Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 380
Healthy volunteers: no

Brief summary:
Primary objective:

To demonstrate that tralokinumab in combination with topical corticosteroids (TCS) is superior to placebo in combination with TCS in treating moderate-to-severe atopic dermatitis (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 the safety of tralokinumab in combination with TCS when used to treat moderate-to-severe AD for 32 weeks.

Detailed description:

Arms:
arm 1: Week 0 to 16 (initial period):

Tralokinumab loading SC injection on Day 0 followed by tralokinumab injection regimen A.

Week 16 to 32 (continuation period):

Tralokinumab continuation SC injection regimen A. arm 2: Week 0 to 16 (initial period):

Tralokinumab loading SC injection on Day 0 followed by tralokinumab injection regimen A.

Week 16 to 32 (continuation period):

Tralokinumab continuation SC injection regimen B. arm 3: Week 0 to 16 (initial period):

Tralokinumab loading SC injection on Day 0 followed by tralokinumab injection regimen A.

Week 16 to 32 (continuation period):

Tralokinumab continuation SC injection regimen A. arm 4: Week 0 to 16 (initial period):

Placebo loading SC injection on Day 0 followed by placebo injection regimen A.

Week 16 to 32 (continuation period):

Tralokinumab continuation SC injection regimen A. arm 5: Week 0 to 16 (initial period):

Placebo loading SC injection on Day 0 followed by placebo injection regimen A.

Week 16 to 32 (continuation period):

Placebo continuation SC injection regimen A.

Interventions: intervention 1: Tralokinumab intervention 2: Placebo
Intervention descriptions: intervention 1: 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 subcutaneous (SC) administration. intervention 2: Placebo contains the same excipients in the same concentration only lacking tralokinumab.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
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 
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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. 
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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. 
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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. 
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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. 
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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. 
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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. 
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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. 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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 
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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).  
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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.
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
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. 
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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 
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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.  
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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. 
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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 
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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.  
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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. 
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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).
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
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 
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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. 
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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 
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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 
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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). 
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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. 
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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.  
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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.
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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.
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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.
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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.
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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.
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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. 
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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.  
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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.
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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. 
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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.  
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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. 
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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).  
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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. 
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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 
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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. 
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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.
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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.
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
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 
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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. 
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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.  
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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.  
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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 
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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
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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 
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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.
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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).  
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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.  
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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. 
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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 
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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).
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
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. 
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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 
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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.  
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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 
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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. 
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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. 
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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. 
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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. 
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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.  
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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. 
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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. 
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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. 
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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. 
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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 
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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.  
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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.  
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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’.
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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 
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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: 
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
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.
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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 
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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. 
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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: 
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
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).
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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.  
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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. 
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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. 
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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. 
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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 
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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). 
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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.  
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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 
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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. 
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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 
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
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.
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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. 
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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. 
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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 
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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.  
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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 
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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. 
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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 
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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). 
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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: 
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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. 
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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. 
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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. 
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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
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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
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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 
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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 
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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). 
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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. 
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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.
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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).  
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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. 
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SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
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: 15-Jul-2019 
 


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Statistical Analysis Plan 
LP0162-1339 
Tralokinumab in combination with topical corticosteroids for 
moderate-to-severe atopic dermatitis 
ECZTRA 3 (ECZema TRAlokinumab trial no. 3)  
Phase 3 -Efficacy and safety trial 
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 who are candidates for systemic therapy  
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LEO Pharma A/S 
Trial ID: 
LP0162-1339 
Date: 
15-JUL-2019
Version: 
Final 
1 Statistical Analysis Plan Approval 
1.1 Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan. 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document. 
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Biostatistics Lead, Global Clinical Operations 
 
Medical Lead, Medical Sciences and Safety 
 
QC Statistician, Biostatistics 
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2 Statistical Analysis Plan Statements 
2.1 Compliance with Good Clinical Practice 
This Statistical Analysis Plan is designed to comply with the standards issued by the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) (E3: Structure and Content of Clinical Study Reports, E6: Good Clinical 
Practice, and E9: Statistical Principles for Clinical Trials). 
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Table of Contents 
1 Statistical Analysis Plan Approval ......................................................................................... 2 
1.1 Approval Statement ........................................................................................................... 2 
2 Statistical Analysis Plan Statements ...................................................................................... 4 
2.1 Compliance with Good Clinical Practice .......................................................................... 4 
3 List of Abbreviations ............................................................................................................. 7 
4 Introduction ........................................................................................................................... 8 
5 Trial Analysis Sets ................................................................................................................. 9 
6 Statistical Analysis ............................................................................................................... 11 
6.1 Baseline characteristics ................................................................................................... 11 
6.2 Disposition ....................................................................................................................... 11 
6.3 Rescue medication ........................................................................................................... 11 
6.4 Compliance ...................................................................................................................... 12 
6.5 Exposure .......................................................................................................................... 12 
6.6 Analysis of efficacy ......................................................................................................... 13 
6.6.1 
Multiple testing procedure ........................................................................................... 13 
6.6.2 
Primary and secondary binary endpoints .................................................................... 14 
6.6.3 
Continuous secondary endpoints ................................................................................. 15 
6.6.4 
Multiple imputation ..................................................................................................... 17 
6.6.5 
Secondary and other efficacy analysis ........................................................................ 19 
6.6.6 
Drug Accountability .................................................................................................... 22 
6.7 Analysis of safety ............................................................................................................ 24 
6.7.1 
Adverse Events ............................................................................................................ 24 
6.7.2 
Vital signs .................................................................................................................... 25 
6.7.3 
ECG ............................................................................................................................. 25 
6.7.4 
Laboratory data ............................................................................................................ 25 
6.7.5 
Urinalysis ..................................................................................................................... 27 
6.7.6 
Pharmacokinetics and anti-drug antibodies ................................................................. 28 
6.8 General Principles ........................................................................................................... 28 
6.8.1 
Baseline value .............................................................................................................. 28 
6.8.2 
Definition of trial periods and date of permanent discontinuation of IMP ................. 29 
6.8.3 
Incomplete recordings ................................................................................................. 30 
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6.8.4 
Conventions regarding time of day for efficacy assessments and concomitant 
medication ................................................................................................................... 32 
6.8.5 
Treatment Completers ................................................................................................. 33 
6.8.6 
Early termination and unscheduled visits .................................................................... 33 
6.8.7 
Handling drop-outs and missing values ...................................................................... 33 
6.8.8 
Treatment labels .......................................................................................................... 34 
6.8.9 
Protocol deviations ...................................................................................................... 34 
7 References ........................................................................................................................... 35 
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3 List of Abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
ADaM 
analysis data model 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
anatomical therapeutic chemical 
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 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
Investigator’s Global Assessment 
IMP 
investigational medicinal product 
LOCF 
last observation carried forward 
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 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
TCS 
topical corticosteroid(s) 
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4 Introduction 
The statistical analysis will be performed as outlined in the Clinical Trial Protocol including 
amendments.  
This Statistical Analysis Plan is prepared before the unblinding of the trial and supplements 
the Clinical Trial Protocol, which otherwise describes the originally planned statistical 
analyses of all endpoints in an intended exhaustive manner. The Statistical Analysis Plan 
contains a more technical and detailed elaboration of some points related to the 
implementation of the statistical analyses already described in the Clinical Trial Protocol. 
In addition, the Statistical Analysis Plan includes supplementary statistical analyses and 
aspects that are introduced after the latest protocol amendment, of which all are initiated as 
responses to FDA advices.  
Supplementary analyses introduced according to LEO response to 
 dated 
; Ref ID: 
:
1. A tipping point analysis introduced as a sensitivity analysis number 3 for the primary
estimand (‘composite’) for the primary endpoints (IGA 0/1 and EASI75) and the
secondary endpoint (reduction of Pruritus NRS weekly average of at least 4 (yes/no)).
2. Analyses of a new tertiary estimand (‘composite’) for the continuous secondary
confirmatory endpoints (change in SCORAD and change in DLQI). Analyses apply
non-responder imputation for subjects who received rescue medication. A tipping
point sensitivity analysis is included.
Other supplementary analyses introduced for consistency: 
3. The same analysis and tipping point sensitivity analysis as above implemented as a
new tertiary (‘composite’) estimand for the two secondary additional endpoints
‘Change from baseline to Week 16 in EASI score’ and ‘Change from baseline to Week
16 in Worst Daily Pruritus NRS (weekly average)’
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Modification of the US testing hierarchy introduced by LEO in Meeting Background Material 
for 
 meeting dated 
; Ref ID: 
 to address 
 
 dated 
; Ref ID: 
: 
4. A dedicated modified confirmatory testing hierarchy applied in the US submission.
The originally specified testing hierarchy is kept for non-US submissions (e.g. to EMA
and PMDA).
The first aspect is addressed in section 6.6.2 , the 2nd and 3rd are  addressed in section 6.6.3 
and 6.6.5, respectively,  while 4th  aspect is presented in section 6.6.1.  
5 Trial Analysis Sets 
The trial analysis sets are defined in the protocol and the following modifications to the 
analysis sets for the trial periods are introduced. 
All subjects randomised to initial treatment who were exposed to IMP are included in the full 
analysis set (FAS) and will be analysed for efficacy up to Week 16 (visit 11). For subjects not 
exposed to IMP, the decision to withdraw cannot be biased by knowledge of the assigned 
treatment due to the blinding. This definition of the FAS implements the consideration 
mentioned in the protocol regarding special excluded cases with reference to ICH E9, Section 
5.2.1. 
The safety analysis set comprises all subjects randomised to initial treatment who were 
exposed to IMP. The protocol further specifies to exclude subjects from the safety analysis set 
for whom no post-baseline safety data are available. However, since all subjects receive the 
first dose of IMP in connection with the Week 0 visit and are subsequently monitored for 
immediate drug reactions, all exposed subjects are considered to have post-baseline safety 
data available and no such further exclusions will be made. 
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The continuation treatment analysis set is defined in the protocol as subjects in the full 
analysis set who have not withdrawn from trial prior to or at the Week 16 visit. In addition to 
this, subjects who are not exposed to continuation treatment will be excluded from the 
continuation treatment analysis set. This follows the same principle that leads to exclusion of 
unexposed subjects from the full analysis set and is therefore in alignment with ICH E9. 
The continuation treatment safety analysis set is identical to the continuation treatment 
analysis set. 
For the follow-up period the safety follow-up analysis set will be used as the basis for 
evaluation of adverse events during the follow-up period. It comprises all subjects for whom 
date of last contact is after the date of exposure end, where exposure end is defined as the 
Week 32 visit for subjects completing the treatment period, and otherwise the date of 
permanent discontinuation of IMP for subjects not completing the treatment period. See also 
section 6.8.2 for further details. 
For analysis of efficacy subjects will be included ‘as randomised’. 
For analysis of safety, if a subject is mistakenly given an experimental therapy other than that 
to which they were randomized, they should be analysed ‘as-treated’, thus included in the 
group according to the therapy received by the subject. The below rules will be applied. 
Subjects who received at least one dose of tralokinumab during the initial treatment period 
will be analysed in the tralokinumab treatment group. Although this may dilute the AE rate in 
the tralokinumab treatment group slightly by including in the denominator subjects who only 
received one dose of active treatment, it will ensure that no significant drug reactions to 
tralokinumab will erroneously be assigned to placebo. 
In the continuation period, subjects will be presented in tables according to planned treatment. 
Any placebo responders who received one or more doses of active treatment will be described 
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as protocol deviations. Similarly, it will be described if there are subjects who only received 
placebo doses among subjects assigned to tralokinumab Q2W or Q4W.  
6 Statistical Analysis 
6.1 Baseline characteristics 
Baseline characteristics will be summarised and listed. 
Duration of AD in years will be calculated as (age at Week 0) minus (age at onset of AD). 
The table of concomitant medication at baseline will include medication starting before the 
first dose of IMP and ongoing at the time of first dose of IMP. For further details, see Section 
6.8.3 and Section 6.8.4. 
6.2 Disposition 
Subject disposition will be summarised and listed. 
6.3 Rescue medication 
Rescue medication is defined by the following algorithm:  
Concomitant medications with Dermatitis atopic or Dermatitis infected as the preferred term 
for the indication and  

ATC2 code H02
or 

Preferred name Methotrexate, Ciclosporin, Azathioprine, Mycophenolate-mofetil,
Mychophenolate-acid, Mycophenolate-sodium, Dupilumab, Crisaborole or
Alitretinoin
or 

ATC4 code D07AD or D07BD or D07CD or D07XD
or 
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
confirmed rescue medication (by investigator) in reported term for the indication and
ATC4 code D07AB or D07BB or D07CB or D07XB or D07AC or D07BC or D07CC
or D07XC.
According to the protocol, investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue medication. Therefore, if 
rescue medication has start date the same day as an efficacy assessment, then the assumption 
will be that the assessment is not influenced by the rescue medication, see also Section 6.8.4. 
Rescue medication will be summarised separately for the initial and the continuation 
treatment period. In addition, a summary table of rescue medication by type (topical and 
systemic) and by overall group (corticosteroids, immunosuppressants and other) will be made. 
For subjects assigned to continuation treatment at Week 16, the table of rescue medication 
during initial treatment period will include rescue medication taken (but not necessarily 
initiated) between the first dose of initial treatment and the first dose of continuation 
treatment. For subjects who do not continue with continuation treatment, the table of rescue 
medication during initial treatment period will include medications taken after the first dose 
and before the (nominal) Week 16 visit (or before day 7*16=112 after first dose, in case the 
(nominal) Week 16 visit did not take place).  
The table of rescue medication during the continuation treatment period will include rescue 
medication taken (but not necessarily initiated) after the first continuation dose and exclude 
rescue medication initiated during the follow-up period.  
6.4 Compliance 
Compliance will be summarised and listed. 
6.5 Exposure 
The exposure time during the initial and continuation periods, respectively, will be defined as 
detailed in Section 6.8.1. Exposure time will be summarised and listed. 
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Patient years of exposure (PYE) for a period will be calculated as the difference between the 
start date and time and the end date and time for the period divided by 60x60x24x365.25. 
6.6 Analysis of efficacy 
Efficacy will be analysed as described in the Clinical Trial Protocol. 
6.6.1 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 and maintenance treatment will for the US 
submission follow a dedicated modified confirmatory testing hierarchy as outlined in Panel 1 
below. 
Figure 1 Testing procedure for US submission 
Arrows indicate order of testing when superiority is shown for all endpoints within a box. 
DLQI, Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema Area and Severity Index 
score; IGA, Investigator’s Global Assessment. 
IGA 0/1 at Week 16 between tralokinumab and placebo is evaluated at a 5% significance 
level. If the test is significant, EASI75 at Week 16 between tralokinumab and placebo is 
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evaluated at a 5% significance level. If the second test is also significant, Pruritus at Week 16 
between tralokinumab and placebo is evaluated at a 5% significance level. 
If all three tests are significant, the evaluations of the other two secondary endpoints 
SCORAD and DLQI at Week 16 between tralokinumab and placebo will use the Holm 
method (3) for 2 ordered p-values at a 5% significance level to adjust for multiplicity. 
For non-US submissions, the testing hierarchy defined in the protocol will be applied. 
6.6.2 Primary and secondary binary endpoints 
Sensitivity analysis 2 for the primary estimand (primary endpoints) 
In the sensitivity Analysis 2 for the primary estimand, the protocol specifies that "If subjects 
have withdrawn due to an AE or due to lack of efficacy, they are still considered non-
responders". Such subjects will be identified based on their reason for permanent 
discontinuation of IMP.  
Sensitivity analysis 3 for the primary estimand (binary endpoints) 
A tipping point analysis using multiple imputation (MI) as an additional sensitivity analysis 
(not described in the protocol) for the primary estimand for the primary endpoints (IGA 0/1 
and EASI75) and the secondary binary endpoint (reduction of Pruritus NRS weekly average 
of at least 4 (yes/no); Pruritus NRS ≥ 4) will be done.  
The purpose of the sensitivity analysis is to assess the robustness of results of the primary 
analysis for the primary estimand with respect to the assumption regarding missing Week 16 
data among subjects who did not use any rescue medication. The procedure will be as 
follows: subjects in the tralokinumab arm with missing Week 16 data will per default be 
considered non-responders while missing Week 16 data (i.e. response yes (=1)/ no (=0)) for 
subjects in the placebo arm who did not use rescue medication will be imputed from a 
Bernoulli distribution with parameter p (ranging from 0 to 1). By varying the parameter p, 
different percentages of placebo subjects will be assumed to be responders (deviating from the 
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default zero (0) percent of the primary estimand). The tipping-point is then found as the value 
of p (in the range from 0 to 1) which changes the conclusion (of the primary analysis) from 
significant to non-significant 
Based on published data from other placebo-controlled clinical trials conducted in subjects 
with moderate-severe atopic dermatitis2, the response rate for IGA 0/1, EASI75 and Pruritus 
NRS ≥ 4 at Week 16 among all placebo subjects is low (in the order of 10% for IGA 0/1 and 
Pruritus NRS ≥ 4, and 15% for EASI75, respectively). Thus, a tipping-point value (p) above 
0.1 for IGA 0/1 and Pruritus NRS ≥ 4 and above 0.15 for EASI75, respectively, is not 
considered to be clinically plausible. As indicated above, p=0 corresponds to the primary 
analysis for the primary estimand. The MI procedure will include the following steps for each 
value of p: 

100 copies of the dataset will be generated (seed=11109939). and missing Week 16
data will be imputed for subjects in the placebo arm from a Bernoulli distribution with
parameter p.

For each of the 100 complete data sets, the difference in response rates will be
analysed as specified for the primary analysis for the primary estimand and the
estimates and standard errors from the 100 analyses will be combined using Rubin’s
rule to form a unique point estimate and standard error.
6.6.3 Continuous secondary endpoints 
Primary analysis of primary estimand (continuous secondary endpoints) 
It is specified in the protocol that the continuous secondary endpoints will be analysed using a 
repeated measurements model on the post baseline responses up to Week 16. Data collected 
after permanent discontinuation of IMP or after initiation of rescue medication will not be 
included in the analysis.  
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However, some subjects may not have any post-baseline data collected before initiation of 
rescue medication. To ensure that all subjects are included in the analysis, the baseline value 
will for these subjects be carried forward as the first post-baseline assessment, corresponding 
to imputing a change of 0 at the first post-baseline assessment. 
Tertiary (composite) estimand (continuous secondary endpoints) 
For the continuous secondary endpoints (i.e. change in SCORAD and DLQI), an analysis is 
introduced where subjects who received rescue medication are considered non-responders. 
This new analysis aims to estimate the treatment effect for a ‘Composite‘ estimand which is 
currently not pre-specified in the protocol for the continuous secondary endpoints. Thus, a 
new tertiary ‘Composite’ estimand for the continuous secondary endpoints is introduced.  
Primary analysis for the tertiary (composite) 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. Subjects who prior to the Week 16 visit have received rescue 
medication will be considered non-responders by using worst observation carried forward 
(including the baseline value).   
Missing Week 16 data among subjects who did not use rescue medication will be imputed 
using MI (100 copies of the dataset, seed=11109939) assuming missing at random (MAR) 
within arms (based on sequential use of an ANCOVA model for Week 2, 4, 6, ... and 16). For 
subjects who dropout without any use of rescue medication, missing data at subsequent visits 
will be imputed under the assumption that the subject adheres to the randomised treatment 
regimen, i.e. the stepwise imputation model will be estimated based on available data from all 
subjects but excluding individual subject data captured after initiation of rescue medication or 
permanent discontinuation of IMP. For each of the 100 imputed datasets, the continuous 
secondary endpoint will be analysed using an ANCOVA model with effects of treatment, 
region, baseline disease severity (IGA 3 or 4), and baseline value. The estimates and standard 
errors from the 100 analyses will be combined using Rubin’s rule to form a unique point 
estimate and standard error. 
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As a sensitivity analysis for the tertiary estimand, a tipping point analysis using MI will be 
performed with the purpose to assess the robustness of results of the primary analysis for the 
tertiary estimand with respect to the MAR assumption regarding missing Week 16 data among 
subjects who did not use any rescue medication.  The tipping analysis will assess how severe 
the departure from the MAR assumption in the tralokinumab arm has to be in order to impact 
the results (i.e. changes the conclusion of primary analysis of the tertiary estimand) from 
significant to non-significant).  
The tipping point analysis will be performed using the MAR imputed Week 16 data from 
primary analysis of the tertiary estimand. For each of the 100 imputed datasets, Δ will be 
added to the imputed values for subjects in the tralokinumab arm (Δ = 0 implies MAR) and 
thereby the imputed values will be ‘shifted’ by Δ. Each of the 100 modified imputed datasets 
will then be analysed in the same way as for the primary analysis for the tertiary estimand. 
The tipping-point is then found as the value of Δ which changes the conclusion (of the 
primary analysis) from significant to non-significant and will be judged from a clinical point 
of view.  
The implications of the missing not at random assumptions will be compared to the 
implication of the missing at random assumptions by visual inspection.  
Tertiary (composite) estimand (continuous additional secondary endpoints) 
The two continuous secondary additional endpoints ‘Change from baseline to Week 16 in 
EASI score’ and ‘Change from baseline to Week 16 in Worst Daily Pruritus NRS (weekly 
average)’ will be analysed as described for the two continuous secondary endpoints above, 
including the tipping point sensitivity analysis. 
6.6.4 Multiple imputation 
For the analysis of the primary and secondary endpoints, multiple imputation will be carried 
out as specified in the protocol, using SAS PROC MI. For multiple imputations related to the 
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treatment policy estimand and the hypothetical estimand sensitivity analyses, the seed 
11109939 will be used. The remaining seeds are specified in the protocol. 
When performing multiple imputation of continuous parameter values, imputed values at 
visits prior to Week 16 outside the relevant parameter scale shall be used as is. Values imputed 
at Week 16 shall be truncated to the nearest upper or lower bound on the given scale. For 
example, negative imputed EASI values at Week 16 will be set to 0.  
For imputation of IGA values, the LIKELIHOOD=AUGMENT option will be used (1). 
For imputation of IGA values, it may occur that the observed data from which the imputation 
model is fitted does not contain all levels of the IGA predictors necessary for the imputation. 
For example, the imputation model for IGA values at Week 8 will be based on observed data 
from the subset of subjects with observed IGA values at both Week 6 and Week 8. If only the 
IGA values (0,1,2,3) are observed at Week 6 in this subset of subjects, the imputation model 
will not be able to predict IGA values at Week 8 for a subject with an IGA value of 4 at Week 
6. To avoid this situation, in this specific example IGA values of 3 and 4 at Week 6 will be
combined into a single category for the imputation. In general, if this situation arises, IGA 
categories will be combined into a single category at the specific visit for the specific 
imputation, according to the rules in Table 1. 
Table 1: Adjacent IGA categories combined in case of missing predictors in observed data 
IGA value(s) missing in imputation model 
IGA categories combined 
0 
(0,1) 
1 
(0,1) 
2 
(2,3) 
3 
(2,3) 
4 
(3,4) 
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6.6.5 Secondary and other efficacy analysis 
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 
The analyses will be based on subjects in the FAS with a baseline Pruritus NRS weekly 
average of at least 4. 
The binary endpoint was to be analysed as described for the primary endpoint EASI75 using 
all three estimands. It is however expected that subjects will not fill in the eDiary when they 
have discontinued treatment, and it is considered likely, there will be no nominal Week 16 
data available for discontinued subjects. If this is the case, the primary analysis of the tertiary 
estimand will not be estimated for this endpoint. The corresponding sensitivity analysis for 
the tertiary estimand, analysing subjects with missing Week 16 data as non-responders, while 
otherwise using observed data for the remining subjects, will still be conducted. 
Calculation of Weekly average of pruritus NRS 
The weekly average will only be calculated if at least 4 assessment are available. When 
calculating the baseline value for the weekly average of Worst Daily Pruritus, the daily 
assessments in the 7 days preceding the randomisation will be used, including the day of 
randomisation. 
For the initial treatment period, the NRS weekly average for Week 1 will be calculated based 
on scores recorded on day 1 to day 7 (where day 0 is the day of the first dose). Similarly, for 
Weeks 2 to Week 15, the weekly average for Week x will be calculated based on scores 
recorded on day 7*x-6 to day 7*x (where day 0 is the day of first dose). Since continuation 
treatment may be initiated between day 106 and day 112, the Week 16 weekly average will 
instead be based on the last 7 days before (and including) the day of the Week 16 visit, thus 
ensuring that the Week 16 weekly average is based on data from the initial treatment phase 
only and ensuring alignment in timing with other Week 16 efficacy endpoints. Also, for the 
calculation of Week 1 to Week 15 weekly averages, any scores recorded after the Week 16 
visit date will be disregarded (only relevant if Week 16 visit is out of window). 
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For Week 17 of the continuation treatment period, the weekly average will be based on the 
first 7 days after (not including) the Week 16 visit. For Week 18 to Week 32 of the 
continuation treatment period, the weekly average for Week x will be calculated based on 
scores recorded on day 7*x-6 to day 7*x (where day 0 is the day of the first dose).  
Evaluation of Worst Daily Pruritus NRS related endpoints at Week 15 
It is specified in the protocol that Change from baseline in Worst Daily Pruritus NRS (weekly 
average) and Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from 
baseline to each scheduled assessment through Week 4 to 14 will be evaluated. The weekly 
average of pruruitus NRS is also assessed at Week 15 and will be evaluated. 
PGI-B and PGI-S 
For the PGI-B and PGI-S, which are not numerical, the worst score recorded during the week 
will be presented instead of weekly averages, but otherwise the same rules apply as for 
weekly average pruritus NRS described above. The daily scores will be presented graphically. 
Percentage change in EASI score, initial treatment period 
In addition to the repeated measurements analysis of absolute reduction in EASI score during 
the initial treatment period which was planned in the protocol, the same analysis will be 
conducted for the percentage change from baseline in EASI scores during the initial treatment 
period. 
Subgroup analyses 
To access consistency of number of responders for the primary estimand across subgroup the 
following subgroup analyses will be performed: 

IGA 0/1 by baseline IGA

IGA 0/1 by region

EASI75 by baseline IGA

EASI75 by region
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Maintenance analyses 
As specified in the protocol, the maintenance of effect of tralokinumab in combination with 
TCS will be evaluated at Week 32 for subjects who achieved clinical response at Week 16 
without rescue medication.  
Time to relapse- continuation treatment period 
The following 2 types of relapse will be considered: 

Relapse according to IGA: first assessment of an IGA≥2 or initiation of rescue
medication after initiation of continuation treatment among subjects in the
continuation analysis set who obtained an IGA 0/1 at Week 16 without rescue
medication after initial randomisation to tralokinumab.

Relapse according to EASI75: first time of not achieving EASI75 or initiation of
rescue medication after initiation of continuation treatment among subjects in the
continuation analysis set who obtained EASI75 at Week 16 without rescue medication
after initial randomisation to tralokinumab.
Kaplan-Meier curves of time to relapse will be estimated and presented. 
Scoring of PROs 
POEM 
Scored according to: 
https://www.nottingham.ac.uk/research/groups/cebd/documents/methodological-
resources/poem-for-self-completion.pdf 
DLQI 
Scored according to: 
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-
index-dlqi/dlqi-instructions-for-use-and-scoring/ 
EQ-5D-
5L 
Index values calculated according to: 
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https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-
sets/crosswalk-index-value-calculator/ 
The UK value sets will be used. 
HADS 
The HADS consists of 14 items, 7 of which are related to anxiety and 7 related 
to depression. The maximum score is 21 for each subscale (anxiety and 
depression).  
If one question is missing within a subscale, the response to that question will 
be imputed as the mean of the remaining questions in that subscale. If more than 
one question is missing within a subscale, the subscale is considered missing.  
Missing baseline assessments 
When the baseline value is missing, endpoints concerning a change from baseline cannot be 
derived, and such subjects will be excluded from the analysis. Since the missingness of 
baseline values are unrelated to the assigned treatment, bias should not be a concern with this 
approach.  
6.6.6 Drug Accountability 
Each subject is dispensed with a batch of tubes of Non Investigational Medicinal Product 
(NIMP) at each visit (4 x 45 g tubes of class 4 TCS in North America and 2 x 100 g tubes of 
class 3 TCS in Europe) and all tubes in the batch are to be returned to site at the next visit for 
the weighing. All returned tubes within a batch are weighed together.  
For each subject, the weight of TCS used for a given visit interval (WGTUSED) will be 
calculated as the difference between the weight of the tubes dispensed (WGTDISP) and the 
weight of the returned tubes (WGTRET):  

if WGTRET ≤ WGTDISP then WGTUSED=WGTDISP-WGTRET

if WGTRET > WGTDISP then WGTUSED = 0.
When tubes are not returned as specified in the protocol, the following rules will be applied: 
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
If tubes are returned at the wrong visit, the amount of TCS used from these tubes will
be assumed to be used in the period from the tubes being dispensed to the subject's
subsequent next dispensing visit.

If a tube is not returned at all and the subject remains in the study, two different
approaches will be applied to explore two extreme assumptions:
1. It will be assumed that the missing tube has been fully used by the subject in the
period between the date the tube was dispensed and the date of the next subsequent
visit attended by the subject. Estimated content (45/100 g) for the kit number will
be used as a contribution to the WGTRET.
2. It will be assumed that the missing tube has not been used at all by the subject in
the period between the date the tube was dispensed and the date of the next
subsequent visit attended by the subject, i.e. contribution from the tube to the
WGTRET is set to 0.
If subject do not attend a planned visit, daily usage (DAYUSE) is calculated for the period 
between the tubes being dispensed and the subsequent dispensing visit, i.e. 
DAYUSE=WGTUSED/DURATION where DURATION =ENDDATE (date of the subsequent 
dispensing visit)-STARTDATE (date of the tubes being dispensed). If all tubes in the batch 
are not dispensed at the same time, date of the first dispensed tube in the batch is used. The 
amount of the TCS used for each visit in the period (missing visit(s) and the first visit after the 
tubes being dispensed) is calculated by multiplying daily usage (DAYUSE) by the number of 
days between the visit and the previous visit.  
In the case where tubes are not returned due to the subject being withdrawn from the study or 
lost to follow up, the amount of TCS used from these tubes will not be calculated (i.e. set to 
missing).  
The amount of TCS used and the number of days without topical treatment use will be 
analysed as specified in the protocol. The number of days without topical treatment is 
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collected as Patient Days of Topical Treatment Use in the eDiary and will be determined by a 
week instead of a visit. 
6.7 Analysis of safety 
6.7.1 Adverse Events 
Adverse events will be summarised and listed. 
Assignment of AEs to periods 
An adverse event will be assigned to a given period (initial, continuation or follow-up) if the 
start date is after the start date and before the end date of that period (see Section 6.8.2, Table 
4). 
For AEs with start day on the same day as the first dose was given, only AEs starting after the 
first dose was given will be considered treatment emergent and assigned to the initial 
treatment period.  
AEs with start date on the same day as the first dose of continuation treatment will be 
assigned to the initial or continuation period depending on whether the AE started before or 
after the dose was given. 
AEs starting on the day of exposure end (as defined in Section 6.8.2) will be assigned to the 
last treatment period. 
For handling of incomplete start dates of adverse events, see Section 6.8.3. 
Sort order of AE tables 
Generally, AE tables by system organ class and/or preferred term will be sorted by decreasing 
number of affected subjects: 
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
For the initial treatment period, AE tables will be sorted by decreasing number of affected
subjects in the Tralokinumab Q2W+TCS group.

For the continuation treatment period, AE tables will be sorted by decreasing total number
of affected subjects in the Tralokinumab treatment groups (sum of Q2W+TCS and
Q4W+TCS).

For the entire treatment period, AE tables will be sorted by decreasing number of affected
subjects in the “Tralokinumab total” group.

For the follow-up period, AE tables will be sorted by decreasing total number of affected
subjects in the Tralokinumab treatment groups (sum of Q2W+TCS and Q4W+TCS).
6.7.2 Vital signs 
Vital signs will be summarised and listed. 
For the summary tables of vital signs by visit, the last pre-dose vital sign assessment will be 
presented. If no dosing occurs at a visit, the last assessment recorded at the visit will be 
presented. For the first 3 IMP dosing visits in both the initial and open-label treatment period, 
subjects will be monitored after IMP administration for immediate drug reactions for a 
minimum of 2 hours with vital signs taken every 30 minutes or until stable, these 
measurements will only be listed. 
6.7.3 ECG 
ECG data will be summarised and listed. The overall central evaluation of ECG will be 
presented using shift tables. 
6.7.4 Laboratory data 
Laboratory data will be summarised and listed. 
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For the laboratory values, if the value is below the lower limit of quantification, half of the 
lower limit will be used for quantitative summaries. If the value if above the upper limit of 
quantification, the upper limit value will be used. 
If more than one laboratory value is reported for the same visit and time point, the latest value 
will be used in summary statistics and analyses. 
Potentially clinically significant values will be defined as displayed in Table 2. 
Table 2: Potentially clinically significant biochemistry and haematology values 
Protocol Lab parameter SI Unit 
PCS low 
PCS High 
Biochemistry 
Sodium 
mmol/L < 129 mmol/L, 
< 125 mmol/L 
> 160 mmol/L
Potassium 
mmol/L < 3 mmol/L,  
< 2.5 mmol/L 
> 6.5 mmol/L,
> 7.5 mmol/L
Creatinine 
umol/L 
N/A 
> 1.5xULN, > 3xULN
Calcium 
mmol/L < 1.9 mmol/L 
> 3.0 mmol/L,
> 3.5 mmol/L
Alkaline phosphatase 
U/L 
N/A 
> 3xULN
Aspartate 
aminotransferase 
U/L 
N/A 
> 3xULN, > 5xULN,
> 10xULN, > 20xULN
Alanine aminotransferase 
U/L 
N/A 
> 3xULN, > 5xULN,
> 10xULN, > 20xULN
Bilirubin 
umol/L 
N/A 
> 2xULN
Cholesterol 
mmol/L N/A 
> 6.2 mmol/L
LDL cholesterol 
mmol/L N/A 
> 4.1 mmol/L,
> 4.9 mmol/L
HDL cholesterol 
mmol/L N/A 
> 1.6 mmol/L
Triglycerides 
mmol/L N/A 
> 2.3 mmol/L,
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> 5.6 mmol/L
Glucose (non-fasting) 
mmol/L < 3.9 mmol/L 
>11.1 mmol/L
Haematology 
Haemoglobin 
g/L 
<110 g/L, < 80 g/L 
> 185 g/L for male,
> 165 g/L for female
Neutrophils, absolute 
count 
109/L 
< 1.5 109/L, < 1.0 109/L, 
< 0.5 109/L 
N/A 
Lymphocytes, absolute 
count 
109/L 
< 1.0 x 109/L, 
< 0.5 x 109/L 
> 5.0 x 109/L
Monocytes, absolute count 109/L 
< 0.1 x 109/L 
> 0.8 x 109/L
Eosinophils, absolute 
count 
109/L 
N/A 
> 1.5, > 5.0
Basophils, absolute count 
109/L 
N/A 
> 0.2
Thrombocytes 
109/L 
< 100 x 109/L, 
< 30 x 109/L,  
< 10 x 109/L 
> 450 x 109/L
PCS: potentially clinically significant; ULN: Upper limit of normal, i.e. upper limit of normal reference range. 
6.7.5 Urinalysis 
Urinalysis data will be summarised and listed. 
Potentially clinically significant values will be defined as displayed in Table 3. 
Table 3: Potentially clinically significant urinalysis values 
Protocol lab parameter 
(ACM lab parameter) 
SI Unit 
PCS low 
PCS High 
Erythrocytes 
/HPF 
N/A 
> 3, >10, >25, >30
Leucocytes 
/HPF 
N/A 
> 10
Casts (Hyaline casts) 
/LPF 
N/A 
> 2
Casts (WBC casts) 
/LPF 
N/A 
Few, Moderate, Many 
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Casts (RBC casts) 
/LPF 
N/A 
Few, Moderate, Many 
Casts (Waxy casts) 
/LPF 
N/A 
Few, Moderate, Many 
Casts (Granular casts) 
/LPF 
N/A 
Few, Moderate, Many 
PCS: potentially clinically significant; HPF: high power field; LPF: low power field; ULN: Upper limit of normal, i.e. upper 
limit of normal reference range. 
6.7.6 Pharmacokinetics and anti-drug antibodies 
Pharmacokinetics and anti-drug antibodies data will be summarised and listed. 
The ADA status will be categorised as follows: 

Positive
1. Pre-existing: ADA-positive at baseline, no post-baseline ADA response ≥ 4-fold
over baseline titre level, and at least 1 non-missing post-baseline ADA assessment.
2. Treatment-boosted: ADA-positive at baseline and at least 1 post-baseline ADA
response ≥ 4-fold over baseline titre level.
3. Treatment-emergent: ADA negative or missing at baseline and at least 1 positive
post-baseline ADA response.

Negative
1. ADA negative or missing at baseline, all post-baseline ADA assessments negative.

No post-baseline ADA assessment.
6.8 General Principles 
6.8.1 Baseline value 
Unless otherwise specified, the baseline value is defined as the latest pre-dose assessment. 
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6.8.2 Definition of trial periods and date of permanent discontinuation of 
IMP 
Date of permanent discontinuation of IMP 
Defined for subjects who have a reason for permanent discontinuation of IMP recorded. 
The latest of date of early termination visit (if existing) or date of onset of latest AE leading to 
withdrawal of trial product, otherwise date of the last visit, excluding safety follow-up and 
nominal Week 16 visit.  
Exposure start  
Date and time of first dose. 
Exposure end  
Date of Week 32 visit (if existing) at time 23:59:00, otherwise date of permanent 
discontinuation of IMP at time 23:59:00, otherwise date of last IMP administration at time 
23:59:00. 
Trial periods 
The time from exposure start to exposure end will be divided into initial period and 
continuation period. The remaining time after exposure end will be assigned to the follow-up 
period as shown in Table 4 (ADaM variable APHASE). The ADaM variable APERIODC will 
indicate the latest treatment (initial or continuation) at any given time point, thus not 
including a follow-up period (Table 5).  
Table 4: Start and end time of trial periods (ADaM variable APHASE). 
APHASE 
Start of period 
End of period (only if start date exists) 
Initial period Exposure start 
Date and time (minus 1 second) of first continuation 
dose (if existing) 
else 
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Exposure end 
Continuation 
period 
Date and time of 
first continuation 
dose (if existing) 
Exposure end 
Follow-up 
period1
Exposure end 
(plus 1 second) 
Date of safety follow-up visit (if existing) at time 
23:59:00 
else 
Date of last contact at time 23:59:00 
1) Only applicable if date of last contact is not equal to date of exposure end.
Table 5: Start and end time of trial periods (ADaM variable APERIOD). 
APERIODC Start of period 
End of period (only if start date exists) 
Initial period 
Exposure start 
Date and time (minus 1 second) of first continuation 
dose (if existing) 
else 
Date of last contact at time 23:59:00  
Continuation 
period 
Date and time of 
first continuation 
dose (if existing) 
Date of last contact at time 23:59:00 
6.8.3 Incomplete recordings 
Adverse events 
If the AE start day is missing, but AE start month and year are not missing, the following rules 
apply: 

If the year and month of the AE start is before the year and month of the exposure
start, or if the AE end date is complete and before the exposure start, the AE will not
be considered treatment emergent.
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
If the year and month of the AE start is the same as the year and month of the
exposure start, the AE will be considered treatment emergent and assigned to the
initial treatment period, unless the AE has a complete end date which is before
exposure start.

If the year and month of the AE start is after the year and month of exposure start, it
will be assumed that the AE started on the first day of the month and the AE will be
assigned to the initial, continuation, or follow-up period accordingly.
If the AE start month is missing, but AE start year is not missing, the following rules apply: 

If the year of the AE start is before the year of the exposure start, or if the AE end
month is not missing and before the month of the exposure start, or if the AE has a
complete end date which is before the exposure start date, the AE will not be
considered treatment emergent.

If the year of the AE start is the same as the year of the exposure start, the AE will be
considered treatment emergent and assigned to the initial treatment period, unless the
AE end month is not missing and before the month of the exposure start or the AE has
a complete end date which is before the exposure start date.

If the year of the AE start is after the year of exposure start, it will be assumed that the
AE started on the 01 January and the AE will be assigned to the initial, continuation,
or follow-up period accordingly.
Concomitant medication 
For incomplete start dates of concomitant medication, the following rules apply: 

If a medication start day is missing, but start month and year is not missing, it will be
assumed that the start day is the first day of the month. If the medication start day and
month is missing, but start year is not missing, it will be assumed that the start day is
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01 January. If the medication start day, month and year is missing, it will be assumed 
that the medication was started before study start. 
For incomplete end dates of concomitant medication, the following rules apply: 

If a medication end day is missing, but end month and year is not missing, it will be
assumed that the end day is the last day of the month. If the medication end day and
month is missing, but end year is not missing, it will be assumed that the end day was
31 December. If the medication end day, month and year is missing, it will be assumed
that the medication was ongoing at the end of the study, and the date will appear as
missing in the data.
6.8.4 Conventions regarding time of day for efficacy assessments and 
concomitant medication 
Efficacy assessments 
For the purpose of assigning trial periods to efficacy assessments, the convention will be that 
efficacy assessments are performed at time 00:00:00 in the morning. Consequently, efficacy 
assessments performed on the day of transfer between two periods will be assigned to the first 
of the two periods.  
Concomitant medication 
For the purpose of associating concomitant medication with trial periods, the convention will 
be that the start time of day of concomitant medications is 23:59:59, and end time is 00:00:00, 
unless the start day is equal to the end day in which case both start and end time will be 
assumed to be 23:59:59. As a consequence, rescue medication starting on the day of transfer 
between two periods will be associated with the latter period only, and rescue medication 
ending on the day of transfer between two periods will be associated with the first period only 
(unless the start day is equal to the end day).  
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Unlike adverse events which are assigned to a single period based on their start date only, a 
concomitant medication can be associated with more than one period. 
6.8.5 Treatment Completers 
A subject who has not permanently discontinued IMP before Week 32 will be defined as a 
treatment completer. 
6.8.6 Early termination and unscheduled visits 
When no data is available from a certain scheduled post-baseline visit for a subject, data from 
early termination visits and unscheduled visits have the potential to replace data from that 
scheduled visit in data summaries, provided the data is collected between 6 days before and 7 
days after the planned time point for the scheduled visit, as displayed below.  
Visit (Target day) 
Visit window (Day is date of assessment 
minus date of first dose) 
Week 2 (Day 14) 
Day 8 to 21 
Week x (Day 7*x) (where x= 6, 8, ..., 52) 
Day 7*x-6 to 7*x+7 
Safety follow-up 
106-119 days after last dose
When both unscheduled and early termination visits exist within the given visit window, the 
early termination visit will be selected for analysis. When no early termination visit and 
several unscheduled visits exist, the unscheduled visit closest to the target day will be selected 
for analysis. If the difference is a tie, the latest unscheduled visit will be selected. 
6.8.7 Handling drop-outs and missing values 
Missing values will be handled as described in the Clinical Trial Protocol. 
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7 References 
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