;
the same investigator should preferably perform all the evaluations for a given
subject throughout the entire trial period) in the following order:
1. SCORAD component C, then component A and B.
2. IGA.
3. EASI.
4. AD flares

Safety and laboratory assessments.

Administration of IMP.

Dispensing of NIMP (TCS).
Subjects may also need to be seen at unscheduled visits during the course of the trial. The 
assessments to be performed at an unscheduled visit are left at the investigator’s discretion 
(could include any assessment performed at an early termination visit) (Panel 3), except if the 
reason is an AD flare in which case IGA, EASI, concomitant medications/procedures, and 
AEs should be collected (see Section 10.3.1.4). 
Subjects participating in the trial will be under careful supervision of a dermatologist or 
allergist. Investigators must be experienced in treating AD and have documented experience 
and/or training in use of the assessments required by the protocol and must be either a 
physician, certified physician’s assistant, or advanced registered nurse practitioner. The 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 63 of 129 
investigators performing the assessments must not be involved in the administration of 
IMP (see Section 9.2.1).  
10.2 Assessments performed only at screening/baseline 
Assessments performed only at the screening and/or baseline visit include: assessment of 
eligibility criteria (including review of scores on the Columbia-Suicide Severity Rating Scale 
[C-SSRS] Screening version), demographics, medical history, height and weight, and body 
surface area (BSA) affected by AD. These are described in further detail below. Laboratory 
tests include hepatitis B, hepatitis C, HIV-1, HIV-2, and serum pregnancy test (see 
Sections 10.4.4 and 10.4.5). 
10.2.1 Columbia-Suicide Severity Rating Scale 
The C-SSRS Screening version is a rater-administered instrument used to assess the lifetime 
history and severity of suicidal ideation and suicidal behaviour through a series of simple, 
plain-language questions (25). The C-SSRS must be completed at screening to check that 
exclusion criterion no. 24 does not apply. Further details on the assessment according to the 
C-SSRS are included in the efficacy assessment & C-SSRS manual.
10.2.2 Demographics  
The following demographic data will be recorded: 

Age: Month and/or year of birth.

Sex.

Race: American Indian or Alaska Native, Asian (Japanese), Asian (others),
Black or African American, Native Hawaiian or Other Pacific Islander, White,
Other.

Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or
Latino.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 64 of 129 
10.2.3 Medical history 
Relevant past and concurrent medical history must be recorded and includes: 

Skin disease history: all past and current skin disease history including:
o
Alopecia.
o
Vitiligo.
o
Herpes simplex.

Atopy history:
o
Duration of AD in years.
o
Previous AD treatments.
o
Asthma.
o
Food allergy.
o
Hay fever.
o
Allergic conjunctivitis.
o
Atopic keratoconjunctivitis.
o
Eczema herpeticum.

Other medical and surgical history including concurrent diagnoses.
Relevant medical history includes also diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
10.2.4 Height and weight 
The subject’s height must be measured (without shoes) and weight must be determined (in 
indoor clothing and without shoes). 
10.2.5 Body surface area involvement 
The total BSA affected by AD will be assessed by the investigator for each section of the body 
as component A of SCORAD (see Section 10.3.1.3) and will be reported as a percentage of all 
major body sections combined. The following body regions will be assessed (brackets show 
the highest possible score for each region): head and neck (9%), anterior trunk (18%), 
back (18%), upper limbs (18%), lower limbs (36%), and genitals (1%). The total BSA score 
will be assessed according to the schedule of procedures (Section 4).  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 65 of 129 
10.3 Efficacy assessments 
10.3.1 Investigator assessments  
10.3.1.1 Investigator’s Global Assessment 
The IGA is an instrument used in clinical trials to rate the severity of the subject’s global AD 
and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 6). The IGA score 
will be assessed according to the schedule of procedures (Section 4). The assessment will be 
based on the condition of the disease at the time of evaluation and not in relation to the 
condition at a previous visit. Whenever possible, the IGA should be assessed by the same 
investigator at each visit to reduce inter-rater variability. The IGA is included in the efficacy 
assessment & C-SSRS manual. 
Panel 6  Investigator’s Global Assessment 
Score 
Disease 
severity 
Standard IGA scale 
IGA morphological descriptors 
0 
Clear 
No inflammatory signs of 
atopic dermatitis. 
No erythema and no elevation 
(papulation/infiltration). 
1 
Almost 
clear 
Just perceptible erythema, and 
just perceptible 
papulation/infiltration. 
Barely perceptible erythema and/or minimal 
lesion elevation (papulation/infiltration) that is 
not widespread. 
2 
Mild 
disease 
Mild erythema and mild 
papulation/infiltration. 
Visibly detectable, light pink erythema and very 
slight elevation (papulation/infiltration). 
3 
Moderate 
disease 
Moderate erythema and 
moderate 
papulation/infiltration. 
Dull red, clearly distinguishable erythema and 
clearly perceptible but not extensive elevation 
(papulation/infiltration). 
4 
Severe 
disease 
Severe erythema and severe 
papulation/infiltration. 
Deep/dark red erythema, marked and extensive 
elevation (papulation/infiltration). 
10.3.1.2 Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (26). Details on the scoring of severity and extent of AD according 
to EASI are included in the efficacy assessment & C-SSRS manual. 
The EASI score will be assessed according to the schedule of procedures (Section 4). The 
assessment will be based on the condition of the disease at the time of evaluation and not in 
relation to the condition at a previous visit. Whenever possible, the EASI should be assessed 
by the same investigator at each visit to reduce inter-rater variability.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 66 of 129 
The EASI is a composite index with scores ranging from 0 to 72, with higher values 
indicating more severe and/or more extensive condition. The index will be calculated as 
shown in Panel 7. Briefly, the investigator will assess the severity of 4 AD disease 
characteristics (erythema, induration/papulation, excoriation, and lichenification) on the 
4 body regions (head/neck, trunk, upper extremities, lower extremities); severity will be 
assessed according to the scale shown in Panel 8. For each body region, a severity sum score 
will be calculated which will be multiplied by an area score (Panel 8) and by a weighting 
factor. The EASI score equals the sum of the scores obtained for each body region (Panel 7). 
Panel 7  Calculation of the Eczema Area and Severity Index 
Body region 
Erythema 
Induration/ 
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
×  AS 
× 0.1 
Trunk 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
×  AS 
× 0.3 
Upper extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
×  AS 
× 0.2 
Lower extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
×  AS 
× 0.4 
The EASI score is the sum of the 4 body region scores 
(range 0-72) 
Abbreviations: AS, area score; EASI, Eczema Area and Severity Index; SS, severity score. 
Modified from (27). 
Panel 8  EASI severity score scale and area score scale 
Severity score scale 
Area score scale 
0 
None/absent 
0 
0% affected area 
1 
Mild 
1 
1% to 9% affected area 
2 
Moderate 
2 
10% to 29% affected area 
3 
Severe 
3 
30% to 49% affected area 
Half-points (0.5; 1.5; 2.5) may also be 
used. 
4 
50% to 69% affected area 
5 
70% to 89% affected area 
6 
90% to 100% affected area 
Abbreviations: EASI, Eczema Area and Severity Index. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 67 of 129 
10.3.1.3 Scoring Atopic Dermatitis 
The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with 
subjective symptoms (28). Details on the scoring of extent and severity of AD according to 
SCORAD are included in the efficacy assessment & C-SSRS manual. The maximum total 
score is 103, with higher values indicating more severe disease. SCORAD will be assessed 
according to the schedule of procedures (Section 4). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit. Whenever possible, SCORAD should be 
assessed by the same investigator at each visit to reduce inter-rater variability. 
The assessment consists of 3 components: A = extent, B = intensity, and C = subjective 
symptoms. 
Extent (A) 
The extent of AD is assessed as a percentage of each defined body area and reported as the 
sum of all areas (maximum score = 100%) 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, oedema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) is assessed by the investigator on an average 
representative area using the following scale:  
0 
= 
None/absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Note: dryness is evaluated on uninvolved areas. 
The sum of intensity score of the 6 symptoms will be reported (maximum score = 18). 
Subjective symptoms (C) 
A subjective assessment of the average itch and sleeplessness over the last 3 days/nights is 
recorded for each symptom by the subject on a visual analogue scale, where 0 is no itch (or 
sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum 
possible score of 20. 
The SCORAD is calculated as: A/5+7B/2+C 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 68 of 129 
10.3.1.4 Atopic dermatitis flares 
An AD flare is defined as an acute, clinically significant worsening of signs and symptoms of 
AD requiring therapeutic intervention (29). For the purpose of this protocol, AD flares are 
defined as worsening of the disease that requires escalation/intensification of AD treatment 
reported after initiation of IMP; this will also include initiation or intensification of the TCS 
(NIMP) supplied to the subjects. Flares will be assessed at the clinic according to the schedule 
of procedures (see Section 4). Subjects who experience disease worsening between scheduled 
trial visits should return to the clinic for an unscheduled visit for assessment of flare before 
initiating the treatment escalation; subjects who return to the clinic for assessment of flares at 
an unscheduled visit should undergo IGA and EASI assessments, and information on 
concomitant medications/procedures and AEs should be collected. 
Details on rescue treatments and prohibited concomitant medications and procedures for 
treatment of AD are provided in Sections 9.6 and 9.5. 
10.3.2 Subject assessments 
Six PROs will be assessed daily using an eDiary: 

Eczema-related Sleep NRS (Section 10.3.2.1).

Worst Daily Pruritus NRS (Section 10.3.2.2).

Average Daily Pruritus NRS (Section 10.3.2.3).

Patient Days of Topical Treatment Use (Section 10.3.2.4).

Patient Global Impression of Bother (PGI-B) (Section 10.3.2.5.

Patient Global Impression of Severity (PGI-S) (Section 10.3.2.6).
Subjects will receive eDiary training at the screening visit 14 days before baseline (Week -2; 
visit 2) and start the eDiary. 
In addition, 4 PROs will be completed by the subjects at the site: 

Patient Oriented Eczema Measure (POEM) (Section 10.3.2.7).

Dermatology Life Quality Index (DLQI) (Section 10.3.2.8).

EuroQoL 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L)
(Section 10.3.2.9).
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 69 of 129 

Hospital Anxiety and Depression Scale (HADS) (Section 10.3.2.10).
10.3.2.1 Eczema-related Sleep numeric rating scale 
Subjects will rate how much their eczema interfered with their sleep the last night using an 
11-point NRS (0 indicating that it ‘did not interfere’ and 10 indicating that it ‘completely
interfered’). Subjects will complete the Eczema-related Sleep NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 32. The Eczema-related Sleep NRS is 
included in the investigator trial file. 
10.3.2.2 Worst Daily Pruritus numeric rating scale 
Subjects will assess their worst itch severity over the past 24 hours using an 11-point NRS 
(‘Worst Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Worst Daily Pruritus NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 32. The Worst Daily Pruritus NRS is 
included in the investigator trial file.  
10.3.2.3 Average Daily Pruritus numeric rating scale 
Subjects will assess their average itch over the past 24 hours using an 11-point NRS 
(‘Average Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Average Daily Pruritus NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 32. The Average Pruritus NRS is 
included in the investigator trial file. 
10.3.2.4 Patient Days of Topical Treatment Use 
Subjects will assess their use of topical AD treatment use over the past 24 hours using a 
response scale (‘yes’, ‘no’). Subjects will complete the Patient Days of Topical Treatment Use 
as part of an eDiary each day in the morning from baseline (Week 0 [visit 3]) until Week 32. 
The Patient Days of Topical Treatment Use is included in the investigator trial file. 
10.3.2.5 Patient Global Impression of Bother 
The PGI-B is a single item designed to capture the subject’s perception of how bothered they 
have been by their AD over the past 24 hours at the time of completion. A 5-point categorical 
response scale will be used (‘not at all’, ‘slightly’, ‘somewhat’, ‘a lot’, ‘very much’). Subjects 
will complete this item as part of the eDiary each day in the morning from Week -2 (visit 2) 
until Week 32. The PGI-B is included in the investigator trial file. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 70 of 129 
10.3.2.6 Patient Global Impression of Severity 
The PGI-S is a single item designed to capture the subject’s perception of overall eczema 
symptom severity over the last 24 hours on a 4-point categorical response scale (‘no 
symptoms’ to ‘severe’). Subjects will complete this item as part of the eDiary each day in the 
morning from Week -2 (visit 2) until Week 32. The PGI-S is included in the investigator trial 
file. 
10.3.2.7 Patient-Oriented Eczema Measure 
The POEM is a validated questionnaire used to assess disease symptoms in atopic eczema 
patients in both clinical practice and clinical trials (30). The tool consists of 7 items each 
addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and 
dryness). Subject will score how often they have experienced each symptom over the previous 
week on a 5-point categorical response scale (0 = ‘no days’; 1 = ‘1 to 2 days’; 2 = ‘3 to 
4 days’; 3 = ‘5 to 6 days’; 4 = ‘every day’). The total score is the sum of the 7 items (range: 
0 to 28) and reflects disease-related morbidity; a high score is indicative of a worse disease 
severity. The POEM will be completed electronically on the device supplied to the trial site 
according to the schedule of procedures (Section 4). The POEM is included in the investigator 
trial file. 
10.3.2.8  Dermatology Life Quality Index 
The DLQI is a validated questionnaire with content specific to those with dermatology 
conditions. It consists of 10 items addressing the subject’s perception of the impact of their 
skin disease on different aspects of their HRQoL over the last week such as dermatology-
related symptoms and feelings, daily activities, leisure, work or school, personal relationships, 
and the treatment (31). Each item is scored on a 4-point Likert scale (0 = ‘not at all ⁄not 
relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). The total score is the sum of the 10 items 
(0 to 30); a high score is indicative of a poor HRQoL. The DLQI will be completed 
electronically on the device supplied to the trial site according to the schedule of procedures 
(Section 4). The DLQI is included in the investigator trial file. 
10.3.2.9 EQ-5D-5L 
The EQ-5D-5L is a standardised measure of health status developed by the EuroQol group to 
provide a simple, generic measure of health for clinical and economic appraisal (32). The 
EQ-5D-5L is a self-administered questionnaire used to assess health status ‘today’ and is 
divided into 2 sections: The first section includes 5 dimensions (mobility, self-care, usual 
activity, pain/discomfort, and anxiety/depression); each dimension will be assessed by the 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 71 of 129 
subject using a 5-point scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe 
problems’, and ‘extreme problems’). The second section consists of a vertical visual analogue 
scale anchored at 0 (‘the worst health you can imagine’) and 100 (‘the best health you can 
imagine’). The EQ-5D-5L will be completed electronically on the device supplied to the trial 
site according to the schedule of procedures (Section 4). The EQ-5D-5L is included in the 
investigator trial file. 
10.3.2.10 Hospital Anxiety and Depression Scale 
The HADS is a Likert-scale tool widely used to detect states of anxiety and depression in a 
general hospital setting (33). The tool consists of 14 items that assess the subject’s anxiety 
(7 items) and depression (7 items) during the last week. Each question is scored from 0 to 3, 
with high scores indicating a poor state. The HADS will be completed electronically on the 
device supplied to the trial site according to the schedule of procedures (Section 4). The 
HADS is included in the investigator trial file. 
10.4 Safety assessments 
10.4.1 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the schedule of procedures (Section 4). Vital signs will be measured in supine position 
following at least 5 minutes’ rest. 
For the first 3 IMP dosing visits in both the initial treatment period (i.e., Weeks 0, 2, and 4) 
and the continuation treatment period (i.e. Weeks 16, 18, and 20), subjects will be monitored 
after IMP administration for immediate drug reactions for a minimum of 30 minutes with vital 
signs taken at 30 minutes or until stable, whichever is later (Section 9.1.3.1).  
If an abnormal vital sign at screening is considered by the investigator to be clinically 
significant, it will be at the investigator’s discretion if the subject should be randomised into 
the trial (respecting exclusion criterion no. 26).  
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position to verify the first measurement. 
Should the repeated measurement result in a normal value, the measurement must be repeated 
once more. If the third measurement verifies the second (normal) value, the first measurement 
should be considered as false. If the third measurement confirms the first measurement 
(abnormal) the second measurement will be considered as false. Only the last value measured 
and considered as correct will be recorded in the eCRF.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 72 of 129 
Clinically significant abnormal vital signs at the first screening visit will be documented as 
medical history in the eCRF. If an abnormal vital sign at any other visit than the first 
screening visit is considered by the investigator to be clinically significant, it will be reported 
as an AE in accordance with Section 11.2. Further, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness 
observed after screening will be reported as an AE in accordance with Section 11.2. 
10.4.2 Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin 
and auscultation of heart, lungs and abdomen; palpation of the abdominal organs and basic 
neurological status must be performed according to the schedule of procedures (Section 4). 
If an unacceptable abnormal finding is identified during the physical examination at the 
screening visit, the subject must not be randomised into the clinical trial (respecting exclusion 
criterion no. 26). 
Clinically significant abnormal physical examination findings at the first screening visit will 
be documented as medical history in the eCRF. If an abnormal finding at any other visit than 
the first screening visit is considered by the investigator to be clinically significant, it will be 
reported as an AE in accordance with Section 11.2. Further, any clinically significant 
deterioration of a pre-existing condition as well as any new clinically significant sign, 
symptom, or illness observed after screening will be reported as an AE in accordance with 
Section 11.2. 
10.4.3 Digital ECG 
A single 12-lead resting digital ECG will be recorded after the subject has been supine for at 
least 5 minutes at the visits indicated in the schedule of procedures (Section 4). 
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. At a minimum, date of ECG collection will be recorded in the source 
documents.  
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. 
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date. The investigator has the final decision on the clinical 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 73 of 129 
significance of ECG abnormalities. If a result is abnormal at the screening visit and 
considered by the investigator to be clinically significant, it will be up to the investigator’s 
discretion if the subject should be enrolled into the trial (respecting exclusion criterion 
no. 26); if such a subject is enrolled, the investigator will provide a justification in the medical 
record.  
Clinically significant abnormal ECG findings at the first screening visit will be documented 
as medical history in the eCRF. If an abnormal ECG finding at any other visit than the first 
screening visit is considered by the investigator to be clinically significant, it will be reported 
as an AE in accordance with Section 11.2. Further, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness 
observed after screening will be reported as an AE in accordance with Section 11.2. 
Test dummy transmissions will be undertaken prior to trial conduct to ensure that 
transmissions can be made and that date and time settings are correctly set. 
The collection and transmission of ECG data will be described in a separate ECG manual. 
10.4.4 Pregnancy test 
A serum pregnancy test must be taken at the screening visit in female subjects of 
child-bearing potential as described in the schedule of procedures in Section 4. 
A urine pregnancy test (human chorionic gonadotropin; dipstick) must be performed at the 
trial site at baseline prior to randomisation in female subjects of child-bearing potential. The 
test must be repeated every 4 weeks as shown in the schedule of procedures in Section 4. 
Note that pregnant subjects must discontinue the IMP and NIMP immediately (Section 9.7.1). 
10.4.5 Laboratory testing 
The following safety samples will be analysed by a central laboratory: chemistry, 
haematology, serology, and serum pregnancy, see Panel 9 for an overview of the individual 
laboratory parameters assessed in this trial. Urine samples will be tested at the trial site with a 
dipstick; if abnormal, a urine sample will be sent to the central laboratory for further analysis. 
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information 
specific to this trial. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 75 of 129 
The central laboratory will provide results in SI units to trial sites in Europe and in 
conventional units to sites in North America; results that are transferred to the trial database 
will be in SI and conventional units. 
Handling, storage, destruction and shipment instructions are provided in a separate laboratory 
manual. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be enrolled into the trial (respecting 
exclusion criteria no. 26, 27, and 28).  
Clinically significant abnormal laboratory findings at the first screening visit will be 
documented as medical history in the eCRF. If an abnormal finding at any other visit than the 
first screening visit is considered by the investigator to be clinically significant, it will be 
reported as an AE in accordance with Section 11.2. Further, any clinically significant 
deterioration of a pre-existing condition as well as any new clinically significant sign, 
symptom or illness observed after screening will be reported as an AE in accordance with 
Section 11.2. 
10.4.6 Pharmacokinetic assessments 
Blood samples for PK assessments must be collected at the time points specified in the 
schedule of procedures (Section 4). 
Collection, handling and shipment instructions for PK blood samples are provided in a 
laboratory manual.  
Serum samples for determination of tralokinumab concentrations will be analysed by a 
laboratory using a validated bioanalytical method. Details of the analytical method used will 
be described in the bioanalytical report. 
Samples will be retained for as long as the quality of the material permits evaluation but for 
no longer than 12 months after completion of the clinical trial report (CTR). 
10.4.7 Anti-drug antibodies measurements 
Blood samples will be collected for determination of anti-tralokinumab antibody levels at 
pre-determined time points according to the schedule of procedures (Section 4).  
Collection, handling and shipment instructions for ADA blood samples are provided in a 
separate laboratory manual. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 76 of 129 
Serum samples for determination of presence or absence of ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titre determination and will be analysed for the presence of neutralising 
antibodies (nAB). Details of the analytical method used will be described in the ADA 
bioanalytical report. 
Samples will be retained for as long as the quality of the material permits evaluation but for 
no longer than 15 years after marketing authorisation. 
10.5 Estimate of total blood volume collected 
Blood samples will be drawn for safety (chemistry, haematology, and serology), PK, and 
ADAs. The total volume of blood to be withdrawn is approximately 180 mL which is less 
than the volume of blood drawn during a blood donation (approximately 500 mL).  
11Adverse events 
AEs and SAEs are defined in Appendix 1: Definitions of adverse events and serious adverse 
events. 
Classification of AEs in terms of severity, causality and outcome are defined in Appendix 2: 
Classification of adverse events. 
11.1 Collection of adverse events 
AEs must be collected from time of first trial-related activity after the subject has signed the 
informed consent form (ICF) until completion of the clinical trial (defined as the safety 
follow-up visit 16 weeks after last injection of IMP). For subjects entering the long-term 
extension trial (LP0162-1337, ECZTEND), any (S)AE with onset before the final visit in 
LP0162-1339 should be reported in LP0162-1339. If ongoing, the (S)AE will also be 
recorded as medical history in ECZTEND. 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for. It is important that the investigator also observes the subject for any changes not 
reported by the subject and records these changes. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 77 of 129 
Clinically significant abnormal findings related to vital signs, physical examination, ECGs, or 
laboratory tests after the first screening visit must be reported as an AE in accordance with 
Section 11.2; also see Sections 10.4.1 (vital signs), 10.4.2 (physical examination), 10.4.3 
(ECGs), and 10.4.5 (laboratory tests) for further details. 
11.2 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (i.e. not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’).  
The duration of the AE must be reported by the start date and stop date of the event. In 
addition, it must be recorded whether the AE started prior to start of IMP. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 2: Classification of adverse events. 
Action taken with trial treatment: Any action taken with IMP or NIMP (TCS) as a 
consequence of the AE must be recorded (dose not changed, dose reduced, dose increased, 
drug interrupted, drug withdrawn, not applicable, unknown). 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concomitant procedure). 
Withdrawn due to AE: it must be recorded whether the AE leads to withdrawal from the trial. 
11.3 Reporting of serious adverse events 
The criteria that define an AE as serious (i.e., an SAE) are defined in Appendix 1: Definitions 
of adverse events and serious adverse events. 
11.3.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO on the (paper) SAE Form within 24 hours of first 
knowledge. This report should contain an assessment of available information on seriousness, 
severity, causal relationship to the IMP or IMP device, causal relationship to NIMP, 
comparator or trial procedure, the action taken, the outcome to date, and a narrative 
description of the course of the event. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 78 of 129 
The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO using the e-mail address or fax number below: 
Global Pharmacovigilance, LEO 
E-mail address: drug.safety@leo-pharma.com
Fax number: +45 7226 3287 
It may be relevant for the investigator to enclose other information with the SAE form, such 
as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Pharmacovigilance, LEO may request further information in order to 
fully assess the SAE. The investigator must forward such information to LEO upon request by 
fax or e-mail (see contact details above). 
The investigator must notify the local institutional review board(s) (IRB[s])/ independent 
ethics committee(s) (IEC[s]) of SAEs as required by current applicable legislation for the 
concerned country. 
SAEs occurring after the completion of the clinical trial (i.e., after the safety follow-up visit at 
Week 46) should not be routinely sought or collected. However, such events should be 
reported to LEO (see contact details above) if the investigator becomes aware of them. 
11.3.2 LEO reporting responsibilities 
Global Pharmacovigilance, LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference document for this clinical trial is: 
For the IMP, the Investigator’s Brochure, edition 16 and subsequent updates must be used. 
For the NIMP (mometasone furoate, 0.1% cream) the latest version of the approved label 
must be used. 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 79 of 129 
For all countries except the US, all SAEs which are assessed as causally related to the IMP(s) 
by either the investigator or LEO (ICH E2A Guideline), and which are unexpected 
(Suspected, Unexpected Serious Adverse Reactions [SUSARs]), are subject to expedited 
reporting to regulatory authorities and IRB(s)/IEC(s) according to the current applicable 
legislation in the concerned countries. Investigators will be notified of such SUSARs and the 
evolving safety profile on an ongoing basis.  
For the US, as per Guidance for Industry and Investigators - Safety Reporting Requirements 
for INDs and BA/BE Studies, only those events for which the sponsor determines there is a 
reasonable possibility of a causal relationship are subject to IND Safety Reporting. 
Investigators will be notified of the evolving safety profile on an ongoing basis. 
11.4 Other events that require expedited reporting 
11.4.1 Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Follow Up Form (Part I). All such pregnancies 
must be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Follow Up Form (Part II) within 24 hours of first knowledge. 
The completed Pregnancy Follow Up Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO. Contact details are given in Section 11.3.1. 
Pregnant subjects must permanently discontinue IMP (see Section 9.7.1). 
11.5 Reporting of other events 
11.5.1 Adverse events of special interest 
The events listed in Panel 10 are considered adverse events of special interest (AESIs) in this 
trial and will require that the investigator provides additional information to LEO. An AESI 
may be serious (requiring expedited reporting, Section 11.3) or non-serious. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 80 of 129 
Panel 10  Adverse events of special interest 
Adverse event of special interest 
Additional information to be provided (if available1) 
Eczema herpeticum 
Skin findings: 

Lesion type.

Disseminated / localised.

Location.

Present in an area with visible eczema / no visible
eczema / present in areas with and without eczema.

Monomorphic / polymorphic.
Confirmation of herpes simplex virus. 
Malignancies diagnosed after 
randomisation, excluding basal 
cell carcinoma, localised squamous 
cell carcinoma of the skin, and 
carcinoma in situ of the cervix 

Histology report.

Oncology assessment.

Treatments (surgery, radiation, chemotherapy, other).
Skin infections requiring systemic 
treatment 
Skin swab 

Outcome.
Conjunctivitis 

Aetiology (viral, bacterial, allergic, unknown).

Bacterial culture outcome (for events with bacterial
aetiology).

Diagnosis confirmed by ophthalmologist.
Keratoconjunctivitis 

Aetiology (infectious, non-infectious, other,
unknown).

Bacterial culture outcome (for events with bacterial
aetiology).

Diagnosis confirmed by ophthalmologist.
Keratitis 

Aetiology (infectious, non-infectious, other,
unknown).

Bacterial culture outcome (for events with bacterial
aetiology).

Diagnosis of herpes simplex keratitis (for events with
viral aetiology).

Diagnosis confirmed by ophthalmologist.
1The additional data to be recorded in the eCRF are not a requirement, but are to be reported 
by the investigator, if available, for example as part of standard clinical practice. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 81 of 129 
11.5.2 Overdose 
An overdose is defined as a subject receiving a dose of IMP in excess of that specified in this 
protocol.  
The term overdose must be documented on the AE form of the eCRF. In addition, AEs 
originating from overdose must be documented on a separate line. 
LEO does not recommend specific treatment for an overdose. The investigator will use 
clinical judgment to treat any overdose if necessary. 
11.5.3 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP while in the control of the investigator or subject. Broadly, medication errors fall into 
four categories: wrong medication, wrong dose (including strength, form, concentration, 
amount), wrong route of administration, or wrong subject. 
The medication error must be documented on the AE form in the eCRF. In addition, AEs 
originating from a medication error must be documented on a separate line specifying the 
category of error (see definitions above). 
If the medication error is due to device malfunction, such malfunction must be reported as a 
device complaint as described in Section 9.10. 
11.5.4 Misuse 
Misuse refers to situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
The term misuse must be documented on the AE form in the eCRF. In addition, AEs 
originating from misuse must be documented on a separate line. 
11.5.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term abuse must be documented on the AE form in the eCRF. In addition, AEs 
originating from abuse must be documented on a separate line. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 82 of 129 
11.5.6 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to screening, must be reported as an AE. 
11.6 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as of possible/probable relationship to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. SAEs must be 
followed up until a final outcome has been established, i.e. the follow-up may continue 
beyond the end of the clinical trial. For SAEs, which have stabilised and cannot be expected 
to recover during trial or safety follow-up periods, for example chronic illnesses, the final 
outcome should be considered recovered and a statement that the SAE has stabilised should 
be added to the narrative in the SAE form.  
11.7 Handling of an urgent safety measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined within the EU Directive as “…the occurrence of any new event 
relating to the conduct of the trial or the development of the investigational medicinal product 
where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (34). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO, regulatory authority(ies), or IRB(s)/IEC(s). 
The investigator must immediately inform LEO - by contacting the clinical project manager 
or medical expert - of this change in the clinical trial procedure or of the temporary halt 
providing full details of the information and the decision-making process leading to the 
implementation of the urgent safety measure. 
LEO must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 83 of 129 
12 Statistical methods 
12.1 Sample size 
A total of 369 subjects will be randomised 2:1 to initial treatment in this trial (246 subjects in 
the tralokinumab+TCS arm; 123 subjects in the placebo+TCS arm).  
The primary endpoints for initial treatment, IGA 0/1 and EASI75 at Week 16, are to be 
evaluated hierarchically testing both hypotheses of no difference between active and placebo 
at the 5% significance level. The hypothesis for IGA 0/1 will be tested first; if significant, the 
EASI75 hypothesis will be tested. 
The null hypothesis for the first primary endpoint is that there is no difference at Week 16 in 
obtaining IGA 0/1 between tralokinumab+TCS and placebo+TCS. The null hypothesis for the 
second primary endpoint is that there is no difference at Week 16 in obtaining EASI75 
between tralokinumab+TCS and placebo+TCS. Each hypothesis will be tested against the 
2-sided alternative that there is a difference between the 2 treatment groups.
For the single endpoint IGA 0/1 at Week 16, a sample size of 369 subjects randomised 2:1 
will provide 90% power to detect a difference between the 2 arms, assuming response rates of 
30% for tralokinumab+TCS and 15% for placebo+TCS. For the single endpoint EASI75 at 
Week 16, a sample size of 369 will provide a nominal power >99.9% to detect a difference 
between tralokinumab+TCS and placebo+TCS, assuming EASI75 response rates of 40% and 
15%, respectively. The combined power for demonstrating a significant difference for both 
endpoints is therefore effectively also 90% with a sample size of 369 subjects, even when 
assuming no correlation between the 2 primary endpoints. In all cases, the evaluations will be 
made with a 2-sided 5% significance level. 
12.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomised to initial treatment are included in the full analysis set and will be 
analysed for efficacy up to Week 16. Exclusions from the full analysis set can be considered 
in special cases as described in ICH E9, Section 5.2.1, Full Analysis Set. If it is decided to 
exclude a randomised subject from the full analysis set, a justification addressing ICH E9 will 
be given. 
A per protocol analysis set will be used as an efficacy subset for the analysis of the primary 
endpoints up to Week 16, and analyses based on the per protocol analysis set will be 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 84 of 129 
performed to support the results obtained for the full analysis set. The per protocol analysis 
set will be defined by excluding subjects from the full analysis set for whom any of the 
following conditions apply:  

receive no treatment with the IMP.

provide no assessment of IGA or EASI following start of treatment.

are known to have taken the wrong IMP throughout the initial treatment period
of the trial.

do not fulfil the inclusion criteria no. 3, 6, 7, and 8.
A safety analysis set will be defined by excluding subjects from the full analysis set who 
either received no treatment with IMP and/or for whom no post-baseline safety data are 
available.  
A continuation treatment analysis set will be defined as subjects in the full analysis set who 
have not withdrawn from trial prior to or at the Week 16 visit (visit 11). 
A continuation treatment safety analysis set will be defined as subjects who are exposed to 
IMP at or after the Week 16 visit (visit 11). 
Based on the above-mentioned rules, the inclusion/exclusion of subjects from the trial 
analysis sets will be documented in the statistical analysis plan update before breaking the 
randomisation code. 
12.3 Statistical analysis 
12.3.1 Disposition of subjects 
Subject disposition will be presented separately for subjects in initial treatment and 
continuation treatment. For all randomised subjects and for subjects in the continuation 
treatment analysis set, the reasons for permanent discontinuation of IMP and for leaving the 
trial in the initial treatment period will be presented by last visit attended and by treatment 
group.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 85 of 129 
12.3.2 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented 
separately for all randomised subjects and for the continuation treatment analysis set. The 
presentations will be overall and by treatment group. Presentations of age, sex, ethnicity, race, 
baseline disease severity, and Worst Daily Pruritus NRS weekly average at baseline will also 
be given by region and by baseline disease severity (IGA 3 or 4). 
Demographics include age, sex, race, and ethnicity. Other baseline characteristics include vital 
signs (including height, weight, body mass index), duration of AD, concurrent diagnoses 
(from medical history and indications for concomitant medication), concomitant medication, 
and previous AD treatments.  
12.3.3 Exposure and treatment compliance 
12.3.3.1 Exposure 
Exposure to treatment will be presented for the safety analysis set (initial treatment) and 
continuation treatment safety analysis set (continuation treatment) as days of exposure per 
treatment group. 
For the full trial period, the days of exposure on tralokinumab irrespective of treatment group 
will be summarised - subtracting potential periods on placebo - for the safety analysis set.  
12.3.3.2 Treatment compliance 
Adherence to treatment regimen will be recorded in the eCRF. The log of drug administration 
may be used as source. If any complications or deviations in administration are observed, 
these will be described as protocol deviations. 
Adherence will be presented for the safety analysis set (initial treatment) and for the 
continuation treatment safety analysis set (continuation treatment) for each treatment group. 
12.3.4 Multiple testing procedure 
To control the overall type 1 error rate, the primary analyses of the primary estimands for the 
primary and secondary endpoints for the initial treatment period will follow the hierarchical 
testing procedure outlined in Panel 11. The hypothesis relating to a specific endpoint cannot 
be rejected unless all hypotheses relating to endpoints earlier in the hierarchy are also 
rejected.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 86 of 129 
Panel 11  Testing procedure for primary and secondary endpoints 
Abbreviations: DLQI, Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema Area and 
Severity Index score; IGA, Investigator’s Global Assessment. 
The procedure will be as follows: 
IGA 0/1 at Week 16 between tralokinumab+TCS and placebo+TCS will be evaluated at a 5% 
significance level. If the test is significant, EASI75 at Week 16 between tralokinumab+TCS 
and placebo+TCS will be evaluated at a 5% significance level.  
If both these tests are significant, the 5% significance level (alpha) will be propagated to the 
three secondary endpoints: SCORAD at Week 16, Pruritus at Week 16, and DLQI at Week 16. 
The evaluations of the three secondary endpoints between tralokinumab+TCS and 
placebo+TCS will use the Holm method (35) for 3 ordered p-values at a 5% significance level 
to adjust for multiplicity. 
12.3.5 Analysis of primary endpoints 
Three estimands addressing different aspects of the trial objectives will be defined: 

Primary estimand: ‘composite’.

Secondary estimand: ‘hypothetical’.

Tertiary estimand: ‘treatment policy’.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 87 of 129 
The applied estimands incorporate two main types of events that influence how the treatment 
effects are estimated: 

Initiation of rescue medication: Some of the estimands use the initiation of rescue
medication as an event that modifies the applied value of an endpoint, e.g. by defining a
subject receiving rescue medication as a non-responder.

Permanent discontinuation of IMP: This event occurs when a subject is permanently
withdrawn from the treatment or the trial as described in section 8.5. This can either
happen at his/her own initiative or at the investigator’s discretion. The event also includes
the possibility of a subject being lost to follow-up. The timing of the event is defined as
the date of the early termination visit for withdrawn subjects or – in the case of a subject
lost to follow-up – the date of the last known visit to the clinic. As for the rescue
medication, the event type is used to modify an applied endpoint value.
All analyses will be based on the full analysis set unless otherwise specified. 
12.3.5.1 Primary estimand: ‘composite’ 
The primary estimand for the primary endpoints will be: 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
achieved without rescue medication, regardless of treatment discontinuation.
The primary estimand assesses the expected difference in response rates (defined as response 
obtained without initiation of any rescue medication) after 16 weeks, resulting from initiation 
of a treatment regimen with tralokinumab+TCS compared to a treatment regimen with 
placebo+TCS.  
Primary analysis for the primary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Subjects who prior to the Week 16 visit have 
received rescue medication will be considered non-responders, reflecting an assumption that 
initiation of rescue medication indicates failure of the randomised treatment to achieve 
response, and that a (possible) observed positive response after initiation of rescue medication 
is not attributable to the randomised treatment. Missing data for subjects who do not attend 
the Week 16 visit and where rescue medication has not been used prior to Week 16, will be 
imputed as non-responders.  
The difference in response rates between treatment groups will be analysed using the 
Cochran-Mantel-Haenszel test stratified by region (Europe and North America) and baseline 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 88 of 129 
disease severity (IGA 3 or 4). The treatment estimate and the corresponding 95% CI will be 
presented. The null hypothesis of no difference in response rates between tralokinumab+TCS 
and placebo+TCS will be tested against the 2-sided alternative that there is a difference.  
The primary endpoints will be tested sequentially at a 5% significance level. IGA 0/1 will be 
tested first, and, if significant, then EASI75 will be tested. If both primary null hypotheses are 
rejected, the secondary endpoints will be tested.  
Sensitivity analyses for the primary estimand 
Two sensitivity analyses are specified for the primary estimand. In both cases the same 
Cochran-Mantel-Haenszel test as used for the primary analysis will be applied including 
stratification by region and baseline disease severity. 
The purpose of the analyses is to assess the robustness of results of the primary analysis with 
respect to the retrieved data at Week 16 and assumptions regarding missing Week 16 data.  
Sensitivity analysis 1: All subjects who have permanently discontinued IMP prior to Week 16 
will be imputed as non-responders, even if no rescue medication has been used. This is to 
reflect a situation where retrieved efficacy data and concomitant medications could be 
registered less accurately for subjects who have discontinued treatment.  
Sensitivity analysis 2: Rather than imputing all subjects who do not attend the Week 16 visit 
and where rescue medication has not been used as non-responders, the following approach 
will be applied. If subjects have withdrawn due to an AE or due to lack of efficacy, they are 
still considered non-responders. Data missing for other reasons will be imputed using last 
observation carried forward (LOCF), hereby assuming that the last value is a more reliable 
estimate of the missing response (than a non-response). 
Supplementary analysis 
The primary analysis of the primary estimand is repeated based on the per protocol analysis 
set. 
12.3.5.2 Secondary estimand: ‘hypothetical’ 
The secondary estimand for the primary endpoints will be: 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 89 of 129 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
if all subjects adhered to the treatment regimen in the sense that they did not
discontinue IMP permanently and no rescue medication was made available
before Week 16.
The secondary estimand assesses the expected difference in response rates achieved when 
adhering to the treatment regimen tralokinumab+TCS with no rescue medication as compared 
to a treatment regimen with placebo+TCS with no rescue medication.  
Primary analysis of the secondary estimand 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be applied in the analysis.  
IGA 0/1 responder imputation  
Imputation of missing binary IGA 0/1 data at Week 16 will be done using multiple 
imputations of the underlying 5-point IGA values within the 2 groups defined according to 
randomised treatment arm assuming that data is missing at random within each arm. 
1. In each group, intermittent missing values will be imputed using LOCF to obtain a
monotone missing data pattern.
2. An ordinal logistic regression model assuming proportional odds will be fitted to the
IGA value at Week 2. The model will include effects of region, and baseline disease
severity (IGA 3 or 4) as factors. The estimated parameters, and their variances, will be
used to impute missing IGA values at Week 2. 100 copies of the dataset will be
generated (seed=111099).
3. For each of the 100 copies of the dataset, missing values at Week 4 will be imputed in
the same way as for Week 2. The imputations will be based on a proportional odds
logistic regression model with effects of region and baseline disease severity (IGA 3 or
4) together with the IGA value at Week 2 as factors. The estimated parameters, and
their variances, will be used to impute missing values at Week 4. 
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the IGA values from the two preceding visits
will be included as factors in addition to region and baseline disease severity. The
missing binary IGA 0/1 response at Week 16 will be derived from the corresponding
underlying imputed IGA value.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 90 of 129 
EASI75 responder imputation 
Imputation of missing binary EASI75 data at Week 16 will be done using multiple 
imputations of the underlying 72-point EASI values within the two groups defined according 
to randomised treatment arm assuming that data is missing at random within each arm.  
1. Intermittent missing values will be imputed in each group using a Markov Chain
Monte Carlo method to obtain a monotone missing data pattern and 100 copies of the
dataset will be generated (seed=290997).
2. An ANCOVA model is fitted to the EASI value at Week 2. The model will include
effects of baseline EASI as a covariate, and region, and baseline disease severity (IGA
3 or 4) as factors. The estimated parameters, and their variances, will be used to
impute missing EASI values at Week 2. 100 copies of the dataset will be generated
(seed=111099).
3. For each of the 100 copies of the dataset, missing EASI values at Week 4 will be
imputed in the same way as for Week 2. The imputations will be based on the same
ANCOVA model with effects of baseline EASI as a covariate, and region, and baseline
disease severity (IGA 3 or 4) as factors together with the EASI value at Week 2 as
covariate. The estimated parameters, and their variances, will be used to impute
missing values at Week 4.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the EASI values from the preceding two visits
will be included as covariates in addition to baseline EASI as a covariate, and region
and baseline disease severity as factors. The missing binary EASI75 response at
Week 16 will be derived from the corresponding underlying imputed EASI value.
Analysis of Week 16 response 
For each of the 100 complete data sets, the difference in response rates (either the IGA 0/1 or 
the EASI75) between treatment groups will be analysed using the Cochran-Mantel-Haenszel 
test stratified by region (Europe and North America) and baseline disease severity (IGA 3 or 
4). The estimates and standard errors from the 100 analyses will be pooled to one estimated 
treatment difference and associated standard error using Rubin’s rule to draw inference. From 
these pooled estimates, the 95% CI for the treatment difference will be calculated.  
Sensitivity analysis for the secondary estimand 
Rather than assuming that observations are missing at random within each treatment arm, it is 
assumed that missing data from subjects who discontinue IMP permanently/receive rescue 
medication in the tralokinumab+TCS arm will resemble missing data from subjects from the 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 91 of 129 
placebo arm who do not discontinue IMP permanently/receive rescue medication. The 
underlying assumption is that the effect of tralokinumab following rescue medication or 
permanent treatment discontinuation is similar to the effect of placebo. It should be noticed 
that this assumption is pronouncedly conservative in favour of placebo as it tends to minimise 
the differences between arms.  
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab+TCS arm as well as the placebo+TCS arm will be imputed 
from observed data in the placebo+TCS arm (using a so-called copy-reference approach). 
With this exemption, the stepwise multiple imputation procedure and subsequent analysis will 
be conducted in the same way as specified for the primary analysis of the secondary estimand. 
12.3.5.3 Tertiary estimand: ‘treatment policy’ 
The tertiary estimand for the primary endpoints will be: 

Treatment difference in response rate after 16 weeks between
tralokinumab+TCS and placebo+TCS regardless of rescue medication and
treatment discontinuation.
The tertiary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab+TCS and additional rescue medication as 
compared to a treatment regimen with placebo+TCS and additional rescue medication.  
Primary analysis for the tertiary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued treatment prior to 
Week 16 will be included in the analysis.  
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment arm and whether or not subjects have 
permanently discontinued IMP prior to Week 16. Within a given treatment arm, retrieved data 
from discontinued subjects will be used to impute missing data for other discontinued 
subjects. Similarly, the available data from not discontinued subjects will be used to impute 
data for such patients where the Week 16 value is missing.  
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way as specified for the primary analysis of the secondary estimand. 
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16 will be too small to facilitate the same imputation model as mentioned above. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 92 of 129 
Consequently, an imputation model with only region and baseline effects (IGA as a factor and 
EASI as a covariate [only for EASI75]) will be applied for discontinued subjects. Some 
factors may have to be omitted, depending on the observed data, e.g. if retrieved subjects only 
come from one region or if they all have the same baseline severity. 
The imputed datasets will be analysed in the same way as specified for the primary analysis of 
the secondary estimand. 
Sensitivity analyses for the tertiary estimand 
Rather than imputing Week 16 data as described in the primary analysis of the tertiary 
estimand, missing observations will be imputed as ‘non-responders’. The assumption reflects 
that discontinued subjects without retrieved data at Week 16 are more likely to be non-
responders than resembling discontinued subjects with retrieved data at Week 16. 
12.3.6 Analysis of secondary endpoints 
The 3 secondary endpoints evaluate the impact of 16 weeks of treatment on (i) severity and 
extent of AD, (ii) itch, and (iii) HRQoL. The corresponding endpoints are (i) the change from 
baseline to Week 16 in SCORAD, (ii) reduction (Y/N) of Worst Daily Pruritus NRS average 
score for the past week (hereinafter ‘Worst Daily Pruritus NRS weekly average’) of at least 4 
from baseline to Week 16, and (iii) change from baseline to Week 16 in DLQI score. 
Subject-reported worst daily itch over the last week prior to baseline (Day -6 to 0) will be 
used to calculate the baseline itch (see also inclusion criterion no. 9).  
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 is a binary endpoint, and 
it will be analysed as described for the primary endpoint EASI75 using all three estimands 
with the modification of the ANCOVA imputation model that Reduction of Worst Daily 
Pruritus NRS weekly average replaces EASI where preceding values are used as covariates.  
The change from baseline to Week 16 in SCORAD and DLQI, respectively, are continuous 
endpoints and will be analysed as described below. 
All analyses will be based on the full analysis set unless otherwise specified. 
12.3.6.1 Primary estimand for the continuous secondary endpoints: 
‘hypothetical’ 
The primary estimand for the continuous secondary endpoints will be: 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 93 of 129 

Treatment difference in change from baseline to Week 16 in SCORAD and DLQI,
respectively, if all subjects adhered to the treatment regimen in the sense that they did
not discontinue IMP permanently and no rescue medication was made available before
Week 16.
The primary estimand assesses the expected benefit when adhering to the treatment regimen 
tralokinumab+TCS with no rescue medication as compared to a treatment regimen with 
placebo+TCS with no rescue medication.  
Primary analysis of the primary estimand (continuous secondary endpoints) 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be included in the analysis.  
The endpoints will be analysed using a repeated measurements model on the post baseline 
responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger 
approximation to estimate denominator degrees of freedom, and the mean modelled as 
follows (shown for change from baseline in SCORAD): 
Change from baseline in SCORAD 
= treatment × visit + baseline SCORAD × visit + region + baseline IGA 
This model assumes that data is missing at random within each treatment arm. The estimates 
will be presented with nominal p-values and 95% CI at each visit. The primary comparison 
between tralokinumab+TCS and placebo+TCS will be at Week 16. 
Sensitivity analysis for the primary estimand (continuous secondary endpoints) 
Rather than assuming that observations are missing at random within each treatment arm it is 
assumed that missing data from subjects who discontinue treatment/receive rescue medication 
in the tralokinumab+TCS arm will resemble data from subjects from the placebo+TCS arm 
who do not discontinue treatment/receive rescue medication. Imputation of missing data at 
Week 16 will be done using a pattern mixture model where missing data in the 
tralokinumab+TCS arm as well as the placebo+TCS arm will be imputed from the 
placebo+TCS arm (using a so-called copy-reference approach). The procedure for the change 
from baseline in SCORAD at Week 16 is described below. The same procedure will be 
applied for the DLQI endpoint. 
1. Intermittent missing values will be imputed in each group using a Markov Chain
Monte Carlo method to obtain a monotone missing data pattern and 100 copies of the
dataset will be generated (seed=290997).
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 94 of 129 
2. For each of the 100 copies of the dataset, an ANCOVA model will be fitted to the
SCORAD value at Week 2 in the placebo+TCS group. The model will include effects
of baseline SCORAD as a covariate, and region and baseline disease severity (IGA 3
or 4) as factors. The estimated parameters, and their variances, will be used to impute
missing values at Week 2 for the placebo+TCS group as well as the
tralokinumab+TCS group (seed=111099).
3. For each of the 100 copies of the dataset, missing values at Week 4 will be imputed in
the same way as for Week 2. The imputations will be based on a similar ANCOVA
model, but with SCORAD value at Week 2 included as an additional covariate. The
parameters from the model will be estimated based on data from the placebo+TCS
group. The estimated parameters, and their variances, will be used to impute missing
values at Week 4 for both treatment groups.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the SCORAD values from the preceding two visits included as covariates
in addition to baseline SCORAD as a covariate, and region and baseline disease
severity as factors.
For each of the 100 imputed dataset, the change from baseline in SCORAD at Week 16 will 
be analysed using an ANCOVA model with effects of treatment, region, baseline disease 
severity (IGA 3 or 4), and baseline SCORAD value. The estimated difference at Week 16 will 
be derived together with the associated standard error. The estimates and standard errors from 
the 100 analyses are pooled to one estimate and associated standard error using Rubin’s rule 
to draw inference. From these pooled estimates, the 95% CI for the treatment difference will 
be calculated.  
12.3.6.2 Secondary estimand for the continuous secondary endpoints: 
‘treatment policy’ 
The secondary estimand for the continuous secondary endpoints will be: 

Treatment difference in change from baseline to Week 16 in SCORAD and
DLQI, respectively, between tralokinumab+TCS and placebo+TCS regardless
of rescue medication use and treatment discontinuation.
The secondary estimand assesses the average difference in change from baseline in SCORAD 
and DLQI after 16 weeks, resulting from initiation of a treatment regimen with 
tralokinumab+TCS and additional rescue medication as compared to a treatment regimen with 
placebo+TCS and additional rescue medication.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 95 of 129 
Primary analyses for the secondary estimand (continuous secondary endpoints) 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Missing Week 16 data will be imputed using 
multiple imputations assuming that data is missing at random within the groups used for 
imputation. 
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment arm and whether or not subjects have 
discontinued treatment prior to Week 16. Within a given treatment arm, retrieved data from 
discontinued subjects will be used to impute missing data for other discontinued subjects. 
Similarly, the available data from not discontinued subjects will be used to impute data for 
such subjects where the Week 16 value is missing.  
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way as specified for the imputation of the underlying EASI values in the primary 
analysis of the secondary estimand for the binary endpoints. 
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16 will be too small to facilitate the same imputation model as mentioned just above. 
Consequently, an imputation model with only region and baseline effects (IGA as a factor and 
baseline SCORAD / DLQI as a covariate) will be applied for discontinued subjects. Some 
factors may have to be omitted, depending on the observed data, e.g. if retrieved subjects only 
come from one region or if they all have the same baseline severity. 
Each of the 100 imputed datasets will be analysed as described in the sensitivity analyses for 
the primary estimand for the continuous secondary endpoints. 
Sensitivity analyses for the secondary estimand (continuous secondary endpoints) 
Rather than assuming that observations are missing at random, it is assumed that missing data 
from subjects in the tralokinumab+TCS arm who have/have not discontinued treatment prior 
to Week 16 will resemble data from subjects from the placebo+TCS arm who have/have not 
discontinued treatment prior to Week 16.  
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab+TCS arm as well as the placebo+TCS arm will be imputed 
from the placebo+TCS arm (copy-reference approach). With this exemption, the multiple 
imputation procedure and analysis will be conducted in the same way as described for the 
primary analysis of the secondary estimand for the continuous secondary endpoints. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 96 of 129 
12.3.7 Analysis of additional secondary endpoints 
Initial treatment period 
The analysis of the below additional secondary endpoints will be based on the primary 
analyses of the primary estimand as specified above for the relevant primary dichotomous 
endpoints and continuous secondary endpoints, respectively. 
The following dichotomous additional secondary endpoints will be analysed according to the 
primary analysis of the primary estimand for the primary endpoints:  

EASI50 at Week 16.

EASI90 at Week 16.

SCORAD50 at Week 16.

SCORAD75 at Week 16.

Reduction from baseline (Y/N) of DLQI of ≥4 points (in subjects with baseline
DLQI ≥4) at Week 16.
The change from baseline to Week 16 in EASI score and the change from baseline to Week 16 
in Worst Daily Pruritus NRS weekly average will be analysed according to the primary 
analysis of the primary estimand for the continuous secondary endpoints.  
To evaluate the efficacy related to health care resource utilisation, the amount of TCS used 
(assessed as the amount of TCS used between visits), and the number of days without topical 
treatment use (collected as Patient Days of Topical Treatment Use in the eDiary) will be 
determined by 2-week periods. The amount of TCS used and the number of days without 
topical treatment use will each be analysed by a repeated measurements model with an 
unstructured covariance matrix and the mean modelled as follows: 
Y = treatment × visit + region + baseline IGA 
Results obtained after initiation of rescue treatment will be excluded from the analyses. 
AD flares will be summarised descriptively as the proportion of subjects having had AD flares 
at Week 16, the number of AD flares from baseline to Week 16, and the rate of AD flares from 
baseline to Week 16. The rate of AD flares will be defined as the number of AD flares divided 
by time at risk, where the time at risk for each subject is the time from treatment start to last 
visit attended up to Week 16. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 97 of 129 
Continuation treatment period 
To support the maintenance objective of the trial, IGA of 0/1 at Week 32 among subjects with 
IGA of 0/1 at Week 16 and EASI75 at Week 32 among subjects with EASI75 at Week 16, 
both after initial randomisation to tralokinumab, will be summarised descriptively by 
treatment group of the continuation treatment period. 
To support the maintenance objective of the trial, IGA 0/1, EASI75, EASI50, EASI90, 
SCORAD75, and SCORAD50, all at Week 32, will be summarised descriptively by treatment 
group of the continuation treatment period.  
12.3.8 Analysis of other endpoints 
12.3.8.1 Efficacy related other endpoints 
To further pursue the objectives supported by the five Week 16 endpoints in the confirmatory 
test hierarchy, the same endpoints will be evaluated at each scheduled assessment up to Week 
14, including also the weekly average of Worst Daily Pruritus NRS: 

IGA 0/1 at each scheduled assessment until Week 14.

EASI75 at each scheduled assessment until Week 14.

Change in SCORAD from baseline to each scheduled assessment until
Week 14.

Change from baseline to each scheduled assessment through Week 4 to 14 in
Worst Daily Pruritus NRS (weekly average).

Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from
baseline to each scheduled assessment through Week 4 to 14.

Change in DLQI score from baseline to each scheduled assessment until
Week 14.
Nominal p-values for test of a treatment difference and 95% CI for the difference will be 
presented at each scheduled visit using the same approach as applied for the primary analysis 
of the relevant endpoint in the primary estimand. 
For the binary endpoints, the same Cochran-Mantel-Haenszel test as for the Week 16 
assessment will be applied. For the continuous endpoints, the repeated measurements model 
already described previously for the Week 16 assessments facilitates that the p-values, 
treatment differences and 95% CIs can be derived for each visit up to Week 14 in the same 
analysis that already will be made for the corresponding Week 16 assessments. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 98 of 129 
12.3.8.2 Patient-reported outcomes 
The PROs POEM, DLQI, EQ-5D-5L, and HADS will be summarised by treatment group and 
visit using descriptive statistics. The summaries will be made separately for initial treatment 
and continuation treatment. Data from the initial treatment period will be presented for the 
full analysis set and data from the continuation treatment period will be presented for the 
continuation treatment analysis set.  
The PROs collected daily in the eDiaries (Worst Daily Pruritus NRS, Average Daily Pruritus 
NRS, Eczema-related Sleep NRS, PGI-B, and PGI-S) will all be summarised over time by 
treatment group using descriptive statistics. The summaries will be separate for initial 
treatment and continuation treatment. Data from the initial treatment period will be presented 
for the full analysis set and data from the continuation treatment period will be presented for 
the continuation treatment analysis set. 
The Average Daily Pruritus NRS collected over the last week prior to baseline (Day -6 to 0) 
will be used to calculate the baseline average daily itch. A minimum of 4 Average Daily 
Pruritus NRS scores out of the 7 days is required to calculate the baseline average score. 
To investigate a possible early onset of itch relief, a reduction in Worst Daily Pruritus NRS 
weekly average of at least 4 from baseline to Week 2 as well as a reduction of at least 3 from 
baseline to Week 2 will be summarised by treatment group. Furthermore, to investigate itch 
relief during initial treatment a reduction in Worst Daily Pruritus NRS weekly average of at 
least 3 from baseline to Week 16 will be summarised. These three endpoints will each be 
analysed according to the primary analysis of the primary estimand for the dichotomous 
primary endpoints. 
In the subgroup of subjects with either HADS anxiety or HADS depression subscale score ≥8 
at baseline, the proportion of subjects with both HADS anxiety and HADS depression 
subscale score <8 at Week 16 will be summarised by treatment group and analysed as 
described for the primary analysis of the primary estimand for the primary endpoints. 
In the subgroup of subjects with a baseline POEM score ≥4, the proportion of subjects with a 
reduction in POEM score ≥4 at Week 16 will be summarised by treatment group and analysed 
as described for the primary analysis of the primary estimand for the primary endpoints. 
The change from baseline to Week 2 in Worst Daily Pruritus NRS weekly average, and the 
change from baseline to Week 16 in Eczema-related Sleep NRS weekly average, HADS, 
POEM, and the EQ-5D-5L index will be summarised by treatment group and domain, where 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 99 of 129 
applicable, and analysed according to the primary analysis of the primary estimand for the 
continuous secondary endpoints. For the Eczema-related Sleep NRS score, the mean over the 
last 7 days prior to randomisation (Day -6 to 0) will be used as the baseline value. 
For the PGI-B, a day of ‘no or slight bother’ is defined as answering the question with “not at 
all” or “slightly”. The subjects’ number of days of ‘no or slight bother’ will be tabulated per 
treatment group for the initial treatment period. The mean number of days will be presented 
with 95% CIs and compared between the 2 treatment groups using an analysis of variance 
model including treatment, region, and baseline IGA as factors.  
12.3.9 Analysis of safety 
The analyses of safety will be based on the safety analysis set. The reporting of safety data 
will be presented separately for initial treatment and continuation treatment. 
12.3.9.1 Adverse events 
To assess the safety of tralokinumab in combination with TCS when used to treat moderate-
to-severe AD for 32 weeks, the frequency of AEs and SAEs are included as additional 
secondary endpoints.  
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred terms and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised, however, all AEs recorded during the course of 
the trial will be included in the subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP or if started before the first use of IMP 
(applicable if subject had a wash-out) and worsened in severity thereafter. The tabulations 
described in the following will only include the treatment-emergent events. In each of the 
tabulations, AEs will be defined by MedDRA preferred terms within primary SOC. 
An overall summary of the number of treatment-emergent AEs and the number (percentage) 
of subjects with any treatment-emergent AEs, deaths, SAEs, premature discontinuations from 
the trial due to AEs, treatment-related AEs and severe AEs will be presented. 
The number of AEs and the number of subjects experiencing each type of AE will be 
tabulated by treatment group. The percentage of subjects with AEs in the initial treatment 
period will be compared between treatment groups by a chi-square test or Fisher’s exact test 
(if expected cell count <5). 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 100 of 129 
The severity for each type of AE will be tabulated by treatment group. 
The causal relationship to IMP and NIMP (TCS) for each type of AE will be tabulated by 
treatment group.  
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
experiencing each type of related AE will be tabulated. The percentage of subjects with 
related AEs in the initial treatment period will be compared between treatment groups by a 
chi-square test or Fisher’s exact test (if expected cell count <5). 
SAEs and AESIs will be evaluated separately. A narrative for each SAE will be given. AESIs 
and AEs leading to withdrawal from trial or permanent discontinuation of IMP will be 
tabulated and listed. 
12.3.9.2 Vital signs 
The change in vital signs (blood pressure, heart rate, body temperature) from baseline to each 
visit will be summarised by visit and treatment group as mean, standard deviation, median, 
minimum and maximum values for the safety analysis set and the continuation treatment 
safety analysis set. 
12.3.9.3 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit and treatment group as mean, standard deviation, median, minimum and 
maximum values for the safety analysis set and the continuation treatment safety analysis set. 
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at end of treatment. Subjects with 
laboratory parameters outside the reference range will be listed. 
12.3.9.4 Pharmacokinetics 
All the PK samples in the trial are trough samples. The trough concentration (Ctrough) will be 
listed by treatment group and descriptive statistics will be applied.  
Ctrough values from subjects with positive ADA/nAB will be compared to values from subjects 
with negative ADA/nAB if data permits.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 101 of 129 
The PK data will be merged with those from other clinical trials with tralokinumab for a 
population-based meta-analysis. Results of the meta-analysis will be presented in a separate 
pharmacometrics report outside of the CTR. 
12.3.9.5 Anti-drug antibodies 
The frequency of ADAs is an additional secondary endpoint included to assess the safety and 
tolerability (immunogenicity) of tralokinumab in combination with TCS.  
ADA status (positive versus negative) at each visit will be summarised by treatment group for 
the initial treatment and continuation treatment. If considered relevant, descriptive statistics 
including number of subjects, mean, standard deviation, median, and range of the actual ADA 
titres by treatment group and visit will be provided. The ADA status across the trial for each 
subject (positive vs. negative) will also be classified and summarised by treatment group. 
The association of ADA status across the trial (positive vs. negative) with AEs/SAEs may be 
evaluated. In addition, the association of ADA titres (≥ median titre in positive subjects versus 
< median titre) with AE/SAEs may be evaluated for ADA-positive treated subjects only. The 
ADA-positive subjects across the trial may also be divided into persistent positive versus 
transient positive. A subject will be considered as persistent positive if he/she has positive 
ADA for at least 2 consecutive visits with ADA assessment. Otherwise, the subject will be 
considered as transient ADA positive. The associations between ADA and AE/SAEs may be 
summarised for both persistent positive subjects versus transient positives subjects.  
For subjects who develop ADA, the IGA score and change in EASI at end of treatment will be 
listed.  
Evaluations of nAB will be conducted on those serum samples that test positive for ADA. The 
test sample is deemed positive or negative for the presence of nAB to tralokinumab relative to 
a pre-determined (in assay validation) statistically derived cut point. 
All ADA positive subjects with titre information will be listed. 
12.3.10 
Interim analysis 
No interim analysis is planned. 
12.3.11 
Analysis of data up to Week 32 
To support submission for marketing approval, a 32-week analysis will be performed on data 
up to Week 32. All analyses pertaining to efficacy endpoints will be final in this 32-week 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 102 of 129 
analysis and will be included in a CTR in the original submission. No adjustments in 
significance level of the primary and secondary analyses will therefore be applied. Blinding of 
investigators and other site staff involved in the conduct of the trial will be maintained for the 
entire duration of the trial (please refer to Section 9.2.1 for further details). 
The safety results for the safety follow-up period (Week 32 to 46) for all subjects will be 
included in an addendum to the original CTR and will be submitted as part of the 120-Day 
Safety Update. 
12.3.12 
General principles 
Unless otherwise stated, all significance tests will be two-sided using the 5% significance 
level. All CIs will be presented with 95% degree of confidence. 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation, minimum and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan update will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan update and/or in 
the CTR dependent on the type of deviation.  
12.3.13 
Handling of missing values 
Procedures for handling of missing values are included under the sections describing the 
individual analyses. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 103 of 129 
13  References 
1. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and
other health and demographic factors: a US population-based study. J Allergy Clin
Immunol. 2013;132(5):1132-1138.
2. Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A
population-based survey of eczema prevalence in the United States. Dermatitis.
2007;18(2):82-91.
3. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-1494.
4. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023):1109-1122.
5. Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, et al. Atopic dermatitis
is associated with a decrement in health-related quality of life. Int J Dermatol.
2002;41(3):151-158.
6. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in
lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295(11):459-464.
7. Omori-Miyake M, Yamashita M, Tsunemi Y, Kawashima M, Yagi J. In vitro assessment of
IL-4- or IL-13-mediated changes in the structural components of keratinocytes in mice
and humans. J Invest Dermatol. 2014;134(5):1342-1350.
8. Aleksza M, Lukács A, Antal-Szalmás P, Hunyadi J, Szegedi A. Increased frequency of
intracellular interleukin (IL)-13 and IL-10, but not IL-4, expressing CD4+ and CD8+
peripheral T cells of patients with atopic dermatitis. Br J Dermatol.
2002;147(6):1135-1141.
9. Purwar R, Werfel T, Wittmann M. IL-13-stimulated human keratinocytes preferentially
attract CD4+CCR4+ T cells: possible role in atopic dermatitis. J Invest Dermatol.
2006;126(5):1043-1051.
10. Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T. TRPAA1-dependent pruritus in
IL-13-induced chronic atopic dermatitis. J Immunol. 2013;191(11):5371-5382.
11. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of
interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest
Dermatol. 2009;129:742-751.
12. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two
phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med.
2016;375(24):2335-2348.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 104 of 129 
13. May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. Preclinical
development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe
uncontrolled asthma. Br J Pharmacol. 2012;166(1):177-193.
14. Thom G, Minter R. Optimization of CAT-354, a therapeutic antibody directed against
interleukin-13, using ribosome display. Methods Mol Biol. 2012;805:393-401.
15. Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME. Inhibition of
human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-
interleukin-13 antibody (CAT-354). Clin Exp Allergy. 2005;35(8):1096-1103.
16. Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et al. Guidelines for
treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol.
2012;26(9):1176-1193.
17. Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al.
Guidelines of care for the management of atopic dermatitis: section 2. Management and
treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol.
2014;71(1):116-132.
18. Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, Bergman JN, et al.
Guidelines of care for the management of atopic dermatitis: section 3. Management and
treatment with phototherapy and systemic agents. J Am Acad Dermatol.
2014;71(2):327-349.
19. Bancroft AJ, Artis D, Donaldson DD, Sypek JP, Grencis RK. Gastrointestinal nematode
expulsion in IL-4 knockout mice is IL-13 dependent.
Eur J Immunol. 2000;30(7):2083-2091.
20. Moffat GJ, Davies R, Kwon G, Retter MW, Chellman GJ, Kanapuram S, et al.
Investigation of maternal and fetal exposure to an IgG2 monoclonal antibody following
biweekly intravaginal administration to cynomolgus monkeys throughout pregnancy.
Reprod Toxicol. 2014;48:132-137.
21. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol.
1980;92(Suppl):44-47.
22. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement:
updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 105 of 129 
23. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised
nomenclature for allergy for global use: report of the Nomenclature Review Committee of
the World Allergy Organization, October 2003. J Allergy Clin Immunol.
2004;113(5):832-836.
24. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et
al. Second symposium on the definition and management of anaphylaxis: Summary report
- Second National Institute of Allergy and Infectious Diseases/Food Allergy and
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397. 
25. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry.
2007;164(7):1035-1043.
26. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and
severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol.
2001;10(1):11-18.
27. Harmonising Outcome Measures for Eczema (HOME). EASI scoring table for aged 8 and
over [homepage on the Internet]. Available from:
http://www.homeforeczema.org/resources.aspx [cited 17-Aug-2017].
28. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the
SCORAD index. Consensus report of the European task force on atopic dermatitis.
Dermatology. 1993;186(1):23-31.
29. Wollenberg A, Oranje A, Deleuran M, Simon D, Szalai Z, Kunz B, et al, European Task
Force on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV Eczema task force
2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric
patients. J Eur Acad Dermatol Venereol. 2016;30(5):729-747.
30. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development
and initial validation of a new tool for measuring atopic eczema severity from the patients'
perspective. Arch Dermatol. 2004;140(12):1513-1519.
31. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
32. Greiner W, Weijnen T, Nieuwenhuizen M, Oppe S, Badia X, Busschbach J, et al. A single
European currency for EQ-5D health states. Results from a six-country study. Eur J Health
Econ. 2003;4(3):222-231.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 106 of 129 
33. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand.
1983;67(6):361-370.
34. European Parliament and Council of The European Union. Directive 2001/20/EC of
4 April 2001 on the approximation of the laws, regulations and administrative provisions
of the Member States relating to the implementation of good clinical practice in the
conduct of clinical trials on medicinal products for human use [2001], article 10.
35. Holm S. A simple sequentially rejective multiple test procedure. Scan J Stat.
1979;6(2):65-70.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 107 of 129 
Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for GCP, E6 [R1]). 
This definition includes: 

Accidental injuries.

Events related to trial procedures.

Reasons for any unfavourable and unplanned change in medication (drug
and/or dose).

Clinically significant worsening of pre-existing conditions.

Reasons for admission to hospital or surgical procedures unless these were
planned before enrolment.
It also includes AEs commonly observed and AEs anticipated based on the pharmacological 
effect of the IMP. In addition, any laboratory abnormality assessed as clinically significant by 
the investigator must be recorded as an AE. 
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 

results in death.

is life-threatening.

requires inpatient hospitalisation or prolongation of existing hospitalisation.
Planned hospitalisation or planned prolonged hospitalisation do not fulfil the
criteria for being an SAE but should be documented in the subject’s medical
record.

results in persistent or significant disability/incapacity.

is a congenital anomaly/birth defect.
or 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 108 of 129 

is a medically important condition. Events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the subject
or may require intervention to prevent one of the other outcomes listed in the
definition above. Examples are intensive treatment in an emergency room or at
home for allergic bronchospasm, blood dyscrasias and convulsions that do not
result in hospitalisation, development of drug dependency or drug abuse.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 109 of 129 
Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the following: 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the IMP. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Follows a known pattern of response to the IMP. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 110 of 129 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the subject. 
Does not reappear or worsen upon re-challenge. 
Does not follow a known pattern of response to the IMP. 
Similarly, the causal relationship to the use of NIMP (TCS) should also be evaluated using the 
same definitions as for the IMP (i.e. probably, possibly, or not related to NIMP).  
Outcome 
The outcome of the event should be classified and handled as follows: 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing. 
Recovered/re
solved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 111 of 129 
Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 

Consensus ethical principles derived from international guidelines including
the current version of the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines.

Current version of applicable ICH GCP Guidelines.

Applicable laws and regulations.
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required.  
The protocol, protocol amendments, subject information leaflet including the informed 
consent form (ICF), Investigator’s Brochure, and other relevant documents (for example 
advertisements) must be submitted to an IRB/IEC by the investigator (in collaboration with 
LEO, if applicable) and reviewed and approved by the IRB/IEC prior to enrolment of 
subjects.  
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs as required prior to the implementation. 
The investigator will be responsible for the following: 

Providing written summaries of the status of the trial to the IRB/IEC annually
or more frequently in accordance with the requirements, policies, and
procedures established by the IRB/IEC.

Notifying the local IRB/IEC of SAEs or other significant safety findings as
required by IRB/IEC procedures.

Providing oversight of the conduct of the trial at the trial site and adherence to
applicable national and international legislation.
Appendix 3B: Informed consent process 
Subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 112 of 129 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial must be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 
GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if applicable.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IWRS 
cannot be performed. 
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO and shall not be used by the 
investigator for purposes other than this clinical trial. 
The investigator agrees that LEO may use any and all information, data and results from this 
clinical trial in connection with the development of the IMPs and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners. 
Subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records or 
datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
Subjects must be informed that their personal trial-related data will be used by LEO in 
accordance with local data protection law.  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 113 of 129 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by LEO, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example age, gender, health 
condition, height, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO and third parties acting on behalf of LEO. 
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing and transfer of personal data in the 
clinical trial. In certain cases, an agreement on transfer of personal data may also be required. 
Investigators and LEO must ensure that collection, processing, and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy. 
Subjects (or their legally acceptable representative) must be asked to consent to the collection, 
processing and transfer of their personal data to EU and non-EU countries for the purpose of 
conducting the clinical trial, research and development of new or existing products/services, 
improving existing products/services, applying for marketing authorisations for 
products/services, marketing of products/services and other related activities. 
LEO has obtained the necessary authorisations for the processing of personal data collected in 
the trial.  
Appendix 3D: Record keeping, quality control, and data handling 
Case report forms 
Data will be collected by means of electronic data capture in an eCRF unless transmitted to 
LEO or designee electronically (e.g., laboratory data). The investigator or staff authorised by 
the investigator will enter subject data into eCRFs. Data recorded in the eCRFs will be 
accessible to the trial site and LEO personnel immediately after entry. The eCRFs must be 
maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRFs used. This signature information will be kept in the audit trail 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 114 of 129 
and cannot be altered. Any correction(s) made by the investigator or authorised site staff to 
the eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data, and the date, time and reason for the change will be identified in the audit trail. 
Source data 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be one source defined at any time for 
any data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 

Date(s) of conducting the informed consent process, including date of
provision of subject information.

A statement from the investigator to verify that each of the eligibility criteria
are met.

Subject ID.

The fact that the subject is participating in a clinical trial in AD including
treatment with tralokinumab or placebo for 32 weeks.

Other relevant medical information.
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to perform ongoing source data verification to confirm that data entered into the 
eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; (ii) to confirm that the safety and rights of subjects are being protected; and (iii) 
to confirm that the trial is being conducted in accordance with the currently approved protocol 
and any other trial agreements, ICH GCP, and all applicable regulatory requirements. 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 115 of 129 
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. LEO will assess all 
protocol deviations and decide if any of these deviations must be reported to the regulatory 
authorities as a serious breach of GCP and the protocol, as required by local legislation. 
Protocol deviations will be included in the CTR 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
during or after the trial. The investigator and the site staff as well as LEO staff have an 
obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant 
to the clinical trial. This includes permission to examine, verify and reproduce any records 
and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO must be notified 
immediately.  
Data handling 
Subject data should be entered into the eCRF as soon as possible after each visit in 
accordance with the requirements described in the Clinical Trial Agreement, if applicable. 
Queries for discrepant data will be generated automatically by the system upon entry or 
manually by the CRA, sponsor’s medical expert, or the data manager. All queries will be 
raised electronically within the electronic data capture system. This systematic validation will 
ensure that a clean and consistent database is provided for the statistical analysis. 
An electronic PRO (ePRO) solution will be used to capture patient-reported data (data from 
questionnaires completed at the trial site and eDiary data). By the use of an ePRO, data will 
be available immediately after data entry and available for monitors and site personnel, 
including the investigator, with read access only. The ePRO system is a separate application 
from the eCRF and data captured from the eCRF and the ePRO will be stored on different 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 116 of 129 
servers during data capture. Data from both systems will be included in the final trial 
database. 
External data transfers from vendors to LEO will be transmitted and handled via a secure file 
transfer protocol site. Transmissions of electronic data from external data providers and of 
ePRO data to the clinical database are illustrated in Panel 12. 
Panel 12  Transmission of electronic data 
Abbreviations: CMO, contract manufacturing organisation; CTR, clinical trial report; ECG, electrocardiogram; 
eCRF, electronic case report form; ePRO, electronic patient-reported outcome; Lab, laboratory; TCS, topical 
corticosteroid. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the Investigator Trial File (ICH E6, Guideline for Good Clinical 
Practice) until LEO informs the investigator that the documents are no longer to be retained or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 117 of 129 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No records may be destroyed during the retention period without the written approval of 
LEO. No records may be transferred to another location or party without written acceptance 
from LEO. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with a copy of the eCRFs and 
ePRO data for all subjects enrolled at the trial site. This is done after completion of the trial 
and before access to the eCRF/ePRO is revoked. Audit trail information will be included. 
eCRFs and ePRO data must be available for inspection by authorised representatives from 
LEO, from regulatory authorities, and/or IEC/IRBs. 
Appendix 3E: Registration, reporting, and publication policy 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO in accordance with 
LEO’s Position on Public Access to Clinical Trial Information, latest 12 months after trial 
completion. Results may also become reported in www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination.  
In the case of a multi-centre trial the first publication will be a joint multi-centre publication. 
Multi-centre publications will be prepared in collaboration between LEO and the members of 
a writing group, which shall be appointed by LEO. 
Publication by an investigator of his/her trial results shall not be made public before the first 
multi-centre publication. 
If no multi-centre publication has been submitted for publication within 18 months after the 
clinical trial has been completed or terminated at all trial sites and all data have been received, 
defined as database lock of the clinical trial, the investigator shall have the right to publish the 
results from the clinical trial generated by the investigator, subject to the following notice 
requirements: 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 118 of 129 
Prior to submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 
investigator shall remove any confidential information (other than results generated by the 
investigator) prior to submitting or presenting the manuscripts. The investigator shall, upon 
the request of LEO, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO and the writing group may also delay the publication or presentation if the 
manuscript is deemed to harm the ongoing multi-centre publication. 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
LEO complies with recommendations from the International Committee of Medical Journal 
Editors and with the positions of the International Federation of Pharmaceutical 
Manufacturers & Associations (IFPMA), European Federation of Pharmaceutical Industries 
and Associations (EFPIA), Japan Pharmaceutical Manufacturers Association (JPMA) and 
Pharmaceutical Research and Manufacturers of America (PhRMA) on disclosure of 
information about clinical trials, trial results and authorship. 
Appendix 3F: Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO with sufficient, accurate financial information as requested to 
allow LEO to submit complete and accurate financial certification or disclosure statements to 
the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 119 of 129 
Appendix 3H: Trial and site closure 
Premature termination of trial or trial site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the clinical 
trial, part of the trial or a trial site at any time, but agreement on procedures to be followed 
must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO must promptly inform IRB/IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit-risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO or investigator may include but are not 
limited to: 

Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, LEO’s procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.

Discontinuation of further IMP development.
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Trial enrolment will be 
stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO will undertake arrangements for the 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 120 of 129 
Appendix 3I: Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(consolidated) clinical trial protocol, including any amendment(s) and the CTR on behalf of 
all clinical trial investigators and as agreed to in an International Coordinating Investigator 
Agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a National Coordinating Investigator Agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a Clinical Trial Agreement. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 121 of 129 
Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD (21) 
Major Features: must have 3 or more of the following: 

Pruritus

Typical morphology and distribution:
o
Flexural lichenification or linearity in adults
o
Facial and extensor involvement in infants and children

Chronic or chronically-relapsing dermatitis

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Features: should have 3 or more of the following: 

Xerosis

Ichthyosis, palmar hyperlinearity, or keratosis pilaris

Immediate (type 1) skin-test reactivity

Raised serum IgE

Early age of onset

Tendency toward cutaneous infections (especially S. aureus and herpes
simplex) or impaired cell-mediated immunity

Tendency toward non-specific hand or foot dermatitis

Nipple eczema

Cheilitis

Recurrent conjunctivitis

Dennie-Morgan infraorbital fold

Keratoconus

Anterior subcapsular cataracts

Orbital darkening

Facial pallor or facial erythema

Pityriasis alba

Anterior neck folds

Itch when sweating

Intolerance to wool and lipid solvents

Perifollicular accentuation

Food intolerance

Course influenced by environmental or emotional factors

White dermographism or delayed blanch
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 122 of 129 
Appendix 5: Guidance for anaphylaxis diagnosis (24) 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a 
serious allergic reaction that is rapid in onset and may cause death. They recognise 
3 categories of anaphylaxis, with criteria designated to capture from 80% of cases 
(category 1) to >95% of all cases of anaphylaxis (for all 3 categories).  
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING: 

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor,
reduced peak expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated symptoms of end-organ
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen for
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush,
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor,
reduced PEF, hypoxemia)

Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope,
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that patient (minutes to several
hours):

Infants and children: low systolic BP (age specific) or greater than 30%
decrease in systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from
that person’s baseline
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 123 of 129 
Appendix 6: Contact list 
Contact list of LEO, protocol authors, vendors, and trial committees 
Contact details for the clinical project manager, national lead CRA (NLCRA), and sponsor’s 
medical expert are provided to the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO’ or ‘the sponsor’ in this clinical trial protocol) is the 
sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
International coordinating investigator 
Associate Professor Jonathan Silverberg, MD, PhD, MPH, Departments of Dermatology, 
Preventive Medicine and Medical Social Sciences, Northwestern University Feinberg School 
of Medicine, United States 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 124 of 129 
CROs/vendors 
Service 
Name and address 
Data management 
Quanticate Ltd. 
Bevan House, 9-11 Bancroft Court, Hitchin, Hertfordshire SG5 1LH 
United Kingdom 
ePRO 
CRF Health Management Ltd. 
3rd Floor, Brook House, 229-243 Shepherds Bush Road, Hammersmith, 
London W6 7AN 
United Kingdom 
ECG 
Cardiabase S.A.S. 
Villa Alsacienne, 78 Avenue du XXe Corps, 54000 Nancy 
France 
Central laboratory 
ACM Global Central Laboratory 
23 Hospital Fields Road, York YO10 4DZ 
United Kingdom 
Bioanalysis of PK and 
ADA samples 
Covance Laboratories Ltd. 
Otley Road, Harrogate, North Yorkshire HG3 IPY 
United Kingdom 
IWRS 
Quanticate Ltd. 
Bevan House, 9-11 Bancroft Court, Hitchin, Hertfordshire SG5 1LH 
United Kingdom 
CMO 
Almac Clinical Services Ltd. 
Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD 
United Kingdom 
Emergency unblinding 
CRO 
C3i, Inc 
25 Lindsley Drive, Morristown, NJ 07960 
United States of America 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 125 of 129 
Appendix 7: Protocol amendment history 
The Protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents. 
Amendment 2 (10-Apr-2018) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The reason for the amendment is a change in the procedure for safety monitoring of the trial 
subjects in relation to the administration of investigational medicinal product (IMP). This 
change is endorsed by the Safety Review Board at LEO Pharma A/S, following an evaluation 
of safety data from: 

1 completed phase 2b trial with tralokinumab in AD (trial D2213C00001):
153 subjects exposed to tralokinumab (12-week treatment period).

2 ongoing phase 3 trials with tralokinumab in AD (trial LP0162-1325 and
LP0162-1326): 1089 subjects treated for ≥ 4 weeks (blinded safety data
evaluated, cut-off: 02-Mar-2018).

2 completed phase 3 trials with tralokinumab in asthma (trial D2210C00007
and D2210C00008): 1627 subjects exposed to tralokinumab (52-week
treatment periods).
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 126 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 4 
Schedule of trial 
procedures 
The visit window for screening visit 2 has been 
corrected from ±3 to -3 days. 
The visit window for baseline (visit 3) has been set to 
‘Not applicable’. 
To ensure that subjects 
will have no less than 
14 days between 
screening and baseline. 
As all subsequent visits 
should be planned to 
maintain the visit 
schedule relative to 
baseline (as already stated 
in Section 4). 
Footnote 6 to Panel 2: 
For the first 3 IMP dosing visits (visits 3 to 5) and 
after re-randomisation (visits 11 to 13), subjects will 
be monitored after IMP administration for immediate 
drug reactions for a minimum of 30 minutes 2 hours 
with vital signs taken at every 30 minutes or until 
stable, whichever is later (see Section 9.1.3.1). 
Based on the 
endorsement by the 
Safety Review Board at 
LEO Pharma A/S, 
following an evaluation 
of the safety data from 
3 completed and 
2 ongoing trials with 
tralokinumab. 
Section 7.1 
Overall trial 
design 
All subjects will attend a screening visit 14 days 
before baseline (Week -2; visit 2) where they will 
receive electronic diary (eDiary) training and start the 
eDiary. Data entered into the eDiary during the 2 
weeks before randomisation (including the data 
collected on the day of the baseline visit [visit 3]) 
will be used to calculate baseline values of the patient 
reported outcomes (PROs). 
Clarification of how the 
baseline values for the 
PROs will be calculated. 
Section 8.2 
Inclusion 
criteria (no. 9) 
Worst Daily Pruritus NRS at baseline will be 
calculated from daily assessments of worst itch 
severity (Worst Daily Pruritus NRS) during the 
7 days immediately preceding randomisation (Day -6 
to 0). 
Clarification of how 
Worst Daily Pruritus 
NRS at baseline will be 
calculated. 
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 127 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Section 9.1.3.1 
Administration 
of IMP  
Section 10.4.1 
Vital Signs 
For the first 3 IMP dosing visits (visits 3 to 5) and 
after re-randomisation (visits 11 to 13), subjects will 
be monitored after IMP administration for immediate 
drug reactions for a minimum of 30 minutes 2 hours 
with vital signs taken at every 30 minutes or until 
stable, whichever is later 
Based on the 
endorsement by the 
Safety Review Board at 
LEO Pharma A/S, 
following an evaluation 
of the safety data from 
3 completed and 2 
ongoing trials with 
tralokinumab. 
Section 9.5 
Prohibited 
medication and 
procedures 
The following medications are prohibited during the 
trial from randomisation through safety follow-up 
(Week 0 to 46): 

Other topical medications used for the
treatment of AD other than the supplied
TCS, except lower potency TCS or TCI
which may be used at the investigator’s
discretion on areas of the body where use
of the supplied TCS is not advisable.

Investigational agents other than
tralokinumab.

Immunoglobulin or blood products.

etc.
Clarification of which 
topical medications (other 
than the supplied TCS) 
are to be considered 
disallowed during the 
trial. 
Section 12.3.6 
Analysis of 
secondary 
endpoints 
Subject reported worst daily itch over the last week 
prior to baseline (Day -6 to 0) will be used to 
calculate the baseline itch (see also inclusion 
criterion no. 9). 
Clarification of how the 
baseline values for the 
PROs will be calculated 
for the analyses. 
Section 12.3.8.2 
Patient-reported 
outcomes 
The Average Daily Pruritus NRS collected over the 
last week prior to baseline (Day -6 to 0) will be used 
to calculate the baseline average daily itch. 
For the Eczema-related Sleep NRS score, the mean 
over the last 7 days prior to randomisation (Day -6 to 
0) will be used as the baseline value.
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 128 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
Throughout 
Minor editorial and document formatting revisions. 
Minor, have therefore not 
been summarised. 
Amendment 1 (15-Dec-2017) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union or subsequent regulation because it neither significantly impacts the safety or 
physical/mental integrity of subjects nor the scientific value of the study. 
Overall rationale for the amendment 
The reason for the amendment is an operational change related to the non-investigational 
medicinal product (TCS) to be handed out to the subjects. The need for this change was 
identified after finalisation of the original protocol.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
Section no. and 
name 
Description of change 
Brief rationale 
Protocol synopsis 
Section 2  
Trial identification 
ClinicalTrials.gov identifier 
(NCT03363854) added. 
As the identifier has become 
available since the time of 
protocol finalisation. 
Protocol synopsis 
Section 9.1.2 
Non-investigational 
medicinal product 
Section 9.1.3.2 
Administration of 
The mometasone furoate 0.1% 
cream will be provided in kit sizes 
of 180–225 g (instead of 200 g) 
every 2 weeks. 
To provide flexibility across 
regions due to differences in the 
available pack sizes of 
mometasone furoate (0.1% 
cream).  
TMF-000005673 - Version
4. 0

Trial ID: LP0162-1339 
Date: 29-Aug-2018 
Version: 4.0 
Page 129 of 129 
Section no. and 
name 
Description of change 
Brief rationale 
NIMP 
Section 9.8.1.2 
Labelling and 
packaging of NIMP 
Section 8.2 
Inclusion criteria 
(no. 11) 
The subjects must have used the 
contraceptive method continuously 
for at least 1 month prior to the 
pregnancy test at baseline. 
Clarification that female 
subjects of childbearing 
potential must have used a 
highly effective form of birth 
control for at least 1 month 
prior to baseline. 
Section 11.3.2 
LEO reporting 
responsibilities 
For the NIMP (mometasone furoate, 
0.1% cream) the latest version of 
the approved label must be used 
(see the Elocon® Summary of 
Product Characteristics [Europe], 
December 2015 edition and 
subsequent updates; the Elocon® 
Prescribing Information [USA], 
April 2013 edition and subsequent 
updates; or the Elocom® Product 
Monograph [Canada], May 2014 
edition and subsequent updates). 
Specification that mometasone 
furoate will be supplied as 0.1% 
cream. Details regarding the 
approved labels have been 
omitted. 
Section 11.5.6 
Aggravation of 
condition 
Any clinically significant 
aggravation/exacerbation/worsening 
of any medical condition(s), 
compared to baseline screening, 
must be reported as an AE. 
Clarification that AE reporting 
starts at screening, not baseline. 
This is in alignment with the 
information given in 
Section 11.1 and Appendix 3D. 
TMF-000005673 - Version
4. 0

Signature Page for TMF-000005673 v4.0
Electronic signatures made within eTMF LEO are considered to be a
legally binding equivalent of traditional handwritten signatures.
Reason for signing: Approved
Manage
Verdict(s)
Name: 
Capacit
Date of signature: 29-Aug-2018 20:22:18
GMT+0000
Reason for signing: Approved
Manage
ver Verdict(s)
Name: 
Capacit
Date of signature: 30-Aug-2018 09:14:53
GMT+0000
Reason for signing: Approved
Manage
s)
Name: 
Capacit
Date of signature: 31-Aug-2018 05:51:34
GMT+0000
TMF-000005673 - Version
4. 0
PPD
PPD
PPD