A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multi-centre Trial to Evaluate the Efficacy, Safety, and Tolerability of Tralokinumab Monotherapy in Adolescent Subjects With Moderate-to-severe Atopic Dermatitis (AD) Who Are Candidates for Systemic Therapy
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: LEO Pharma

 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: Tralokinumab monotherapy for adolescent subjects with moderate-to-severe atopic derma-
titis ECZTRA 6 (ECZema TRAlokinumab trial no. 6) 
LEO Pharma number: LP0162-1334 
NCT number: NCT03526861 
Date: 06-Feb-2020 
 

CONFIDENTIAL
Updated Clinical Trial Protocol
LP0162-1334
Tralokinumab monotherapy for adolescent subjects with 
moderate-to-severe atopic dermatitis
ECZTRA 6 (ECZema TRAlokinumab trial no. 6)
Phase 3 – efficacy and safety trial
A randomised, double-blind, placebo-controlled, parallel-group, multi-centre trial to 
evaluate the efficacy, safety, and tolerability of tralokinumab monotherapy in adolescent 
subjects with moderate-to-severe atopic dermatitis who are candidates for systemic therapy.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP 
and the applicable regulatory requirement(s).
LEO Pharma A/S
Trial ID:
LP0162-1334
Date:
06-Feb-2020
EudraCT no
2017-005143-33
Version:
7.0 
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Protocol amendment summary of changes
Document
Protocol version
Date
Type of protocol amendment
Amendment 6
(substantial)
7.0
06-Feb-2020
Global
Amendment 5 
(non-substantial)
6.0
19-Jun-2019
Global
Amendment 4 
(non-substantial)
5.0
11-Feb-2019
Global
Amendment 3 
(non-substantial)
4.0
21-Nov-2018
Global
Amendment 2 
(substantial)
3.0
12-Jun-2018
Global
Amendment 1 
(non-substantial)
2.0
01-May-2018
Country-specific (Japan)
Original protocol
1.0
20-Mar-2018
NA
A protocol amendment summary of changes table for the previous amendment is provided in 
Appendix 10.
Amendment 6 (06-Feb-2020)
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 
(65).
Overall rationale for the amendment
The main reasons for this amendment are:
x
To introduce the possibility for eligible subjects in selected countries of the 
present LP0162-1334 trial to continue in a long-term extension trial (conducted 
under a separate protocol [LP0162-1337, ECZTEND]). Eligible subjects from 
the present trial will be allowed to enter ECZTEND after completion of the 
treatment period and up to 26 weeks from their last investigational medicinal 
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product (IMP) injection in the present trial to their first IMP injection in 
ECZTEND (baseline). 
x
To fulfil the commitments in the paediatric investigation plan (PIP) and the 
paediatric study plan (PSP), unblinding at Week 52 of the present trial is 
introduced, as production of a pharmacokinetic (PK) model in adolescents will 
inform tralokinumab dose selection for paediatric subjects.    
Additional changes included in the amendment are also presented in the table below. The 
table below presents the changes in each section. Changes have either been summarised 
(written in 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
1 Protocol synopsis
3 Schematic of trial 
design
7.1 Trial design 
The following text has been added (bold) to Section 7.1 Trial 
design and summarised in Section 1 Protocol synopsis and 
Section 3 Schematic of trial design: 
Safety follow-up period (Week 52 to Week 66)
After completion of the treatment periods or premature 
discontinuation of IMP, all subjects will complete an 
off-treatment follow-up period for the assessment of safety, 
PK, and immunogenicity (i.e. ADA), except subjects who 
transfer to ECZTEND before Week 66 (see below). During 
follow-up, subjects will be allowed to receive standard of AD 
care (excluding biologic therapies) at the investigator’s 
discretion, if needed.
Long-term extension trial (LP0162-1337, ECZTEND)
Eligible subjects from selected countries 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 52) under the current protocol 
(LP0162-1334). Subjects may enter ECZTEND up to 26 
weeks from their last IMP injection in the present trial 
(Week 50) to their first IMP injection in ECZTEND 
(baseline). Subjects may therefore enter ECZTEND 
(baseline) without completing the safety follow up visit 
(16 weeks after their last IMP injection) in the present trial, 
and those subjects will have their safety follow-up visit in 
ECZTEND.
Introduced to allow 
for subjects in the 
present trial 
(LP0162-1334) to 
continue in 
ECZTEND, and to 
clarify when the 
subjects can transfer 
to ECZTEND.
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Section no. and name
Description of change
Brief rationale
Panel 3 Schedule of 
trial procedures:
maintenance treatment 
period
Panel 4 Schedule of 
trial procedures: open-
label tralokinumab 
treatment
Panel 5 Schedule of 
trial procedures: 
follow-up including 
early termination
Added to footnote 1 of the panels:
An end of treatment form must be completed in the eCRF for 
all randomised subjects (see Section 11.9 for further details). 
All subjects will have a safety follow-up 16 weeks after last 
injection of IMP (see Panel 5). This is considered the end of 
trial visit. For subjects who enrol in the long-term extension 
trial (conducted under a separate protocol [LP0162-1337, 
ECZTEND]), the end of trial visit will be the last visit in the 
present trial before transfer to ECZTEND (between 
Week 52 and Week 66); subjects who transfer to 
ECZTEND before completing the safety follow-up visit in 
the present trial will have their safety follow-up visit in 
ECZTEND.
To clarify in the 
trial procedures 
which visit is 
considered the end 
of trial visit for 
subjects who 
transfer to 
ECZTEND.
1 Protocol synopsis
7.1 Overall trial 
design
9.3.1 Blinding
The following text has been added in Section 9.3.1 Blinding
and summarised in Section 1 Protocol synopsis and Section 7.1 
Overall trial design:
Analysis of data per last subject’s Week 52 visit
To fulfil the commitments in the PIP and the PSP, an 
analysis of trial data up to and including visit 29 (Week 52) 
will be performed and will require unblinding of data. To 
perform this analysis, an analysis group consisting of 
Clinical Pharmacologists, Medical Experts, Safety 
Advisors, Statisticians, Statistical Programmers and 
Medical Writers will be unblinded to individual subject 
treatment allocation following database lock for the 
52-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.
To clarify that an
analysis group, not 
including trial staff 
or investigator
involved in the trial 
conduct, will be 
unblinded after all 
subjects have 
completed the 
treatment period and 
before all subjects 
have completed the 
safety follow-up 
period.
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 final safety 
follow-up visit at Week 66. Subjects who enter the long-term 
extension trial (LP0162-1337, ECZTEND) after completion 
of the end of treatment visit (Week 52) will also be 
considered as trial completers.
To clarify who will 
be considered trial 
completers.
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Section no. and name
Description of change
Brief rationale
9.7 Prohibited 
medication and 
procedures
The text in the section about prohibited medication and 
procedures has been optimised.
To clarify the 
section of 
prohibited 
medications in the 
protocol in relation 
to rescue 
medications.
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 from selected 
countries who qualify for the long-term extension trial 
(LP0162-1337, ECZTEND) may be offered participation 
(see Section 7.1). 
To reflect the 
opportunity to 
continue in 
ECZTEND.
11.9 End of trial
Added bullet to end of trial form:
Has the subject been transferred to the open-label 
ECZTEND trial (LP0162-1337)? If yes, which was the last 
visit (including phone call) the subject attended in this 
trial?
To clarify how it is 
to be documented if 
subjects transfer to 
ECZTEND.
13.2 Collection of 
adverse event reports
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 IMP injection). For 
subjects entering the long-term extension trial 
(LP0162-1337, ECZTEND), any (S)AE with onset before 
the subject’s final visit in the LP0162-1334 trial should be 
reported in the LP0162-1334 trial. If ongoing, the (S)AE 
will also be recorded as medical history in ECZTEND.
To clarify the 
reporting of (S)AEs 
during transfer from 
trial LP0162-1334 
to ECTZEND.
13.4.1 Investigator 
reporting 
responsibilities
For subjects entering the long-term extension trial 
(LP0162-1337, ECZTEND), any SAE(s) with onset before 
the final visit in the present trial, must be reported in the 
LP0162-1334 trial eCRF, including any follow-up data 
requested by Global Safety.
SAEs occurring after the completion of the present clinical 
trial (i.e., after the last safety follow up visit) should not be 
routinely sought or collected. However, such events should be 
reported to Global Safety at LEO Pharma (see contact details 
above) if the investigator becomes aware of them. For 
To clarify the 
reporting of SAEs 
during transfer from 
trial LP0162-1334 
to ECTZEND.
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Section no. and name
Description of change
Brief rationale
subjects who transfer to ECZTEND, SAEs occurring after 
the last visit in the present trial and up to entering 
ECZTEND (defined as baseline), must be recorded as 
medical history in ECZTEND.
13.7 Follow-up for 
final outcome of 
adverse events
Added to this section: 
For SAEs which have stabilised and from which the subject 
cannot be expected to recover during the trial or the safety 
follow-up periods, for example chronic or stabilised 
conditions, the final outcome at the investigator's discretion 
should be reported as 'recovering/resolving' or ‘not 
recovered/not resolved’. In addition, a statement that the 
SAE has stabilised or is chronic should be added to the 
narrative description of the SAE on the SAE form.
To provide 
clarification on how 
to handle SAEs 
where the final 
outcome is 
recovering/resolving 
at the end of the 
trial.
14.3.10 Analysis of 
data per last subject’s 
Week 52 visit
Addition of a section describing the analysis of data per last 
subject’s Week 52 visit: 
To fulfil the commitments in the PIP and the PSP, the trial 
will be unblinded once all randomised subjects have 
completed the Week 52 visit. At the cut-off date of the last 
subject’s Week 52 visit, all efficacy, safety, PK, and ADA 
data for the treatment periods have been collected and all 
endpoints used to test pre-specified hypotheses are final. 
Thus, no adjustments in significance level of the primary 
and secondary efficacy analyses are relevant. The CTR will 
include all data from all randomised subjects from the 
initial, maintenance, and open-label treatment periods and 
all available data from the safety follow up period as per 
data cut-off date.
To clarify that data 
will be unblinded
(to an analysis 
group), analysed 
and reported when 
all subjects have 
completed the 
treatment period and 
before all subjects 
have completed the 
safety follow-up 
period.
Appendix 3E: 
Registration, reporting 
and publication policy
Results of this clinical trial will be posted on the corporate 
website of LEO Pharma in accordance with LEO Pharma’s 
Position on Public Access to Clinical Trial Information no later 
than 12 months 6 months after trial completion.
To clarify that the 
reporting of the trial 
results will be 6 
months from trial 
completion as this 
trial includes 
adolescent subjects.
Appendix 3I Trial and 
site closure
When the trial has been completed, randomisation code has 
been broken, the investigators will receive information about 
the treatment allocation for the subjects randomised at their 
To clarify when the 
investigator will be 
unblinded in this 
trial.
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Section no. and name
Description of change
Brief rationale
respective sites and will be asked to record this in the subject’s 
medical record.
Appendix 8 Country-
specific requirements: 
Japan
Updated with the changes made in Section 13.4.1 and Section 
13.7 (see above).
To reflect the 
changes made to the 
protocol.
Throughout
Minor editorial and document formatting revisions.
Minor, therefore not 
summarised.
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Table of contents 
 
Protocol amendment summary of changes ............................................................................ 3 
Table of contents ....................................................................................................................... 9 
List of panels ........................................................................................................................... 14 
List of abbreviations ............................................................................................................... 15 
1 Protocol synopsis ............................................................................................................... 18 
2 Trial identification ............................................................................................................. 25 
3 Schematic of trial design ................................................................................................... 26 
4 Schedule of trial procedures ............................................................................................. 27 
5 Introduction and trial rationale ....................................................................................... 39 
5.1   Atopic dermatitis ......................................................................................................... 39 
5.2   Experience with investigational medicinal product .................................................... 40 
5.3   Trial rationale .............................................................................................................. 41 
5.4   Justification for dose ................................................................................................... 42 
5.5   Ethical considerations ................................................................................................. 43 
5.6   Benefit/risk assessment ............................................................................................... 44 
6 Trial objectives and endpoints ......................................................................................... 47 
7 Trial design ......................................................................................................................... 50 
7.1   Overall trial design ..................................................................................................... 50 
7.2   Number of subjects needed ......................................................................................... 54 
7.3   End of trial definition ................................................................................................. 54 
7.4   Software ....................................................................................................................... 54 
8 Trial population ................................................................................................................. 55 
8.1   Subject eligibility ........................................................................................................ 55 
8.2   Inclusion criteria ......................................................................................................... 55 
8.3   Exclusion criteria ........................................................................................................ 57 
8.4   Screening and screening failures................................................................................. 60 
9 Treatments .......................................................................................................................... 62 
9.1   Trial product description ............................................................................................. 62 
9.2   Administration of IMP ................................................................................................ 62 
   
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9.3   Treatment assignment ................................................................................................. 65 
9.3.1    Blinding .......................................................................................................... 65 
9.3.2    Emergency unblinding of individual subject treatment ................................ 66 
9.4   Background treatment ................................................................................................. 67 
9.5   Rescue treatment ......................................................................................................... 67 
9.6   Concomitant medication and concurrent procedures ................................................. 68 
9.7   Prohibited medication and procedures ........................................................................ 69 
9.8   Treatment logistics and accountability ....................................................................... 70 
9.8.1    Labelling and packaging of trial products ..................................................... 70 
9.8.2    Storage of trial products ................................................................................ 70 
9.8.3    Drug accountability ....................................................................................... 71 
9.8.4    Treatment compliance ................................................................................... 72 
9.8.5    Trial product destruction ............................................................................... 72 
9.9   Provision for subject care following trial completion ................................................ 72 
9.10 Reporting product complaints .................................................................................... 72 
10 Discontinuation and withdrawal ...................................................................................... 74 
10.1 General principles ....................................................................................................... 74 
10.2 IMP discontinuation rules ........................................................................................... 74 
10.2.1  Reasons for permanent discontinuation of IMP ............................................ 74 
10.2.2  Reasons for temporary discontinuation of IMP ............................................ 75 
10.3 Early termination assessments .................................................................................... 75 
10.4 Lost to follow-up......................................................................................................... 77 
11 Trial assessments and procedures .................................................................................... 78 
11.1 Overview ..................................................................................................................... 78 
11.2 Assessments performed only at screening/baseline .................................................... 79 
11.2.1   Demographics ............................................................................................... 79 
11.2.2   Medical history .............................................................................................. 80 
11.2.3   Body surface area involvement ..................................................................... 80 
11.2.4   Columbia-Suicide Severity Rating Scale ...................................................... 81 
11.3 Efficacy assessments ................................................................................................... 81 
11.3.1   Investigator’s Global Assessment ................................................................. 81 
11.3.2   Eczema Area and Severity Index .................................................................. 82 
11.3.3   Scoring Atopic Dermatitis ............................................................................. 83 
11.3.4   Patient-reported outcomes ............................................................................. 84 
     
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11.4 Safety assessments ...................................................................................................... 86 
11.4.1   Vital signs ...................................................................................................... 86 
11.4.2   Physical examination .................................................................................... 87 
11.4.3   Electrocardiogram ......................................................................................... 88 
11.4.4   Laboratory testing ......................................................................................... 88 
11.4.5   Anti-drug antibody measurements ................................................................ 91 
11.5 Pharmacokinetic assessments ..................................................................................... 91 
11.6 Pharmacodynamic assessments: blood biomarkers .................................................... 92 
11.7 Other assessments ....................................................................................................... 92 
11.7.1   Skin swabs: Staphylococcus aureus colonisation ......................................... 92 
11.7.2   Skin barrier function ..................................................................................... 93 
11.7.3   Height and weight ......................................................................................... 94 
11.8 Estimate of total blood volume collected ................................................................... 94 
11.9 End of trial ................................................................................................................... 94 
11.10Storage of biological samples ..................................................................................... 95 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 96 
13 Adverse events ................................................................................................................... 99 
13.1 Definition and classification of adverse events .......................................................... 99 
13.2 Collection of adverse event reports ............................................................................. 99 
13.3 Reporting of adverse events ....................................................................................... 99 
13.4 Reporting of serious adverse events ......................................................................... 100 
13.4.1  Investigator reporting responsibilities ......................................................... 100 
13.4.2  LEO Pharma reporting responsibilities ....................................................... 101 
13.5 Other events that require expedited reporting: pregnancy ........................................ 102 
13.6 Reporting of other events ......................................................................................... 103 
13.6.1  Adverse events of special interest ............................................................... 103 
13.6.2  Overdose ...................................................................................................... 104 
13.6.3  Medication error .......................................................................................... 105 
13.6.4  Misuse .......................................................................................................... 105 
13.6.5  Abuse ........................................................................................................... 105 
13.6.6  Aggravation of condition ............................................................................ 105 
13.7 Follow-up for final outcome of adverse events ........................................................ 106 
13.8 Handling of an urgent safety measure ...................................................................... 106 
14 Statistical methods ........................................................................................................... 107 
     
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14.1 Sample size ................................................................................................................ 107 
14.2 Trial analysis sets ...................................................................................................... 107 
14.3 Statistical analysis ..................................................................................................... 108 
14.3.1  Disposition of subjects ................................................................................ 108 
14.3.2  Demographics and other baseline characteristics ........................................ 108 
14.3.3  Exposure and treatment compliance ............................................................ 109 
14.3.4  Multiple testing strategy .............................................................................. 109 
14.3.5  Analysis of initial treatment ........................................................................ 112 
14.3.6  Analysis of maintenance treatment ............................................................. 124 
14.3.7  Analysis of open-label treatment ................................................................. 124 
14.3.8  Analysis of safety ........................................................................................ 125 
14.3.9  Interim analysis ........................................................................................... 127 
14.3.10 Analysis of data per last subject’s Week 52 visit ........................................ 127 
14.3.11 General principles ....................................................................................... 127 
14.3.12 Handling of missing values ......................................................................... 128 
15 References......................................................................................................................... 129 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 136 
Appendix 2: Classification of adverse events ..................................................................... 138 
Appendix 3: Trial governance considerations ................................................................... 141 
Appendix 3A: Regulatory and ethical considerations .............................................. 141 
Appendix 3B: Informed consent process ................................................................. 142 
Appendix 3C: Subject and data confidentiality ....................................................... 143 
Appendix 3D: Record keeping, quality control, and data handling ......................... 144 
Appendix 3E: Registration, reporting and publication policy ................................. 148 
Appendix 3F: Insurance ........................................................................................... 149 
Appendix 3G: Financial disclosure .......................................................................... 150 
Appendix 3H: Committee structure ......................................................................... 150 
Appendix 3I: Trial and site closure .......................................................................... 151 
Appendix 3J: Responsibilities .................................................................................. 152 
Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD (36) .......................... 153 
Appendix 5: Guidance for anaphylaxis diagnosis (38) ..................................................... 154 
Appendix 6: WHO model prescribing information for classification of topical 
corticosteroids .................................................................................................................. 155 
Appendix 7: Eligibility criteria ........................................................................................... 157 
Appendix 8: Country-specific requirements: Japan ......................................................... 160 
   
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Appendix 9: Contact list ...................................................................................................... 165 
Appendix 10: Protocol amendment history ....................................................................... 166 
                                                                                         
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List of panels 
 
Panel 1: Trial design ................................................................................................................. 26 
Panel 2: Schedule of trial procedures: screening and initial treatment period ......................... 27 
Panel 3: Schedule of trial procedures: maintenance treatment period ..................................... 31 
Panel 4: Schedule of trial procedures: open-label tralokinumab treatment ............................. 34 
Panel 5: Schedule of trial procedures: follow-up including early termination ........................ 37 
Panel 6: Objectives and endpoints ........................................................................................... 47 
Panel 7: Identification of investigational medicinal products .................................................. 62 
Panel 8: Investigator’s Global Assessment .............................................................................. 81 
Panel 9: Calculation of the Eczema Area and Severity Index .................................................. 82 
Panel 10: Eczema Area and Severity Index severity score scale and area score scale ............ 83 
Panel 11: Clinical laboratory tests ............................................................................................ 89 
Panel 12: Adverse events of special interest .......................................................................... 103 
Panel 13: Global (non-US) testing procedure for the primary and secondary endpoints ...... 110 
Panel 14: US testing procedure for the primary and secondary endpoints ............................ 111 
Panel 15: Transmission of electronic data .............................................................................. 147 
Panel 16: Classification of topical corticosteroids ................................................................. 155 
                                 
 
 
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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 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSA 
body surface area 
CCL 
C-C motif chemokine ligand 
CDISC 
Clinical Data Interchange Standards Consortium 
CDLQI 
Children’s Dermatology Life Quality Index 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CONSORT 
consolidated standards of reporting trials 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
Ctrough 
trough concentration 
DMC 
data monitoring committee 
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 
eSAE section 
electronic section for the reporting of SAEs in the eCRF 
EMA 
European Medicines Agency 
ePRO 
electronic patient-reported outcome 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
    
 
 
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HCP 
healthcare professional 
HDL 
high density lipoprotein 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IgG4 
immunoglobulin G4 
IL 
interleukin 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
LDL 
low density lipoprotein 
LEO 
LEO Pharma A/S 
nAB 
neutralising antibodies 
NRS 
numeric rating scale 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PD 
pharmacodynamics 
PDCO 
(EMA’s) Paediatric Committee 
PDE-4 
phosphodiesterase 4 
PIP 
Paediatric Investigational Plan 
PK 
pharmacokinetics 
POEM 
Patient-Oriented Eczema Measure 
PRO 
patient-reported outcome 
PSP 
Paediatric Study Plan 
PUVA 
psoralen and ultraviolet A therapy 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
QoL 
quality of life 
S. aureus 
Staphylococcus aureus 
SAE 
serious adverse event 
SC 
subcutaneous 
    
 
 
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SCORAD 
Scoring Atopic Dermatitis 
SCORAD50 
at least 50% reduction in SCORAD score 
SDTM 
study data tabulation model 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
TEWL 
transepidermal water loss 
Th2 
T-helper-2 
ULN 
upper limit of normal (range) 
UV 
ultraviolet 
WHO 
World Health Organization 
                                                                       
 
 
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1.
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).
2.
The EASI is a validated measure used in clinical practice and clinical trials 
to assess the severity and extent of AD. The EASI is a composite index 
with scores ranging from 0 to 72, with higher values indicating more severe 
and/or more extensive condition.
3.
The SCORAD is a validated tool to evaluate the extent and severity of AD 
lesions, along with subjective symptoms. The maximum total score is 103, 
with higher values indicating more severe disease.
4.
The Adolescent Pruritus NRS is used by subjects to assess their worst itch 
over the past 24 hours using an 11-point NRS with 0 indicating 'no itch' and 
10 indicating 'worst itch possible'.
5.
The CDLQI 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 various aspects of their 
quality of life over the last week such as dermatology-related symptoms 
and feelings, leisure, school or holidays, personal relationships, sleep, and 
the treatment. Each item is scored on a 4-point Likert scale (0 = ‘not at all’; 
1 = ‘only a little’; 2 = ‘quite a lot’; 3 = ‘very much’). Item 7 (on school 
time) has one additional response category ‘prevented school’, which is 
also scored ‘3’. The total score of the CDLQI is the sum of the 10 items 
(0 to 30); a high score is indicative of a poor quality of life.
Final collection of 
data for the 
primary endpoint
Week 16
Trial design
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*Clinical response (IGA = 0, 1; or EASI75) achieved without use of rescue treatment 
from Week 2 to Week 16. Abbreviations: EASI75, at least 75% reduction in Eczema 
Area and Severity Index; IGA, Investigator’s Global Assessment; No, number; TCI,  
topical calcineurin inhibitor; TCS, topical corticosteroid; w, week.
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 maintenance 
treatment period of 36 weeks (Weeks 16 to 52), and a 14-week safety follow-up
period for the assessment of safety (Weeks 52 to 66). Subjects who transfer to 
ECZTEND before completing the safety follow-up visit in the present trial will have 
their safety follow-up visit in ECZTEND.
Initial treatment period
Subjects will be randomised in a 1:1:1 ratio to receive multiple SC doses of 
tralokinumab 300 mg, tralokinumab 150 mg, or placebo every 2 weeks (Q2W) 
following a loading dose (double dose compared to randomised dose) on Day 0
(baseline). Randomisation will be stratified by region and baseline disease 
severity (according to IGA).
Maintenance treatment period
Subjects with a clinical response* at Week 16 (achieved without use of rescue 
treatment from Week 2 to Week 16) will continue into maintenance treatment
which may last until Week 52 (with last dose of investigational medicinal 
product [IMP] given at Week 50). The treatment during the maintenance 
treatment period will depend on the regimen received in the initial treatment 
period as described below. *Clinical response is defined as IGA of 0 or 1 or 
EASI75.
Subjects randomised to tralokinumab in the initial treatment period will be re-
randomised 1:1 (at the randomised dose) in the maintenance treatment period.
Re-randomisation will be stratified by region and IGA response at Week 16 
(IGA 0/1 or IGA >1).
Subjects initially randomised to tralokinumab 300 mg will either receive:
x
Tralokinumab 300 mg Q2W.
x
Tralokinumab 300 mg every 4 weeks (Q4W): alternating dose 
administrations of tralokinumab 300 mg or placebo.
Subjects initially randomised to tralokinumab 150 mg will either receive:
x
Tralokinumab 150 mg Q2W.
x
Tralokinumab 150 mg Q4W: alternating dose administrations of 
tralokinumab 150 mg or placebo.
Subjects randomised to placebo in the initial treatment period will receive 
placebo Q2W in the maintenance treatment period.
Transfer to open-label treatment
Subjects without clinical response at Week 16 and subjects who have received 
rescue treatment from Week 2 to Week 16 will be transferred to open-label 
treatment (tralokinumab 300 mg Q2W with optional use of topical 
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corticosteroids [TCS] or topical calcineurin inhibitors [TCI]) at Week 16, if 
considered appropriate by the investigator.
During the maintenance treatment period, subjects may be transferred from 
maintenance treatment to open-label treatment (tralokinumab 300 mg Q2W 
with optional use of TCS or TCI) if they meet any of the criteria listed below, 
and if considered appropriate by the investigator:
x
Subjects with IGA=0 at Week 16: IGA of at least 2 and not achieving 
EASI75 over at least a 4-week period (i.e., over 3 consecutive visits).
x
Subjects with IGA=1 at Week 16: IGA of at least 3 and not achieving 
EASI75 over at least a 4-week period (i.e., over 3 consecutive visits).
x
Subjects with IGA >1 at Week 16: not achieving EASI75 over at least 
a 4-week period (i.e., over 3 consecutive visits).
x
Subjects who receive rescue treatment (from Week 16 or later).
Transfer to open-label treatment may occur at any visit from Week 16 while the 
subject is in the maintenance treatment period.
Safety follow-up period
After completion of the treatment periods (at Week 52) or discontinuation of 
IMP, all subjects will enter a 14-week safety follow-up period for assessment 
of safety, pharmakokinetics (PK), and immunogenicity, except subjects who 
transfer to ECZTEND before Week 66 (see below). During follow-up, subjects 
will be allowed to receive standard of AD care (excluding biologic therapies) at 
the investigator’s discretion, if needed.
Long-term extension trial (LP0162-1337, ECZTEND)
Eligible subjects from selected countries 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 52) under the current protocol (LP0162-1334). 
Subjects may enter ECZTEND up to 26 weeks from their last IMP injection in 
the present trial (Week 50) to their first IMP injection in ECZTEND (baseline). 
Subjects may therefore enter ECZTEND (baseline) without completing the 
safety follow-up visit (16 weeks after their last IMP injection) in the present 
trial, and those subjects will have their safety follow-up visit in ECZTEND.
Background treatment
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). 
Main assessments
Investigator efficacy assessments:
x
IGA.
x
EASI.
x
SCORAD.
Patient-reported efficacy assessments:
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x
Adolescent Pruritus NRS.
x
CDLQI.
x
Patient-Oriented Eczema Measure (POEM).
Safety assessments:
x
Adverse events.
x
Laboratory testing.
x
Anti-drug antibodies.
Pharmacokinetics 
Main criteria for 
inclusion
x
Age 12 to 17.
x
Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria 
for AD.
x
History of AD for ≥1 year.
x
History of topical corticosteroid (TCS; Europe: Class 3 or higher;
US: Class 4 or lower) and/or topical calcineurin inhibitor (TCI) 
treatment failure or subjects for whom these topical AD treatments are 
medically inadvisable.
x
AD involvement of ≥10% body surface area at screening and baseline.
x
Stable dose of emollient twice daily (or more, as needed) for at least
14 days before randomisation.
Main criteria for 
exclusion
x
Active dermatologic conditions that may confound the diagnosis of 
AD.
x
Use of tanning beds or phototherapy within 6 weeks prior to 
randomisation.
x
Treatment with systemic immunosuppressive/immunomodulating 
drugs and/or systemic corticosteroid within 4 weeks prior to 
randomisation.
x
Treatment with TCS, TCI, or topical phosphodiesterase 4 (PDE-4) 
inhibitor within 2 weeks prior to randomisation.
x
Receipt of any marketed biological therapy (i.e. immunoglobulin, 
anti-immunoglobulin E) including dupilumab or investigational 
biologic agents.
x
Active skin infection within 1 week prior to randomisation.
x
Clinically significant infection within 4 weeks prior to randomisation.
x
A helminth parasitic infection within 6 months prior to the date 
informed consent is obtained.
x
Tuberculosis requiring treatment within the 12 months prior to 
screening.
x
Known primary immunodeficiency disorder.
Investigational 
medicinal 
products
Tralokinumab
x
Tralokinumab is a human recombinant monoclonal antibody of the 
immunoglobulin G4 (IgG4) subclass that specifically binds to human 
interleukin (IL) 13 and blocks interaction with the IL-13 receptors.
x
Active substance: tralokinumab.
x
Dosage form: solution (in accessorised pre-filled syringe, 1.0 mL fill 
volume).
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x
Concentration: 150 mg/mL.
x
Dose: 600 mg or 300 mg initial loading dose, then 300 mg or 150 mg 
every second week.
x
Method of administration: SC administration.
Placebo
x
Placebo contains the same excipients in the same concentration only 
lacking tralokinumab. 
Duration of 
treatment
Approximately 52 weeks.
Number of 
subjects
A total of 294 subjects will be randomised 1:1:1 to tralokinumab 300 mg,
tralokinumab 150 mg, or placebo.
Number and 
distribution of 
trial sites
Approximately 80 sites in Europe, US, Canada, Australia, and Japan.
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 (IGA 3 or 4). Subjects with missing data and subjects who 
receive rescue treatment from the Week 2 to Week 16 visit will be considered 
as non-responders in the analysis.
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 Adolescent 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 CDLQI will be analysed the same way as 
change in SCORAD.
Testing strategy:
The overall type I error rate in the tests of primary and secondary endpoints 
will be protected by a combination of hierarchical testing and Holm-Bonferroni 
multiplicity adjustment embedded in a graphical approach.
Within each dose level, the 2 co-primary endpoints, IGA 0/1 and EASI75 at 
Week 16, will be tested hierarchically, followed by a Holm-Bonferroni 
adjustment of the testing of the 3 secondary endpoints.
The 2 co-primary endpoints for the tralokinumab 300 mg dose will first be 
tested hierarchically at an overall 5% significance level, after which the 
significance level will be split evenly between testing of the same primary 
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endpoints for the tralokinumab 150 mg dose and a Holm-Bonferroni testing 
procedure for the secondary endpoints for the tralokinumab 300 mg dose. 
If all the hypotheses of no difference to placebo for the tralokinumab 300 mg 
dose are rejected, then the 2.5% significance level will be passed on to the 
testing of all the endpoints for the tralokinumab 150 mg dose. Similarly, if the 
hypotheses of no difference to placebo for all the endpoints of the tralokinumab 
150 mg dose are rejected the 2.5% significance level will be passed on to the 
testing of the secondary endpoints of the tralokinumab 300 mg dose. 
To fulfil the commitments in the paediatric investigation plan (PIP) and the 
paediatric study plan (PSP), the trial will be unblinded to an analysis group 
once all randomised subjects have completed the Week 52 visit and available 
data will be analysed and reported. 
Signatory 
investigator 
Professor [Name], MD, [Contact] 
[Contact] 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
                                                             
 
 
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2 Trial identification 
EudraCT number: 2017-005143-33 
NCT number: NCT03526861  
IND number: 123797 
The clinical trial protocol will be registered in local registries if required by local legislation. 
                                                                            
T 
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3 Schematic of trial design
Panel 1: Trial design
*Subjects with clinical response at Week 16 (achieved without use of rescue treatment from Week 2 to Week 16) 
will enter the maintenance treatment period. Clinical response is defined as subjects achieving IGA of 0 (clear) 
or 1 (almost clear) or EASI75. Subjects without a clinical response at Week 16 and subjects who use rescue 
treatment from Week 2 to Week 16 will be transferred to open-label treatment (300 mg tralokinumab every 
2 weeks with optional use of TCS and/or TCI) at Week 16, if considered appropriate by the investigator.
During the maintenance treatment period, subjects will be transferred from maintenance treatment to open-label 
treatment if they lose their clinical response (based on pre-defined criteria) or if they receive rescue treatment 
(from Week 16 or later).
Note: Eligible subjects from selected countries may enter a long-term extention trial (LP0162-1337, ECZTEND)
after the last visit in the treatment period (Week 52) and up to 26 weeks from their last IMP injection in the 
present trial (Week 50) to their first IMP injection in ECZTEND (baseline). Subjects may therefore enter 
ECZTEND (baseline) without completing the safety follow up visit (16 weeks after their last IMP injection) in 
the present trial, and those subjects will have their safety follow-up visit in ECZTEND.
Abbreviations: EASI75, at least 75% reduction in Eczema Area and Severity Index; IGA, Investigator’s Global 
Assessment; IMP, investigational medicinal product; No, number; TCI, topical calcineurin inhibitor, TCS, 
topical corticosteroid; w, week.
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4.
The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and 
wash-out of disallowed medications.
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.
6.
Subjects who achieve a clinical response (IGA 0/1 or EASI75) at Week 16 (achieved without use of rescue treatment from Week 2 to Week 16) will be re-
randomised into the maintenance period and then receive the first injections of maintenance treatment. Subjects who do not achieve clinical response at 
Week 16 and subjects who have received rescue treatment from Week 2 to Week 16 will be transferred to open-label tralokinumab treatment (300 mg every 
2 weeks with optional use of TCS and/or TCI, see Panel 4), if considered appropriate by the investigator. The first injections of open-label treatment will be 
administered at Week 16.
7.
For the first 3 IMP dosing visits in the initial treatment period and for non-responders transferring to open-label tralokinumab treatment at Week 16, subjects 
will be monitored prior to and after IMP administration for immediate drug reactions for a minimum of 2 hours with vital signs taken every 30 minutes or until
stable, whichever is later (see Section 9.2).
8.
The eDiary consists of Eczema-related Sleep NRS, Adolescent Pruritus NRS, and Adolescent PGI-S (today recall). The eDiary will be completed daily from 
Week -2 to Week 52, albeit the Adolescent PGI-S (today recall) will only be completed daily from Week -2 to Week 16.
9.
Subject age (in years) must be recorded at visits where chemistry, haematology, and serology are sampled.
10. IgE not assessed at screening.
Abbreviations: ADA, anti-drug antibodies; BSA, body surface area; CDLQI, Children’s Dermatology Life Quality Index; C-SSRS, Columbia Suicide Severity 
Rating Scale; EASI, Eczema Area and Severity Index; EASI75, at least 75% reduction in EASI score; ECG, electrocardiogram; eDiary, electronic diary; 
HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; NA, 
not applicable; NRS, numeric rating scale; PGI-C: Patient Global Impression of Change; PGI-S, Patient Global Impression of Severity; POEM, Patient-
Oriented Eczema Measure; SCORAD, SCORing Atopic Dermatitis.
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The first injections of open-label treatment will be given at the visit in the maintenance period where the subject meets these criteria, if considered appropriate 
by the investigator, but not sooner than 5 half-lives after the last dose of systemic rescue treatment. When the first injections of open-label treatment are given, 
subjects will be monitored prior to and after IMP administration for immediate drug reactions for a minimum of 2 hours with vital signs taken every 30 minutes 
or until stable, whichever is later (see Section 9.2).
4.
The eDiary for the maintenance treatment period consists of Eczema-related Sleep NRS and Adolescent Pruritus NRS and will be completed daily to Week 52.
5.
Subject age (in years) must be recorded at visits where chemistry, haematology, and serology are sampled.
Abbreviations: ADA, anti-drug antibodies; CDLQI, Children’s Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; EASI75, at least 75% 
reduction in EASI score; ECG, electrocardiogram; eCRF, electronic case report form; eDiary, electronic diary; HADS, Hospital Anxiety and Depression Scale; 
IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; NRS, numeric rating scale; POEM, Patient-Oriented 
Eczema Measure; SCORAD, SCORing Atopic Dermatitis; TCS, topical corticosteroid.
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Abbreviations: ADA, anti-drug antibodies; CDLQI, Children’s Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; ECG, electrocardiogram; 
eCRF, electronic case report form; eDiary, electronic diary; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; 
IgE, immunoglobulin E; IMP, investigational medicinal product; NRS, numeric rating scale; POEM, Patient-Oriented Eczema Measure; SCORAD, SCORing 
Atopic Dermatitis.
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1.
The visit will be conducted as a telephone visit. If the subject experiences a worsening of their AD during 
follow-up, a visit at the clinic may be conducted as an unscheduled visit at the investigator’s discretion.
2.
An end of treatment form and end of trial form must be completed in the eCRF for all randomised subjects. 
See Section 11.9 for further details. All subjects will have a safety follow-up 16 weeks after last injection of 
IMP. This is considered the end of trial visit. For subjects who enrol in the long-term extension trial 
(conducted under a separate protocol [LP0162-1337, ECZTEND]), the end of trial visit will be the last visit 
in the present trial before transfer to ECZTEND (between Week 52 and Week 66); subjects who transfer to 
ECZTEND before completing the safety follow-up visit in the present trial will have their safety follow-up 
visit in ECZTEND.
3.
Assessments and procedures to be performed at an unscheduled visit are left at the investigator’s discretion.
4.
Subjects who permanently discontinue IMP or withdraw from the trial will be followed up as described in 
Section 10. All subjects will have a final safety follow-up visit 16 weeks after last dose of IMP.
5.
If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned 
to maintain the visit schedule relative to randomisation/baseline.
6.
The eDiary consists of Eczema-related Sleep NRS, Adolescent Pruritus NRS, and Adolescent PGI-S (today 
recall). The eDiary will be completed daily from Week -2 to Week 52, albeit the Adolescent PGI-S (today 
recall) will only be completed daily from Week -2 to Week 16.
7.
Subject age (in years) must be recorded at visits where chemistry, haematology, and serology are sampled.
8.
Only to be performed if the subject discontinues IMP prior to Week 16.
Abbreviations: ADA, anti-drug antibodies; CDLQI, Children’s Dermatology Life Quality Index; EASI, Eczema 
Area and Severity Index; ECG, electrocardiogram; eCRF, electronic case report form; eDiary, electronic 
diary; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; 
IgE, immunoglobulin E; IMP, investigational medicinal product; NRS, numeric rating scale; PGI-C: Patient 
Global Impression of Change; PGI-S, Patient Global Impression of Severity; POEM, Patient-Oriented 
Eczema Measure; SCORAD, SCORing Atopic Dermatitis.
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5 Introduction and trial 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 increased susceptibility to bacterial, viral, and fungal skin 
infections (1-4). AD rash distribution varies with patient age (5). In infants <2 years, AD 
usually involves the scalp, face, neck, and extensor surfaces of the extremities. In children 
from 2 years of age to puberty, the flexural surfaces of the extremities, head and neck, and 
wrists and ankles are more often involved. In adolescents and adults, eczematous changes are 
typically seen on the head and neck, flexural surfaces of the extremities, and hands and feet. 
AD is associated with a substantial patient burden that typically includes poor quality of life 
(QoL) and sleep disturbance (6).
AD is characterised by an activated T-helper-2 (Th2) pathway with increased skin expression 
of key Th2 cytokines including interleukin (IL) 13 (7, 8). 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 (7, 9).
IL-13 acts on keratinocytes to release C-C motif chemokine ligand (CCL) 22 and recruit more 
IL-13 expressing Th2 cells, decrease differentiation, and contribute to decreased barrier 
function (10). 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 (11, 12). 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 that also binds IL-13) with the monoclonal 
antibody dupilumab leads to clinical improvement in subjects with AD (13).
Even if the clinical manifestations of AD in children and adults are different with regard to the 
anatomical distribution, IL-13 is an important player in the pathogenesis of AD in both 
children and adults. Counts of IL-13-positive CD4+ lymphocytes in the peripheral blood of 
children with AD are significantly correlated with AD severity (14). Also, increased levels of 
IL-4 and IL-13 together with eosinophils in blood correlate with disease severity in both 
paediatric and adult patients with AD (15). Furthermore, IL-4/IL-13 polymorphisms have 
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been shown to be associated with an increased incidence of AD in children at age 2 (16, 17). 
Thus, across age groups there is compelling evidence for IL-13 as a central mediator of the 
AD skin phenotype.
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 (18–20). 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, 14 clinical trials with tralokinumab have been completed to date, with phase 3 
development ongoing in AD. A phase 2b dose-finding trial has been completed in AD. Other 
clinical trials with tralokinumab have been conducted in subjects with asthma, ulcerative 
colitis, idiopathic pulmonary fibrosis, and in healthy subjects.
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, and 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 2,300 subjects have been treated with tralokinumab (cut-off date: 
18-Aug-2018). Adolescent subjects with asthma have been investigated in a single-dose phase 
1 trial (20 adolescent subjects exposed to tralokinumab) as well as in 2 completed phase 3 
trials (58 adolescent subjects exposed to tralokinumab). In these trials, the tralokinumab PK 
and safety profile (based on reporting of AEs, SAEs, and AEs leading to discontinuation of 
IMP) was largely similar in the adult and adolescent trial populations with asthma.
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All doses studied so far have had an acceptable benefit/risk profile and no major safety 
concerns have been identified. Possible risks associated with use of tralokinumab are 
summarised in Section 5.6.
5.3 Trial rationale
AD is a chronic inflammatory skin disease which is more prevalent in children than in adults. 
No curative treatment of the disease is currently available. There is a clear and compelling 
unmet medical need for more effective and safe treatments for moderate-to-severe AD in the 
paediatric age groups as current immunosuppressive medications, such as cyclosporine, 
methotrexate, and azathioprine, are associated with long-term toxicities. TCS, especially those 
of high potency, are associated with a variety of long-term safety concerns, including the 
systemic effects of absorbed corticosteroids such as adrenal suppression, poor growth, 
hypertension, hyperglycaemia, insulin resistance, and cataracts, as well as local skin damage 
and atrophy. These safety concerns are increased in paediatric patients, whose greater body 
surface area-to-weight ratio is thought to increase percutaneous absorption (21). Furthermore, 
AD is recognised to cause substantial morbidity and to have a serious impact on the 
psychological wellbeing and QoL in children (22).
Also to fulfil the regulatory requirements under the US Pediatric Research Equity Act (PREA) 
(23), the EU regulation on medicinal products for paediatric use (24) and International 
Council for Harmonisation (ICH) E11 (Guideline on the clinical investigation of medicinal 
products in the pediatric population) (25), LEO Pharma A/S (hereafter LEO Pharma) is 
committed to conduct a trial with tralokinumab in adolescent subjects with AD, aged 12 to 
<18 years. Hence, the present trial is part of the paediatric clinical development programme of 
tralokinumab for AD, investigating the efficacy and safety of tralokinumab monotherapy in 
the treatment of adolescent subjects with moderate-to-severe AD who are inadequately 
controlled with topical therapies. Furthermore, the trial is designed to gain valuable 
information on the PK of tralokinumab in this population and to select the doses for a 
PK/safety trial in younger children (2 to <12 years). Based on input from the European 
Medicines Agency’s (EMA’s) Paediatric Committee (PDCO), 2 doses of tralokinumab will be 
evaluated in this trial to assess whether 300 mg or 150 mg tralokinumab would be the optimal 
dose in the adolescent population.
The primary objective of this trial is to evaluate whether tralokinumab provides more 
effective control of the skin manifestations of AD than does placebo. In addition, secondary 
endpoints addressing symptom scores and extent of AD (SCORAD), itch-related sleep loss 
and itch severity, and health-related quality of life (HRQoL) measures related to AD are also 
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included. As an exploratory component, the present trial will also investigate biomarkers 
related to AD, skin barrier function (in a subgroup of subjects), skin microbiology, and the 
potential impact of tralokinumab on these.
As AD is a chronic disease requiring long-term treatment, it is also relevant to evaluate the 
efficacy of tralokinumab as maintenance treatment. After the 16-week initial treatment period, 
the trial will evaluate 2 different treatment options for maintenance therapy, that is, dosing 
every 2 (Q2W) or every 4 weeks (Q4W).
Thus, the trial will contribute to the characterisation of the benefit/risk profile of tralokinumab 
in the adolescent population.
5.4 Justification for dose
The selected doses for the initial treatment period in this trial is subcutaneously administered 
300 mg and 150 mg tralokinumab Q2W. All subjects randomised to receive treatment with 
tralokinumab will get an initial loading dose on Day 0 (baseline); subjects randomised to 
300 mg will receive a loading dose of 600 mg and subjects randomised to 150 mg will receive 
300 mg. 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 300 mg Q2W dose is also used in the ongoing phase 3 trials in adults.
Based on a phase 1 trial in 20 adolescents (12 to 17 years) with asthma 
(trial CD-RI-CAT-354-1054), the PK profile of a single SC dose of tralokinumab (300 mg) 
has been evaluated. Overall, the PK parameters including maximum serum concentration 
(Cmax), time of maximum serum concentration (Tmax), and absolute clearance (CL/F) were 
largely similar to that observed in the adult population. Tralokinumab was well tolerated, no 
serious adverse events (SAEs) were reported, and no confirmed anti-drug antibodies (ADA) 
were detected after dosing. Further, the data from this phase 1 trial in adolescents with 
asthma, along with all available adult PK and pharmacodynamic (PD) data, were combined in 
a population PK-PD model. This model supported the finding that tralokinumab PK is dose-
linear and stationary with time, and that overall exposure and variability are similar between 
weight-based and non-weight-based dosing at the dose level of 300 mg Q2W.
The PK profile in adult subjects with AD in the phase 2b trial was comparable to the PK 
profile in adult and adolescent subjects with asthma. Given the relatively shallow dose-
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response between 150 mg and 300 mg and because the safety profile of tralokinumab 300 mg 
was acceptable, both these doses will be included in this trial in adolescent subjects with AD, 
to establish the optimal dose in this population.
In the maintenance treatment period, subjects in 2 of the treatment arms will be dosed with 
tralokinumab (either 300 mg or 150 mg) Q4W. This approach will allow the sponsor of the 
trial, LEO Pharma, to evaluate whether less frequent dosing of tralokinumab (every 4 vs. 
every 2 weeks) may be sufficient for long-term maintenance of efficacy.
5.5 Ethical considerations
Participation in this trial is voluntary and subjects can withdraw at any time. The subject’s 
legally authorised representative(s) will give informed consent, and subjects must give their 
informed consent (assent) as appropriate and according to national laws and regulations. No 
vulnerable subject incapable of giving informed consent will be enrolled in this clinical trial. 
Furthermore, female subjects who are pregnant, breastfeeding, or trying to become pregnant 
will not be enrolled. Female subjects of childbearing potential who are sexually active, 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 investigational 
medicinal product (IMP). In addition, all female subjects of childbearing potential will have a 
pregnancy test performed before, during, and at end of treatment to ensure that no foetuses are 
exposed to the IMP.
AD is a chronic and recurrent skin disorder and no curative treatment of the disease is 
currently available. Further, there is a clear and compelling unmet need for more effective, 
safe treatments for moderate-to-severe AD in the paediatric age groups. AD is widely 
prevalent in children including adolescents (26–28). Although AD usually presents as mild 
disease in the paediatric age group, around 10-30% of children with AD may have moderate-
to-severe disease (29–31). AD is recognised to cause substantial morbidity and to have a 
serious impact on the psychological wellbeing and QoL in children (22).
The efficacy of 2 doses of tralokinumab will be evaluated in adolescent subjects with 
moderate-to-severe AD who are otherwise healthy. Tralokinumab treatment will be compared 
with placebo control treatment. There are several reasons why this trial is a placebo-controlled 
monotherapy trial. First, this will allow for a better understanding of the clinical benefits of 
tralokinumab in adolescents without confounding data interpretation by concomitant use of 
TCS therapy. Second, the pivotal phase 3 trials in adults are also conducted as monotherapy 
trials, and the comparison and extrapolation of data from the adult to the adolescent 
population is considered to be most appropriate if the present trial is conducted in the 
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monotherapy setting. Third, TCS and topical calcineurin inhibitors (TCI) have limited 
efficacy in patients with moderate-to-severe disease.
Placebo control was considered to provide the best design for efficient assessment of both 
benefit and risk in adolescents (12 to <18 years). Recognising that prolonged placebo 
treatment may not be optimal in this population, a 2:1 (tralokinumab:placebo) randomisation 
is planned to increase the opportunity for subjects to receive active treatment. Furthermore, 
subjects who do not achieve a clinical response at Week 16 (including subjects randomised to 
placebo) will get the opportunity to receive open-label tralokinumab 300 mg Q2W treatment 
with optional use of TCS, if considered appropriate by the investigator. In addition, subjects 
may receive rescue treatment at the discretion of the investigator if medically necessary (i.e., 
to control intolerable AD symptoms) through treatment and follow-up.
To ensure subject safety, investigators are informed only to enrol subjects they expect can 
complete wash-out of previous AD medications during the screening period without 
experiencing intolerable worsening of AD symptoms. In addition, subjects and/or their legally 
authorised representatives will be informed to contact the investigator, if the subject’s AD 
worsens significantly.
In accordance with the current version of the ICH Good Clinical Practice (GCP) guidelines, 
qualified medical personnel employed by LEO Pharma will be readily available to advise on 
trial-related medical questions. Medical monitoring will be performed throughout the trial. 
Safety data will be reviewed regularly by Global Safety at LEO, and by an independent Data 
Monitoring Committee (DMC, see Appendix 3H) 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 is 
regarded as ethically justified and adherent with ethical requirements.
5.6 Benefit/risk assessment
Tralokinumab is a new biological therapy under investigation for the treatment of moderate-
to-severe AD in both the adult and paediatric age groups. Based on the benefits in treating AD 
reported with dupilumab, a monoclonal antibody that blocks the effects of IL-4 and IL-13 by 
targeting a common receptor subunit (13, 32–34), there is a reasonable expectation that 
tralokinumab will prove to be an effective treatment of moderate-to-severe AD.
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Tralokinumab has already demonstrated efficacy in moderate-to-severe AD and the evidence 
discussed in Section 5.2 further supports the hypothesis that tralokinumab may benefit 
individuals with AD.
An important aspect in the benefit/risk evaluation is the reassuring safety profile of 
tralokinumab in AD, asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in trials 
with healthy subjects. Throughout an extensive clinical development programme in asthma, 
no safety concern has been identified with the use of tralokinumab, and tralokinumab was 
well tolerated. The AE profile for tralokinumab has been comparable to that for placebo in 
controlled clinical trials. Injection-site reactions have generally been mild and ADAs have 
been detected in very few subjects exposed to tralokinumab for up to one year; concerns 
about neutralising antibodies have not been raised. 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:
x
Close monitoring of subjects during the trial with trial visits every 2 weeks 
during the treatment period as described in the schedule of trial procedures 
(Section 4).
x
Close monitoring of subjects during the post dosing period (at the first 3 IMP 
dosing visits in the initial treatment period and in open-label treatment) as a 
precautionary measure against hypersensitivity reactions (further details are 
given in Section 11.4.1).
x
Monitoring of subjects for clinical manifestations that may be associated with 
the development of specific antibodies to tralokinumab (i.e., immune complex 
disease).
x
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) [35]).
x
Exclusion of subjects with a history of tuberculosis requiring treatment within 
12 months prior to the screening visit.
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x
Exclusion of subjects with a history of a clinically significant infection 
(defined as a systemic or serious skin infection requiring parenteral antibiotics, 
antiviral, or antifungal 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 possible risks that have been previously identified and to closely monitor each 
subject. The current benefit/risk profile is considered favourable and supports the 
administration of tralokinumab for the purposes of achieving the objectives of this trial.
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7 Trial design
7.1 Overall trial design
Overview
This is a phase 3, randomised, double-blinded, placebo-controlled trial in adolescent subjects 
aged 12 to <18 years 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 maintenance treatment period of 36 weeks (Weeks 16 to 52). The primary endpoint is 
assessed at Week 16, and the final efficacy assessment will be conducted at Week 52. 
A 14-week follow-up period for the assessment of safety is also included (Weeks 52 to 66). 
Subjects who transfer to ECZTEND before completing the safety follow-up visit in the 
present trial will have their safety follow-up visit in ECZTEND. Subjects without clinical 
response at Week 16, subjects who receive rescue treatment from the Week 2 visit to the Week 
16 visit (hereinafter “Week 2 to Week 16”), and subjects who lose their response during the 
maintenance period will be transferred to open-label treatment (tralokinumab 300 mg Q2W 
with optional use of TCS and/or TCI) if they meet certain criteria (see below), and if 
considered appropriate by the investigator. Transfer to open-label treatment may occur at any 
visit from Week 16 while the subject is in the maintenance treatment period.
A schematic of the trial design is provided in Panel 1.
Screening period (Week -6 to Week 0)
Prior to attending any trial procedure, a signed informed consent must be obtained from the 
subject’s legally authorised representative(s) and from the subject (as appropriate and 
according to national laws and regulations). 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 the individual subject depends on the length of any wash-
out period needed (as also specified in the exclusion criteria in Section 8.3):
x
6 weeks for subjects using tanning beds or phototherapy.
x
4 weeks for subjects using systemic immunosuppressive/immunomodulating drugs, 
systemic corticosteroid use, or ≥3 bleach baths during any week within the 4 weeks.
x
2 weeks for subjects using TCS, TCI, or topical phosphodiesterase 4 (PDE-4) 
inhibitors.
If no wash-out or a 2-week wash-out 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 
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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 completion of the electronic patient-
reported outcome (ePRO) questionnaires in the eDiary. Data entered into the eDiary during 
the 2 weeks before randomisation 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.
Initial treatment period (Week 0 to Week 16)
Following the screening period, approximately 294 subjects will be randomised 1:1:1 to one 
of the following groups stratified by region (Europe, North America, Australia, and Japan) 
and baseline disease severity (IGA of 3 or 4):
x
Tralokinumab 300 mg Q2W: tralokinumab 600 mg (loading dose) at baseline, 
then tralokinumab 300 mg Q2W.
x
Tralokinumab 150 mg Q2W: tralokinumab 300 mg (loading dose) at baseline, 
then tralokinumab 150 mg Q2W.
x
Placebo Q2W: placebo (loading dose) at baseline, then placebo Q2W.
To ensure blinding, all treatment groups will receive the same number of injections at each 
visit. Thus, the tralokinumab 150 mg group will receive both tralokinumab and placebo 
injections at all dosing visits.
Maintenance treatment period (Week 16 to Week 52)
Subjects achieving a clinical response at Week 16 without use of rescue treatment (from 
Week 2 to Week 16) will continue into maintenance treatment that runs until Week 52.
Clinical response is defined as IGA of 0 or 1, or at least 75% reduction in EASI score from 
baseline (EASI75). 
Subjects randomised to tralokinumab in the initial treatment period will be re-randomised 1:1 
to one of the following maintenance regimens stratified by region and IGA response at 
Week 16 (IGA 0/1 or IGA >1). 
Subjects initially randomised to tralokinumab 300 mg will receive:
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x
Tralokinumab 300 mg Q2W.
x
Tralokinumab 300 mg Q4W: alternating dose administrations of tralokinumab 
300 mg or placebo.
Subjects initially randomised to tralokinumab 150 mg will receive:
x
Tralokinumab 150 mg Q2W.
x
Tralokinumab 150 mg Q4W: alternating dose administrations of tralokinumab 
150 mg or placebo.
Subjects randomised to placebo in the initial treatment period who achieve a clinical response 
at Week 16 without use of rescue treatment from Week 2 to Week 16 will continue to receive 
placebo Q2W in the maintenance treatment period.
Open-label treatment (Week 16 to Week 52)
Subjects without clinical response at Week 16 and subjects who have received rescue 
treatment from Week 2 to Week 16 will be transferred to open-label treatment (tralokinumab 
300 mg Q2W with optional use of TCS and/or TCI) at Week 16, if considered appropriate by 
the investigator.
In addition, subjects may be transferred from maintenance treatment to open-label treatment if 
they meet any of the criteria listed below, and if considered appropriate by the investigator. 
Transfer to open-label treatment may occur at any visit from Week 16 while the subject is in 
the maintenance treatment period.
Subjects with IGA=0 at Week 16:
x
IGA of at least 2 and not achieving EASI75 over at least a 4-week period (i.e., 
over 3 consecutive visits).
Subjects with IGA=1 at Week 16:
x
IGA of at least 3 and not achieving EASI75 over at least a 4-week period (i.e., 
over 3 consecutive visits).
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Subjects with IGA >1 at Week 16:
x
Not achieving EASI75 over at least a 4-week period (i.e., over 3 consecutive 
visits).
Subjects who receive rescue treatment:
x
If rescue treatment is administered during the maintenance treatment period, 
subjects should be transferred to open-label treatment.
For subjects who receive systemic rescue treatment, the open-label treatment 
may not be initiated sooner than 5 half-lives after the last dose of the systemic 
rescue treatment.
Subjects who are transferred to open-label treatment will continue their scheduled visit 
sequence. The open-label treatment will extend to Week 52 (last dose administered at 
Week 50).
Safety follow-up period (Week 52 to Week 66)
After completion of the treatment periods or premature discontinuation of IMP, all subjects 
will complete an off-treatment follow-up period for the assessment of safety, PK, and 
immunogenicity (i.e. ADA), except subjects who transfer to ECZTEND before Week 66 (see 
below). During follow-up, subjects will be allowed to receive standard of AD care (excluding 
biologic therapies) at the investigator’s discretion, if needed.
Long-term extension trial (LP0162-1337, ECZTEND)
Eligible subjects from selected countries 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 52) under the current 
protocol (LP0162-1334). Subjects may enter ECZTEND up to 26 weeks from their last IMP 
injection in the present trial (Week 50) to their first IMP injection in ECZTEND (baseline). 
Subjects may therefore enter ECZTEND (baseline) without completing the safety follow up 
visit (16 weeks after their last IMP injection) in the present trial, and those subjects will have 
their safety follow-up visit in ECZTEND.
Analysis of data per last subject’s last Week 52 visit
To fulfil the commitments in the paediatric investigation plan (PIP) and the paediatric study 
plan (PSP), the trial will be unblinded to an analysis group once all randomised subjects have 
completed the Week 52 visit and available data will be analysed and reported (See 
Section 9.3.1 for details).
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7.2 Number of subjects needed
Assuming a screening failure rate of 25%, approximately 392 subjects will be screened and 
approximately 294 subjects will be randomly assigned to the initial treatment period (1:1:1 to 
tralokinumab 300 mg, tralokinumab 150 mg, or placebo). 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 maintenance treatment period. Randomisation and re-
randomisation will be handled using the interactive response technology (IRT) to ensure 
continued blinding in the trial.
The statistical power considerations for this sample size are described in Section 14.1.
This trial will be conducted at approximately 80 sites in Europe, North America, Australia, 
and Japan. The anticipated minimum number of randomised subjects per trial site is 3 and the 
maximum number of subjects per trial site 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 final safety follow-up visit at Week 66. Subjects who enter the long-term 
extension trial (LP0162-1337, ECZTEND) after completion of the end of treatment visit 
(Week 52) 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.
Final collection of data for the primary endpoint occurs at Week 16.
7.4 Software
CDISC controlled terminology dated 22-Dec-2017 (or newer) was used for definition of 
controlled terminology throughout this protocol and will be used for statistical programming 
and output. Study Data Tabulation Model (SDTM) version 1.4 and SDTM implementation 
guide version 3.2 will be used for data tabulations.
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8 Trial population
8.1 Subject eligibility
The investigator should only include 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. 
Hence, subjects are expected to complete wash-out of previous AD medications without 
experiencing intolerable worsening of AD symptoms during the screening period.
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Panel 2. It will be recorded in the electronic case report 
form (eCRF) if the subject has met all the inclusion criteria and none of the exclusion criteria.
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
institutional review boards (IRBs) / independent ethics committees (IECs), as applicable.
8.2 Inclusion criteria
For inclusion into this trial, subjects must fulfil all of the following criteria:
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. Signed and dated informed consent must be provided by the subject’s 
legal representative(s) and by the subject (as applicable according to national laws or 
regulations).
2. Age 12 to 17 years.
3. Body weight at baseline ≥30.0 kg.
4. Diagnosis of AD (as defined by Hanifin and Rajka [1980] criteria for AD [36; 
Appendix 4]).
5. History of AD for ≥1 year.
6. History of TCS (Europe: potent/Class 3 or higher; US: mid-strength/Class 4 or lower 
[Appendix 6]) and/or TCI treatment failure (due to inadequate response or intolerance) 
or subjects for whom these topical AD treatments are medically inadvisable.
7. AD involvement of ≥10% body surface area at screening and baseline (visit 3) 
according to component A of SCORAD.
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8. An EASI score of ≥12 at screening and ≥16 at baseline.
9. An IGA score of ≥3 at screening and at baseline, equivalent to moderate-to-severe AD.
10. An Adolescent Pruritus numeric rating scale (NRS) average score of ≥4 during the 
week prior to baseline.
x
Adolescent Pruritus NRS at baseline will be calculated from daily assessments 
of worst itch (Adolescent Pruritus NRS) during the 7 days immediately 
preceding randomisation (Day -6 to 0). A minimum of 4 Adolescent 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.
11. Subjects must have applied a stable dose of emollient twice daily (or more, as needed) 
for at least 14 days before randomisation.
12. Female subjects must be of either:
x
Non-childbearing potential, i.e. premenarchal or have a confirmed clinical 
history of sterility (e.g. the subject is without a uterus or has tubal litigation).
x
Childbearing potential (defined as Tanner stage ≥3 or menarche) provided 
there is a confirmed negative pregnancy test at screening and randomisation to 
rule out pregnancy.
13. Female subjects of childbearing potential must use a highly effective* form of birth 
control throughout the trial and for at least 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).
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8.3 Exclusion criteria
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Current participation in any other interventional clinical trial.
2. Previously screened in this clinical trial.
3. Previous randomisation in tralokinumab trials.
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 immunomodulatory medications or bleach baths within 
4 weeks prior to randomisation:
x
Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, 
cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitors).
x
Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).
x
3 or more bleach baths during any week within the 4 weeks.
8. Treatment with the following topical medications within 2 weeks prior to 
randomisation:
x
TCS.
x
TCI.
x
Topical PDE-4 inhibitor.
9. Receipt of live attenuated vaccines within 30 days prior to the date of randomisation 
and during the trial including the safety follow-up period:
x
Receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed, 
provided they are not administered within 5 days before/after any trial visit.
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10. Receipt of any marketed biological therapy or investigational biologic agents 
(including immunoglobulin, anti-IgE, or dupilumab):
x
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.
x
Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to 
randomisation.
11. Subjects who have received treatment with any non-marketed drug substance (that is, 
an agent which has not yet been made available for clinical use following registration) 
within 3 months or 5 half-lives, whichever is longer, prior to randomisation.
12. Inability or unwillingness to receive IMP injections at randomisation.
13. Receipt of blood products within 4 weeks prior to screening.
14. 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.
15. Major surgery within 8 weeks prior to screening, or planned inpatient surgery or 
hospitalisation during the trial period.
16. Known or suspected hypersensitivity to any component of the IMP.
17. History of any active skin infection within 1 week prior to randomisation.
18. 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:
x
A systemic infection.
x
A serious skin infection requiring parenteral (intravenous or intramuscular) 
antibiotics, antiviral, or antifungal medication.
19. 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.
20. History of anaphylaxis following any biological therapy.
21. History of immune complex disease.
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22. History of cancer:
x
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.
x
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.
23. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation 
will be according to local guidelines as per local standard of care.
24. 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.
25. Subject or subject’s legally authorised representative(s) known or suspected of being 
unlikely to comply with the clinical trial protocol (e.g., due to alcoholism, drug 
dependency or psychotic state) in the opinion of the investigator.
26. History of attempted suicide or 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).
27. Any disorder which is not stable and in the investigator’s opinion could:
x
Affect the safety of the subject throughout the trial.
x
Influence the findings of the trial.
x
Impede the subject’s ability to complete the trial.
Examples include but are not limited to cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
immunological, and psychiatric disorders and major physical impairment.
28. Any abnormal finding which in the investigator’s opinion may:
x
Put the subject at risk because of their participation in the trial.
x
Influence the results of the trial.
x
Influence the subject’s ability to complete the trial.
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The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis.
29. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times 
the upper limit of normal (ULN) at screening.
30. 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.
31. Subjects afraid of blood withdrawals or unwilling to comply with the assessments of 
the trial.
32. Subject or subject’s legally authorised representative(s) has a language barrier, mental 
incapacity, unwillingness or lacking ability to understand the trial-related procedures.
33. Subjects who are legally institutionalised.
34. Female subjects who are pregnant or lactating.
35. Female subjects of childbearing potential who are sexually active but unwilling to use 
adequate methods of contraception.
36. 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 Screening and screening failures
Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to 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 IRT system 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.
Subjects for whom the subject’s legally authorised representative(s) have given written 
informed consent for their participation in the trial (including subjects who have given written 
assent to participate in the trial, as appropriate and according to national laws and regulation) 
and who have been assigned a subject ID are considered ‘screened’ subjects.
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The investigator will maintain a log of all consented subjects at the trial site (subject 
identification list). This log will include each subject’s identity, date of consent, and 
corresponding subject ID so that any subject may be identified if required for any reason. The 
log must not be copied or retained by LEO. In addition, the investigator will maintain a log of 
all subjects considered for screening, whether written informed consent (and assent [as 
appropriate and according to national laws and regulation]) has been provided or not 
(screening log). This log will be anonymous and will include the reason(s) for not entering the 
trial, if applicable, or the allocated subject ID.
Screening failures 
Screening failures are defined as subjects for whom consent to participate in the trial has been 
obtained but who 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 (37) and to respond to queries from regulatory authorities.
The following data will be collected in the eCRF for screening failures:
x
Date of informed consent.
x
Demographics (age, sex, ethnicity, race).
x
Reason for screen failure:
o
Failure to meet randomisation criteria.
o
Lost to follow-up.
o
Withdrawal by subject.
o
Withdrawal by parent/guardian.
o
Other.
x
Date of screen failure.
x
Any adverse events (AEs) and serious AEs (SAEs).
In case of any SAEs, these must be followed up as described in Section 13.7.
Re-screening of screening failures is not allowed. 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 eCRF). Individuals who are 
re-screened will get a new subject ID.
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9 Treatments
9.1 Trial product description
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 accessorised pre-filled syringe (see Panel 7 for further details).
Panel 7: Identification of investigational medicinal products
IMP
Dosage form
Active ingredient and 
concentration
Pack size
Source
Tralokinumab
Solution for 
injection
Nominal concentration of 
tralokinumab 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.
1.0 mL pre-filled 
accessorised 
syringe1
MedImmune
Placebo
Solution for 
injection
Placebo contains the same 
excipients, in the same 
concentration only lacking 
tralokinumab.
1.0 mL pre-filled 
accessorised 
syringe1
MedImmune
1.
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.
Abbreviations: IMP, investigational medicinal product.
No active comparators will be used in this trial.
9.2 Administration of IMP
The IRT will assign the required kit numbers for each subject at each dispensing visit.
Dosing visits are shown in the schedule of trial procedures (Section 4). The last administration 
of IMP will occur at Week 50. To ensure blinding, all treatment groups will receive the same 
number of injections at each visit; thus, the tralokinumab 150 mg group will receive both 
tralokinumab and placebo injections at all dosing visits.
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The first day of dosing is considered Day 0 (visit 3, baseline). Each subject will receive 4 SC 
injections (each of 1 mL) to receive a loading dose of tralokinumab or placebo. At subsequent 
visits in the initial treatment period, each subject will receive 2 SC injections (each of 1 mL).
Hence, subjects in the initial treatment period will receive either:
x
Tralokinumab 300 mg Q2W: tralokinumab 600 mg (4 mL) at baseline, then 
tralokinumab 300 mg (2 mL) Q2W.
x
Tralokinumab 150 mg Q2W: tralokinumab 300 mg (2 mL) + placebo (2 mL) at 
baseline, then tralokinumab 150 mg (1 mL) + placebo (1 mL) Q2W.
x
Placebo Q2W: placebo (4 mL) at baseline, then placebo (2 mL) Q2W.
At Week 16, subjects with a clinical response (achieved without use of rescue treatment from 
Week 2 to Week 16) will continue to receive 2 SC injections (each of 1 mL) of maintenance 
treatment until Week 50:
x
Tralokinumab Q2W:
o
Tralokinumab 300 mg: tralokinumab 300 mg (2 mL).
o
Tralokinumab 150 mg: tralokinumab 150 mg (1 mL) + placebo 
(1 mL).
x
Tralokinumab Q4W (alternating dose administrations of tralokinumab and 
placebo):
o
Tralokinumab 300 mg: tralokinumab 300 mg (2 mL) or 2 mL 
placebo.
o
Tralokinumab 150 mg: tralokinumab 150 mg (1 mL) + placebo 
(1 mL) or 2 mL placebo.
x
Placebo Q2W: 2 SC injections (each 1 mL) of placebo.
Subjects who are transferred to open-label treatment will receive 2 SC injections (each 1 mL) 
of tralokinumab 150 mg at each dosing visit.
IMP will be administered by a qualified, unblinded healthcare professional (HCP; see 
Section 9.3.1 for blinding details). A minimum interval of 7 days is required between 2 dosing 
visits. No specific treatment for an overdose is recommended. The investigator will use 
clinical judgement to treat any overdose if necessary. See Section 13.6.2 for further details 
regarding overdose.
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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 an IMP 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 in open-label treatment, subjects will be monitored prior to and after IMP administration 
for immediate drug reactions for a minimum of 2 hours with vital signs taken every 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) (38). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5. 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 rescheduling of IMP administration 
If any of the following should occur, the investigator should reschedule the visit and IMP 
should not be administered until the rescheduled visit:
x
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).
x
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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9.3 Treatment assignment
Randomisation 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised centrally at baseline (Day 0) to receive treatment 
with either tralokinumab 300 mg, tralokinumab 150 mg, or placebo, stratified by baseline 
disease severity (IGA 3 or 4) and region (Europe, North America, Australia, and Japan).
Subjects eligible for the maintenance part of the trial will be re-randomised to maintenance 
treatment at Week 16. Subjects randomised to tralokinumab (150 or 300 mg) who have a 
clinical response at Week 16 (i.e. IGA 0/1 or EASI75, achieved without use of rescue 
treatment from Week 2 to Week 16), will be re-randomised to the maintenance treatment 
period at the randomised dose 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 (achieved without use of rescue treatment from 
Week 2 to Week 16) will continue on placebo.
Subjects who are not eligible for the maintenance part of the trial will be transferred to open-
label tralokinumab 300 mg Q2W treatment (with optional TCS and/or TCI use), if considered 
appropriate by the investigator.
The IRT will be used to control randomisation, re-randomisation, and stratification factors, 
along with IMP supply chain and expiry tracking.
9.3.1 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 Pharma 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 
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assessments. If needed, the unblinded HCP may perform the safety assessments (except 
assessment of AEs) for subjects in open-label treatment.
If treatment allocation for a subject becomes known to the investigator or other trial staff 
involved in the management of trial subjects, LEO Pharma 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. See 
Section 9.10 for details on reporting of product complaints.
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.
Analysis of data per last subject’s Week 52 visit
To fulfil the commitments in the PIP and the PSP, an analysis of trial data up to and including 
visit 29 (Week 52) will be performed and will require unblinding of data. To perform this 
analysis, an analysis group consisting of Clinical Pharmacologists, Medical Experts, Safety 
Advisors, Statisticians, Statistical Programmers and Medical Writers will be unblinded to 
individual subject treatment allocation following database lock for the 52-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.
9.3.2 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, HCPs who are not members of the trial staff, or authorised LEO 
Pharma 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 
IRT. For a requester who is not a member of the trial staff and who does not have access to the 
IRT (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 
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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 divert the requester to the medical cover.
9.4 Background treatment
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. Subjects must continue their background emollient treatment throughout the trial.
9.5 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. Prohibited medications 
and procedures are described in Section 9.7.
Subjects who receive topical rescue treatment (TCS of any WHO class [see Appendix 6], or 
TCI) will continue treatment with IMP.
If possible, investigators should attempt to limit the first step of rescue treatment to topical 
treatments, and escalate to systemic treatments only for subjects who do not respond 
adequately after at least 14 days of topical treatment. However, systemic rescue treatment 
may be instituted immediately, if considered appropriate by the investigator.
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 10.2.2, reasons for temporary 
discontinuation of IMP). After the treatment with these medications is completed, IMP may 
be resumed if deemed appropriate by the investigator, but not sooner than 5 half-lives after the 
last dose of systemic rescue treatment. The use of biological rescue treatment will be 
disallowed for the entire trial duration.
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.
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If rescue treatment is administered from Week 2 to Week 16 in the initial treatment period, the 
subject does not qualify for the maintenance part of the trial and will be transferred to open-
label treatment at Week 16, if considered appropriate by the investigator. If rescue treatment is 
administered during the maintenance treatment period (from Week 16 to Week 50), the subject 
will be transferred to open-label treatment, but not sooner than 5 half-lives after the last dose 
of systemic rescue treatment.
Open-label tralokinumab arm only 
Subjects in the open-label treatment arm may use mild to moderate strength TCS and/or TCI 
as needed on lesional skin at the investigator’s discretion (see Appendix 6 for TCS 
classification and examples), from Week 16 through safety follow-up (Week 66). Use of TCS 
and TCI should be recorded as concomitant medication in the eCRF (see Section 9.6 below 
for further details).
9.6 Concomitant medication and concurrent procedures
Any medication or vaccine that the subject receives from 3 months prior to screening through 
safety follow-up (Week 66) must be recorded in the subject’s medical record and the eCRF 
along with details such as:
x
Medication name.
x
Indication.
x
Start and stop date of administration (it will also be recorded if the medication is 
ongoing).
x
Dosage information, including dose, unit, and frequency.
x
Route of administration.
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded: procedure, condition, diagnosis, and start 
and stop date (it will also be recorded if the procedure is ongoing). Note: in this trial, only 
surgical procedures and procedures related to AD treatment (e.g. phototherapy or bleach 
baths) will be recorded.
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy.
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The following concomitant medications related to AD treatment are permitted from screening 
through safety follow-up (Week 66):
x
Oral antibiotics, antiviral, or antifungal therapy for skin infections as appropriate.
x
Stable doses of an emollient (subjects must apply such emollients twice daily [or 
more, as needed] for at least 14 days before baseline and throughout trial 
participation).
x
Oral antihistamines.
9.7 Prohibited medication and procedures
The medications and procedures below are prohibited during the trial. For specifications on 
allowed rescue treatment for AD symptoms, please refer to Section 9.5. Please note that 
medications and procedures disallowed prior to randomisation are covered in the exclusion 
criteria (see Section 8.3).
From randomisation through end of treatment (Week 52):
x
TCS of any WHO class (except for subjects in open-label treatment).
x
TCI (except for subjects in open-label treatment).
x
Phosphodiesterase 4 (PDE-4) inhibitors.
x
UVA or UVB, psoralen + UVA (PUVA), other phototherapy, or tanning beds.
x
3 or more bleach baths per week.
From randomisation through safety follow-up (Week 66) or until first IMP injection in the 
long-term extension trial (LP0162-1337, ECZTEND):
x
Systemic corticosteroids (nasal, ophthalmic, and inhaled corticosteroids are allowed).
x
Systemic treatment with an immunosuppressive/immunomodulating agent (e.g. 
cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, Janus kinase 
inhibitors, interferon-gamma, dupilumab, or other biologics).
In case prohibited systemic medications are received, IMP dosing must be suspended as 
described in Section 10.2.2. 
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The sponsor’s medical expert must be notified if a subject receives any of the following 
prohibited medications from randomisation through safety follow-up (Week 66):
x
Investigational agents other than tralokinumab.
x
Immunoglobulin or blood products.
x
Allergen immunotherapy.
x
Live (attenuated) vaccine.
The sponsor’s medical expert will determine whether IMP discontinuation is required. Please 
note that receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed, provided 
they are not administered within 5 days before/after any trial visit.
In case any prohibited treatments are used during the trial, they must be recorded as 
concomitant medication (Section 9.6).
9.8 Treatment logistics and accountability
9.8.1 Labelling and packaging of trial products
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.
9.8.2 Storage of trial products
All LEO Pharma 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 2-8°C at the trial site. The temperature during storage should 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.
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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:
x
Temperature excursion upon receipt or during storage at the trial site.
x
Damaged kit upon receipt.
x
Damaged syringe.
Damaged IMP should be documented in the IRT and reported as a product complaint to 
Global Safety, LEO Pharma (see Section 9.10). Damaged IMP may not be used.
Further details regarding IMP storage (including handling of temperature excursions upon 
receipt or during storage at the trial site) and handling of damaged IMP (including kits 
damaged upon receipt) are provided in the IMP handling manual.
9.8.3 Drug 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.
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable.
An inventory must be kept of the IMP administered to each subject randomised in the trial. 
This inventory must be available during monitoring visits and will be checked by the CRA to 
verify correct dispensing of the IMP. Full drug accountability will be performed in the IRT.
The trial site will maintain trial kit cartons from used kits until reconciliation. Used kits can 
be stored at room temperature and must be stored separately from non-allocated trial product. 
The IMP must be fully accounted for by the CRA with the help of the unblinded HCP. 
Following reconciliation, the trial kit cartons from used kits may be discarded.
All unused IMP supplied by the contract manufacturing organisation (CMO) on behalf of 
LEO Pharma will be returned to the CMO. Prior to their return, the IMP must be fully 
accounted for by the CRA with the help of site staff responsible for dispensing the IMP. 
Accountability must be documented in the IRT.
Reporting in eCRF 
In the eCRF, the IMP kit numbers as well as the date and time of IMP administration will be 
recorded. In addition, the site of IMP injection should be given.
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9.8.4 Treatment compliance
All IMP injections will be performed by site staff (unblinded HCP) who will also keep the 
accountability records up to date. Any non-compliance and the reason for it must be recorded 
in the eCRF.
9.8.5 Trial product destruction
Used and unused IMP will be destroyed by the CMO according to approved procedures 
and/or local requirements.
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 IMP 
in sharps bins which will be shipped to the CMO.
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 from selected countries who qualify for the long-term 
extension trial (LP0162-1337, ECZTEND) may be offered participation (see Section 7.1). 
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 Safety at LEO 
Pharma on the trial-specific (paper) Complaint Form within 3 days of first knowledge.
Critical complaints (defined as any defect, issue, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., SAE or large particles in the syringe]) must 
be reported to Global Safety, LEO Pharma within 24 hours.
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 device deficiency will be reported by the investigator as described in 
Sections 13.3 and 13.4.
Refer to the IMP handling manual for information on how to update the kit status in the IRT.
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During the investigation of the product complaint, the IMP or device must be stored at 
labelled conditions unless otherwise instructed; the trial site will be notified whether the IMP 
or device needs to be returned for further investigation or may be destroyed.
Global Safety, LEO Pharma contact information for reporting product complaints:
Fax number: +45 7226 3287
Email address: drug.safety@leo-pharma.com
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10 Discontinuation and withdrawal
10.1 General principles
A subject may permanently discontinue trial treatment (IMP) or withdraw from the trial at any 
time (prior to first dose or during the treatment period) if the subject, the subjects’ legally 
authorised representative(s), the investigator, or LEO Pharma considers that it is not in the 
subject’s best interest to continue.
In order to obtain the most representative efficacy evaluation of tralokinumab in adolescents, 
it is key to assess the efficacy status of each trial participant at the planned primary endpoint 
visit (nominal Week 16 visit [visit 11x, Panel 2]), irrespective of whether the subject has 
discontinued IMP or not. Therefore, permanent discontinuation of IMP is evaluated as a 
separate occurrence that does not necessitate that the subject also withdraws from the trial. 
This is to enable selected subsequent trial visits to be conducted, including the nominal 
Week 16 visit (if discontinuation of IMP occurs prior to Week 16).
Hence, permanent discontinuation of IMP and withdrawal from trial are considered to be 
2 (potentially) separate occurrences:
x
Permanent discontinuation of IMP occurs when all further trial treatment is 
stopped. The subject will continue to participate in selected trial visit activities 
as outlined in Section 10.2.1.
x
Withdrawal from trial occurs when stop of all trial activities takes place 
before the last planned safety follow-up visit (Week 66). This may either 
happen at the time of permanent discontinuation of IMP or later.
Subjects who permanently discontinue IMP and subjects who withdraw from the trial will not 
be replaced.
10.2 IMP discontinuation rules
10.2.1 Reasons for permanent discontinuation of IMP
Subjects will permanently discontinue IMP in the event of:
x
Anaphylactic reaction or other severe systemic reaction to IMP injection.
x
An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing.
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x
Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the 
cervix, or localised squamous or basal cell carcinoma of the skin.
x
Evidence of pregnancy.
x
Any infection that is opportunistic, such as active tuberculosis and other 
infections whose nature or course may suggest an immuno-compromised 
status.
x
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 in open-label treatment (tralokinumab 300 mg Q2W with optional use of TCS and/or 
TCI) who in the opinion of the subject, the subjects’ legally authorised representative(s), or 
investigator have unacceptable treatment effect of tralokinumab may discontinue open-label 
treatment and enter the safety follow-up period.
10.2.2 Reasons for temporary discontinuation of IMP
IMP dosing may be temporarily suspended in the event of:
x
Other intercurrent illnesses or major surgery.
x
An infection that requires parenteral treatment with antibiotic, antifungal, 
antiviral, anti-parasitic, or anti-protozoal agents.
x
Treatment with systemic corticosteroids or non-steroidal 
immunosuppressive/immunomodulating medications (e.g., cyclosporine, 
methotrexate, azathioprine, mycophenolate mofetil, Janus kinase inhibitors, 
biologic agents).
After the treatment with these medications is completed, IMP may be resumed if deemed 
appropriate by the investigator, but not sooner than 5 half-lives after the last dose of systemic 
therapy.
10.3 Early termination assessments
Permanent discontinuation of IMP
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. See 
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the schedule of trial procedures (Section 4) for data to be collected at these visits. The 
investigator will review any AEs which will be followed up according to Section 13.7, if the 
subject agrees.
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend:
x
Early termination visit.
x
Nominal Week 16 visit (16 weeks after randomisation).
x
Final 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:
x
Early termination visit.
x
Final safety follow-up visit (16 weeks after last administration of IMP).
Withdrawal from trial
A subject may withdraw from the trial at any time and for any reason. Subjects who withdraw 
from the trial should attend an early termination visit (if applicable), see the schedule of trial 
procedures (Section 4) for data to be collected at an early termination visit. The investigator 
will review any AEs which will be followed up according to Section 13.7, if the subject 
agrees. If a subject withdraws from the trial, they may request destruction of any samples 
taken and not tested, and the investigator must document this in the site’s trial records.
Data to be recorded in the eCRF
The primary reason for permanent discontinuation of IMP must be recorded in the medical 
records and on the end of treatment form in the eCRF. Similarly, the primary reason for 
withdrawal from trial must be recorded in the medical records and on the end of trial form in 
the eCRF. In both instances, the following reasons will be used in the eCRF: lack of efficacy, 
AE, withdrawal by subject, withdrawal by parent/guardian, lost to follow-up, death, other.
For subjects who do not attend the nominal Week 16 visit (visit 11x) or the safety follow-up 
visit, the primary reason for not attending these visits will be recorded in the medical records 
and in the eCRF using the following reasons: lack of efficacy, AE, withdrawal by subject, 
withdrawal by parent/guardian, lost to follow-up, death, other.
If ‘adverse event’ or ‘other’ is selected, a specification must be provided in the eCRF.
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10.4 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.
The following actions must be taken if a subject fails to return to the trial site for a required 
visit:
x
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 or not the subject wishes to continue 
in the trial.
x
Before a subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject. 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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11 Trial assessments and procedures
11.1 Overview
During the trial, there are 30 scheduled site visits at the clinic and 2 visits planned as 
telephone contacts for subjects attending the safety follow-up period. Evaluations to be done 
at each visit are shown in the schedule of trial procedures in Section 4:
x
Panel 2 includes the assessments during screening and initial treatment 
(including the nominal Week 16 visit [for subjects who permanently 
discontinue IMP prior to Week 16]).
x
Panel 3 includes the assessments during maintenance treatment.
x
Panel 4 includes the assessments for subjects who are transferred to open-label 
treatment.
x
Panel 5 includes the assessments during follow-up (including early termination 
and unscheduled visits).
Refer to Section 7.1 for further details on the trial design.
Assessments/procedures at any trial visit should be performed in the following order:
x
PROs in the following order:
1. Children’s Dermatology Life Quality Index (CDLQI).
2. Patient-Oriented Eczema Measure (POEM).
3. Adolescent Patient Global Impression of Severity (PGI-S [past week 
recall]).
4. Patient Global Impression of Change (PGI-C).
5. Hospital Anxiety and Depression Scale (HADS).
x
Investigator assessments (performed only by adequately trained investigators) 
in the following order:
1. SCORAD component C, then component A and B.
2. IGA.
3. EASI.
x
Safety and laboratory assessments (including PK and blood biomarkers).
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x
Other assessments (skin swabs, skin tape stripping [if applicable], 
transepidermal water loss [if applicable], height and weight).
x
Administration of IMP.
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).
Subjects participating in the trial will be under careful supervision of a principal investigator 
who must be 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.
AEs must be assessed by medically qualified personnel (Section 13.2).
To reduce inter-rater variability, the same investigator should preferably perform all the 
efficacy evaluations (IGA, EASI, SCORAD) for a given subject throughout the entire trial 
period.
The investigators performing the assessments must not be involved in the administration of 
IMP (Section 9.3.1).
11.2 Assessments performed only at screening/baseline
11.2.1 Demographics
The following demographic data will be recorded:
x
Age (in years) and year of birth.
x
Sex: female, male.
x
Race: American Indian or Alaska native, Asian, black or African American, native 
Hawaiian or other Pacific islander, white, other.
x
Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or 
Latino.
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11.2.2 Medical history
Relevant past and concurrent medical history must be recorded:
x
Skin disease history. All past and current skin disease history including but not 
limited to:
o
Alopecia.
o
Vitiligo.
o
Herpes simplex infection.
x
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.
x
Other medical and surgical history including concurrent diagnoses.
For each condition, diagnosis, or surgical procedure, the start date and stop date will be 
recorded; it will also be recorded if the condition, diagnosis, or surgical procedure is ongoing.
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria.
11.2.3 Body surface area involvement
The total body surface area affected by AD will be assessed by the investigator for each 
section of the body as component A of SCORAD (see Section 11.3.3) 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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11.2.4 Columbia-Suicide Severity Rating Scale
The C-SSRS Screening version is a rater-administered instrument used to assess severity of 
suicidal ideation and suicidal behaviour through a series of simple, plain-language 
questions (40). The C-SSRS must be completed at the screening visit to check that exclusion 
criterion no. 26 does not apply.
11.3 Efficacy assessments
11.3.1 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 8). The IGA score 
will be assessed according to the schedule of trial 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. The IGA is included in the efficacy assessment & C-SSRS 
manual.
Panel 8: 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).
Abbreviations: IGA, Investigator’s Global Assessment.
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11.3.2 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 (41). The EASI score will be assessed according to the schedule of 
trial 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. Details on the 
scoring of severity and extent of AD according to EASI are included in the efficacy 
assessment & C-SSRS manual.
The EASI is a composite index with scores ranging from 0 to 72, with higher values 
indicating more severe or more extensive condition. The index will be calculated as shown in 
Panel 9. 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 10. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 10) and by a weighting factor. The EASI 
score equals the sum of the scores obtained for each body region (Panel 9).
Panel 9: 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 )
x  AS
x 0.1
Trunk
( SS   +
SS   +
SS   +
SS )
x  AS
x 0.3
Upper extremities
( SS   +
SS   +
SS   +
SS )
x  AS
x 0.2
Lower extremities
( SS   +
SS   +
SS   +
SS )
x  AS
x 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 (42).
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Panel 10: Eczema Area and Severity Index 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
Note: half-steps (0.5, 1.5, 2.5) are allowed.
4
50% to 69% affected area
5
70% to 89% affected area
6
90% to 100% affected area
11.3.3 Scoring Atopic Dermatitis
The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with 
subjective symptoms (43). The maximum total score is 103, with higher values indicating 
more severe disease. SCORAD will be assessed according to the schedule of trial 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.
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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
11.3.4 Patient-reported outcomes
11.3.4.1 Overview
3 PROs will be assessed using an eDiary:
x
Eczema-related Sleep NRS.
x
Adolescent Pruritus NRS.
x
Adolescent Patient Global Impression of Severity (PGI-S [today recall]).
Subjects will receive eDiary training at the screening visit 14 days before baseline (Week -2; 
visit 2) and then start the eDiary.
In addition, 5 PROs will be completed by the subjects at the site:
x
CDLQI.
x
POEM.
x
Adolescent PGI-S (past week recall).
x
Patient Global Impression of Change (PGI-C).
x
HADS.
All PROs are included in the investigator trial file.
11.3.4.2 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 52.
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11.3.4.3 Adolescent Pruritus numeric rating scale
Subjects will assess their worst itch over the past 24 hours using an 11-point NRS 
(‘Adolescent Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
possible’. Subjects will complete the Adolescent Pruritus NRS as part of an eDiary each day 
in the morning from Week -2 until Week 52.
11.3.4.4 Adolescent Patient Global Impression of Severity (today recall)
The Adolescent PGI-S (today recall) is a single item designed to capture the subject’s 
perception of overall eczema symptom severity on the day of assessment on a 4-point 
categorical response scale (‘not bad at all’ to ‘very bad’). Subjects will complete this item as 
part of the eDiary each day in the morning from Week -2 until Week 16.
11.3.4.5 Children’s Dermatology Life Quality Index
The CDLQI questionnaire is designed and validated in subjects with dermatological 
conditions from 5 to 16 years (45-47). The CDLQI is available in text and cartoon versions 
(48-50). The text version will be used in this trial. It consists of 10 items addressing the 
subject’s perception of the impact of their skin disease on various aspects of their QoL over 
the last week such as dermatology-related symptoms and feelings, leisure, school or holidays, 
personal relationships, sleep, and the treatment (51). Each item is scored on a 4-point Likert 
scale (0 = ‘not at all’; 1 = ‘only a little’; 2 = ‘quite a lot’; 3 = ‘very much’). The item on 
school time (item 7) has one additional response category ‘prevented school’, which is also 
scored ‘3’. The total score is the sum of the 10 items (0 to 30); a high score is indicative of a 
poor QoL. The CDLQI will be completed at the trial site according to the schedule of trial 
procedures in Section 4.
11.3.4.6 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 (52). The tool consists of 7 items each 
addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and 
dryness). Subjects 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 at the trial site according to the schedule of 
trial procedures in Section 4.
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11.3.4.7 Adolescent Patient Global Impression of Severity (past week recall)
The Adolescent PGI-S (past week recall) is a single item designed to capture the subject’s 
perception of overall itch symptom severity over the past week on a 4-point categorical 
response scale (‘none’ to ‘severe’ The Adolescent PGI-S (past week recall) will be completed 
at the trial site according to the schedule of trial procedures in Section 4.
11.3.4.8 Patient Global Impression of Change
The PGI-C is a single item questionnaire designed to assess the subject’s impression of 
changes (44). The subjects select the one response from the response options (‘much better’, 
‘a little better’, ‘no change’, ‘a little worse’, or ‘much worse’) that best describes the overall 
change in their itch since they started IMP treatment. The PGI-C will be completed at the trial 
site according to the schedule of trial procedures in Section 4.
11.3.4.9 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 (53). 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 in Section 4.
11.4 Safety assessments
11.4.1 Vital signs
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the schedule of trial procedures (Section 4). Vital signs will be measured in a supine or 
sitting position following at least 5 minutes of rest.
For the first 3 IMP dosing visits in the initial treatment period (i.e., Weeks 0, 2, and 4) and in 
open-label treatment, subjects will be monitored prior to and after IMP administration for 
immediate drug reactions for a minimum of 2 hours with vital signs taken every 30 minutes or 
until stable, whichever is later (Section 9.2).
If an abnormal vital sign at screening is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator if the subject should be randomised 
into the trial (respecting exclusion criterion no. 28).
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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 false. If the third measurement confirms the first measurement 
(abnormal), the second measurement should be considered false. Only the last value measured 
and considered correct will be recorded in the eCRF.
Reporting in eCRF
Vital signs and the date and time they were measured will be recorded in the eCRF; if vital 
signs were not assessed, a reason should be given. Clinically significant abnormal vital signs 
at the screening visit will be documented as medical history in the eCRF. At subsequent visits, 
any clinically significant deterioration of a pre-existing condition as well as any new 
clinically significant sign, symptom, or illness will be reported as an AE in accordance with 
Section 13.3.
11.4.2 Physical examination
A thorough physical examination of the subject including whole body inspection of the skin; 
auscultation of heart, lungs and abdomen; palpation of the abdominal organs; and basic 
neurological status must be performed according to the schedule of trial 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. 28).
Reporting in eCRF
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’); if a physical examination was not performed, a reason should be 
given.
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a pre-
existing condition as well as any new clinically significant sign, symptom or illness will be 
reported as an AE in accordance with Section 13.3.
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11.4.3 Electrocardiogram
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 trial procedures (Section 4).
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. As a minimum, the 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 evaluation. If a result is abnormal at the screening 
visit and considered by the investigator to be clinically significant, it will be at the 
investigator’s discretion if the subject should be enrolled into the trial (respecting exclusion 
criterion no. 28); if such a subject is enrolled, the investigator will provide a justification in 
the medical record.
The collection and transmission of ECG data will be described in a separate ECG manual.
Reporting in eCRF
It will be recorded in the eCRF if an ECG was performed and, if applicable, the investigator’s 
assessment of ECG results (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’) based on the evaluation of the ECG report received from the ECG 
service company; if an ECG was not performed, a reason should be given.
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness will 
be reported as an AE in accordance with Section 13.3.
11.4.4 Laboratory testing
11.4.4.1 Overview
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4).
The evaluations shown in Panel 11 will be performed.
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investigator must evaluate all results outside the reference range (‘clinically significant’ or 
‘not clinically significant’) and sign and date the evaluation. The signed and dated version 
will be filed with the investigator’s trial documentation. Clinically significant abnormal tests 
(at randomisation and onwards) must be repeated to confirm the abnormality.
At each visit, the site staff will record in the eCRF if a sample was taken and, if applicable, 
the date and time as well as the investigator’s assessment of the results (‘normal’, ‘abnormal, 
not clinically significant’, ‘abnormal, clinically significant’). In addition, the subject’s age (in 
years) must be provided in the eCRF at each visit where chemistry, haematology, and, 
serology is sampled.
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 randomised into the trial 
(respecting exclusion criteria no. 28, 29, and 30).
A serum pregnancy test must be taken at the screening visit in female subjects of childbearing 
potential to rule out pregnancy prior to subject randomisation.
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial.
Tests performed at the trial site
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.
At each visit, the site staff will record in the eCRF if a urine sample was taken and, if 
applicable, the investigator’s assessment of the result (‘normal’, ‘abnormal’).
Female subjects of childbearing potential will have a urine pregnancy test performed at the 
trial site at baseline prior to randomisation. The test will be repeated every 4 weeks as shown 
in the schedule of trial procedures in Section 4. The date and the outcome of the urine 
pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). For female subjects who 
become of childbearing potential during the trial (defined as Tanner stage ≥3 [54] or 
menarche), the investigator must reassess whether contraceptive measures are in place (if 
applicable), perform a urine pregnancy test and conduct pregnancy testing hereafter according 
to the schedule of trial procedures (see Section 4).
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Reporting in eCRF
It will be recorded in the eCRF if clinical laboratory tests were performed; if the clinical 
laboratory tests were not performed, a reason should be given.
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness will 
be reported as an AE in accordance with Section 13.3.
11.4.5 Anti-drug antibody measurements
Blood samples will be collected to determine ADA levels at pre-determined time points 
according to the schedule of trial procedures (Section 4). It will be recorded in the eCRF if the 
sample was taken; if not, a reason will be provided.
Collection, handling and shipment instructions for ADA blood samples are provided in a 
laboratory manual.
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 an ADA 
bioanalytical report.
11.5  Pharmacokinetic assessments
Blood samples for PK assessments will be collected at the time points specified in the 
schedule of trial procedures (Section 4).
It will be recorded in the eCRF if the PK sample was taken; if not, a reason will be provided.
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.
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11.6 Pharmacodynamic assessments: blood biomarkers
All subjects will have blood samples taken for analysis of biomarkers according to the 
schedule of trial procedures (Section 4). It will be recorded in the eCRF if the biomarker 
samples were taken; if not, a reason will be provided.
Protein markers of inflammation will be measured and include, but are not limited to, CCL17 
(also known as thymus and activation regulated chemokine [TARC]) and IL-22. The blood 
sample taken for safety assessment of IgE (see Panel 11) will also be used for biomarker 
analysis. In addition, biomarker mRNA from whole blood will be assessed. In addition, 
mRNA expression in blood mononuclear cells will be measured to assess the response to 
treatment.
Collection, handling and shipment instructions for blood biomarker samples are provided in a 
separate laboratory manual.
11.7 Other assessments
11.7.1 Skin swabs: Staphylococcus aureus colonisation
Samples (skin swabs) will be taken from a representative lesion and from non-lesional skin 
according to the schedule of trial procedures (Section 4). It will be recorded in the eCRF if the 
skin swabs were taken; if not, a reason will be provided. In addition, the body location for 
each skin swab will be documented in the eCRF (upper limb, lower limb, trunk, head). Efforts 
will be made to swab the same lesional and non-lesional skin sites at all time points, even if 
the lesion has cleared.
Subjects should not shower, bathe, or otherwise wash the lesion and non-lesional skin where 
the swabs will be taken from, within 12 hours of sample collection.
S. aureus colonisation will be determined using quantitative real-time polymerase chain 
reaction. This will provide data on treatment effects on subclinical infections with S. aureus 
that is very frequent in AD patients. In addition, the skin microbiome will be characterised 
using next-generation sequencing.
Details regarding collection, handling and shipment instructions for skin swabs are provided 
in a separate laboratory manual.
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11.7.2 Skin barrier function
11.7.2.1 Skin tape stripping (selected trial sites)
At selected trial sites, skin tape strips will be collected from both lesional and non-lesional 
skin according to the schedule of trial procedures (Section 4). It will be recorded in the eCRF 
if the samples were taken including the time of sampling; if not, a reason will be provided. In 
addition, the body location for each skin tape strip will be documented in the eCRF (upper 
limb, lower limb, trunk, head). Efforts will be made to collect skin tape strips from the same 
lesional and non-lesional skin sites at all time points, even if the lesion has cleared.
Subjects should not use emollients on the skin areas where the skin tape strip samples will be 
taken from within 8 hours of sample collection.
Biomarkers of skin barrier integrity and skin inflammation will be assessed. These will 
include but are not limited to: ceramides and natural moisturising factors such as pyrrolidone 
carboxylic acid (PCA) and urocanic acid (UCA).
Collection, handling and shipment instructions for skin tape strip samples are provided in a 
separate laboratory manual.
11.7.2.2 Transepidermal water loss (selected trial sites)
At selected trial sites, transepidermal water loss (TEWL) will be assessed on a representative 
lesion and on non-lesional skin to evaluate skin barrier function. TEWL (in g/m2/h) will be 
measured at the clinic by a non-invasive assessment of skin evaporation according to the 
schedule of trial procedures (Section 4), using a Tewameter® or a similar device.
At each assessment, 3 measurements from a representative lesion and 3 measurements from 
non-lesional skin will be recorded in the eCRF. It will also be recorded if the TEWL 
assessment was performed including the time of assessment; if not, a reason will be 
provided.In addition, the body location for each TEWL assessment will be documented in the 
eCRF (upper limb, lower limb, trunk, head). Efforts will be made to perform TEWL 
assessments at the same skin sites (lesion and non-lesional skin) at all time points, even if the 
lesion has cleared.
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11.7.3 Height and weight
The subject’s height (without shoes) and the subject’s weight (in indoor clothing and without 
shoes) will be measured according to the schedule of trial procedures (Section 4).
11.8 Estimate of total blood volume collected
Blood samples will be drawn for haematology, biochemistry, serology, PK, ADA, and 
biomarkers. The total volume of blood to be drawn is approximately 110 mL. The largest 
volume of blood drawn at any visit during the trial is 21 mL, to be drawn at visit 11 
(Week 16).
11.9  End of trial
An end of treatment form will be completed in the eCRF for all subjects when they have had 
their last administration of IMP. This form will also be completed for subjects who 
permanently discontinue IMP and subjects who withdraw from trial (see Section 10.3 for 
early termination assessments).
It will be recorded on the end of treatment form if the subject completed the treatment. If not, 
the primary reason for permanent discontinuation of IMP must be recorded (see 
Section 10.2.1).
An end of trial form must be completed in the eCRF for all randomised subjects. The 
following data will be collected:
x
Did the subject complete the trial? If not, the primary reason for discontinuation 
from trial must be recorded (lack of efficacy, adverse event, withdrawal by subject, 
withdrawal by parent/guardian, lost to follow-up, death, other).
x
Did the subject attend the nominal Week 16 visit? If not, the primary reason for not 
attending the visit must be recorded (lack of efficacy, adverse event, withdrawal by 
subject, withdrawal by parent/guardian, lost to follow-up, death, other).
x
Did the subject attend the safety follow-up visit? If not, the primary reason for not 
attending the visit must be recorded (lack of efficacy, adverse event, withdrawal by 
subject, withdrawal by parent/guardian, lost to follow-up, death, other). 
x
Has the subject been transferred to the open-label ECZTEND trial (LP0162-1337)? 
If yes, which was the last visit (including phone call) the subject attended in this 
trial?
x
Date of last contact.
The end of trial form will be completed when the subject has had their last visit.
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11.10 Storage of biological samples
PK samples, blood biomarker samples, skin swabs, and skin tape strips (if applicable) 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 CTR.
Samples for ADA evaluation will be retained for as long as the quality of the material permits 
evaluation but for no longer than 15 years after marketing authorisation.
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12 Scientific rationale for trial design and appropriateness of assessments
Scientific rationale for trial design
LEO Pharma is aiming for a global paediatric development programme for tralokinumab, and 
the trial design of the present trial has been submitted to both the European (EMA and PDCO) 
and American health authorities (US Food and Drug Administration [FDA]) for review.
The trial is designed to evaluate the efficacy and safety of tralokinumab versus placebo in 
adolescent 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 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. 
Stratification by region (Europe, North America, Australia, and Japan) 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 differences in effects between genders and across the 
adolescent age range.
By using a placebo-controlled parallel-group design for the initial treatment period, 
superiority of tralokinumab to placebo can be investigated and will allow for a better 
understanding of tralokinumab efficacy in relation to PK in adolescents. This contrasts with a 
design where tralokinumab is used as add-on to best standard of care (e.g. TCS) where there 
will be confounding influence by the concomitant therapy on the efficacy assessments, 
particularly in case of unbalanced use. Precise dose-finding is essential because going forward 
unnecessary exposure should be avoided in adolescents and because the PK modelling also 
guides dose-selection for younger age groups in future paediatric trials with tralokinumab.
The most important inclusion criterion for entry into the trial is a diagnosis of AD (as defined 
by the Hanifin and Rajka 1980 criteria for AD) (36) 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.
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AD is a chronic condition and the 52-week treatment duration has been chosen to evaluate the 
maintenance of effect as well as the safety and tolerability of tralokinumab in adolescents 
with AD.
Appropriateness of assessments
The clinical efficacy of tralokinumab treatment will be assessed by IGA, EASI, and 
SCORAD:
x
IGA is a key instrument used in clinical trials to rate the severity of the 
subject’s global AD.
x
EASI is a validated measure used in clinical practice and clinical trials to 
assess the severity and extent of AD (41).
x
SCORAD is a validated tool to assess the extent and severity of AD lesions 
and subjective symptoms (43).
The 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, EU, and Japan.
Several validated patient-reported questionnaires (CDLQI, POEM, HADS) have been 
included to assess the efficacy of tralokinumab on patient-reported outcomes and HRQoL.
Blood concentrations of tralokinumab will be analysed using validated bioanalytical methods 
and standard PK parameters will be derived to evaluate the tralokinumab exposure in 
adolescents.
The pharmacodynamic effect of tralokinumab treatment will be assessed using established 
assays to quantify serum levels of selected cytokines (IL-22 and CCL17) as well as IgE. In 
this trial, biomarker mRNA expression will be analysed from blood mononuclear cells to 
assess the response to treatment and to identify new biomarkers of relevance for AD. In 
patients with AD, cytokine mRNA in blood mononuclear cells has been shown to be 
differentially expressed compared to healthy subjects (55).
Normal skin is colonised by a wide variety of microorganisms, including fungi, viruses, and 
bacteria. The skin microbiome is complex and diverse, and varies between individuals and 
anatomical sites (56). Staphylococcus aureus (S. aureus) colonisation has been proposed to 
play a key role in AD pathophysiology via bacterial production of specific virulence 
factors (57). Resolution of active disease in AD in response to therapy correlates with 
reduction of S. aureus colonisation and increases in microbiome diversity (58). Skin swabs on 
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lesional skin will be used for evaluating the effect of tralokinumab treatment on the skin 
microbiome. This method was also used in the tralokinumab phase 2b trial in adult subjects 
with moderate-to-severe AD to demonstrate that the frequency of subjects testing positive for 
S. aureus was lower following treatment with tralokinumab compared with placebo. Global 
analyses of microbiome diversity will also be included in a phase 3 trial in adults 
(LP0162-1325), with results expected in 2019. The present trial will, if considered 
appropriate, also use gene sequencing to identify specific microbial strains present on the skin 
and further characterise the treatment effects on the skin microbiome in adolescent subjects 
with AD.
AD is a recurrent form of dermatitis where subjects have a high susceptibility to itching and 
irritants or allergens even on non-lesional skin, which is characterised clinically by atopic dry 
skin and functionally by cutaneous barrier disruption and water deficiency. Previous studies 
have shown that the barrier-disrupted dry skin of AD patients mainly is attributable to 
significantly decreased levels of ceramides in the stratum corneum (59). Skin barrier function 
will be assessed (in a subgroup of subjects) using skin tape stripping and TEWL. The skin 
tape stripping is a minimally invasive method that has been used for assessment of biomarkers 
reflecting the integrity of the skin barrier in AD patients (60, 61) as well as for obtaining 
information about the inflammatory processes in the skin of AD patients (62). TEWL is a 
method used for assessing the impaired cutaneous permeability barrier of the stratum corneum 
in AD skin (60, 63). Systemic treatment of AD has been shown to improve the barrier 
integrity by decreasing TEWL (64).
Data on antibodies against tralokinumab (ADAs) will be collected and the potential for 
immunogenicity will be evaluated until 16 weeks after the last dose of tralokinumab, to 
ensure adequate wash-out (approximately 5 times the half-life). The serum samples for 
determination of presence or absence ADA will be analysed using a validated bioanalytical 
method.
Safety will be assessed using standard clinical methods of subject evaluations, such as AE 
monitoring, ECG, vital sign and clinical laboratory measurements.
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13 Adverse events
13.1 Definition and classification of adverse events
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1.
Classification of AEs in terms of severity, causality and outcome is defined in Appendix 2.
13.2 Collection of adverse event reports
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 IMP injection). For subjects entering the long-term 
extension trial (LP0162-1337, ECZTEND), any (S)AE with onset before the subject’s final 
visit in the LP0162-1334 trial should be reported in the LP0162-1334 trial. 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.
Refer to Sections 11.4.1 to 11.4.4 for principles for data entry in the eCRF.
13.3 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 (that is, 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 (it will 
also be recorded if the event is ongoing). In addition, it will be recorded if 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.
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Action taken with IMP: any action taken with IMP 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, concurrent procedure).
13.4 Reporting of serious adverse events
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. 
13.4.1 Investigator reporting responsibilities
Any SAE must be reported to LEO Pharma within 24 hours of first knowledge. The SAE 
report should be completed in accordance with the eCRF completion guidelines provided for 
the automatic transmission or the SAE report should be reported on the paper form (as 
applicable).
In case the eSAE section in the eCRF is unavailable, the SAE provided to the investigator 
should be reported using the (paper) SAE form according to the SAE form completion 
guidelines. The SAE form must be submitted immediately to the Sponsor (within 24 hours of 
first knowledge), by fax or email to Global Safety at LEO Pharma using the email address or 
fax number below:
Global Safety at LEO Pharma
Email address: drug.safety@leo-pharma.com
Fax number: +45 7226 3287
Once the eSAE is available again, all information from the paper SAE form must be 
transferred to the eSAE section.
If relevant, other information must be sent to Global Safety at LEO Pharma by fax or email 
using the email address or fax number above. Examples of such information are anonymised 
reports of diagnostic procedures, hospital records, or autopsy reports.
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The requested information must be reported to LEO Pharma in the follow-up 
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section in the eCRF, and the eCRF must be updated accordingly. In case the eSAE section in 
the eCRF is unavailable, the requested information must be provided via an updated SAE 
form sent by fax or e-mail (see contact details above) and the eCRF must be updated 
accordingly when the eSAE section becomes available. For subjects entering the long-term 
extension trial (LP0162-1337, ECZTEND), any SAE(s) with onset before the final visit in the 
present trial, must be reported in the LP0162-1334 trial eCRF, including any follow-up data 
requested by Global Safety. 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country.
SAEs occurring after the completion of the present clinical trial (i.e., after the last safety 
follow-up visit) should not be routinely sought or collected. However, such events should be 
reported to Global Safety at LEO Pharma (see contact details above) if the investigator 
becomes aware of them. For subjects who transfer to ECZTEND, SAEs occurring after the 
last visit in the present trial and up to entering ECZTEND (defined as baseline), must be 
recorded as medical history in ECZTEND.
13.4.2 LEO Pharma reporting responsibilities
Global Safety at LEO Pharma is responsible for assessing whether or not an SAE is expected. 
The relevant reference safety information document for this clinical trial is:
For the IMP, the investigator’s brochure, edition 17 and subsequent updates must be used.
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.
The IRBs/IECs will be notified of SAEs according to the current applicable legislation for the 
concerned countries.
For all non-US countries, the following reporting requirements apply: all SAEs which are 
assessed as causally related to the IMP(s) by either the investigator or LEO Pharma (ICH 
E2A Guideline), and which are unexpected (Suspected, Unexpected Serious Adverse 
Reactions [SUSARs]), are subject to expedited reporting to regulatory authorities, IECs/IRBs 
according to the current applicable legislation in the concerned countries. Investigators will be 
notified of the evolving safety profile of the IMP on an ongoing basis.
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For the US, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMP(s) by LEO Pharma (Guidance for Industry and Investigators - 
Safety Reporting Requirements for INDs and BA/BE Studies; Guidance for Clinical 
Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human 
Subject Protection) and which are unexpected (Serious and Unexpected Suspected Adverse 
Reactions [IND safety report]) are subject to expedited reporting to regulatory authorities, 
IRBs. Investigators will be notified of the evolving safety profile of the IMP on an ongoing 
basis.
13.5 Other events that require expedited reporting: pregnancy
Any pregnancy occurring during the clinical trial must be reported to LEO Pharma within 
24 hours of first knowledge using the (paper) Pregnancy Form (Part I). All pregnancies must 
be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Form (Part II) within 24 hours of first knowledge.
The completed Pregnancy Forms must be faxed or scanned and e-mailed to Global Safety at 
LEO. Contact details are given in Section 13.4.1.
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3).
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13.6  Reporting of other events
13.6.1 Adverse events of special interest
The events listed in Panel 12 are considered adverse events of special interest (AESIs) in this 
trial and will require additional details to be recorded in the eCRF. LEO Pharma may request 
that the investigator forward test results, as appropriate. An AESI may be serious (requiring 
expedited reporting, Section 13.4) or non-serious.
Panel 12: Adverse events of special interest
AESI 
Additional data to be recorded in the eCRF (if available1)
Eczema herpeticum
Skin findings:
x
Lesion type (papules, vesicles, crusts, eroded pits, 
other).
x
Disseminated/localised.
x
Location (face, scalp, back, chest, upper limb, lower 
limb, genitals).
x
Present in an area with visible eczema / no visible 
eczema / present in areas with and without eczema.
x
Monomorphic/polymorphic.
Confirmation of herpes simplex virus (not confirmed, PCR, 
viral culture, Tzanck, other).
Malignancy diagnosed after 
randomisation, excluding basal cell 
carcinoma, localised squamous cell 
carcinoma of the skin, and 
carcinoma in situ of the cervix
x
Histology report available.
x
Oncology assessment available.
x
Treatments (surgery, radiation, chemotherapy, 
other).
Skin infection requiring systemic 
treatment
x
Location (face, scalp, back, chest, upper limb, lower 
limb, genitals).
x
Outcome of pathogenic swab (positive, negative, not 
performed). 
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Panel 13: Adverse events of special interest (continued)
AESI 
Additional data to be recorded in the eCRF (if available1)
Conjunctivitis
x
Aetiology (viral, bacterial, allergic, unknown).
x
Bacterial culture outcome (for events with bacterial 
aetiology).
x
Diagnosis confirmed by ophthalmologist.
Keratoconjunctivitis
x
Aetiology (infectious, non-infectious, other, 
unknown).
x
Bacterial culture outcome (for events with bacterial 
aetiology).
x
Diagnosis confirmed by ophthalmologist.
Keratitis
x
Aetiology (infectious, non-infectious, other, 
unknown).
x
Bacterial culture outcome (for events with bacterial 
aetiology).
x
Diagnosis of herpes simplex keratitis (for events 
with viral aetiology).
x
Diagnosis confirmed by ophthalmologist.
1.
The 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.
Abbreviations: AESI, adverse event of special interest; eCRF, electronic case report form; PCR, polymerase 
chain reaction.
13.6.2 Overdose
An overdose is defined as a subject receiving a dose of IMP in excess of that specified in this 
protocol.
The term ‘overdose’ including a specification of why it occurred (accidental or intentional) 
must be documented on the AE form of the eCRF. In addition, AEs originating from overdose 
must be documented on a separate line. If the AE originating from the overdose qualifies as 
an SAE, expedited reporting is required (Section 13.4).
If the overdose is accidental and due to a device deficiency, the device deficiency must be 
reported as a product complaint as described in Section 9.10.
LEO Pharma does not recommend specific treatment for an overdose. The investigator will 
use clinical judgement to treat any overdose if necessary.
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13.6.3 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 
4 categories: wrong medication, wrong dose (including strength, form, concentration, 
amount), wrong route of administration, or wrong subject.
The medication error category 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. If the AE 
originating from the medication error qualifies as an SAE, expedited reporting is required 
(Section 13.4).
If the medication error is due to a device deficiency, the device deficiency must be reported as 
a product complaint as described in Section 9.10.
13.6.4 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. If the AE originating from 
misuse qualifies as an SAE, expedited reporting is required (Section 13.4).
13.6.5 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. If the AE originating from 
abuse qualifies as an SAE, expedited reporting is required (Section 13.4).
13.6.6 Aggravation of condition
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to screening must be reported as an AE. If the AE originating from aggravation of 
condition qualifies as an SAE, expedited reporting is required (Section 13.4).
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13.7 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, that is, the follow-up may continue 
beyond the end of the clinical trial. For SAEs which have stabilised and from which the 
subject cannot be expected to recover during the trial or the safety follow-up periods, for 
example chronic or stabilised conditions, the final outcome at the investigator's discretion 
should be reported as 'recovering/resolving' or ‘not recovered/not resolved’. In addition, a 
statement that the SAE has stabilised or is chronic should be added to the narrative 
description of the SAE on the SAE form.
13.8 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 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.” (65).
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 authorities, or IRBs/IECs.
The investigator must immediately inform LEO Pharma – 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 Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation.
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14 Statistical methods
14.1 Sample size
A total of 294 subjects will be randomised 1:1:1 to initial treatment (tralokinumab 300 mg, 
tralokinumab 150 mg, and placebo) in this trial. The sample size is chosen to provide a 
sufficient power for demonstrating efficacy of tralokinumab versus placebo for the primary 
endpoints.
Under the assumption that the IGA 0/1 responder rates at Week 16 for the tralokinumab 
300 mg dose and placebo are 30% and 10%, respectively, the power to detect a difference 
between tralokinumab 300 mg and placebo will be approximately 94% at a 2-sided 5.0% 
significance level.
Further, assuming corresponding responder rates of 40% and 15% for EASI75 at Week 16 
will imply a nominal power of approximately 98% to detect a difference between 
tralokinumab 300 mg and placebo for that endpoint.
The combined power for detecting a difference between tralokinumab 300 mg and placebo in 
both primary endpoints at a 5.0% significance level is then at least 92%.
For the tralokinumab 150 mg dose, the accumulated power for subsequently rejecting the 
2 hypotheses of no difference to placebo for the primary IGA 0/1 and EASI75 endpoints at a 
2.5% significance level becomes approximately 84% and 80%, when using the same 
assumptions as for the tralokinumab 300 mg dose.
14.2 Trial analysis sets
All screened subjects will be accounted for in the CTR.
All subjects randomised to initial treatment will be included in the full analysis set and will be 
analysed for efficacy. 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 (visit 11), and analyses based on the per protocol analysis set will be 
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:
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x
Receive no treatment with the IMP.
x
Have no assessment of IGA or EASI following start of treatment.
x
Are known to have taken the wrong IMP throughout the initial treatment period of 
the trial.
x
Do not fulfil the inclusion criteria no. 4, 7, 8, and 9.
A maintenance analysis set will be defined as all subjects who receive tralokinumab in the 
initial treatment period and who are re-randomised to maintenance treatment.
A safety analysis set will be defined by excluding subjects from the full analysis set who 
receive no treatment with IMP.
A maintenance safety analysis set will be defined as subjects in the full analysis set who 
receive maintenance treatment at Week 16 (visit 11).
An open-label safety analysis set will be defined as subjects in the full analysis set who 
receive open-label treatment.
Based on the above-mentioned rules, the inclusion/exclusion of subjects from the trial 
analysis sets will be documented in an analysis set definition document before breaking the 
randomisation code.
14.3 Statistical analysis
14.3.1 Disposition of subjects
Subject disposition will be presented separately for subjects in initial treatment and in 
maintenance treatment. For all randomised subjects, the reasons for permanent 
discontinuation of IMP and for leaving the trial in the initial treatment period will be 
presented by treatment group. Likewise, for subjects in the maintenance safety analysis set, 
the reasons for permanent discontinuation of IMP and for leaving the trial will be presented 
by the assigned treatment group at Week 16. For subjects in the open-label safety analysis set, 
the reasons for permanent discontinuation of IMP and for leaving the trial will be presented.
14.3.2 Demographics and other baseline characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented 
separately for all randomised subjects and for the maintenance analysis set. The presentations 
will be overall and by treatment group. Presentations of age, sex, ethnicity, race, baseline 
disease severity, and Adolescent Pruritus NRS weekly average at baseline will also be given 
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by region (Europe, North America, Australia, and Japan) 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.
14.3.3 Exposure and treatment compliance
Exposure
Exposure to treatment will be presented for the safety analysis set (initial treatment), the 
maintenance safety analysis set (maintenance treatment), and open-label safety analysis set 
(open-label 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 for the safety analysis set.
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 
maintenance safety analysis set (maintenance treatment) for each treatment group. Adherence 
will also be presented for the open-label safety analysis set (open-label treatment).
14.3.4 Multiple testing strategy
The overall type I error rate for the primary analysis of the primary estimands for the primary 
and secondary endpoints will be protected by a combination of hierarchical testing and Holm-
Bonferroni multiplicity adjustment. Two different multiplicity adjustment procedures will be 
used, a US submission procedure and a global (non-US) procedure. For a graphical 
presentation of the 2 procedures, see Panel 13 and Panel 14. 
In the global (non-US) procedure, within each dose level, the 2 co-primary endpoints, IGA 
0/1 and EASI75 at Week 16, will be tested hierarchically, followed by a Holm-Bonferroni 
adjustment of the testing of the 3 secondary endpoints.
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In the US procedure, within each dose level, the 2 co-primary endpoints and the secondary 
endpoint Pruritus at Week 16 will be tested hierarchically, followed by a Holm-Bonferroni 
adjustment of the testing of the 2 secondary endpoints, SCORAD and CDLQI at Week 16.
In both testing procedures, the 2 co-primary endpoints for the tralokinumab 300 mg dose will 
first be tested hierarchically at an overall 5% significance level, after which the significance 
level will be split evenly between:
x
Testing of the primary endpoints for the tralokinumab 150 mg dose and a Holm-
Bonferroni testing procedure for the secondary endpoints for the tralokinumab 300 
mg dose in the global (non-US) procedure.
x
Testing of the primary endpoints for the tralokinumab 150 mg dose and testing of the 
secondary endpoint Pruritus at Week 16 for the tralokinumab 300 mg dose in the US 
procedure.
Panel 13: Global (non-US) testing procedure for the primary and secondary endpoints
Note: To protect the family-wise type I error. The numbers in parentheses indicate significance levels that have 
been passed on from rejected hypotheses for the other tralokinumab dose level.
Abbreviations: CDLQI, Children’s Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema 
Area and Severity Index score; IGA, Investigator’s Global Assessment; SCORAD, SCORing Atopic 
Dermatitis.
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Panel 14: US testing procedure for the primary and secondary endpoints
Note: To protect the family-wise type I error. The numbers in parentheses indicate significance levels that have 
been passed on from rejected hypotheses for the other tralokinumab dose level.
Abbreviations: CDLQI, Children’s Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema 
Area and Severity Index score; IGA, Investigator’s Global Assessment; SCORAD, SCORing Atopic 
Dermatitis.
If all the hypotheses of no difference to placebo for the tralokinumab 300 mg dose are 
rejected, then the 2.5% significance level will be passed on to the testing of all the endpoints 
for the tralokinumab 150 mg dose. Similarly, if the hypotheses of no difference to placebo for 
all the endpoints of the tralokinumab 150 mg dose are rejected, the 2.5% significance level 
will be passed on to:
x
The Holm-Bonferroni testing procedure of the secondary endpoints for the 
tralokinumab 300 mg dose in the global (non-US) procedure.
x
The testing of all secondary endpoints for the tralokinumab 300 mg dose in the US 
procedure.
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14.3.5 Analysis of initial treatment
14.3.5.1 Analysis of primary efficacy endpoints
14.3.5.1.1 Overview
3 estimands addressing different aspects of the trial objectives will be defined:
x
Primary estimand: 'composite'.
x
Secondary estimand: 'hypothetical'.
x
Tertiary estimand: 'treatment policy'.
The applied estimands incorporate 2 main types of events that influence how the treatment 
effects are estimated:
x
Initiation of rescue treatment: Some of the estimands use rescue treatment (from the 
Week 2 visit to the Week 16 visit [hereinafter “Week 2 to Week 16”]) as an event that 
modifies the applied value of an endpoint, e.g. by defining a subject receiving rescue 
treatment as a non-responder.
x
Permanent discontinuation of IMP: This event occurs when a subject is permanently 
withdrawn from the treatment or the trial as described in Section 10.2.1. 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 treatment, 
the event type is used to modify an applied endpoint value.
All analyses will be based on the full analysis set unless otherwise specified.
14.3.5.1.2 Primary estimand: ‘composite’
The primary estimand for the primary endpoints will be:
x
Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks 
achieved without rescue treatment from Week 2 to Week 16, regardless of 
treatment discontinuation.
The primary estimand assesses the expected difference in response rates at Week 16 (defined 
as response obtained without use of rescue treatment from Week 2 to Week 16), resulting from 
initiation of a treatment regimen with tralokinumab 300 mg or 150 mg compared to a 
treatment regimen with placebo.
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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 treatment from Week 2 to Week 16 will be considered non-responders, 
reflecting an assumption that use of rescue treatment from Week 2 indicates failure of the 
randomised treatment to achieve response, and that a (possible) observed positive response 
after use of rescue treatment is not attributable to the randomised treatment. Missing data for 
subjects who did not attend the Week 16 visit and where rescue treatment has not been used 
prior to Week 16, will be imputed as non-responders.
The difference in response rates between the active tralokinumab arms and placebo will be 
analysed separately for each of the tralokinumab dose groups using the Cochran-Mantel-
Haenszel test stratified by region (Europe, North America, Australia, and Japan) and baseline 
disease severity (IGA 3 or 4). The treatment estimates and the corresponding 95% confidence 
intervals (CIs) will be presented. The null hypothesis of no difference in response rates 
between either tralokinumab dose and placebo will be tested against the 2-sided alternative 
that there is a difference.
The primary endpoints will be tested sequentially according to the test procedure outlined in 
Section 14.3.4.
Sensitivity analyses for the primary estimand 
2 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 treatment 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 treatment 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 
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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 will be repeated based on the per protocol 
analysis set.
14.3.5.1.3 Secondary estimand: ‘hypothetical’
The secondary estimand for the primary endpoints will be:
x
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 treatment was used from Week 2 
to Week 16.
The secondary estimand assesses the expected difference in response rates achieved when 
adhering to the tralokinumab treatment regimen with no rescue treatment used from Week 2 to 
Week 16 as compared to a placebo treatment regimen with no rescue treatment in the same 
period.
Primary analysis of the secondary estimand 
Data collected after permanent discontinuation of IMP or after use of rescue treatment from 
Week 2 to Week 16 will not be included 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 3 groups defined according to 
randomised treatment arm assuming that data are missing at random within each arm.
1. In each group, intermittent missing values will be imputed using last observation 
carried forward (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 (Europe, North 
America, Australia, and Japan), 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=11109934).
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 together 
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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 2 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.
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 3 groups defined according to 
randomised treatment arm assuming that data are 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=29099734).
2. An analysis of covariance (ANCOVA) model will be fitted to the EASI value at 
Week 2. The model will include effects of baseline EASI as a covariate, and region 
(Europe, North America, Australia, and Japan) 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=11109934).
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 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 2 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 (for both IGA 0/1 and 
EASI75) between either tralokinumab dose and placebo will be analysed using the Cochran-
Mantel-Haenszel test stratified by region (Europe, North America, Australia, and Japan) and 
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baseline disease severity (IGA 3 or 4). The estimates and standard errors from the 
100 analyses will for each comparison 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 or receive rescue 
treatment in the tralokinumab arms will resemble missing data from subjects in the placebo 
arm who do not discontinue IMP permanently or receive rescue treatment. The underlying 
assumption is that the effect of tralokinumab following rescue treatment or permanent 
treatment discontinuation is similar to the effect of placebo. It should be noted that this 
assumption is pronouncedly conservative in favour of placebo as it tends to minimise the 
differences between treatment arms.
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab arms as well as the placebo arm will be imputed from 
observed data in the placebo 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.
14.3.5.1.4 Tertiary estimand: ‘treatment policy’
The tertiary estimand for the primary endpoints will be:
x
Treatment difference in response rate after 16 weeks between tralokinumab 
and placebo regardless of rescue treatment and treatment discontinuation.
The tertiary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab and additional rescue treatment as 
compared to a treatment regimen with placebo and additional rescue treatment.
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 
6 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 
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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 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. 
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 disease 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.
14.3.5.2 Analysis of secondary efficacy endpoints
14.3.5.2.1 Overview
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 (yes/no) of Adolescent Pruritus NRS average 
score for the past week (hereinafter ‘Adolescent Pruritus NRS weekly average’) of at least 4 
from baseline to Week 16, and (iii) change from baseline to Week 16 in CDLQI score. 
Subject-reported worst daily itch over the last week prior to baseline will be used to calculate 
the baseline itch (see also inclusion criterion no. 10).
Reduction of Adolescent 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 3 estimands with 
the modification of the ANCOVA imputation model that reduction of Adolescent Pruritus 
NRS weekly average replaces EASI where preceding values are used as covariates.
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The change from baseline to Week 16 in SCORAD and CDLQI, respectively, are continuous 
endpoints and will be analysed as described below in Sections 14.3.5.2.2 and 14.3.5.2.3.
All analyses will be based on the full analysis set unless otherwise specified.
14.3.5.2.2 Primary estimand for the continuous secondary endpoints: 
‘hypothetical’
The primary estimand for the continuous secondary endpoints will be:
x
Treatment difference in change from baseline to Week 16 in SCORAD and 
CDLQI, respectively, if all subjects adhered to the treatment regimen in the 
sense that they did not discontinue IMP permanently and no rescue treatment 
was used from Week 2 to Week 16.
The primary estimand assesses the expected benefit when adhering to the tralokinumab 
treatment regimen with no rescue treatment from Week 2 to Week 16 as compared to a 
placebo treatment regimen with no rescue treatment in the same period.
Primary analysis of the primary estimand (continuous secondary endpoints) 
Data collected after permanent discontinuation of IMP or after use of rescue treatment from 
Week 2 to Week 16 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 are 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 either of the tralokinumab doses and placebo 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 treatment 
in the tralokinumab arms will resemble data from subjects from the placebo arm who do not 
discontinue treatment/receive rescue treatment. Imputation of missing data at Week 16 will be 
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done using a pattern mixture model where missing data in the tralokinumab arms as well as 
the placebo arm will be imputed from the placebo 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 CDLQI 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=29099734).
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 group. The model will include effects of 
baseline SCORAD as a covariate, and region (Europe, North America, Australia, and 
Japan) 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 
group as well as the tralokinumab groups (seed=11109934).
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 the SCORAD value at Week 2 included as an additional covariate. 
The parameters from the model will be estimated based on data from the placebo 
group. The estimated parameters, and their variances, will be used to impute missing 
values at Week 4 for all 3 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 2 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 datasets, the change from baseline in SCORAD at Week 16 will 
be analysed using an ANCOVA model with effects of treatment, region, baseline disease 
severity, and baseline SCORAD value. The estimated differences between each of the 
tralokinumab doses and placebo 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 differences will be calculated.
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14.3.5.2.3 Secondary estimand for the continuous secondary endpoints: 
‘treatment policy’
The secondary estimand for the continuous secondary endpoints will be:
x
Treatment difference in change from baseline to Week 16 in SCORAD and 
CDLQI, respectively, between tralokinumab and placebo regardless of rescue 
treatment use and treatment discontinuation.
The secondary estimand assesses the average difference in change from baseline in SCORAD 
and CDLQI after 16 weeks, resulting from initiation of a treatment regimen with 
tralokinumab and additional rescue treatment as compared to a treatment regimen with 
placebo and additional rescue treatment.
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 are missing at random within the groups used for 
imputation.
Imputation of missing data at Week 16 will be done using multiple imputations within 
6 groups defined according to randomised treatment 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/CDLQI 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.
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Each of the 100 imputed datasets will be analysed and the resulting estimates and standard 
errors pooled 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 arms who have/have not discontinued treatment prior to 
Week 16 will resemble data from subjects from the placebo 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 arms as well as the placebo arm will be imputed from the 
placebo 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.
14.3.5.2.4 Analysis of additional secondary endpoints
To support the primary endpoints, EASI50 at Week 16, at least 90% reduction in EASI score 
(EASI90) at Week 16, and the change from baseline to Week 16 in EASI score will be 
analysed and presented for the full analysis set. EASI50 and EASI90 will be analysed as 
described for the primary analysis of the primary estimand for the primary endpoints, and the 
change from baseline to Week 16 in EASI score will be analysed as described for the primary 
analysis of the primary estimand for the continuous secondary endpoints.
To support the secondary endpoints on severity and extent of AD, at least 75% reduction in 
SCORAD score (SCORAD75) at Week 16, and SCORAD50 at Week 16 will be analysed and 
presented for the full analysis set. Both endpoints will be analysed as described for the 
primary analysis of the primary estimand for the primary endpoints.
To support the secondary endpoint on worst daily itch, the change from baseline to Week 16 
in Adolescent Pruritus NRS weekly average will be analysed and presented for the full 
analysis set as described for the primary analysis of the primary estimand for the continuous 
secondary endpoints. Reduction of Adolescent Pruritus NRS (weekly average) of at least 3 
from baseline to Week 16 will further be analysed as described for the primary analysis of the 
primary estimand for the primary endpoints
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The change from baseline to Week 16 in POEM will be analysed and presented for the full 
analysis set as described for the primary analysis of the primary estimand for the continuous 
secondary endpoints.
Tralokinumab trough concentration (Ctrough) during treatment (Week 16) and at the safety 
follow-up visit will be summarised.
14.3.5.3 Analysis of other endpoints
14.3.5.3.1 Use of rescue treatment
Rescue treatment use (yes/no) from baseline to Week 16 will be summarised by visit and 
Anatomical Therapeutic Chemical (ATC) classification code.
14.3.5.3.2 Analysis of patient-reported outcomes
The PROs CDLQI, POEM, Adolescent PGI-S (past week recall), PGI-C, and HADS will be 
summarised by treatment group and visit using descriptive statistics. Adolescent PGI-S (past 
week recall) and PGI-C will only be assessed in the initial treatment period, and only 
observed data will be presented. For the CDLQI, POEM, and HADS, summaries will be made 
separately for the initial treatment and the maintenance treatment, data from the initial 
treatment period will be presented for the full analysis set and data from the maintenance 
treatment period will be presented for the maintenance analysis set. For the open-label 
treatment arm, CDLQI, POEM, and HADS will be listed and summarised descriptively by 
visit, presenting observed data only.
The PROs collected daily in the eDiaries (Eczema-related Sleep NRS, Adolescent Pruritus 
NRS, and Adolescent PGI-S [today recall]) will all be summarised over time by treatment 
group using descriptive statistics. For the Eczema-related Sleep NRS and Adolescent Pruritus 
NRS, the summaries will be separate for the initial treatment and the maintenance treatment, 
whereas summaries for Adolescent PGI-S (today recall) will only be made for the initial 
treatment. Data from the initial treatment period will be presented for the full analysis set and 
data from the maintenance treatment period will be presented for the maintenance analysis 
set. As for the other PROs, data from the PROs in the eDiary (Eczema-related Sleep NRS and 
Adolescent Pruritus NRS) for the open-label treatment arm will be listed and summarised 
descriptively by visit, presenting observed data only.
The change from baseline to Week 16 in Eczema-related Sleep NRS weekly average and 
HADS will be summarised by treatment group and domain, where applicable, and analysed as 
described above for the primary analysis of the primary estimand of the continuous secondary 
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endpoints. For the Eczema-related Sleep NRS score, the mean over the last 7 days prior to 
randomisation will be used as the baseline value.
In the subgroup of subjects with either HADS anxiety subscale score ≥8 or HADS depression 
subscale score ≥8 at baseline, the proportion of subjects with both HADS anxiety subscale 
score <8 and HADS depression subscale score <8 at Week 16 will be summarised by 
treatment group.
The following binary endpoints will be analysed as described for the primary analysis of the 
primary estimand, with the modification that subjects who use rescue treatment from baseline 
to the Week 2 visit will be considered as non-responders.
x
Reduction of Adolescent Pruritus NRS (weekly average) of at least 4 from 
baseline to Week 2.
x
Reduction of Adolescent Pruritus NRS (weekly average) of at least 3 from 
baseline to Week 2.
Change in Adolescent Pruritus NRS (weekly average) from baseline to Week 2 will be 
analysed as described for the secondary endpoint SCORAD using the primary analysis of the 
primary estimand only, with the modification that subjects who use rescue treatment from 
baseline to the Week 2 visit will be excluded from the analysis, since ignoring data after 
initiation of rescue treatment implies that subjects do not have post baseline responses 
available.
14.3.5.3.3 Biomarkers
Biomarkers will be summarised by visit and treatment group for the subjects in full analysis 
set.
The change from baseline to Week 16 in biomarkers will be summarised by treatment group 
and will be compared between each of the tralokinumab treatment groups and placebo using a 
Mann-Whitney test.
14.3.5.3.4 Skin microbiology
The incidence of skin colonisation with S. aureus will be presented by visit and treatment 
group for the subjects in the full analysis set.
The incidence at Week 16 will be compared between each of the tralokinumab treatment 
groups and the placebo group among subjects who are positive at baseline using a chi-squared 
test.
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14.3.5.3.5 Skin barrier function
Skin barrier function parameters (assessed in a subgroup of subjects) will be summarised by 
visit and treatment group.
The change from baseline to Week 16 in skin barrier function (assessed as change in TEWL) 
will be summarised by treatment group and will be compared between each of the 
tralokinumab treatment groups and placebo using a Mann-Whitney test.
14.3.6 Analysis of maintenance treatment
14.3.6.1 Analysis of maintenance endpoints
To support the maintenance objective of the trial, IGA of 0/1 and EASI75 at Week 52 will be 
analysed using a binomial model separately for the 5 maintenance treatment arms, providing 
response rates and corresponding 95% confidence intervals based on the Wilson score 
method.
Only subjects responding to trial treatment with a clinical response achieved without rescue 
treatment from Week 2 to Week 16 will be included in the analysis and all subjects who prior 
to the Week 52 visit have received rescue treatment (including TCS) and/or been permanently 
discontinued from treatment or have been transferred to open-label treatment will be 
considered non-responders.
14.3.6.2 Continued treatment for non-IGA responders
The number of responders according to IGA 0/1 at Week 52 will be tabulated for the subgroup 
of subjects in the maintenance analysis set who are re-randomised meeting the EASI75 
criterion but not the IGA 0/1 criterion at Week 16. All subjects who prior to the Week 52 visit 
have received rescue treatment (including TCS) and/or been permanently discontinued from 
treatment or have been transferred to open-label treatment will be considered non-responders 
in the analysis.
14.3.7 Analysis of open-label treatment
The efficacy assessments (IGA, EASI and SCORAD) for the open-label treatment arm will be 
listed and summarised descriptively by visit, presenting observed data only.
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14.3.8 Analysis of safety
The analyses of safety will be based on the safety analysis sets. The safety data will be 
presented separately for the safety analysis set, the maintenance safety analysis set, and the 
open-label safety analysis set.
14.3.8.1 Adverse events
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).
Only treatment-emergent AEs will be summarised, but 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, number (and percentage) of 
subjects with any treatment-emergent AEs, SAEs, deaths, 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).
The severity for each type of AE will be tabulated by treatment group.
The causal relationship to IMP 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 will be tabulated and listed.
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14.3.8.2 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, the maintenance safety analysis 
set, and the open-label safety analysis set.
14.3.8.3 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, the maintenance safety analysis set, and the open-
label 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.
14.3.8.4 Anti-drug antibodies
The presence of ADAs (yes/no) is a secondary endpoint included to assess the safety and 
tolerability (immunogenicity) of tralokinumab.
ADA status (positive versus negative) at each visit will be summarised by treatment group for 
the initial treatment, maintenance treatment, and open-label 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 status 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.
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For subjects who develop ADA, the IGA score and change in EASI at end of treatment will be 
listed.
Samples that test positive for ADA will be analysed for nAB. 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.
For ADA, all subjects with titre information will be listed.
14.3.8.5 Pharmacokinetics
The tralokinumab Ctrough concentration by time of assessment will be listed by treatment 
group and descriptive statistics will be provided.
Ctrough values from subjects with positive ADA/nAB will be compared to values from subjects 
with negative ADA/nAB if data permits.
14.3.9 Interim analysis
No interim analysis is planned.
14.3.10
Analysis of data per last subject’s Week 52 visit
To fulfil the commitments in the PIP and the PSP, the trial will be unblinded once all 
randomised subjects have completed the Week 52 visit. At the cut-off date of the last subject’s 
Week 52 visit, all efficacy, safety, PK, and ADA data for the treatment periods have been 
collected and all endpoints used to test pre-specified hypotheses are final. Thus, no 
adjustments in significance level of the primary and secondary efficacy analyses are relevant. 
The CTR will include all data from all randomised subjects from the initial, maintenance, and 
open-label treatment periods and all available data from the safety follow-up period as per 
data cut-off date.
14.3.11
General principles
Unless otherwise stated, all significance tests will be 2-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).
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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 and the analysis set definition 
documents 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.
14.3.12
Handling of missing values
Procedures for handling of missing values are included under the sections describing the 
individual analyses.
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55. Katagiri K, Arakawa S, Hatano Y. In vivo levels of IL-4, IL-10, TGF-beta1 and 
IFN-gamma mRNA of the peripheral blood mononuclear cells in patients with alopecia 
areata in comparison to those in patients with atopic dermatitis. Arch Dermatol Res. 
2007;298(8):397–401.
56. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial 
community variation in human body habitats across space and time. Science. 
2009;326(5960):1694–1697.
57. Cardona ID, Cho SH, Leung DY. Role of bacterial superantigens in atopic dermatitis: 
implications for future therapeutic strategies. Am J Clin Dermatol. 2006;7(5):273–279.
58. Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, et al. Temporal shifts in 
the skin microbiome associated with disease flares and treatment in children with atopic 
dermatitis. Genome Res. 2012;22(5):850–859.
59. Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A. Decreased level of 
ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin? 
J Invest Dermatol. 1991;96:523–526.
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60. Danby SG, Chittock J, Brown K, Albenali LH, Cork MJ. The effect of tacrolimus 
compared with betamethasone valerate on the skin barrier in volunteers with quiescent 
atopic dermatitis. Br J of Dermatol. 2014;170(4):914–921.
61. Riethmuller C, McAleer MA, Koppes SA, Abdayem R, Franz J, Haftek M, et al. Filaggrin 
breakdown products determine corneocyte conformation in patients with atopic dermatitis. 
J Allergy Clin Immunol. 2015;136(6):1573–1580.
62. Dyjack N, Goleva E, Rios C, Kim BE, Bin L, Taylor P, et al. Minimally invasive skin tape 
strip RNA-seq identifies novel characteristics of type 2-high atopic dermatitis disease 
endotype. J Allergy Clin Immunol. 2018[Epub ahead of print];pii:S0091-6749(18)30001-0 
[doi: 10.1016/j.jaci.2017.10.046].
63. Imokawa G. Ceramides as natural moisturizing factors and their efficacy in dry skin. 
In: Leyden JJ, Rawlings AV, editors. Skin moisturization. New York: Marcel Dekker Inc; 
2002. p. 267–302.
64. Kim JE, Shin JM, Ko JY, Ro YS. Importance of concomitant topical therapy in moderate-
to-severe atopic dermatitis treated with cyclosporine. Dermatol Ther. 2016;29(2):120–125.
65. European Parliament and Council of The European Union. Directive 2001/20/EC of 
4 April 2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in the 
conduct of clinical trials on medicinal products for human use [2001], article 10.
66. World Medical Association 2013. Declaration of Helsinki – ethical principles for medical 
research involving human subjects. 7th (Fortaleza) amendment.
67. International Ethical Guidelines for Health-related Research Involving Humans, Fourth 
Edition. Geneva. Council for International Organizations of Medical Sciences (CIOMS); 
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68. International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) 2016. Integrated addendum to ICH E6(R1): Guideline for good 
clinical practice E6(R2).
69. European Parliament and Council of The European Union. Directive 2016/679 of 
27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data, and repealing Directive 95/46/EC 
(General Data Protection Regulation).
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7 January 2003 on Research into pediatric uses for drugs and biological products.
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71. World Health Organization. WHO model prescribing information: drugs used in skin 
diseases. Geneva. 1997.
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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 Good Clinical Practice, 
E6 (R1)).
This definition includes:
x
Accidental injuries.
x
Events related to trial procedures.
x
Reasons for any unfavourable and unplanned change in medication (drug 
and/or dose).
x
Clinically significant worsening of pre-existing conditions.
x
Reasons for admission to hospital or surgical procedures unless these were 
planned before the subject consented to trial participation.
x
AEs commonly observed and AEs anticipated based on the pharmacological 
effect of the IMP.
x
Any laboratory abnormality assessed as clinically significant by the 
investigator (see Section 11.4.4.2).
Serious adverse event definition
An SAE is any untoward medical occurrence that:
x
Results in death.
x
Is life-threatening.
x
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.
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x
Results in persistent or significant disability/incapacity.
x
Is a congenital anomaly/birth defect.
or
x
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.
Adverse events of special interest are described in Section 13.6.1.
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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 investigator’s clinical judgement. The categories are 
defined below.
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.
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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.
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.
Outcome
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below.
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/ 
resolved 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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Note that as per the above definition, LEO Pharma uses “RECOVERED/RESOLVED” only if 
an event has actually stopped. According to the CDISC definition, the category 
“RECOVERED/RESOLVED” also includes events which have improved. However, 
following the LEO Pharma definitions above, such an improved event will instead be 
classified as “NOT RECOVERED/NOT RESOLVED” or “RECOVERING/RESOLVING”.
Similarly, it should be noted that as per the above definition, LEO Pharma uses 
“RECOVERED/RESOLVED WITH SEQUELAE” only if an event has reached a state where 
the residual symptoms are assumed to persist. According to CDISC, an event is considered 
“WITH SEQUELAE”, if it has “retained pathological conditions”. Consequently, it is likely 
that some of the events classified by LEO Pharma with the outcome 
“RECOVERED/RESOLVED WITH SEQUELAE” could have been classified with the 
outcome “RECOVERED/RESOLVED” according to the CDISC definition.
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 to be 
‘not recovered’. In addition, a statement that the SAE has stabilised or is chronic should be 
added to the narrative description of the SAE on the SAE form. Please note that the event 
should not be reported as ‘recovered’ on the SAE form.
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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:
x
Consensus ethical principles derived from international guidelines including the 
current version of the Declaration of Helsinki (66) and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines (67).
x
Current version of applicable ICH GCP Guidelines (68).
x
EU’s General Data Protection Regulation 2016/679 of 27 April 2016 (69).
x
EU’s regulation on medicinal products for paediatric use (24).
x
FDA’s Federal Food, Drug, and Cosmetic Act (FD&C Act) on research of paediatric 
uses for drugs and biological products (70).
x
Applicable laws and regulations.
The appropriate regulatory authorities must be notified of/approve the clinical trial as 
required.
Any documents that the IRB/IEC may need to fulfil its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure, subject information leaflet, ICFs, or 
advertisements) will be submitted to the IRB/IEC. These documents must be reviewed and 
approved by the IRB/IEC before the trial is initiated.
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs, as required, prior to implementation.
The principal investigator will be responsible for the following, if required by local 
legislation:
x
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.
x
Notifying the local IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures.
x
Providing oversight of the conduct of the trial at the trial site and adherence to 
applicable national and international legislation.
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Appendix 3B: Informed consent process 
Subjects and the subject’s legally authorised representative(s) will 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 and 
the subjects’ legally authorised representative(s) will be given an opportunity to ask questions 
and will be given sufficient time to consider before consenting.
The subject’s legally authorised representatives’ signed and dated informed consent must be 
obtained prior to any clinical trial-related procedure being carried out in accordance with ICH 
GCP (Section 4.8) and all applicable laws and regulations. The authorised person obtaining 
the informed consent must also sign the ICF. The subject’s decision not to participate or to 
withdraw will be respected, even if consent is given by the subject’s legally authorised 
representative(s).
The subject’s legally authorised representative(s) will be re-consented to the most current 
version of the ICF(s) during the trial, if applicable.
A copy of the ICF(s) must be provided to the subject’s legally authorised representative.
Subjects must give their written assent as appropriate and according to national laws and 
regulation. 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 (Section 4.8) and all applicable laws and regulations. Subject will be re-
consented to the most current version of the ICF(s) during the trial, if applicable and in 
accordance with national laws or regulations. A copy of the ICF(s) must be provided to the
subject in accordance with national laws or regulations.
Subjects who become of legal age during the trial, will be consented to the most current 
version of the ICF for adult subjects, if required by national laws or regulations. 
Subsequently, these subjects will be re-consented to the most current version of the ICF(s) for 
adult subjects during the trial, if applicable.
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 
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used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
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 Pharma and shall not be 
used by the investigator for purposes other than this clinical trial.
The investigator agrees that LEO Pharma 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.
Trial subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records 
or datasets that are transferred to LEO Pharma will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.
Trial subjects must be informed and consent to that their personal trial-related data will be 
used by LEO Pharma in accordance with local data protection law.
Trial subjects must be informed and consent to that their 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 race, ethnicity, age, 
gender, health condition, medical history, test results) 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 Pharma and third parties acting on behalf of LEO Pharma.
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma 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.
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Investigators and LEO Pharma must ensure that collection, processing and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation.
Subjects (or their legally acceptable representative[s]) 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 Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial.
Appendix 3D: Record keeping, quality control, and data handling 
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 1 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:
x
Date(s) of conducting the informed consent process, including date of 
provision of subject information.
x
A statement from the investigator to verify that each of the eligibility criteria 
are met and documented.
x
Subject ID.
x
The fact that the subject is participating in a clinical trial in AD including 
treatment arms of tralokinumab or placebo for 52 weeks.
x
Other relevant medical information.
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Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to continually verify source data 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 and the 
compliance of the trial site with the protocol and ICH GCP.
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. Protocol deviations 
will be assessed by LEO Pharma and critical protocol deviations will be described in the 
CTR.
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma 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 Pharma 
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 Pharma must be 
notified immediately.
Risk assessment 
In this trial, the risks to critical trial processes and data have been evaluated.
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To ensure consistent data capture with respect to investigator assessment of efficacy (IGA, 
EASI, SCORAD), all investigators will receive training and whenever possible, the efficacy 
assessments will be made by the same investigator at each visit to reduce inter-rater 
variability.
To ensure subject safety, an independent Data Monitoring Committee (DMC) will regularly 
review unblinded safety data from this trial. Furthermore, SAE reporting will be followed 
closely and medical monitoring will be performed on an ongoing basis throughout the trial.
Data quality review meetings will be held during the trial to ensure that improvements in data 
collection can be made and that mistakes are prevented on an ongoing basis. During 
monitoring, the CRA will verify that investigators work according to the protocol.
Data handling 
Data will be collected by means of electronic data capture unless transmitted to LEO Pharma 
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 Pharma 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 
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.
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the Clinical Trial Agreement. 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 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 solution, 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 
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eCRF and data captured from the eCRF and the ePRO will be stored on different servers 
during data capture. Data from both systems will be included in the final trial database.
External data transfers from vendors to LEO Pharma 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 15.
Panel 15: Transmission of electronic data
Abbreviations: CTR, clinical trial report; ECG, electrocardiogram; eCRF, electronic case report form; ePRO, 
electronic patient-reported outcome.
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (68). Essential trial documents must be stored 
until LEO Pharma 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).
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.
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No documents may be destroyed during the retention period without the written approval of 
LEO. No documents 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 an electronic copy of the 
eCRFs and ePRO data for all screened and randomised 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 IRBs/ IECs.
Appendix 3E: Registration, reporting and publication policy 
Trial disclosure 
LEO is committed to be transparent with respect to its clinical trials.
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 Pharma in 
accordance with LEO Pharma’s Position on Public Access to Clinical Trial Information no 
later than 6 months after trial completion. Trial 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.
LEO Pharma may also provide researchers access to anonymised patient level data for further 
research. Publication and access will be in accordance with LEO Pharma’s Position on Public 
Access to Clinical Trials which can be found on LEO Pharma’s website.
Publications 
The investigator shall be entitled to make publications of the results generated by investigator 
in accordance with the process described here.
A multi-centre publication will be 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. After such multi-centre publication is made 
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public, or if no multi-centre publication has been submitted with the above-described 
deadline, the investigator shall have the right to publish the results from the clinical trial 
generated by the investigator, subject to the following notice requirements:
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider LEO 
Pharma’s comments but is not required to modify the manuscript and/or presentation based on 
such comments, provided, however, that the investigator upon the request of LEO Pharma 
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 
Pharma withhold the publication or presentation to allow LEO Pharma to protect its 
inventions and other intellectual property rights described in any such manuscripts.
In case no multi-centre publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma 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.
Any publication must comply with Good Publication Practice (GPP3) standards.
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies 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), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (37).
Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations.
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Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma 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.
Appendix 3H: Committee structure 
Patient safety will be carefully assessed by an independent Data Monitoring Committee 
(DMC). All members will be independent of the trial (that is, they will not be participating 
investigators or employees at participating sites) and of LEO Pharma (that is, they will not be 
LEO Pharma employees). The DMC members are experienced with clinical trials and will be 
responsible for assessing the safety of the subjects through assessment of the safety of the 
treatment regimen during the trial and through monitoring the overall conduct of the trial.
The DMC will review unblinded data on a regular basis. Additional meetings may also be 
called on at an ad hoc basis, as requested by the DMC or LEO. All data collected at the time 
of the data cut-off/scheduled meetings will be included in the summaries for the DMC, 
including data from subjects still ongoing in the trial. The DMC will examine summaries and 
listings of AEs, specific laboratory parameters and subject disposition data as detailed in the 
DMC charter. Full details of the analyses to be presented to the DMC will be specified in a 
separate DMC statistical analysis plan.
The DMC will have an independent statistician and an independent administrator who will 
remain independent of the trial management team.
The chairman of the DMC, in conjunction with the other members, will communicate their 
recommendations to LEO Pharma’s clinical project manager after each meeting. The 
chairman of the DMC will provide written reports to LEO Pharma after each formal review to 
indicate the committee’s recommendation regarding safety concerns and trial continuation. 
Further details on all aspects relating to the DMC are provided in the DMC charter.
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Appendix 3I: Trial and site closure 
Premature termination of trial or trial site 
LEO Pharma, 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 Pharma 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 Pharma or investigator may include but 
are not limited to:
x
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, LEO Pharma’s procedures, or GCP 
guidelines.
x
Inadequate recruitment of subjects by the investigator.
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities 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 Pharma 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 trial has been completed, 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 3J: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a Signatory 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 (36)
Major Features: must have 3 or more of the following:
x
Pruritus
x
Typical morphology and distribution:
o
Flexural lichenification or linearity in adults
o
Facial and extensor involvement in infants and children
x
Chronic or chronically-relapsing dermatitis
x
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Features: should have 3 or more of the following:
x
Xerosis
x
Ichthyosis, palmar hyperlinearity, or keratosis pilaris
x
Immediate (type 1) skin-test reactivity
x
Raised serum IgE
x
Early age of onset
x
Tendency toward cutaneous infections (especially S. aureus and herpes 
simplex) or impaired cell-mediated immunity
x
Tendency toward non-specific hand or foot dermatitis
x
Nipple eczema
x
Cheilitis
x
Recurrent conjunctivitis
x
Dennie-Morgan infraorbital fold
x
Keratoconus
x
Anterior subcapsular cataracts
x
Orbital darkening
x
Facial pallor or facial erythema
x
Pityriasis alba
x
Anterior neck folds
x
Itch when sweating
x
Intolerance to wool and lipid solvents
x
Perifollicular accentuation
x
Food intolerance
x
Course influenced by environmental or emotional factors
x
White dermographism or delayed blanch
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Appendix 5: Guidance for anaphylaxis diagnosis (38)
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., generalised hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
x
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
x
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):
x
Involvement of the skin-mucosal tissue (e.g., generalised hives, itch-flush, 
swollen lips-tongue-uvula)
x
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
x
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
x
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
x
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
x
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: WHO model prescribing information for classification of 
topical corticosteroids
Hydrocortisone and betamethasone are examples of low- and high potency topical 
corticosteroids (TCS). TCS have been ranked in terms of potency into 4 groups consisting of 
7 classes. Class I TCS are the most potent and Class VII TCS are the least potent (Panel 16). 
Efficacy and side-effects are greatest with the Class I ultra high potency preparations which 
should only be used for limited time periods (2‒3 weeks).
Representative preparations by group are listed in the table below according to the WHO 
model prescribing information for drugs used in skin diseases (71). These groups may vary 
depending on the formulation and concentration and should be considered approximate. In 
general, ointments are more potent than creams or lotions. Potency is also increased when 
TCS are used under occlusive dressings or in intertriginous areas.
Panel 16: Classification of topical corticosteroids
Potency
Class Topical corticosteroid
Formulation
Ultra high
I
Clobetasol propionate
Cream, 0.05%
Diflorasone diacetate
Ointment, 0.05%
High
II
Amcinonide 
Ointment, 0.1%
Betamethasone dipropionate
Ointment, 0.05%
Desoximetasone
Cream or ointment, 0.025%
Fluocinonide
Cream, ointment, or gel, 0.05%
Halcinonide
Cream, 0.1%
III
Betamethasone dipropionate
Cream, 0.05%
Betamethasone valerate
Ointment, 0.1%
Diflorasone diacetate
Cream, 0.05%
Triamcinolone acetonide
Ointment, 0.1%
Moderate
IV
Desoximetasone
Cream, 0.05%
Fluocinolone acetonide
Ointment, 0.025%
Fludroxycortide 
Ointment, 0.05%
Hydrocortisone valerate
Ointment, 0.2%
Triamcinolone acetonide
Cream, 0.1%
V
Betamethasone dipropionate
Lotion, 0.02%
Betamethasone valerate
Cream, 0.1%
Fluocinolone acetonide
Cream, 0.025%
Fludroxycortide
Cream, 0.05%
Hydrocortisone butyrate
Cream, 0.1%
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Panel 16: Classification of topical corticosteroids (continued)
Potency
Class Topical corticosteroid
Formulation
Moderate
V
Hydrocortisone valerate
Cream, 0.2%
Triamcinolone acetonide
Lotion, 0.1%
Low
VI
Betamethasone valerate
Lotion, 0.05%
Desonide
Cream, 0.05%
Fluocinolone acetonide
Solution, 0.01%
VII
Dexamethasone sodium phosphate
Cream, 0.1%
Hydrocortisone acetate
Cream, 1%
Methylprednisolone acetate
Cream, 0.25%
Source: WHO model prescribing information: drugs used in skin diseases (71).
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Appendix 7: Eligibility criteria
A short form (maximum 200 characters) version of each of the eligibility criteria for the trial 
is provided below, to be used when data are submitted to the FDA.
No
Inclusion criteria
1
Signed and dated informed consent has been obtained prior to any protocol-related procedures
2
Age 12 to 17 years
3
Body weight at baseline of 30.0 kg or more
4
Diagnosis of AD (as defined by Hanifin and Rajka (1980) criteria for AD)
5
History of AD for 1 year or more
6
History of TCS and/or TCI treatment failure (due to inadequate response or intolerance) or 
subjects for whom these topical AD treatments are medically inadvisable
7
AD involvement of 10% (or more) body surface area at screening and baseline (visit 3) 
according to component A of SCORAD
8
An EASI score of 12 (or more) at screening and 16 (or more) at baseline
9
An IGA score of 3 or more at screening and at baseline, equivalent to moderate-to-severe AD
10
An Adolescent Pruritus numeric rating scale average score of 4 or more during the week prior 
to baseline
11
Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at 
least 14 days before randomisation
12
Female subjects must be of either non-childbearing potential (premenarchal or history of 
sterility) or childbearing potential (defined as Tanner stage of 3 or more; or menarche)
13
Female subjects of childbearing potential must use a highly effective form of birth control 
throughout the trial and for at least 16 weeks after last administration of IMP
No
Exclusion criteria
1
Current participation in any other interventional clinical trial
2
Previously screened in this clinical trial
3
Previous randomisation in tralokinumab trials
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 (NBUVB, UVB, UVA1, PUVA), within 6 weeks prior to 
randomisation
7
Treatment with immunomodulatory medications or bleach baths within 4 weeks prior to 
randomisation 
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No
Exclusion criteria (continued)
8
Treatment with the topical medications TCS, TCI or PDE-4 inhibitor within 2 weeks prior to 
randomisation
9
Receipt of live attenuated vaccines within 30 days prior to the date of randomisation and 
during the trial including the safety follow-up period
10
Receipt of any marketed or investigational biologic agent (e.g cell-depleting agents or 
dupilumab) within 6 months prior to randomisation or until cell counts return to normal, 
whichever is longer
11
Subjects who have received treatment with any non-marketed drug substance within 3 months 
or 5 half-lives, whichever is longer, prior to randomisation
12
Inability or unwillingness to receive IMP injections at randomisation
13
Receipt of blood products within 4 weeks prior to screening
14
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
15
Major surgery within 8 weeks prior to screening, or planned inpatient surgery or 
hospitalisation during the trial period
16
Known or suspected hypersensitivity to any component of the IMP
17
History of any active skin infection within 1 week prior to randomisation
18
History of a clinically significant infection (systemic infection or serious skin infection 
requiring parenteral treatment) within 4 weeks prior to randomisation
19
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
20
History of anaphylaxis following any biological therapy
21
History of immune complex disease
22
History of cancer
23
Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation will be 
according to local guidelines as per local standard of care
24
History of any known primary immunodeficiency disorder including a positive HIV test at 
screening, or the subject taking antiretroviral medications 
25
Subject or subject’s legally authorised representative(s) known or suspected of being unlikely 
to comply with the clinical trial protocol in the opinion of the investigator
26
History of attempted suicide or at significant risk of suicide (either in the opinion of the 
investigator or on the C-SSRS)
27
Any disorder which is not stable and in the investigator’s opinion could affect the safety of the 
subject, influence the findings of the trial, or impede the subject’s ability to complete the trial
28
Any abnormal finding which in the investigator’s opinion may put the subject at risk, 
influence the results of the trial, or influence the subject’s ability to complete the trial
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No
Exclusion criteria (continued)
29
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 2.0 times the ULN 
(upper limit of normal) or more at screening
30
Positive HBsAg, HBsAb, HBcAb or anti-HCV serology at screening. Subjects with positive 
HBsAb may be randomised provided they are hepatitis B vaccinated and have negative 
HBsAg and HBcAb
31
Subjects afraid of blood withdrawals or unwilling to comply with the assessments of the trial
32
Subject or subject’s legally authorised representative(s) language barrier, mental incapacity, 
unwillingness or lacking ability to understand the trial-related procedures
33
Subjects who are legally institutionalised
34
Female subjects who are pregnant or lactating
35
Female subjects of childbearing potential who are sexually active but unwilling to use 
adequate methods of contraception
36
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
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Appendix 8: Country-specific requirements: Japan
This appendix describes requirements and procedures that are specific for Japan. For each 
section, the text from the protocol is presented in normal font. The specific requirements or 
procedures for Japan are presented below in bold font.
Section 8.2 Inclusion criteria - Inclusion criterion no. 1
Written informed consent and any locally required authorisation obtained from the subject 
prior to performing any protocol-related procedures, including screening evaluations.
In Japan, the legal representative must sign the informed consent.
Section 9.8.3 Drug 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.
In Japan, it is the Head of Institute who is responsible for the IMP at the trial site.
Section 9.8.5 Trial product destruction
Used and unused IMP will be destroyed by the CMO according to approved procedures 
and/or local requirements.
Used syringes will be destroyed at the trial site provided the trial site has procedures in place 
for such IMP destruction.
In Japan, used syringes will be destroyed at the trial sites.
Section 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 Safety at LEO 
Pharma on the trial-specific (paper) Complaint Form within 3 days of first knowledge.
Critical complaints (defined as any defect, issue, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., SAE or large particles in the syringe]) must 
be reported to Global Safety, LEO Pharma within 24 hours.
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In Japan, product complaints must be reported to Pharmacovigilance, LEO Pharma 
K.K. using the contact information below:
Fax number: +81 3 4243 3311
E-mail address: clinical_trial_jp@leo-pharma.com
Section 11.1 Overview – Order of assessments
Assessments/procedures at any trial visit should be performed in the following order:
x
PROs in the following order:
1. Children’s Dermatology Life Quality Index (CDLQI).
2. Patient-Oriented Eczema Measure (POEM).
3. Adolescent Patient Global Impression of Severity (PGI-S [past week 
recall]).
4. Patient Global Impression of Change (PGI-C).
5. Hospital Anxiety and Depression Scale (HADS).
x
Investigator assessments (performed only by adequately trained investigators) 
in the following order:
1. SCORAD component C, then component A and B.
2. IGA.
3. EASI.
x
Safety and laboratory assessments (including PK and blood biomarkers).
x
Other assessments (skin swabs, skin tape stripping [if applicable], 
transepidermal water loss [if applicable], height and weight).
x
Administration of IMP.
In Japan, the order of assessments may be changed after the randomisation visit to 
perform safety and laboratory assessments (including PK and blood biomarkers) and 
other assessments (skin swabs, skin tape stripping [if applicable], transepidermal water 
loss [if applicable], height and weight) before the investigator assessments but after the 
PROs. The assessments must be performed in the same order for all subjects at the site.
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Section 11.1 Overview – Qualifications of principal investigators and investigators
Subjects participating in the trial will be under careful supervision of a principal investigator 
who must be 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.
In Japan, investigators must be dermatologists or allergists.
Section 13.4.1 Investigator reporting responsibilities
Any SAE must be reported to LEO Pharma within 24 hours of first knowledge. The SAE 
report should be completed in accordance with the eCRF completion guidelines provided for 
the automatic transmission or the SAE report should be reported on the paper form (as 
applicable).
In Japan, SAEs must be reported using the paper SAE form according to the SAE form 
completion guidelines. The SAE form must be submitted to the Sponsor within 24 hours 
of first knowledge by fax or email to Pharmacovigilance, LEO Pharma K.K. using the 
email address and fax number below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-pharma.com
If relevant, other information on the SAE must be sent to Global Safety at LEO Pharma by 
fax or email using the email address or fax number above.
In Japan, other relevant information must be sent to Pharmacovigilance, LEO Pharma 
K.K. using the email and fax number below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-pharma.com
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The requested information must be forwarded to LEO Pharma via the follow-
up page in the eCRF, and the eCRF must be updated accordingly. 
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In Japan, Global Safety at LEO Pharma may request additional information in order to 
fully assess the SAE. The requested information must be forwarded to 
Pharmacovigilance, LEO Pharma K.K. upon request via a Query Form. The paper SAE 
form must also be updated accordingly (if relevant). The Query Form must be sent by 
fax or email using the email and fax number below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-pharma.com
Section 13.4.2 LEO Pharma reporting responsibilities
Global Safety, LEO Pharma will notify the regulatory authorities and concerned investigators 
of SAEs according to the current applicable legislation for the concerned countries.
In Japan, Pharmacovigilance, LEO Pharma K.K. will be responsible for notifying the 
regulatory authorities and concerned investigators of SAEs.
Section 13.5 Other events that require expedited reporting: pregnancy
Any pregnancy occurring during the clinical trial must be reported to LEO Pharma 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 
Safety, LEO Pharma.
In Japan, any pregnancy must be reported to Pharmacovigilance, LEO Pharma K.K. 
using the contact information below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-pharma.com
Section 13.7 Follow-up for final outcome of adverse events
For SAEs which have stabilised and from which the subject cannot be expected to recover 
during the trial or the safety follow-up periods, for example chronic or stabilised conditions, 
the final outcome at the investigator's discretion should be reported as 'recovering/resolving' 
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or ‘not recovered/not resolved’. In addition, a statement that the SAE has stabilised or is 
chronic should be added to the narrative description of the SAE on the SAE form.
In Japan, a statement that the SAE has stabilised or is chronic should be added to the 
narrative description of the SAE on the SAE form.
Appendix 3A: Regulatory and ethical considerations
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 Japan, the documents will be submitted to the IRB/IEC by the sponsor (LEO Pharma 
K.K.).
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Appendix 9: Contact list 
Contact details for the clinical project manager, appointed CRA, 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 Pharma’ 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 
 
LEO Pharma K.K. is the sponsor of the clinical trial in Japan on behalf of LEO Pharma A/S: 
 
LEO Pharma K.K. 
1-105 
Kanda-Jinbocho 
Chiyoda-ku 
Tokyo 101-0051  
Japan 
 
Coordinating investigators 
Signatory investigator: 
Professor [Name], MD  
[Contact] 
[Contact] 
[Contact] 
[Contact] 
[Contact] 
[Contact] 
 
Telephone no: [Contact] 
                 
T 
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Appendix 10: Protocol amendment history
The protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.
Amendment 1 (01-May-2018)
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 trial.
Overall rationale for the amendment
The reason for the amendment is a change in requirements in Japan regarding the 
qualifications of the investigators in the trial. This change was identified after finalisation of 
the original protocol. The table below presents the change.
Section no. and 
name
Description of change
Brief rationale
Appendix 8
Country-specific 
requirements: 
Japan
In Japan, the investigator will be a 
dermatologist or allergist.
The text regarding the 
requirements for investigators 
(Section 11.1 in Appendix 8) has 
been updated accordingly. 
As adolescents with AD in 
Japan are seen by 
dermatologists and allergists, 
the country-specific 
requirement for Japan, that the 
investigator must only be a 
dermatologist has been 
changed to include allergists. 
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Amendment 2 (12-Jun-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 protocol was updated in response to guidance received from the European Health 
Authorities during their review of the protocol.
The table below presents the changes in each section 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
Section 4
Schedule of trial 
procedures 
(Panel 2 & 
Panel 4)
Section 9.2
Administration of 
IMP
Section 11.4.1
Vital signs
Extension of the post dosing 
observation period:
For the first 3 IMP dosing visits in 
the initial treatment period (i.e., 
Weeks 0, 2, and 4) and in open-label 
treatment, subjects will be monitored 
after IMP administration for 
immediate drug reactions for a 
minimum of 2 hours 30 minutes with 
vital signs taken at every 30 minutes 
or until stable, whichever is later.
The currently available safety 
data including tralokinumab 
exposure in 78 adolescent 
subjects with asthma were not 
deemed sufficient to justify a 
shortening of the post dosing 
observation period following 
the first 3 IMP administrations. 
Hence, this period has been 
extended to 2 hours as this is 
aligned with the post dosing 
period in used in previous 
tralokinumab trials in adults 
with asthma and atopic 
dermatitis.
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Amendment 3 (21-Nov-2018)
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 (65) because it neither significantly impacts the safety or physical/mental 
integrity of subjects nor the scientific value of the trial.
Overall rationale for the amendment
The main reasons for the amendment are to clarify the sections of the protocol describing skin 
swabs, and transepidermal water loss asessments, to update the requirements for IMP 
destruction at sites, and to introduce a country-specific requirement that will allow the order 
of trial procedures to be changed after the randomisation visit at sites in Japan to align with 
standard clinical procedures in Japan. It has been clarified that skin swabs and transepidermal 
water loss assessments will be performed both on lesional and non-lesional skin. The LEO 
trial product handling guideline has been updated and no longer requires sites to be able to 
issue certificates of IMP destruction at sites, this requirement has been deleted from the 
protocol. The standard clinical procedure in Japan is to perform safety and laboratory 
assessments before meeting the principal investigator, a permission for such a change to the 
order of assessments after the baseline visit has been added as a country-specific requirement 
for Japan. The assessments must be performed in the same order for all subjects at the site.
In addition, the amendment includes other changes, as presented in the table below.
The table below presents 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
Section 1
Synopsis
Section 2
Trial identification
The ClinicalTrials.gov identifier for 
the trial has been added.
The ClinicalTrials.gov 
identifier has been obtained 
since the last update of the 
protocol.
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Section no. and 
name
Description of change
Brief rationale
Section 9.7
Prohibited 
medication and 
procedures
Panel 8 has been modified to only 
describe prohibited medications and 
procedures in the period from 
randomisation through safety 
follow-up.
To ensure consistent 
descriptions of prohibited 
medications and procedures 
across the tralokinumab 
development programme. 
Medications and procedures 
disallowed prior to 
randomisation are covered in 
the exclusion criteria.
Section 9.8.5
Trial product 
destruction
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 of 
destruction.
The LEO trial product 
handling guideline has been 
updated and no longer requires 
sites to be able to produce a 
certificate of IMP destruction.
Section 11.4.1
Vital signs
Vital signs will be measured in a 
supine or sitting position following 
at least 5 minutes of rest.
Measurement of vital signs in a 
supine position is impractical 
at the sites. The impact of 
measuring vital signs in a 
supine or sitting position has 
been assessed as insignificant.
Section 11.6
Pharmacodynamic 
assessments: blood 
biomarkers
The biomarker results will not be 
included in the clinical trial report 
(CTR) but will be presented in a 
separate report.
As the biomarker results will 
be described in the clinical trial 
report.
Section 11.7.1
Subjects will have skin swabs taken 
from both lesional and non-lesional 
skin.
Clarification that skin swabs 
will be taken from both 
lesional and non-lesional skin.
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Section no. and 
name
Description of change
Brief rationale
Skin swabs: 
Staphylococcus 
aureus colonisation
The results on S. aureus colonisation 
will not be included in the CTR but 
will be presented in a separate report.
As the S. aureus colonisation 
results will be described in the 
clinical trial report.
Section 11.7.2.1
Skin tape stripping 
(selected trial sites)
In addition, the body location for 
each skin tape strip will be 
documented in the eCRF (upper 
limb, lower limb, trunk, head). 
Efforts will be made to collect skin 
tape strips from the same lesional 
and non-lesional skin sites at all 
time points, even if the lesion has 
cleared.
It has been specified that the 
body location of the skin tape 
stripping must be documented 
in the eCRF and that efforts 
must be made to collect the 
skin tape strips from the same 
skin sites at all time points.
The skin tape strip results will not be 
included in the CTR but will be 
presented in a separate report.
As the skin tape strip results 
will be described in the clinical 
trial report.
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Section no. and 
name
Description of change
Brief rationale
Section 11.7.2.2
Transepidermal 
water loss (selected 
trial sites)
At selected trial sites, transepidermal 
water loss (TEWL) will be assessed 
on a representative lesion and on 
non-lesional skin to evaluate skin 
barrier function. TEWL (in g/m2/h) 
will be measured at the clinic by a 
non-invasive assessment of skin 
evaporation according to the schedule 
of trial procedures (Section 4), using 
a Tewameter® or a similar device.
At each assessment, 3 measurements 
from a representative lesion and 3 
measurements from non-lesional 
skin will be recorded in the eCRF. It 
will also be recorded if the TEWL 
assessment was performed including 
the time of assessment; if not, a 
reason will be provided. 
Updated to describe that 
TEWL assessments will be 
performed on both on lesional 
and non-lesional skin.
In addition, the body location for 
each TEWL assessment will be 
documented in the eCRF (upper 
limb, lower limb, trunk, head). 
Efforts will be made to perform 
TEWL assessments at the same 
skin sites (lesion and non-lesional 
skin) at all time points, even if the 
lesion has cleared.
It has been specified that the 
body location of the TEWL 
assessments must be 
documented in the eCRF and 
that efforts must be made to 
perform TEWL assessments on 
the same skin sites at all time 
points.
The TEWL results will not be 
included in the CTR but will be 
presented in a separate report.
As the TEWL results will be 
described in the clinical trial 
report.
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Section no. and 
name
Description of change
Brief rationale
Section 13.6.1
Adverse events of 
special interest
(Panel 13)
Footnote added:
1. The 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 the additional 
data are only to be reported if 
they are available as part of 
standard clinical practice.
Section 14.3.5.3.3
Biomarkers
Biomarkers at Week 16 will be 
summarised and listed by visit and 
treatment group for the subjects in 
the full analysis set.
The change from baseline to 
Week 16 in biomarkers will be 
summarised by treatment group 
and will be compared between each 
of the tralokinumab treatment 
groups and placebo using a 
Mann-Whitney test.
To clarify that the biomarker 
results will be summarised by 
visit and treatment for all time 
points where they are assessed.
To describe the statistical test 
that will be used for 
comparison of change in 
biomarkers between treatment 
groups.
Section 14.3.5.3.5
Skin barrier 
function
Skin barrier function parameters 
(assessed in a subgroup of subjects) 
at Week 16 will be summarised and 
listed by visit and treatment group.
The change from baseline to 
Week 16 in skin barrier function 
(assessed as change in TEWL) will 
be summarised by treatment group 
and will be compared between each 
of the tralokinumab treatment 
groups and placebo using a 
Mann-Whitney test.
To clarify that the skin barrier 
function results will be 
summarised and listed by visit 
and treatment for all time 
points where they are assessed.
To describe the statistical test 
that will be used for 
comparison of skin barrier 
function between treatment 
groups.
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Section no. and 
name
Description of change
Brief rationale
Section 14.3.8.1
Adverse events
SAEs and AESIs will be evaluated 
separately and a. A narrative for each 
SAE will be given. AESIs and AEs 
leading to withdrawal from trial will 
be tabulated and listed.
Tabulation and listings are 
considered a more practical 
and informative way of 
presenting data on AESIs. This 
will enable easier overview of 
the individual cases.
Appendix 8
Country-specific 
requirements: 
Japan
Section 9.8.5 Trial product 
destruction
Used syringes will be destroyed at the 
trial site provided the trial site has 
procedures in place for such IMP 
destruction.
In Japan, used syringes will be 
destroyed at the trial sites.
To clarify that used syringes 
will be destroyed at the trial 
site in Japan.
Section 9.10 Reporting product 
complaints
In Japan, product complaints must be 
reported to Pharmacovigilance, LEO 
K.K. using the contact information 
below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-
pharma.com
Note: reports sent to the above fax 
number and email address will 
automatically be forwarded to Global 
Pharmacovigilance, LEO.
As the description of an 
internal LEO procedure is not 
considered of relevance for the 
investigator.
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Section no. and 
name
Description of change
Brief rationale
Appendix 8
Country-specific 
requirements: 
Japan (continued)
Section 11.1 Overview – Order of 
assessments
In Japan, the order of assessments 
may be changed after the 
randomisation visit to perform 
safety and laboratory assessments 
(including PK and blood 
biomarkers) and other assessments 
(skin swabs, skin tape stripping [if 
applicable], transepidermal water 
loss [if applicable], height and 
weight) before the investigator 
assessments but after the PROs. 
The assessments must be 
performed in the same order for all 
subjects at the site.
As the standard clinical 
procedure in Japan is to 
perform safety and laboratory 
assessments before subjects 
meet the principal investigator, 
a country-specific requirement 
has been added to allow this 
change in the order of 
assessments after the baseline 
visit.
Section 13.4.1 Investigator reporting 
responsibilities
In Japan, SAEs must be reported to 
Pharmacovigilance, LEO K.K. using 
the contact information below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-
pharma.com
Note: reports sent to the above fax 
number and email address will 
automatically be forwarded to Global 
Pharmacovigilance, LEO.
As the description of an 
internal LEO procedure is not 
considered of relevance for the 
investigator.
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Section no. and 
name
Description of change
Brief rationale
Appendix 8
Country-specific 
requirements: 
Japan (continued)
Section 13.5 Other events that require 
expedited reporting: pregnancy
In Japan, any pregnancy must be 
reported to Pharmacovigilance, LEO 
K.K. using the contact information 
below:
Fax number: +81 3 4243 3311
Email address: clinical_trial_jp@leo-
pharma.com
Note: reports sent to the above fax 
number and email address will 
automatically be forwarded to Global 
Pharmacovigilance, LEO.
As the description of an 
internal LEO procedure is not 
considered of relevance for the 
investigator.
Throughout
Global Pharmacovigilance Safety at 
LEO.
The Global Pharmacovigilance 
department at LEO has 
changed name.
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore have not been 
summarised.
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Amendment 4 (11-Feb-2019)
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 (65) because it neither significantly impacts the safety or physical/mental integrity of 
subjects nor the scientific value of the trial.
Overall rationale for the amendment
The reason for the amendment is a request from the FDA to include 2 patient-reported 
outcomes in the trial. Additionally, prohibited medications and procedures during the trial 
have been clarified.
The table below presents 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
Section 4
Schedule of trial 
procedures 
(Panel 2 and 
Panel 5)
The patient-reported outcomes PGI-C 
and Adolescent PGI-S (past week 
recall) have been added in the intital 
treatment period.
As addition of PGI-C and 
Adolescent PGI-S (past week 
recall) to the protocol has 
been recommended by the 
FDA. Another version of the 
Adolescent PGI-S 
(Adolescent PGI-S [today 
recall]) with a different recall 
period and response options 
has been included in all 
previous versions of the 
protocol and will continue to 
be included.
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Section no. and 
name
Description of change
Brief rationale
Section 4
Schedule of trial 
procedures 
(Panel 2, 
footnote 7)
A footnote 7 has been added to 
assessments of vital signs at Week 16.
7. For the first 3 IMP dosing visits in 
the initial treatment period and for 
non-responders transferring to 
open-label tralokinumab treatment at 
Week 16, 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, whichever is 
later (see Section 9.2).
To clarify that 
non-responders transferring 
to open-label tralokinumab 
treatment at Week 16 must be 
monitored for immediate 
drug reactions for 2 hours 
after IMP administration. 
Section 4 
Schedule of trial 
procedures 
(Panel 3, 
footnote 3)
The first injections of open-label 
treatment will be given at the visit in the 
maintenance period where the subject 
meets these criteria, if considered 
appropriate by the investigator, but not 
sooner than 5 half-lives after the last 
dose of systemic rescue treatment. 
When the first injections of open-
label treatment are given, 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, whichever is 
later (see Section 9.2).
To clarify that 
non-responders transferring 
to open-label tralokinumab 
treatment at during the 
maintenance treatment period 
must be monitored for 
immediate drug reactions for 
2 hours after IMP 
administration.
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Section no. and 
name
Description of change
Brief rationale
Section 9.7
Prohibited 
medication and 
procedures
It has been clarified that the listed 
topical treatments and 
immunosuppressive/immunomodulating 
treatments are prohibited both for the 
treatment of AD and other conditions.
Ophthalmic administration has been 
added to the permitted routes of 
administration of corticosteroids.
It has been clarified that temporary 
discontinuation of IMP does not apply 
in case of treatment with other 
investigational agents, 
immunoglobulins, blood products, 
allergen immunotherapy, or live 
vaccines.
To ensure consistent 
descriptions of prohibited 
medications and procedures 
across the tralokinumab 
development programme.
Section 11
Trial assessments 
and procedures
Appendix 8
Country-specific 
requirements: 
Japan
PGI-C and Adolescent PGI-S (past 
week recall) have been included in the 
overview of assessments/procedures 
and in the overview of patient-reported 
outcomes.
As addition of PGI-C and 
Adolescent PGI-S (past week 
recall) to the protocol has 
been recommended by the 
FDA. Another version of the 
Adolescent PGI-S 
(Adolescent PGI-S [today 
recall]) with a different recall 
period and response options 
has been included in all 
previous versions of the 
protocol and will continue to 
be included.
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Section no. and 
name
Description of change
Brief rationale
Section 11.3.4.7
Adolescent Patient 
Global Impression 
of Severity (past 
week recall)
Section 11.3.4.8
Patient Global 
Impression of 
Change
New sections have been added to the 
protocol to describe the Adolescent 
Patient Global Impression of Severity 
(past week recall) and the Patient 
Global Impression of Change.
As addition of PGI-C and 
Adolescent PGI-S (past week 
recall) to the protocol has 
been recommended by the 
FDA. Another version of the 
Adolescent PGI-S 
(Adolescent PGI-S [today 
recall]) with a different recall 
period and response options 
has been included in all 
previous versions of the 
protocol and will continue to 
be included.
Section 14.3.5.3.2
Analysis of 
patient-reported 
outcomes
The PROs CDLQI, POEM, Adolescent 
PGI-S (past week recall), PGI-C, and 
HADS will be summarised by treatment 
group and visit using descriptive 
statistics. Adolescent PGI-S (past 
week recall) and PGI-C will only be 
assessed in the initial treatment 
period, and only observed data will 
be presented. The For the CDLQI, 
POEM, and HADS, summaries will be 
made separately for the initial treatment 
and the maintenance treatment,, Ddata 
from the initial treatment period will be 
presented for the full analysis set and 
data from the maintenance treatment 
period will be presented for the 
maintenance analysis set. 
As PGI-C and Adolsecent 
PGI-S (past week recall) will 
only be collected from a 
subset of the subjects 
enrolled in the trial. 
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore have not 
been summarised.
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Amendment 5 (19-Jun-2019)
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 (65) because it neither significantly impacts the safety or physical/mental integrity of 
subjects nor the scientific value of the trial.
Overall rationale for the amendment
The main reason for the amendment is a request from the FDA to adjust the multiple testing 
strategy for the US submission. Additionally, electronic reporting of SAEs via the eCRF has 
been introduced and the prohibited medications and procedures during the trial have been 
clarified.
The table below presents the changes in each section. Changes have either been summarised 
(written in 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
Throughout
TCI has been added to the description 
of allowed rescue treatment for subjects 
in the open-label arm.
To clarify that subjects in the 
open-label tralokinumab arm 
are allowed to use TCS as 
well as TCI.
Section 9.7
Prohibited 
medication and 
procedures
The panel with prohibited medications 
and procedures in the previous version 
of the protocol has been replaced with a 
text description.
To ensure clear instructions 
on prohibited medications 
and procedures for 
investigators.
Section 13.4
Reporting of 
serious adverse 
events
The text has been updated to reflect that 
SAE reporting will be done in the eCRF 
instead of on paper forms. SAEs must 
be reported on the paper SAE Form in 
case the eCRF is temporarily 
unavailable.
As SAE reporting will be 
done electronically in the 
trial going forward.
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Section no. and 
name 
Description of change 
Brief rationale 
Section 13.7 
Follow-up for 
final outcome of 
adverse events 
In addition, a statement that the SAE 
has stabilised or is chronic should be 
documented in the eCRF narrative 
section added to the narrative 
description of the SAE on the SAE 
form. 
As SAE reporting will be 
done electronically in the 
trial going forward. 
Section 14.3.4 
Multiple testing 
strategy 
A US multiple testing procedure has 
been introduced in addition to the 
global (non-US) testing procedure. The 
text has been updated to highlight the 
difference between the 2 testing 
procedures. 
As the FDA has requested a 
multiple testing strategy in 
which the secondary 
endpoint Pruritus is tested 
independently of the 
secondary endpoints 
SCORAD and CDLQI. 
Appendix 8 
Country-specific 
requirements: 
Japan 
In Japan, SAE reporting will continue 
to be done using paper SAE forms. The 
country-specific requirements for Japan 
have been updated with exceptions to 
the electronic SAE reporting described 
in Section 13.4 and follow-up for final 
outcome of adverse events described in 
Section 13.7. 
As electronic SAE reporting 
requires investigators to 
frequently access the eCRF, 
which is not standard 
practice in Japan. In Japan, 
data entry in the eCRF is 
outsourced to site 
management organisations, 
and therefore paper forms are 
the preferred way of 
reporting SAEs in Japan. 
Appendix 9 
Contact list 
LEO Pharma K.K. 
3 11 6 Iwamotocho1-105 Kanda- 
Jinbocho 
Chiyoda-ku 
Tokyo 101 0032101-0051 
Japan 
As the LEO Pharma K.K. 
office will move to a new 
location. 
       
T 
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Section no. and 
name
Description of change
Brief rationale
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore not 
summarised.
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