Clinical trial NCT03761537
Conditions: Atopic Dermatitis
Sponsor: LEO Pharma
Start date: 2018-12-13; Completion date: 2020-09-28
Enrollment: 277 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective:

To demonstrate that tralokinumab in combination with topical corticosteroids (TCS) is superior to placebo in combination with TCS in treating severe AD in subjects who are not adequately controlled with or have contraindications to oral cyclosporine A (CSA).

Secondary objectives:

To evaluate the efficacy of tralokinumab in combination with TCS on severity and extent of AD, itch, and health-related quality of life compared to placebo in combination with TCS.

To evaluate the safety of tralokinumab in combination with TCS when treating severe AD in subjects who are not adequately controlled with or have contraindications to oral CSA compared to placebo in combination with TCS.

Detailed description:

Arms: arm 1: 4 subcutaneous (SC) injections of tralokinumab 150 mg as a loading dose on Day 0, followed by 2 SC injections of tralokinumab 150 mg every 2 weeks (Q2W) regimen for 26 weeks. The last administration of the Investigational Medicinal Product (IMP) occurred at Week 24. From Day 0 to Week 24, a Topical corticosteroid (TCS) cream was dispensed to the participants at each IMP dosing visit (e.g., Q2W). Participants were instructed to treat active lesions as needed and to discontinue the TCS treatment when control was achieved. arm 2: 4 subcutaneous (SC) injections of placebo as a loading dose on Day 0, followed by 2 SC injections of placebo every 2 weeks (Q2W) regimen for 26 weeks. The last administration of the Investigational Medicinal Product (IMP) occurred at Week 24. From Day 0 to Week 24, a Topical corticosteroid (TCS) cream was dispensed to the participants at each IMP dosing visit (e.g., Q2W). Participants were instructed to treat active lesions as needed and to discontinue the TCS treatment when control was achieved.
Interventions: intervention 1: Tralokinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for subcutaneous (SC) administration. intervention 2: Placebo contains the same excipients in the same concentration only lacking tralokinumab.

Protocol documents:
Prot_000.pdf: 
Cover Page 
Official title: A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multi-centre, Phase 
3 Trial Investigating the Efficacy, Safety, and Tolerability of Tralokinumab Administered in 
Combination With Topical Corticosteroids to Adult Subjects With Severe Atopic Dermatitis Who 
Are Not Adequately Controlled With or Have Contraindications to Oral Cyclosporine A
LEO Pharma number: LP0162-1346 
NCT number: NCT03761537 
Date: 15-Jun-2020 


Updated Clinical Trial Protocol
LP0162-1346
Tralokinumab in combination with topical corticosteroids in subjects with 
severe atopic dermatitis who are not adequately controlled with or have 
contraindications to oral cyclosporine A
ECZTRA 7 (ECZema TRAlokinumab trial no. 7)
Phase 3 – efficacy and safety trial
A randomised, double-blind, placebo-controlled, parallel-group, multi-centre, phase 3 trial 
investigating the efficacy, safety, and tolerability of tralokinumab administered in 
combination with topical corticosteroids to adult subjects with severe atopic dermatitis who 
are not adequately controlled with or have contraindications to oral cyclosporine A
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:
LP0162-1346
Date:
15-Jun-2020
EudraCT no:
2018-000747-76 
Version:
4.0 
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Clinical trial protocol statements
Approval statement LEO Pharma A/S (hereafter: ‘LEO’)
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document:
, MSc Stat
Biostatistics Lead, Medical Sciences 
, MD, PhD
Medical Lead, Medical Sciences 
, RN, PhD
Clinical Operations Lead, Global Clinical Operations
, MD
Vice President, Medical Sciences
Approval statement signatory investigator
The signatory investigator approves the clinical trial protocol and consolidated clinical trial 
protocol(s) comprising any subsequent amendment(s) by manually signing the Signatory 
Investigator Clinical Trial Protocol Approval Form, which is a separate document appended to 
this document.
The following person has approved this clinical trial protocol:
, Prof. Dr. med
Signatory investigator
Acknowledgement statement investigator
Each participating investigator must agree to the approved clinical trial protocol by signing a 
Clinical Trial Protocol Acknowledgement Form or similar document.
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Protocol amendment summary of changes table
Document history
Document
Date
Type of protocol amendment
Amendment 3 
(substantial)
15-Jun-2020
Global
Amendment 2 
(non-substantial)
19-Aug-2019
Global
Amendment 1 
(substantial)
13-Nov-2018
Global
Original protocol
20-Jun-2018
NA
A protocol amendment summary of changes table for the previous amendment is provided in 
Appendix 10.
Amendment 3 (15-Jun-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.
Overall rationale for the amendment
The main reason for the amendment is to modify the statistical analyses to account for the 
unusually high number of missing information due to the Coronavirus Disease 2019 
(COVID-19) pandemic in this trial. Statistical analysis was therefore revisited to ensure an 
unbiased evaluation of the treatment effect in the trial.
The contingency measures to minimise the impact of the COVID-19 pandemic on this trial 
are already implemented by 2 addendums. The first addendum gives an opportunity for the 
subjects to continue treatment with tralokinumab via home-use (self-injection) to provide 
continued therapy and ensure the safety of the subjects (Appendix 8, COVID-19). The second 
addendum includes the possibility of remote assessments related to efficacy via a mobile 
application (Appendix 9, Imagine for Studies). The second addendum has been submitted to 
the Ethics Committees in Poland and Spain.
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Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it).
Section no. and 
name
Description of change
Brief rationale
Approval 
statement LEO 
Pharma A/S 
(hereafter: ‘LEO’)
Medical Sciences and Safety has been 
changed to Medical Sciences.
Biostatistics is now part of Medical Sciences. 
To reflect a restructuring and 
change of department names
within LEO Pharma.
Synopsis
‘Statistical methods’ section is updated.
To align with the changes in the 
relevant sections.
6 Trial objectives 
and endpoints
Additional endpoints are added to the table.
Supporting primary endpoint
x
Percent change from baseline to
Week 16 in EASI score
Supporting secondary endpoints related to the 
severity and extent of AD
x
Percent change from baseline to
Week 26 in EASI score
x
Percent change from baseline to
Week 16 in SCORAD
x
Percent change from baseline to
Week 26 in SCORAD
Supporting the secondary endpoint related to 
itch
x
Percent change from baseline to
Week 16 in Worst Daily Pruritus
NRS (weekly average)
x
Percent change from baseline to
Week 26 in Worst Daily Pruritus
NRS (weekly average)
x
Percent change from baseline to
Week 16 in Eczema-related Sleep
NRS (weekly average)
x
Percent change from baseline to
Week 26 in Eczema-related Sleep
NRS (weekly average)
Supporting the secondary endpoint related to 
health-related quality of life
x
Change from baseline to Week 16 in
EQ-5D-5L VAS score
x
Change from baseline to Week 26 in
EQ-5D-5L VAS score
To better evaluate the treatment 
effect. 
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Section no. and 
name
Description of change
Brief rationale
x
HADS-anxiety and
HADS-depression scores < 8 at
Week 16
x
HADS-anxiety and
HADS-depression scores < 8 at
Week 26
x
Change from baseline to Week 16 in
HADS-anxiety score
x
Change from baseline to Week 26 in
HADS-anxiety score
x
Change from baseline to Week 16 in
HADS-depression score
x
Change from baseline to Week 26 in
HADS-depression score
14.2 Trial analysis 
sets
All subjects randomised to treatment and
exposed to the IMP will be included in the 
full analysis set (FAS) and will be analysed 
for efficacy.
To exclude subjects who do not 
have any causal relationship 
with the IMP (to be in line with 
ICH E9 guideline).
2 safety analysis sets are defined, one for the 
treatment period and the other for the safety 
follow-up period.
To differentiate the periods of 
active and no IMP treatment. 
The decisions regarding inclusion/exclusion of 
subjects from the trial analysis sets will be 
documented in the statistical analysis plan 
update analysis set definition document
before breaking the randomisation code.
To update with the internal 
LEO process. 
14.3.1
Aspects related to 
the COVID-19
pandemic
New subsection added. 
To elaborate on the COVID-19
pandemic-related aspects that 
require special considerations in 
the statistical analyses.
14.3.2 14.3.1
Disposition of 
subjects 
Permanent discontinuation of IMP due to 
the COVID-19 pandemic will be added to 
the list of reasons and identified based on 
the information documented in the eCRF.
To capture the COVID-19
pandemic-related information.
14.3.4 14.3.3
Exposure and 
treatment 
compliance
Treatment compliance will be presented for
the total missed IMP doses, missed IMP 
doses not due to the COVID-19 pandemic, 
and the missed IMP doses due to the 
COVID-19 pandemic for the safety analysis 
set for each treatment group.
To present the COVID-19
pandemic-related information.
14.3.5 Rescue 
treatment
New subsection added.
To clarify the definition of 
rescue treatment.
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Section no. and 
name
Description of change
Brief rationale
14.3.6 14.3.4
Testing strategy
Hypothesis testing will be based on the 
primary analysis of the primary estimand 
for each associated endpoint.
To add clarification. 
14.3.7
Intercurrent 
events
New subsection added.
To add clarification on the 
intercurrent events.
1 additional intercurrent event and 1 attribute 
have been included.
x
Subject-onset of the COVID-19
pandemic (subject-specific intercurrent
event)
x
Missing due to COVID-19 (data
attribute)
To maintain the trial integrity 
with respect to the original 
research questions and ensure
an unbiased evaluation of the 
treatment effect.
Panel 13 has been added.
To give an overview of the 
handling of data in relation to 
intercurrent events in each 
estimand.
14.3.8 14.3.5
Analysis of 
primary efficacy 
endpoint 
Three 4 estimands addressing different aspects 
of the trial objectives will be defined:
x
Primary estimand: ‘COVID-19
modified composite’
x
SecondaryPrimary estimand: ‘composite’
x
TertiarySecondary estimand: ‘treatment
policy’
x
QuaternaryTertiary estimand:
‘hypothetical’
To maintain the trial integrity 
with respect to the original 
research questions and ensure 
an unbiased evaluation of the 
treatment effect.
14.3.8.1
Primary 
estimand: 
‘COVID-19 
modified 
composite’
New subsection added.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
14.3.8.2 14.3.5.1
Secondary
Primary estimand: 
‘composite’ 
Treatment difference in response rates of 
EASI75 after 16 weeks achieved without 
either rescue treatment or treatment 
discontinuation, as if the COVID 19 
pandemic did not happen
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
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Section no. and 
name
Description of change
Brief rationale
Subjects who prior to the Week 16 visit have 
received rescue treatment or permanently 
discontinued IMP will be considered 
non-responders.
To reflect the new ‘composite’ 
estimand approach.
Removal of stratification variable ‘country 
(Germany: yes/no)’ in the analysis.
Limited number of subjects in 
the strata with ‘country 
(Germany: yes/no) = yes’.
‘Sensitivity analyses for the primary
secondary estimand’ has been re-written.
To reflect the changes in the 
handling of missing data.
14.3.8.3 14.3.5.2
Tertiary 
Secondary
estimand: 
‘treatment policy’
Treatment difference in response rate of 
EASI75 after 16 weeks between 
tralokinumab+TCS and placebo+TCS 
regardless of rescue treatment and IMP 
discontinuation, as if the COVID-19
pandemic did not happen
Data retrieved at Week 16 for subjects who 
prior to Week 16 have permanently 
discontinued IMP prior to Week 16 for other 
reasons than the COVID-19 pandemic will
be included in the analysis.
For subjects who have subject-onset of the 
COVID-19 pandemic prior to Week 16 and 
prior to any permanent discontinuation of 
IMP not due to the COVID-19 pandemic, 
any observed data from these subjects will 
be ignored and treated as missing in the 
same manner as missing data from not 
discontinued subjects in the analysis.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
Removal of stratification variable ‘country 
(Germany: yes/no)’ in the analyses.
Limited number of subjects in 
the strata with ‘country 
(Germany: yes/no) = yes’.
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Section no. and 
name
Description of change
Brief rationale
‘Sensitivity analyses for the secondary
tertiary estimand’ has been edited.
In case the number of discontinued subjects 
attending the nominal Week 16 visit is too 
low to fit the imputation model in the 
primary analysis of the tertiary estimand, 
the sensitivity analysis will become the 
primary analysis of the tertiary ‘treatment 
policy’ estimand.
To reflect the changes in the 
handling of missing data in the 
sensitivity analysis.
14.3.8.4 14.3.5.3 
Quaternary
Tertiary estimand: 
‘hypothetical’
Treatment difference in response rates of 
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 made available before 
Week 16, and as if the COVID-19 pandemic 
did not happen before Week 16.
Data collected after permanent discontinuation 
of IMP or, after initiation of rescue treatment, 
or after subject-onset of the COVID-19
pandemic will not be included in the analysis.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
Removal of stratification variable ‘country
(Germany: yes/no)’ in the analyses.
Limited number of subjects in 
the strata with ‘country 
(Germany: yes/no) = yes’.
Rather than assuming that observations are 
MAR within each treatment group, it is 
assumed that missing data from subjects who
discontinue treatment/receive rescue treatment
had any of the intercurrent events in the 
tralokinumab+TCS group will resemble 
missing data from subjects from the 
placebo+TCS group who do not discontinue 
treatment/receive rescue treatment had none 
of the intercurrent events.
To reflect the changes in the 
handling of missing data.
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Section no. and 
name
Description of change
Brief rationale
14.3.9 14.3.6
Analysis of 
secondary 
endpoints
Only subjects with an average Worst Daily 
Pruritus NRS score of 4 or above at 
baseline will be included in these analyses.
To clarify the further 
specification of the analysis. 
For each of the binary secondary endpoints,
tipping-point analyses using the method 
described for the tipping-point analyses of 
the binary primary endpoint (EASI75 at 
Week 16) will be added as sensitivity 
analyses for the primary estimand.
To align the secondary 
endpoints to the primary 
endpoint.
Interaction between subgroups and treatment 
effect will be tested using the Breslow-Day 
test.conditional logistic regression.
To assess consistency in the 
treatment effect across 
subgroups.
Subgroup analysis of IGA has been added.
To assess consistency in the 
treatment effect across 
subgroups.
3 estimands addressing different aspects of the 
trial objectives are defined:
x
Primary estimand: ‘hypothetical’
x
Secondary estimand: ‘treatment policy’
x
Tertiary estimand: ‘COVID-19
modified composite’
To maintain the trial integrity 
with respect to the original 
research questions and ensure 
an unbiased evaluation of the 
treatment effect.
14.3.9.1 14.3.6.1
Primary estimand 
for the continuous 
secondary 
endpoints: 
‘hypothetical’
Treatment difference in change from baseline 
to Week 16/ Week 26 in SCORAD and DLQI
scores, respectively, if all subjects adhered to 
the treatment regimen in the sense that they 
did not discontinue IMP permanently, and no
rescue treatment was made available, and as if 
the COVID-19 pandemic did not happen 
before Week 16/Week 26.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
Data collected after permanent discontinuation 
of IMP or, after initiation of rescue treatment, 
or after subject-onset of the COVID-19
pandemic will not be included in the analysis.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
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Section no. and 
name
Description of change
Brief rationale
Rather than assuming that observations are 
MAR within each treatment group, it is 
assumed that missing data from subjects who
discontinue treatment/receive rescue treatment
had any of the intercurrent events in the 
tralokinumab+TCS group will resemble 
missing data from subjects from the 
placebo+TCS group who do not discontinue 
treatment/receive rescue treatment had none 
of the intercurrent events.
To reflect the changes in the 
handling of missing data in the 
sensitivity analysis.
14.3.9.2 14.3.6.2
Secondary 
estimand for the 
continuous 
secondary 
endpoints: 
‘treatment policy’
Treatment difference in change from baseline 
to Week 16/ Week 26 in SCORAD and DLQI
scores, respectively, between 
tralokinumab+TCS and placebo+TCS 
regardless of rescue treatment use and 
treatment discontinuation, as if the COVID-
19 pandemic did not happen.
Data retrieved at Week 16 / Week 26 for 
subjects who prior to Week 16 /Week 26 
have permanently discontinued IMP prior to 
Week 16 / Week 26 for other reasons than 
the COVID-19 pandemic will be included in 
the analysis.
For subjects who have subject-onset of the 
COVID-19 pandemic prior to Week 16/ 
Week 26 and prior to any permanent 
discontinuation of IMP not due to the 
COVID-19 pandemic, any observed data 
from these subjects will be ignored and 
treated as missing in the same manner as 
missing data from not discontinued subjects 
in the analysis.
To maintain the trial integrity 
with respect to the original 
research question and ensure an
unbiased evaluation of the 
treatment effect.
In that case, the preferred order of elimination 
of the effects from the imputation model will 
be: country, prior CSA use, country, baseline 
disease severity, and baseline 
SCORAD/DLQI.
To reflect the updated order of 
importance of the stratification 
variables.
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Section no. and 
name
Description of change
Brief rationale
14.3.9.3 14.3.6.3
Tertiary 
estimand for the 
continuous 
secondary 
endpoints: 
‘COVID-19 
modified 
composite’
New subsection added. 
To ensure an unbiased 
evaluation of the treatment 
effect despite unexpected 
increase in missing data caused 
by the COVID-19 pandemic.
14.3.9.4 
Subgroup 
analysis of 
continuous 
endpoints
DLQI endpoints are added for subgroup 
analysis of continuous endpoints.
To be consistent in the efficacy 
assessment across different 
endpoints.
14.3.10 14.3.7 
Analysis of other 
endpoints
To evaluate the efficacy related to health care 
resource utilisation, the amount of TCS used 
(assessed as the amount of TCS used between 
visits) will be determined over 2-week 
periods, and the number of days without 
topical treatment use (collected as Patient 
Days of Topical Treatment Use in the eDiary) 
will be determined over 2 1-week periods.
To better characterise the 
treatment effect over time.
14.3.11 Analysis 
of exploratory 
supporting 
endpoints
New subsection added. 
To evaluate the treatment effect 
over time. 
14.3.13 14.3.9
Analysis of safety 
The analyses of safety will be based on the 
safety analysis set and the safety follow-up 
analysis set.
To align with the change in the 
trial analysis set definition. 
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Section no. and 
name
Description of change
Brief rationale
14.3.13.1 14.3.9.1
Adverse events
Due to the COVID-19 pandemic and the 
implementation of home-use (self-injection) 
with telephone/video follow-up, overall 
safety monitoring could be impacted. To 
assess this, all AEs collected prior to and 
after the start of the COVID-19 pandemic 
will, in addition to being presented 
together, be presented separately for the 
overall summary of AEs and all 
treatment-emergent AEs by SOC and PT.
To report plausible COVID-19
pandemic related issues in the 
data. 
14.3.12.1 14.3.9.1
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, 1st quartile, 3rd quartile, minimum,
and maximum values for the safety analysis 
set and the continuation treatment safety 
analysis set.
To better characterise the 
summary data for vital signs.
To correct a mistake in the text.
Vital signs will be listed for the safety 
follow-up analysis set.
Due to high number of subjects 
proceeding to ECZTEND trial, 
it is not expected to have 
enough subjects to warrant a 
summary.
14.3.13.1 14.3.9.1
Laboratory 
parameters
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, 1st
quartile, 3rd quartile, minimum, and
maximum values for the safety analysis set
and the continuation treatment safety analysis 
set.
To better characterise the 
summary data for vital signs.
To correct a mistake in the text.
Laboratory parameters will be listed for the 
safety follow-up analysis set.
Due to high number of subjects 
proceeding to ECZTEND trial, 
it is not expected to have 
enough subjects to warrant a 
summary.
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Section no. and 
name
Description of change
Brief rationale
14.3.13.4 14.3.9.4 
Anti-drug 
antibodies
Summary will include 1st and 3rd quartiles.
To better characterise the 
summary data for vital signs.
ADA categorisation has been specified
To add more clarification of 
ADA categorisation.
For subjects who develop ADA and are 
considered treatment-boosted or treatment-
emergent, the IGA score, change in EASI at 
end of treatment, and titre information will be 
listed.
To only include data from 
subjects relevant to be listed.
14.3.16 14.3.12 
General principles
Summary will include 1st and 3rd quartiles. 
To better characterise the 
summary data for vital signs.
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 
document will be finalised before breaking 
the randomisation code.
To further clarify the statistical 
analysis plan process.
Appendix 8
New appendix added for protocol addendum 
COVID-19.
Rationale provided in
Appendix 8.
Appendix 9
New appendix added for protocol addendum 
no.2 Imagine for Studies.
Rationale provided in 
Appendix 9.
Throughout
Minor editorial and document formatting 
revisions.
Minor, have therefore not been 
summarised.
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Table of contents
Table of contents ...................................................................................................................... 14
List of panels ............................................................................................................................ 19
List of abbreviations................................................................................................................. 20
1
Protocol synopsis........................................................................................................ 23
2
Trial identification ...................................................................................................... 29
3
Schematic of trial design ............................................................................................ 29
4
Schedule of trial procedures ....................................................................................... 30
5
Introduction and trial rationale ................................................................................... 35
5.1
Atopic dermatitis ........................................................................................................ 35
5.2
Experience with investigational medicinal product.................................................... 35
5.3
Trial rationale.............................................................................................................. 36
5.4
Justification for dose................................................................................................... 37
5.5
Ethical considerations................................................................................................. 37
5.6
Benefit/risk assessment............................................................................................... 38
6
Trial objectives and endpoints.................................................................................... 40
7
Trial design ................................................................................................................. 43
7.1
Overall trial design ..................................................................................................... 43
7.2
Number of subjects needed......................................................................................... 44
7.3
End of trial definition.................................................................................................. 45
7.4
Software...................................................................................................................... 45
8
Trial population........................................................................................................... 46
8.1
Subject eligibility........................................................................................................ 46
8.2
Inclusion criteria......................................................................................................... 46
8.3
Exclusion criteria........................................................................................................ 48
8.4
Screening and screening failures ................................................................................ 52
9
Treatments .................................................................................................................. 54
9.1
Trial product description............................................................................................. 54
9.1.1
Investigational medicinal product (IMP) ...................................................... 54
9.1.2
Auxiliary medicinal product (AxMP) ........................................................... 54
9.2
Administration of trial products.................................................................................. 55
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9.2.1
Administration of IMP .................................................................................. 55
9.2.2
Administration of AxMP............................................................................... 56
9.3
Treatment assignment................................................................................................. 57
9.3.1
Blinding.........................................................................................................57
9.3.2
Emergency unblinding of individual subject treatment ................................ 58
9.4
Background treatment................................................................................................. 58
9.5
Rescue treatment......................................................................................................... 59
9.6
Concomitant medication and concurrent procedures ................................................. 59
9.7
Prohibited medication and procedures........................................................................ 60
9.8
Treatment logistics and accountability ....................................................................... 61
9.8.1
Labelling and packaging of trial products..................................................... 61
9.8.2
Storage of trial products................................................................................ 62
9.8.3
Drug accountability....................................................................................... 63
9.8.4
Treatment compliance ................................................................................... 64
9.8.5
Trial product destruction ............................................................................... 64
9.9
Provision for subject care following trial completion ................................................ 64
9.10 Reporting product complaints..................................................................................... 64
10
Discontinuation and withdrawal................................................................................. 66
10.1 General principles....................................................................................................... 66
10.2 IMP discontinuation rules........................................................................................... 66
10.2.1 Reasons for permanent discontinuation of IMP............................................ 66
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 67
10.3 Early termination assessments.................................................................................... 67
10.4 Lost to follow-up ........................................................................................................ 69
11
Trial assessments and procedures............................................................................... 70
11.1 Overview..................................................................................................................... 70
11.2 Assessments performed only at screening/baseline.................................................... 71
11.2.1 Demographics................................................................................................ 71
11.2.2 Medical history.............................................................................................. 71
11.2.3 Height and weight ......................................................................................... 72
11.2.4 Body surface area involvement..................................................................... 72
11.2.5 Columbia-Suicide Severity Rating Scale ...................................................... 72
11.3 Efficacy assessments .................................................................................................. 73
11.3.1 Investigator’s Global Assessment ................................................................. 73
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11.3.2 Eczema Area and Severity Index .................................................................. 73
11.3.3 SCORing Atopic Dermatitis.......................................................................... 75
11.3.4 Patient-reported outcomes............................................................................. 76
11.4 Safety assessments...................................................................................................... 78
11.4.1 Vital signs...................................................................................................... 78
11.4.2 Physical examination..................................................................................... 79
11.4.3 Electrocardiogram ......................................................................................... 79
11.4.4 Laboratory testing ......................................................................................... 80
11.4.5 Anti-drug antibody measurements ................................................................ 83
11.5 Pharmacokinetic assessments..................................................................................... 83
11.6 Other assessments....................................................................................................... 84
11.6.1 Photography .................................................................................................. 84
11.7 Estimate of total blood volume collected ................................................................... 84
11.8 End of trial.................................................................................................................. 84
11.9 Storage of biological samples..................................................................................... 85
12
Scientific rationale for trial design and appropriateness of assessments.................... 86
13
Adverse events............................................................................................................ 88
13.1 Definition and classification of adverse events .......................................................... 88
13.2 Collection of adverse event reports ............................................................................ 88
13.3 Reporting of adverse events........................................................................................ 88
13.4 Reporting of serious adverse events ........................................................................... 89
13.4.1 Investigator reporting responsibilities........................................................... 89
13.4.2 LEO reporting responsibilities ...................................................................... 90
13.5 Other events that require expedited reporting: pregnancy.......................................... 90
13.6 Reporting of other events............................................................................................ 90
13.6.1 Adverse events of special interest................................................................. 90
13.6.2 Overdose........................................................................................................91
13.6.3 Medication error............................................................................................ 92
13.6.4 Misuse ........................................................................................................... 92
13.6.5 Abuse............................................................................................................. 92
13.6.6 Aggravation of condition .............................................................................. 92
13.7 Follow-up for final outcome of adverse events .......................................................... 93
13.8 Handling of an urgent safety measure ........................................................................ 93
14
Statistical methods...................................................................................................... 94
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14.1 Sample size................................................................................................................. 94
14.2 Trial analysis sets........................................................................................................ 94
14.3 Statistical analysis....................................................................................................... 94
14.3.1 Aspects related to the COVID-19 pandemic................................................. 94
14.3.2 Disposition of subjects .................................................................................. 97
14.3.3 Demographics and other baseline characteristics.......................................... 97
14.3.4 Exposure and treatment compliance ............................................................. 97
14.3.5 Rescue treatment ........................................................................................... 98
14.3.6 Testing strategy ............................................................................................. 99
14.3.7 Intercurrent events......................................................................................... 99
14.3.8 Analysis of primary efficacy endpoint ........................................................ 102
14.3.9 Analysis of secondary endpoints................................................................. 109
14.3.10 Analysis of other endpoints......................................................................... 116
14.3.11 Analysis of exploratory supporting endpoints ............................................ 117
14.3.12 Analysis of patient-reported outcomes........................................................ 117
14.3.13 Analysis of safety........................................................................................ 118
14.3.14 Pharmacokinetics ........................................................................................ 121
14.3.15 Interim analysis ........................................................................................... 121
14.3.16 General principles ....................................................................................... 121
14.3.17 Handling of missing values......................................................................... 122
15
References................................................................................................................. 123
Appendix 1: Definitions of adverse events and serious adverse events................................. 127
Appendix 2: Classification of adverse events ........................................................................ 129
Appendix 3: Trial governance considerations........................................................................ 131
Appendix 3A: Regulatory and ethical considerations.............................................. 131
Appendix 3B: Informed consent process................................................................. 132
Appendix 3C: Subject and data confidentiality ....................................................... 132
Appendix 3D: Record keeping, quality control, and data handling......................... 133
Appendix 3E: Registration, reporting, and publication policy ................................ 137
Appendix 3F: Insurance........................................................................................... 139
Appendix 3G: Financial disclosure.......................................................................... 139
Appendix 3H: Trial and site closure ........................................................................ 139
Appendix 3I: Responsibilities.................................................................................. 140
Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD........................................ 141
Appendix 5: Guidance for anaphylaxis diagnosis.................................................................. 142
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Appendix 6: Eligibility criteria .............................................................................................. 143
Appendix 7: Contact list......................................................................................................... 146
Appendix 8: Clinical Trial Protocol Addendum COVID-19.................................................. 147
Appendix 9: Clinical Trial Protocol Addendum no. 2 Imagine for Studies ........................... 152
Appendix 10: Protocol amendment history............................................................................ 162
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List of panels
Panel 1: Trial design................................................................................................................. 29
Panel 2: Schedule of trial procedures: screening and treatment period ................................... 30
Panel 3: Schedule of trial procedures: follow-up including early termination ........................ 33
Panel 4: Objectives and endpoints ........................................................................................... 40
Panel 5: Identification of IMPs ................................................................................................ 54
Panel 6: Additional visits after permanent discontinuation of IMP ......................................... 68
Panel 7: Investigator’s Global Assessment .............................................................................. 73
Panel 8: Calculation of the Eczema Area and Severity Index.................................................. 74
Panel 9: Eczema Area and Severity Index severity score scale and area score scale .............. 74
Panel 10: Clinical laboratory tests............................................................................................ 81
Panel 11: Adverse events of special interest............................................................................. 91
Panel 12: Testing hierarchy for primary and secondary endpoints .......................................... 99
Panel 13: Handling of intercurrent events and missing data in the primary analysis of 
estimands........................................................................................................ 101
Panel 14: Transmission of electronic data.............................................................................. 136
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List of abbreviations
AD
atopic dermatitis
ADA
anti-drug antibody/ (-ies)
ADAM
analysis data model
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AxMP
auxiliary medicinal product
AWS
Amazon Web Services
BP
blood pressure
Ctrough
trough concentration: lowest concentration reached by a drug before the next dose 
is administered
CDISC
Clinical Data Interchange Standards Consortium
CI
confidence interval
COVID-19
Coronavirus Disease 2019
CMO
contract manufacturing organisation
CRA
clinical research associate
CRO
contract research organisation
CSA
cyclosporine A
C-SSRS
Columbia-Suicide Severity Rating Scale
CTR
clinical trial report
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
EASI50/75/90
at least 50/75/90% reduction in EASI score
ECG
electrocardiogram
ECZTEND
tralokinumab phase 3 long-term extension trial in subjects with AD who 
participated in ECZTRA trials (LP0162-1337)
eCRF
electronic case report form
eDiary
electronic diary
EDC
electronic data capture
ePRO
electronic patient-reported outcome
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EQ-5D-5L
EuroQoL 5-Dimension Health Questionnaire 5 Level
FAS
full analysis set
FU
follow-up visit
GCP
Good Clinical Practice
GDPR
General Data Protection Regulation
GPP3
Good Publication Practice standard
HADS
Hospital Anxiety and Depression Scale
HCP
health care professional
HIPAA
Health Insurance Portability and Accountability Act
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
IG
immunoglobulin
IGA
Investigator’s Global Assessment
IL
interleukin
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
LEO
LEO Pharma A/S
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
nAB
neutralising antibodies
NBUVB
narrow band ultraviolet B
NRS
numeric rating scale
PDE-4
phosphodiesterase-4
PK
pharmacokinetics
POEM
Patient-Oriented Eczema Measure
PRO
patient-reported outcome
PT
preferred term
PUVA
psoralen + ultraviolet A
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Q2W
every other week
SAE
serious adverse event
SC
subcutaneous
SCORAD
Scoring Atopic Dermatitis 
SF-36
36-Item Short Form Health Survey
SFU
safety follow-up
SOC
System organ class
TCI
topical calcineurin inhibitors
TCS
topical corticosteroid
Th2
T-helper-2 (cell)
ULN
upper limit of normal
UV A/B
ultraviolet A/B
WHO
World Health Organization
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1 Protocol synopsis
Trial ID
EudraCT no.
IND no.
LP0162-1346
2018-000747-76
123797
Title of trial
A randomised, double-blind, placebo-controlled, parallel-group, multi-centre,
phase 3 trial investigating the efficacy, safety, and tolerability of tralokinumab 
administered in combination with topical corticosteroids to adult subjects with 
severe atopic dermatitis who are not adequately controlled with or have 
contraindications to oral cyclosporine A – ECZTRA 7 (ECZema 
TRAlokinumab trial no. 7)
Short title of trial
Tralokinumab in combination with topical corticosteroids in subjects with 
severe atopic dermatitis who are not adequately controlled with or have 
contraindications to oral cyclosporine A
Main objectives 
and endpoints
Primary objective
Primary endpoint
To demonstrate that tralokinumab 
in combination with TCS is 
superior to placebo in 
combination with topical
corticosteroids (TCS) in treating 
severe AD in subjects who are not 
adequately controlled with or 
have contraindications to oral 
cyclosporine A (CSA).
At least 75 reduction in EASI score 
(EASI75)1 at Week 16
Secondary objectives
Secondary endpoints
To evaluate the efficacy of 
tralokinumab in combination with 
TCS on severity and extent of 
AD, itch, and health-related 
quality of life compared to 
placebo in combination with TCS.
Severity and extent of AD
x
IGA2 score of 0 (clear) or 1
(almost clear) at Week 16
x
IGA score of 0 (clear) or 1 (almost 
clear) at Week 26
x
Change in SCORAD3 from 
baseline to Week 16
x
Change in SCORAD from 
baseline to Week 26
x
EASI75 at Week 26
Itch
x
Reduction of Worst Daily Pruritus 
NRS4 (weekly average) of at 
least 4 from baseline to Week 16
x
Reduction of Worst Daily Pruritus 
NRS (weekly average) of at 
least 4 from baseline to Week 26
Health-related quality of life
x
Change in DLQI5 score from 
baseline to Week 16
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x
Change in DLQI score from 
baseline to Week 26
To evaluate the safety of 
tralokinumab in combination with 
TCS when treating severe AD in 
subjects who are not adequately 
controlled with or have
contraindications to oral CSA
compared to placebo in 
combination with TCS.
x
Number of adverse events
x
Presence of anti-drug antibodies 
(yes/no)
1 EASI (Eczema Area and Severity Index) 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.
2 IGA (Investigator’s Global Assessment) 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).
3 SCORAD (Scoring Atopic Dermatitis) 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 Subjects will assess their worst itch severity over the past 24 hours using an 
11-point numeric rating scale (‘Worst Daily Pruritus NRS’) with 0 
indicating ‘no itch’ and 10 indicating ‘worst itch imaginable’.
5 DLQI (Dermatology Life Quality Index) is a validated questionnaire with 
content specific to those with dermatology conditions. It consists of 
10 items addressing the subject’s perception of the impact of their skin 
disease on different aspects of their health-related quality of life (HRQoL)
over the last week such as dermatology-related symptoms and feelings, 
daily activities, leisure, work or school, personal relationships, and the 
treatment. Each item is scored on a 4-point Likert scale (0 = not at all ⁄not 
relevant; 1 = a little; 2 = a lot; 3 = very much). The total score is the sum of 
the 10 items (0 to 30); a high score is indicative of a poor HRQoL.
Final collection of 
data for the 
primary endpoint
Week 16
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Trial design
Abbreviations: AD: atopic dermatitis; No: number; TCI: topical calcineurin 
inhibitors; TCS: topical corticosteroids; Q2W: every other week; w: week.
The trial will consist of a screening period of 6 weeks (Weeks -6 to 0) for
washout of previous AD medication (except TCS/TCI), a treatment period of 
26 weeks (Weeks 0 to 26), and a 14-week safety follow-up period for the 
assessment of safety and immunogenicity (Weeks 26 to 40).
Treatment period
Subjects will be randomised in a 1:1 ratio to receive multiple subcutaneous 
(SC) doses of tralokinumab (300 mg) or placebo every 2 weeks (Q2W) 
following an initial loading dose of 600 mg on Day 0 (or 4 mL placebo).
All subjects will receive TCS (mometasone furoate: Europe class 3 [potent]) to 
be used as needed throughout the treatment period. The safety and 
appropriateness of continued or repeated courses of TCS will be monitored and 
supervised by site staff. Lower potency TCS (Europe class <3) or TCI may be 
used at the investigator’s discretion on areas of the body where the supplied 
TCS is not advisable.
Safety follow-up
After completion of the treatment periods (at Week 26) or permanent 
discontinuation of investigational medicinal product (IMP), subjects will enter 
a 14-week safety follow-up period for assessment of safety and 
immunogenicity.
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All subjects will use an emollient twice daily (or more, as needed) for at least 
14 days before randomisation and will continue this treatment throughout the 
trial (including safety follow-up). On lesional skin, emollients should only be 
applied at a time where TCS is not applied; on TCS-untreated areas, the 
emollients may be applied at all times.
Main assessments
Efficacy assessments
x
IGA
x
EASI
x
SCORAD
Patient-reported outcomes: 3 patient-reported outcomes (PROs) will be 
assessed daily using an electronic diary: Eczema-related Sleep NRS, Worst 
Daily Pruritus NRS, and Patient Days of Topical Treatment Use.
5 PROs will be completed by the subjects at the site during trial visits: The 36-
Item Short Form Health Survey (SF-36), Patient-Oriented Eczema Measure 
(POEM), DLQI, EuroQoL 5-Dimension Health Questionnaire 5 Level (EQ-5D-
5L), and Hospital Anxiety and Depression Scale (HADS).
Safety assessments
Vital signs, physical examination, electrocardiograms, laboratory testing, 
anti-drug antibodies, and adverse event reporting.
Pharmacokinetics
Main criteria for 
inclusion
x
Age 18 and above.
x
Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria 
for AD.
x
History of AD for ≥1 year.
x
AD involvement of ≥10% body surface area at screening and baseline 
according to component A of SCORAD.
x
Subjects who have a recent history (within 1 year before the screening 
visit) of inadequate response to treatment with topical medications.
x
Documented history of either no previous CSA exposure and not 
currently a candidate for CSA treatment OR previous exposure to CSA 
in which case CSA treatment should not be continued or restarted.
x
Subjects must have applied a stable dose of emollient twice daily (or 
more, as needed) for at least 14 days before randomisation.
Main criteria for 
exclusion
x
Subjects for whom TCSs are medically inadvisable e.g., due to 
important side effects or safety risks.
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 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.
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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).
x
Concentration: 150 mg/mL.
x
Dose: 300 mg every 2 weeks (Q2W) following an initial loading dose 
of 600 mg
x
Method of administration: Subcutaneous (SC).
Placebo
x
Placebo contains the same excipients in the same concentration only 
lacking tralokinumab.
Auxiliary 
medicinal product
(AxMP)
TCS (Europe: Class 3 [potent])
Mometasone furoate, 0.1% cream provided in kit sizes of 180–225 g every 
2 weeks.
Duration of 
treatment
Each subject’s trial participation will be up to 46 weeks, divided into a
screening period (including washout, if applicable) of up to 6 weeks, a
treatment period of 26 weeks, and a follow-up period of 14 weeks.
Eligible subjects may be invited to enter a long-term extension trial conducted 
under a separate protocol (LP0162-1337, ECZTEND). Subjects who transfer to 
ECZTEND must have had their last visit in the treatment period (Week 26 
under the current protocol).
Number of 
subjects
A total of 250 subjects will be randomised 1:1 to treatment with 
tralokinumab 300 mg+TCS or placebo+TCS.
Number and 
distribution of 
trial sites
Up to 40 clinical sites in Europe are anticipated. Distribution between countries 
will be based on feasibility. Inclusion of subjects from Germany is prioritised. 
Statistical 
methods
Analysis of primary endpoint: For each of 100 imputed data sets, the difference 
in response rates between treatment groups will be analysed using the 
Mantel-Haenszel risk difference stratified by prior CSA use (yes/no) and 
baseline disease severity (IGA 3 or 4). The estimates and standard errors from 
the 100 analyses will be pooled to one estimated treatment difference and 
associated standard error using Rubin’s rule to draw inference. From these 
pooled estimates, the 95% CI for the treatment difference will be calculated.
Subjects who prior to the relevant visit receive rescue treatment or permanently 
discontinue IMP, without prior subject-onset of the COVID-19 pandemic, will 
be imputed as non-responders. Any missing or collected data from subjects 
who have subject-onset of the COVID-19 pandemic as their first prior 
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intercurrent event will be imputed assuming missing at random (MAR). Data 
missing prior to any intercurrent event will be handled as non-response, unless 
data is missing due to the COVID-19 pandemic, in which case it will be 
imputed assuming MAR.
Analysis of secondary efficacy endpoints: Secondary binary endpoints at 
Week 16 and Week 26 will be analysed as described for the primary endpoint.
Secondary continuous endpoints will be analysed using a model for repeated 
measurements approach with prior CSA use (yes/no), country (Germany: 
yes/no), baseline disease severity (IGA 3 or 4) and treatment-by-visit 
interaction as factors and baseline score-by-visit interaction as a continuous 
covariate.
Analysis of secondary safety endpoints: Number of adverse events will be 
summarised by treatment, system organ class, and preferred term. The 
frequency of anti-drug antibodies will be summarised by treatment.
Signatory 
investigator
, Prof. Dr. med
, Germany
Sponsor
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark
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2 Trial identification
EudraCT number: 2018-000747-76
IND number: 123797
The clinical trial protocol will be registered in local registries if required by local legislation.
3 Schematic of trial design
Panel 1: Trial design
Abbreviations: AD: atopic dermatitis; No: number; TCI: topical calcineurin inhibitors; TCS: topical 
corticosteroids; Q2W: every other week; w: week.
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4 Schedule of trial procedures
Panel 2: Schedule of trial procedures: screening and treatment period
Screening
Treatment
Details
(protocol sections)
Visit
11
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week
-6
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Visit window (days)2
±3
-3
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Trial population and eligibility
Informed consent3
X
Appendix 3B
Subject eligibility
X
X
8.1 to 8.3
Trial products and randomisation
Initiation of emollients (background treatment)4
X
9.4
Concomitant medication (including rescue 
treatment)/ concurrent procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
9.6
Randomisation
X
9.3
IMP administration, compliance
X5
X5
X5
X
X
X
X
X
X
X
X
X
X
9.2
TCS (AxMP) dispensing
X
X
X
X
X
X
X
X
X
X
X
X
X
9.2.2
TCS (AxMP) return
X
X
X
X
X
X
X
X
X
X
X
X
X
9.8.3, 9.8.4
Investigator assessments at baseline
C-SSRS
X
11.2.5
Demographics (age), BSA involvement
X
X
11.2.1, 11.2.4
Other demographics and medical history
X
11.2.1, 11.2.2
Height, weight
X
11.2.3
Investigator assessment of efficacy
IGA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
11.3.1
EASI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
11.3.2
SCORAD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
11.3.3
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Panel 2 Schedule of trial procedures: screening and treatment period (continued)
Screening
Treatment
Details
(protocol sections)
Visit
11
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week
-6
-2
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Visit window (days)2
±3
-3
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Subject assessment of efficacy
eDiary training
X
eDiary6
<- =============================================== ->
11.3.4.1 to 11.3.4.3
SF-36
X
X
X
X
11.3.4.4
POEM
X
X
X
X
X
X
X
X
X
11.3.4.5
DLQI
X
X
X
X
X
X
X
X
X
11.3.4.6
EQ-5D-5L
X
X
X
X
X
X
X
11.3.4.7
HADS
X
X
X
X
X
X
X
11.3.4.8
Safety assessments 
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
11.4.1
Physical examination
X
X
X
X
X
11.4.2
ECG
X
X
X
X
X
11.4.3
Serum pregnancy test, hepatitis B, C, HIV
X
11.4.4
Urine pregnancy test
X
X
X
X
X
X
X
X
11.4.4
Serum chemistry, haematology, IgE
X7
X
X
X
X
X
X
X
X
11.4.4
Urinalysis
X
X
X
X
X
X
11.4.4
Anti-drug antibodies
X
X
X
X
11.4.5
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
13
Other assessments 
Pharmacokinetics
X
X
X
11.5
Photography8
X
X
X
X
11.6.1
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1)
For subjects who do not require a washout and subjects who only require washout of topical AD treatment (as specified in the exclusion criteria in Section 8.3), visits 1 and 2 
will be combined and screening will be reduced to 2 weeks. Hence, these subjects will only attend visit 2 (Week -2) which will include all assessments shown under Week -6. 
The screening period has a planned maximum duration of 6 weeks.
2)
If the date of a subject visit does not conform to the trial plan, subsequent visits should be planned to maintain the visit schedule relative to randomisation/baseline.
3)
The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout of disallowed 
medications. Additional informed consent is required for the photography component for the trial sites in scope.
4)
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before randomisation and must continue this treatment throughout the trial (including 
safety follow-up).
5)
For the first 3 IMP dosing visits (visits 3 to 5), subjects will be monitored after IMP administration for immediate drug reactions for a minimum of 30 minutes with vital signs 
taken every 30 minutes or until stable, whichever is later (see Section 9.2.1).
6)
eDiary includes: Eczema-related Sleep NRS, Worst Daily Pruritus NRS, Patient Days of Topical Treatment Use; subjects will complete daily from Week -2 to 26, except for 
Patient Days of Topical Treatment Use which will be completed daily from Week 0 to 26.
7)
IgE not assessed at screening.
8)
Optional, selected trial sites only.
Abbreviations: AxMP, auxiliary medicinal product; BSA, body surface area; C-SSRS, Columbia-Suicide Severity Rating Scale; DLQI, Dermatology Life Quality Index; EASI, 
Eczema Area and Severity Index; ECG, electrocardiogram; eDiary, electronic diary; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS, Hospital Anxiety and 
Depression Scale; HIV, human immunodeficiency virus; 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; SF-36, 36-Item Short Form Health Survey; TCS, topical corticosteroid.
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Panel 3: Schedule of trial procedures: follow-up including early termination
Nominal visit1
(if applicable)
SFU1,2
(end of trial)
Early 
termination1,3
(if applicable)
Unscheduled
visit4 (if
applicable)
Details 
(protocol 
section)
Visit
11x
16x
17
Week
16
26
40
Visit window (days)
±3
±3
±3
Trial products
Concomitant medication (incl. rescue 
treatment)/ concurrent procedures
X
X
X
X
X
9.6
TCS (AxMP) dispensing
X
9.2.2
TCS (AxMP) return
X
X
9.8.3, 9.8.4
Investigator assessment of efficacy
IGA, EASI
X
X
X
X
11.3.1, 11.3.2
SCORAD
X
X
X
X
11.3.3
Subjects assessment of efficacy
eDiary5 completion
X
X
X
X
11.3.4.1 to 
11.3.4.3
SF-36
X
X
X
X
11.3.4.4
POEM
X
X
X
X
11.3.4.5
DLQI
X
X
X
X
11.3.4.6
EQ-5D-5L, HADS
X
X
X
X
11.3.4.7,
11.3.4.8
Safety assessments
Vital signs, physical examination
X
X
X
11.4.1, 11.4.2
ECG
X
X
X
11.4.3
Urine pregnancy test, urinalysis
X
X
X
11.4.4
Serum chemistry, haematology, IgE
X
X
X
11.4.4
Anti-drug antibodies
X
X
X
11.4.5
Adverse events
X
X
X
X
X
13
Other assessments
Pharmacokinetics
X
X
X
11.5
1)
Subjects who permanently discontinue IMP for any reason will be asked to attend all or some of the following additional 
visits, depending on the timepoint of discontinuation: Visit 11x (16 weeks after randomisation), Visit 16x (26 weeks 
after randomisation), SFU visit (16 weeks after last administration of IMP), and early termination visit. For further 
details, please see Section 10.2.1 and Panel 6.
2)
All subjects will have a SFU visit 16 weeks after last administration of IMP (which is also considered end-of-trial visit), 
except subjects who enter the long-term extension trial (conducted under a separate protocol [LP0162-1337, 
ECZTEND]) for whom the end-of-trial visit will be the last visit in the present trial before transfer to ECZTEND.
3)
Assessments and procedures performed at Week 16 (see Panel 2) are also to be done at an early termination visit.
4)
Assessments and procedures to be performed at an unscheduled visit are left at the investigator’s discretion.
5)
eDiary includes: Eczema-related Sleep NRS, Worst Daily Pruritus NRS, and Patient Days of Topical Treatment Use.
Subjects will complete the eDiary daily from Week -2 to 26, except for Patient Days of Topical Treatment Use, which 
will be completed daily from Week 0 to 26. Subjects who permanently discontinue IMP prior to Week 26 will complete 
the eDiary daily until the nominal Week 26 visit.
Abbreviations: AxMP, auxiliary medicinal product; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and 
Severity Index; ECG, electrocardiogram; eDiary, electronic diary; EQ-5D-5L, EuroQoL 5-Dimension Health 
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Questionnaire 5 Level; 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; SFU, safety follow-up; TCS, topical corticosteroid.
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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 is associated with a substantial patient burden that typically includes poor 
quality of life and sleep disturbance (5).
AD is characterised by an activated T-helper-2 (Th2) pathway with increased expression of 
key Th2 cytokines including interleukin (IL)-13 (6,7). The expression of IL-13 is increased in 
lesional skin compared to non-lesional skin, and the proportion of CD4+ and CD8+ cells 
expressing IL-13 is upregulated in AD patients compared to individuals without AD (6, 8).
IL-13 acts on keratinocytes to release C-C motif chemokine ligand 22 and recruit more IL-13 
expressing Th2 cells, decrease differentiation, and contribute to decreased barrier function (9). 
IL-13 also drives immunoglobulin E (IgE) production and contributes to mast cell activation 
status and, once allergen cross-links IgE on the cell surface, drives histamine release and 
induces itch (10, 11). Indeed, itch is a key issue in AD, which drives significant mechanical 
damage to the skin and further facilitates allergen and pathogen entry.
These effects together drive and exacerbate the disease phenotype. A review of the available 
preclinical literature from mouse and human ex vivo models suggests IL-13 as a, if not the, 
central mediator of the AD skin phenotype. Indeed, there is evidence that blocking the IL-4 
receptor (which is part of the receptor complex that also binds IL-13) with the monoclonal 
antibody dupilumab leads to clinical improvement in subjects with AD (12).
5.2 Experience with investigational medicinal product
Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that 
specifically binds to human IL-13 and blocks interaction with the IL-13 receptors (13–15). A 
compilation of clinical and nonclinical data on tralokinumab including pharmacokinetics (PK) 
is given in the current version of the Investigator’s Brochure.
In total, more than 4,340 subjects have been treated with tralokinumab (cut-off date: 
18-Oct-2018) as determined from actual exposure data from completed clinical trials and the 
enrolment/randomisation schemes for ongoing trials. A phase 3 development programme is 
ongoing in AD, and other clinical trials with tralokinumab have been conducted in subjects 
with asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in healthy subjects. All 
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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.
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 other 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).
5.3 Trial rationale
Treatment recommendations for AD include topical therapies, the main being TCS. 
Unfortunately, TCS and topical calcineurin inhibitors (TCIs) have limited efficacy in patients 
with moderate-to-severe disease. TCS and non-biologic systemic therapies (e.g. CSA, 
azathioprine) are all associated with toxicities with long-term use (16-18). Patients that are 
unresponsive or unable to use topical treatments or CSA therefore have few treatment options. 
The recently approved biological agent dupilumab exhibits an acceptable benefit-risk ratio in 
clinical trials investigating subjects with moderate-to-severe AD, however there is limited 
experience with long-term dupilumab use in the post-marketing setting.
The primary objective of this trial is to evaluate the efficacy of tralokinumab in combination 
with TCS compared to placebo in combination with TCS in treating severe AD in subjects 
who are not adequately controlled with or having contraindications to oral CSA. In addition, 
secondary endpoints addressing symptom scores and extent of AD (IGA, SCORAD), itch-
related sleep loss and itch severity, and health-related quality of life (HRQoL) measures 
related to AD are also included.
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Thus, the trial will contribute to the characterisation of the benefit-risk profile of tralokinumab 
by considering a more difficult to treat patient population where treatment options are few.
5.4 Justification for dose
The dose selected for the tralokinumab phase 3 development programme is 300 mg Q2W 
administered subcutaneously. All subjects randomised to treatment with tralokinumab will get 
an initial loading dose of 600 mg on Day 0 (baseline). The administration of the loading dose 
of tralokinumab will allow systemic concentrations to reach steady state faster, and potentially 
reduce the time to onset of clinical effect. The serum concentrations of tralokinumab after the 
600 mg loading dose will not exceed the serum tralokinumab concentrations at steady state 
for the 300 mg Q2W.
The tralokinumab 300 mg Q2W dose was chosen based on the results of the phase 2b trial in 
subjects with moderate-to-severe AD (trial D2213C00001) described in Section 5.2. The 
subjects were treated with 3 different fixed dose regimens of tralokinumab (45, 150, or 
300 mg Q2W) or placebo to evaluate safety and efficacy over a treatment period of 12 weeks. 
In the overall intention-to-treat phase 2b population, a statistically significant improvement in 
EASI change from baseline at Week 12 was observed in the tralokinumab 300 mg group 
versus placebo; however, formal statistical significance was not demonstrated for the co-
primary endpoint IGA. The key secondary and exploratory endpoint results from trial 
D2213C00001 also supported the selection of the tralokinumab Q2W 300 mg dose for 
phase 3 development; and overall, larger numerical differences were observed for 300 mg 
tralokinumab dose than for 150 mg compared to placebo for most of the trial endpoints.
Since the safety profile in trial D2213C00001 was acceptable in all treatment cohorts and no 
clear safety-related dose-response pattern was identified, the dose of 300 mg Q2W has been 
selected for evaluation in the phase 3 development programme for tralokinumab in AD.
5.5 Ethical considerations
No children or other vulnerable subjects incapable of giving informed consent will be 
enrolled in this clinical trial. Furthermore, women who are pregnant, breastfeeding, or trying 
to become pregnant will not be enrolled in this clinical trial. Women of child-bearing 
potential must agree to use a highly effective method of contraception to prevent pregnancy 
during the clinical trial and until 16 weeks after discontinuation of treatment with the 
investigational medicinal product (IMP). In addition, all female subjects of child-bearing 
potential will have a pregnancy test performed before, during, and at end-of-treatment to 
ensure that no foetuses are exposed to the IMP.
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In a 13-week repeated-dose nonclinical study in male cynomolgus monkeys, no adverse 
effects on male reproductive endpoints were observed (Investigator’s Brochure). Coupled 
with the negligible exposure risk for drugs and antibodies by way of semen to achieve 
meaningful pharmacological levels in a pregnant woman or in the conceptus (19), it is not 
considered necessary to impose restrictions on fathering a child or sperm donation in clinical 
trials with tralokinumab.
In this trial in adult subjects with severe AD who are otherwise healthy, the efficacy of 
tralokinumab in combination with TCS therapy will be compared with a placebo control 
group on TCS therapy. The choice of placebo (on the background of TCS) as control is 
appropriate for addressing the objectives of this trial and it will provide information regarding 
treatment with tralokinumab in combination with TCS. Subjects will be under supervision by 
a dermatologist or allergist every second week for the duration of the treatment period, which 
is more frequent than standard clinical practice. All subjects will be treated with TCS 
(Europe: Class 3 [potent]) as needed, and rescue treatment may be given to the subjects at the 
investigator’s discretion for the duration of the trial.
Altogether, the risks associated with participating in this clinical trial are considered very low 
and outweighed by the benefit of a potential future treatment option for severe AD.
In accordance with the current version of the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, qualified medical personnel employed by LEO will 
be readily available to advise on trial-related medical questions. Medical monitoring will be 
performed throughout the trial and safety data will be reviewed regularly by medically 
qualified staff at LEO to ensure that prompt action is taken, if needed, to maximise patient 
safety. In conclusion, the trial design chosen 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. 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 severe AD
who are not adequately controlled with or have contraindications to oral CSA.
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, 
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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 anti-drug 
antibodies (ADA) have been detected in very few subjects exposed to tralokinumab for up to 
one year. 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 treatment period) as a precautionary measure against hypersensitivity 
reactions (further details are given in Section 9.2).
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 [20]).
x
Exclusion of subjects with a history of tuberculosis requiring treatment within 
12 months prior to the screening visit.
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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6 Trial objectives and endpoints
Panel 4: Objectives and endpoints
Objectives
Endpoints
Primary objective
Primary endpoint
To demonstrate that tralokinumab in 
combination with TCS is superior to 
placebo in combination with TCS in 
treating severe AD in subjects who are 
not adequately controlled with or have 
contraindications to oral CSA
x
EASI75 at Week 16
Secondary objective
Secondary endpoints
To evaluate the efficacy of 
tralokinumab in combination with TCS 
on severity and extent of AD, itch, and 
health-related quality of life compared 
to placebo in combination with TCS
Severity and extent of AD
x
IGA score of 0 (clear) or 1 (almost clear) at Week 16
x
IGA score of 0 (clear) or 1 (almost clear) at Week 26
x
Change in SCORAD from baseline to Week 16
x
Change in SCORAD from baseline to Week 26
x
EASI75 at Week 26
Itch
x
Reduction of Worst Daily Pruritus NRS (weekly average) of 
at least 4 from baseline to Week 16
x
Reduction of Worst Daily Pruritus NRS (weekly average) of 
at least 4 from baseline to Week 26
Health-related quality of life
x
Change in DLQI score from baseline to Week 16
x
Change in DLQI score from baseline to Week 26
To evaluate the safety of tralokinumab 
in combination with TCS when treating 
severe AD in subjects who are not 
adequately controlled with or having 
contraindications to oral CSA 
compared to placebo in combination 
with TCS
x
Number of AEs
x
Presence of ADA (yes/no)
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Objectives
Endpoints
Other objectives
Other endpoints
To support the primary and secondary 
objectives in the trial
Supporting primary endpoint
x
EASI90 at Week 16
x
Change from baseline to Week 16 in EASI score
x
Percent change from baseline to Week 16 in EASI score
Supporting secondary endpoints related to the severity and extent of 
AD
x
EASI90 at Week 26
x
Change from baseline to Week 26 in EASI score
x
Percent change from baseline to Week 26 in EASI score
x
Percent change from baseline to Week 16 in SCORAD
x
Percent change from baseline to Week 26 in SCORAD
Supporting the secondary endpoint related to itch
x
Change from baseline to Week 16 in Worst Daily Pruritus 
NRS (weekly average)
x
Percent change from baseline to Week 16 in Worst Daily 
Pruritus NRS (weekly average)
x
Change from baseline to Week 26 in Worst Daily Pruritus 
NRS (weekly average)
x
Percent change from baseline to Week 26 in Worst Daily 
Pruritus NRS (weekly average)
x
Change from baseline to Week 16 in Eczema-related Sleep 
NRS (weekly average)
x
Percent change from baseline to Week 16 in Eczema-
related Sleep NRS (weekly average)
x
Change from baseline to Week 26 in Eczema-related Sleep 
NRS (weekly average)
x
Percent change from baseline to Week 26 in Eczema-
related Sleep NRS (weekly average)
Supporting the secondary endpoint related to health-related quality 
of life
x
Reduction from baseline to Week 16 of DLQI of ≥4 points 
among subjects with baseline DLQI ≥4
x
Reduction from baseline to Week 26 of DLQI of ≥4 points 
among subjects with baseline DLQI ≥4
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Objectives
Endpoints
To evaluate the efficacy of 
tralokinumab in combination with TCS 
on patient-reported outcomes 
compared to placebo in combination 
with TCS.
x
Change from baseline to Week 16 in SF-36 score
x
Change from baseline to Week 26 in SF-36 score
x
Change from baseline to Week 16 in POEM
x
Change from baseline to Week 26 in POEM
x
Reduction from baseline to Week 16 of POEM of ≥4 points 
among subjects with baseline POEM ≥4
x
Reduction from baseline to Week 26 of POEM of ≥4 points 
among subjects with baseline POEM ≥4
x
Change from baseline to Week 16 in EQ-5D-5L score
x
Change from baseline to Week 26 in EQ-5D-5L score
x
Change from baseline to Week 16 in EQ-5D-5L VAS score
x
Change from baseline to Week 26 in EQ-5D-5L VAS score
x
Change from baseline to Week 16 in HADS
x
Change from baseline to Week 26 in HADS
x
HADS-anxiety and HADS-depression scores < 8 at Week 
16
x
HADS-anxiety and HADS-depression scores < 8 at Week 
26
x
Change from baseline to Week 16 in HADS-anxiety score
x
Change from baseline to Week 26 in HADS-anxiety score
x
Change from baseline to Week 16 in HADS-depression 
score
x
Change from baseline to Week 26 in HADS-depression 
score
To evaluate the efficacy of 
tralokinumab in combination with TCS 
on health care resource utilisation 
compared to placebo with TCS.
x
Amount of TCS used from baseline to Week 16
x
Amount of TCS used from baseline to Week 26
x
Number of days without topical treatment use from 
baseline to Week 16
x
Number of days without topical treatment use from 
baseline to Week 26
Abbreviations: AD, atopic dermatitis; ADA, anti-drug antibodies; CSA, cyclosporine A; DLQI, Dermatology 
Life Quality Index; EASI, Eczema Area and Severity Index; EASI75/90, at least 75/90% reduction in EASI 
score; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS, Hospital Anxiety and 
Depression Scale IGA, Investigator’s Global Assessment; NRS, numeric rating scale; POEM, Patient-Oriented 
Eczema Measure; SCORAD, Scoring Atopic Dermatitis; SF-36: Short Form-36 questionnaire; TCS, topical 
corticosteroids.
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7 Trial design
7.1 Overall trial design
Overview
This is a randomised, double-blind, placebo-controlled, parallel-group, multi-centre, phase 3 
clinical trial in adult subjects with severe AD ineligible to treatment with CSA. The trial will 
consist of a screening period, a treatment period, and a safety follow-up period. The primary 
endpoint is assessed at Week 16, and the final efficacy assessment will be conducted at 
Week 26.
A schematic of the trial design is provided in Panel 1.
Screening period (Week -6 to Week 0)
The screening period has a minimum duration of 2 weeks and a planned maximum duration 
of 6 weeks. The exact duration of the screening period for the individual subject depends on 
the length of any washout 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 topical PDE-4 inhibitors.
If no washout or a 2-week washout period is required, screening will be reduced to 2 weeks 
and reduced to 1 visit (Week -2; visit 2), i.e., the 2 planned screening visits will be merged. 
Eligibility will be assessed at the (first) screening visit and on Day 0 (hereinafter “baseline”) 
prior to randomisation.
All subjects will attend a screening visit 14 days before baseline (Week -2; visit 2) where they 
will receive electronic diary (eDiary) training and start 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. On lesional skin, 
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emollients should only be applied at a time where TCS is not applied; on TCS-untreated areas, 
the emollients may be applied at all times.
Treatment period (Week 0 to Week 26)
Following the screening period, approximately 250 subjects will be randomised 1:1 to one of 
the following groups stratified by prior CSA use (yes/no), country (Germany: yes/no), and 
baseline disease severity (IGA 3 or 4):
x
Tralokinumab 300 mg Q2W: tralokinumab 600 mg (loading dose) at baseline, then 
tralokinumab 300 mg Q2W.
x
Placebo Q2W: placebo (loading dose) at baseline, then placebo Q2W.
The last dose of IMP will be administered at Week 24.
Subjects in both treatment groups will apply a thin film of a supplied TCS once daily to areas 
with active lesions as needed; lower potency TCS or TCI may be prescribed if needed on body 
areas where the supplied TCS is not advisable or on areas where continued treatment with TCS 
is considered unsafe. Topical therapy will be discontinued when control is achieved; 
discontinuation should preferably be gradual. The safety and appropriateness of continued or 
repeated courses of TCS therapy will be monitored and supervised by the site staff.
Safety follow-up period (Week 26 to Week 40)
Subjects, except those who enter the long-term extension trial (LP0162-1337, ECZTEND, see 
below), will complete a 14-week off-treatment follow-up period for the assessment of safety, 
PK, and ADA.
Long-term extension trial (selected countries)
Eligible subjects may be invited to enter a long-term extension trial conducted under a separate 
protocol (LP0162-1337, ECZTEND). Subjects who transfer to ECZTEND must have had their 
last visit in the treatment period (Week 26 under the current protocol).
7.2 Number of subjects needed
Assuming a screening failure rate of 25%, approximately 333 subjects will be screened and 
approximately 250 subjects will be randomly assigned 1:1 to tralokinumab 300 mg+TCS or 
placebo+TCS. 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.
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This trial will be conducted at approximately 40 sites in Europe. The anticipated minimum 
number of randomised subjects per trial site is 4 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 40. Subjects entering the long-term 
extension trial (LP0162-1337, ECZTEND) after completion of the end-of-treatment visit 
(Week 26) 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 30-Mar-2018 (or later) 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 (or newer) 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.
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 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 
IRBs/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.
2. Age 18 and above.
3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (21; 
Appendix 4)
4. History of AD for ≥1 year.
5. Subjects who have a recent history (within 1 year before the screening visit) of 
inadequate response to treatment with topical medications.
x
Inadequate response is defined as failure to achieve and maintain remission or 
a low disease activity state (comparable to IGA 0=clear to 2=mild) despite 
treatment with a daily regimen of TCS of medium to higher potency (±TCI as 
appropriate), applied for at least 28 days or for the maximum duration 
recommended by the product prescribing information (e.g., 14 days for 
super-potent TCS), whichever is shorter.
x
Subjects with documented systemic treatment for AD in the past year are also 
considered as inadequate responders to topical treatments and are potentially 
eligible for treatment with tralokinumab after appropriate washout.
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6. AD involvement of ≥10% body surface area at screening and baseline according to 
component A of SCORAD.
7. EASI score ≥20 at screening and baseline
8. An IGA score of ≥3 at screening and at baseline
9. A Worst Daily Pruritus numeric rating scale (NRS) average score of ≥4 during the 
week prior to baseline.
x
Worst Daily Pruritus NRS score at baseline will be calculated from daily 
assessments of worst itch severity (Worst Daily Pruritus NRS) during the 
7 days immediately preceding randomisation (Day -6 to 0). A minimum of 
4 Worst Daily Pruritus NRS scores out of the 7 days is required to calculate the 
baseline average score. For subjects who do not have at least 4 scores reported 
during the 7 days immediately preceding the planned randomisation date, 
randomisation should be postponed until this requirement is met, but without 
exceeding the 6 weeks’ maximum duration for screening.
10. Subjects must have applied a stable dose of emollient twice daily (or more, as needed) 
for at least 14 days before randomisation.
11. Women of child-bearing potential must use a highly effective* form of birth control 
(confirmed by the investigator) throughout the trial and at least for 16 weeks (5 half-
lives) after last administration of IMP.
*A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), combined (oestrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), sexual 
abstinence (when this is in line with the preferred and usual life style of the subject), 
vasectomised partner (given that the subject is monogamous). The subjects must have 
used the contraceptive method continuously for at least 1 month prior to the pregnancy 
test at baseline. A female is defined as not being of child-bearing potential if she is 
postmenopausal (at least 12 months with no menses without an alternative medical 
cause prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy).
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12. Documented history by a physician of either:
x
No prior CSA exposure and not currently a candidate for CSA treatment due to 
any of the following:
i. medical contraindications (e.g., uncontrolled hypertension on 
medication) or hypersensitivity to CSA active substance or excipients
ii. use of prohibited concomitant medications (e.g., statins, digoxin, 
macrolide, antibiotics, barbiturates, anti-seizure, non-steroidal anti-
inflammatory drugs, diuretics, angiotensin-converting-enzyme 
inhibitors, St John's Wort)
iii. increased susceptibility to CSA-induced renal damage (elevated 
creatinine) and liver damage (elevated function tests), or increased risk 
of serious infections
x
Previously exposed to CSA, and CSA treatment should not be continued or 
restarted due to any of the following:
i. intolerance or unacceptable toxicity (e.g., elevated creatinine, elevated 
liver function tests, uncontrolled hypertension, paraesthesia, headache, 
nausea, hypertrichosis)
ii. inadequate response to CSA (defined as flare of AD on CSA tapering 
after a maximum of 6 weeks of high dose [5 mg/kg/day] to 
maintenance dose [2 to 3 mg/kg/day] or a flare after a minimum of 
3 months on maintenance dose). Flare is defined as increase in signs or 
symptoms leading to escalation of therapy, which can be an increase in 
dose, a switch to a higher potency class of TCS, or the start of another 
systemic non-steroidal immunosuppressive drug
iii. requirement for CSA at doses >5 mg/kg/day, or duration beyond those 
specified in the prescribing information (>1 year)
8.3 Exclusion criteria
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled:
1. Subjects for whom TCS are medically inadvisable e.g., due to important side 
effects or safety risks (including intolerance to treatment, hypersensitivity 
reactions, significant skin atrophy, systemic effects etc.) in the opinion of the 
investigator.
2. Concurrent enrolment in another interventional clinical trial.
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3. Previous randomisation in a tralokinumab clinical trial.
4. Active dermatologic conditions that may confound the diagnosis of AD or would 
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or 
psoriasis.
5. Known active allergic or irritant contact dermatitis that is likely to interfere with 
the assessment of severity of AD.
6. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], 
ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]), 
within 6 weeks prior to randomisation.
7. Treatment with the following medications within 4 weeks prior to randomisation:
x
Systemic immunosuppressive/immunomodulating drugs (e.g. 
methotrexate, CSA, azathioprine, mycophenolate mofetil, Janus kinase 
inhibitors).
x
Systemic corticosteroid use (excludes topical, inhaled, or intranasal 
delivery).
x
Three or more bleach baths during any week within the 4 weeks.
8. Treatment with topical 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.
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.
10. Receipt of any marketed biological therapy (i.e. immunoglobulin, anti-IgE) 
including dupilumab or investigational biologic agents:
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. Receipt of any investigational non-biologic agent within 5 half-lives prior to 
randomisation.
12. Receipt of blood products within 4 weeks prior to screening.
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13. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period.
14. Known or suspected allergy or reaction to any component of the IMP or AxMP 
formulation.
15. History of any active skin infection within 1 week prior to randomisation.
16. History of a clinically significant infection within 4 weeks prior to randomisation 
which, in the opinion of the investigator or sponsor’s medical expert, may 
compromise the safety of the subject in the trial, interfere with evaluation of the 
IMP, or reduce the subject’s ability to participate in the trial. Clinically significant 
infections are defined as:
x
a systemic infection.
x
a serious skin infection requiring parenteral (intravenous or intramuscular) 
antibiotics, antiviral, or antifungal medication.
17. A helminth parasitic infection within 6 months prior to the date informed consent 
is obtained that has not been treated with, or has failed to respond to, standard of 
care therapy.
18. History of anaphylaxis following any biological therapy.
19. History of immune complex disease.
20. History of cancer:
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.
21. Tuberculosis requiring treatment within the 12 months prior to screening. 
Evaluation will be according to local guidelines as per local standard of care.
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22. History of any known primary immunodeficiency disorder including a positive 
human immunodeficiency virus (HIV) test at screening, or the subject taking 
antiretroviral medications as determined by medical history and/or subject’s verbal 
report.
23. History of chronic alcohol or drug abuse within 12 months prior to screening, or 
any condition associated with poor compliance as judged by the investigator.
24. History of attempted suicide or at significant risk of suicide (either in the opinion 
of the investigator or defined as a “yes” to suicidal ideation questions no. 4 or 5 or 
answering “yes” to suicidal behaviour on the Columbia-Suicide Severity Rating 
Scale [C-SSRS] Screening version).
25. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, immunological, psychiatric, or major physical impairment that is 
not stable, in the opinion of the investigator, and could:
x
Affect the safety of the subject throughout the trial.
x
Influence the findings of the trial or their interpretations.
x
Impede the subject’s ability to complete the entire duration of trial.
26. Any clinically significant abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the 
screening period, which in the opinion of the investigator, may put the subject at 
risk because of his/her participation in the trial, or may influence the results of the 
trial, or the subject’s ability to complete entire duration of the trial.
27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 
≥2.0 times the ULN (upper limit of normal) at screening.
28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody 
(HBsAb), hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-
HCV) serology at screening. Subjects with positive HBsAb may be randomised 
provided they have a history of hepatitis B vaccination and have negative HBsAg 
and HBcAb serology.
29. Subjects who are not willing to abstain from donating blood and/or plasma from 
the time of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.
30. Subjects who are legally institutionalised.
31. Pregnant, breastfeeding, or lactating women.
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32. Employees of the trial site or any other individuals directly involved with the 
planning or conduct of the trial, or immediate family members of such individuals.
8.4 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 
who have given written informed consent to participate in the trial and who have been 
assigned a subject ID are considered ‘screened’ subjects.
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 they have provided written informed consent 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 who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements (22) 
and to respond to queries from regulatory authorities. The following data will be collected in 
the eCRF for screening failures:
The following data will be collected in the eCRF for screening failures:
x
Date of informed consent.
x
Demographics (age, sex, race, and ethnicity).
x
Reason for screen failure:
o
Failure to meet randomisation criteria.
o
Lost to follow-up.
o
Withdrawal by subject.
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o
Other.
x
Date of screen failure.
x
Any 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
9.1.1 Investigational medicinal product (IMP)
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 5 for further details).
Panel 5: Identification of IMPs
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.
9.1.2 Auxiliary medicinal product (AxMP)
Each subject will be prescribed an auxiliary medicinal product (AxMP): the subjects will 
receive a TCS cream (Europe: Class 3 [potent]) from randomisation (Week 0) to Week 26. 
This will be provided as mometasone furoate, 0.1% cream in kit sizes of 180–225 g every 
2 weeks. This should be the only TCS product applied to the body during this period, 
excluding areas of the body where the supplied TCS is not advisable or where continued use 
is considered unsafe (see Section 9.2.2 for further details).
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9.2 Administration of trial products
9.2.1 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 24. To ensure blinding, both treatment groups will receive the same 
number of injections at each visit.
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 treatment period, each subject will receive 2 SC injections (each of 1 mL).
Hence, subjects in the 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
Placebo Q2W: placebo (4 mL) at baseline, then placebo (2 mL) Q2W.
IMP will be administered by a qualified, unblinded health care 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.
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 the trial product handling manual. 
IMP administration must be carried out according to these instructions.
After IMP administration 
For the first 3 IMP dosing visits in the treatment period (i.e., Weeks 0, 2, and 4), subjects will 
be monitored after IMP administration for immediate drug reactions for a minimum of 
30 minutes with vital signs taken at 30 minutes or until stable, whichever is later. Vital signs 
will be documented in the eCRF.
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organization has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
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(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) (23). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5. 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.
LEO does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat any overdose if necessary.
9.2.2 Administration of AxMP
The IRT will assign the required AxMP (TCS) kit numbers for each subject at each dispensing 
visit. The TCS will be provided as mometasone furoate, 0.1% cream in kit sizes of 180–225 g 
Q2W. If needed, additional TCS kit(s) may be dispensed to the subject at a scheduled or 
unscheduled visit at the investigator’s discretion. The amount of additional TCS dispensed 
must be recorded in the eCRF.
Subjects will be instructed to apply a thin film of the dispensed TCS (Europe: Class 3 
[potent]) once daily to active lesions, as needed. The TCS should be discontinued when 
control is achieved; discontinuation should preferably be gradual and the maximum duration 
of treatment should not exceed 3 weeks. The safety and appropriateness of continued or 
repeated courses of TCS therapy will be monitored and supervised by site staff.
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From randomisation (Week 0) and until last administration (at Week 24), the TCS will be 
dispensed and the subject must return used and unused TCS tubes at each subsequent trial 
visit, to assess the amount of medication used. The subjects must be instructed by the site staff 
on the importance of returning all used and unused TCS tubes. The site staff will return used 
and unused TCS tubes to the contract manufacturing organisation (CMO). The TCS tubes will 
be weighed at the CMO before shipment to the trial sites and again upon return.
An additional, lower potency TCS or TCI may be used at the investigator’s discretion on areas 
of the body where use of the supplied TCS is not advisable such as areas of thin skin (face, 
skin fold areas, genital areas, etc.) or on areas where continued treatment is considered unsafe. 
The lower potency TCS and TCI will not be provided by LEO and will not be weighed, but 
must be registered in the eCRF as concomitant medications (see Section 9.6).
Further details on TCS dispensing are provided in the trial product handling manual. TCS 
administration must be carried out according to these instructions.
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+TCS or placebo+TCS, stratified by prior CSA use (yes/no), 
country (Germany: yes/no), and baseline disease severity (IGA 3 or 4).
The IRT will be used to control randomisation and stratification factors, along with trial 
product 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 the investigator or LEO staff who are involved in the 
treatment or clinical evaluation and monitoring of the subjects will be aware of the treatment 
received.
The packaging and labelling of the IMPs will contain no trace of 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 
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will not be involved in the management of trial subjects and who will not perform any of the 
assessments.
If treatment allocation for a subject becomes known to the investigator or other trial staff 
involved in the management of trial subjects, LEO must be notified immediately.
Should an issue arise with the IMP (e.g., damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g., a 
malfunction during IMP administration]), the unblinded HCP at the site will contact the 
clinical research associate (CRA) to determine whether any specific actions are required. 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.
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 
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 
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.
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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. If possible, investigators 
should attempt to limit the first step of rescue therapy to topical medications (i.e. higher 
potency TCS, Europe class >3), and escalate to systemic medications only for subjects who 
do not respond adequately after at least 14 days of topical treatment. The subject will be 
monitored for signs of local or systemic TCS toxicity and the safety and appropriateness of 
continued use will be supervised by site staff.
Subjects who receive topical rescue treatment (higher potency TCS, Europe class >3) will 
continue IMP treatment.
If a subject receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (methotrexate, mycophenolate mofetil, azathioprine, etc.), IMP will 
be immediately discontinued (see Section 10.2.2). 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. In the primary efficacy analyses, subjects who receive higher 
potency TCS (Europe Class >3) or systemic rescue treatment during the treatment period will 
be considered as non-responders.
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 40) 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.
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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.
The following concomitant medications related to AD treatment are permitted from screening 
through safety follow-up (Week 40):
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 listed below are prohibited during the trial from randomisation. Medications 
and procedures disallowed prior to randomisation are covered in the exclusion criteria (see 
Section 8.3). In case any prohibited treatments are used during the trial, they must be recorded 
as concomitant medication.
From randomisation through end of treatment (Week 26):
x
PDE-4 inhibitors.
x
TCS of higher potency (Europe class >3).
x
Use of 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 40):
x
Investigational agents other than tralokinumab.
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x
Systemic corticosteroids (nasal and inhaled corticosteroids are allowed).
x
Systemic treatment for AD with an immunosuppressive/immunomodulating agent 
(examples include: cyclosporine A, mycophenolate mofetil, azathioprine, 
methotrexate, Janus kinase inhibitors, interferon-gamma, dupilumab, or other 
biologics).
In case prohibited systemic medications are received (for any indication), IMP dosing must be 
suspended as described in Section 10.2.2.
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 40):
x
Allergen immunotherapy.
x
Live (attenuated) vaccine.
x
Immunoglobulins.
x
Blood products.
The sponsor’s medical expert will determine whether IMP discontinuation is required. Please 
note that receipt of inactive/killed vaccines (e.g. inactive influenza) is allowed, provided they 
are not administered within 5 days before/after any trial visit.
9.8 Treatment logistics and accountability
9.8.1 Labelling and packaging of trial products
Investigational medicinal product
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.
Auxiliary medicinal product
The AxMP (TCS) will be packaged in individually numbered kits that contain tubes of TCS 
cream with a total weight of 180–225 g. Primary and secondary packaging materials (tube and 
outer kit carton, respectively) will be individually labelled.
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The labelling of AxMPs 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
Storage of IMP
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed.
The IMP must be stored at 2-8°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.
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 (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 trial product handling manual.
Storage of AxMP
All LEO supplied AxMP (TCS) must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed.
The TCS must be stored at the site according to the approved label for mometasone furoate. 
The temperature during storage must be recorded 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 TCS 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 TCS 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.
Damaged TCS should be documented via IRT (refer to the IRT instructions for further details) 
and reported as a product complaint to Global Safety, LEO (see Section 9.10). Damaged TCS 
should not be used.
9.8.3 Drug accountability
Trial product accountability will be performed in the IRT.
IMP accountability
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. Dispensing of IMPs may 
be delegated, e.g., to a hospital pharmacy, as locally applicable.
Individual drug accountability of the IMP administered to each subject randomised in the trial 
must be documented. The individual drug accountability must be available during monitoring 
visits and will be checked by the CRA to verify correct dispensing of the IMP. Drug 
accountability information will be entered in the IRT, where also inventory status of all IMP at 
the trial site will be maintained. For more information about IMP and AxMP accountability, 
please refer to the trial product handling manual.
The IMPs must be fully accounted for by the CRA with the help of site staff responsible for 
dispensing the IMPs. All unused IMPs supplied by the CMO on behalf of LEO will be 
returned to the CMO.
AxMP accountability
The number of TCS tubes returned by the subject must be documented in the eCRF by the 
trial staff. The subject will at each dispensing visit return used, partly used, and unused TCS 
tubes (including empty kit cartons) to the site. Once reconciled and accounted for, the site will 
return all of the above to the CMO. For further details, please see the trial product handling 
manual.
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All returned AxMP tubes will be weighed by the CMO to determine the amount of TCS used 
by the subject. The detailed procedure for weighing of AxMP tubes and subsequent transfer of 
tube weight data to the clinical database will be documented.
Reporting in eCRF
The IMP kit numbers as well as the date and time of IMP administration will be recorded in 
the eCRF. In addition, the site of IMP injection should be given. For AxMP (TCS), the 
kit/tube number, date of dispensation and return, and number of tubes dispensed and returned 
will be recorded in the eCRF.
9.8.4 Treatment compliance
IMP injections will be performed by site staff that will also hand out TCS for self-
administration and keep the accountability records up to date. Any non-compliance with IMP 
administration and dispensing and return of TCS and the reason for it must be recorded in the 
eCRF.
9.8.5 Trial product destruction
Please refer to the trial product handling manual regarding details for trial product destruction.
9.9 Provision for subject care following trial completion
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. Subjects who qualify for the long-term extension trial (see 
Section 7.1) may be offered participation (selected countries).
9.10 Reporting product complaints
Any defects or issues with the IMP, AxMP (TCS) as well as any IMP device deficiency 
(including malfunctions, use errors, and inadequate labelling) must be reported to Global 
Safety at LEO 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 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 
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Sections 13.3 and 13.4. Similarly, any defects or issues with TCS must be reported to Global 
Safety using the same complaint procedure as for the IMP and device.
Refer to the IRT training manual for information on how to update the kit status in the IRT.
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 contact information for reporting product complaints:
Fax number: +45 7226 3287
E-mail 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 investigator, or LEO 
considers that it is not in the subject’s best interest to continue.
In order to obtain the most representative efficacy evaluation of tralokinumab, it is key to 
assess the efficacy status of each trial participant at the planned primary and secondary 
endpoints (nominal Week 16 and 26 visits), irrespective of whether the subject has 
discontinued IMP or not (see Panel 2). Hence, permanent discontinuation of IMP and 
withdrawal from trial are considered to be (potentially) 2 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 10.3 (see Panel 6 for additional visits required following permanent 
discontinuation of IMP).
x
Withdrawal from trial occurs when stop of all trial activities takes place before the last 
planned safety follow-up visit (Week 40). 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.
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.
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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).
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., 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 additional 
visits as indicated below (Panel 6). See the schedule of trial procedures for data to be 
collected at these visits (Section 4). The investigator will review any AEs which will be 
followed up according to Section 13.7, if the subject agrees.
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Panel 6: Additional visits after permanent discontinuation of IMP
IMP discontinuation stage
Additional visits required
Prior to Week 16
x
Early termination visit
x
Nominal Week 16 visit (16 weeks after randomisation)
x
Nominal Week 26 visit (26 weeks after randomisation)
x
Final SFU visit (16 weeks after last administration of IMP)
After Week 16 and prior to 
Week 26
x
Early termination visit
x
Nominal Week 26 visit (26 weeks after randomisation)
x
Final SFU visit (16 weeks after last administration of IMP)
After Week 26 and prior to
Week 40
x
Early termination visit
x
Final SFU visit (16 weeks after last administration of IMP)
Abbreviations: IMP, investigational medicinal product; SFU, safety follow-up.
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 and medical records
The reason for permanent discontinuation of IMP must be recorded in the medical records and 
in the eCRF (on the end-of-treatment form and end-of-trial form). The reason for subject 
withdrawal must be recorded in the medical records and in the eCRF (end-of-trial form). For 
subjects who do not attend the nominal visits at Week 16 or Week 26 or the safety follow-up 
visit, the reason for not attending will be recorded in the medical records and in the eCRF.
The categories for assigning reasons in the eCRF are: ‘lack of efficacy’, ‘AE’, ‘withdrawal by 
subject’, ‘lost to follow-up’, ‘death’, or ‘other’. If ‘AE’ 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 (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject’s medical record. 
Should the subject continue to be unreachable, they will be considered to have withdrawn 
from the trial with a primary reason of lost to follow-up.
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11 Trial assessments and procedures
11.1 Overview
During the trial there are 17 scheduled site visits at the clinic. 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 treatment.
x
Panel 3 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 order assigned below:
x
PROs:
o
DLQI
o
EQ-5D-5L
o
POEM
o
HADS
o
SF-36
x
Investigator assessments/procedures:
o
SCORAD component C, then component A and B
o
IGA
o
EASI
x
Safety and laboratory assessments (including PK)
x
Other assessments (photographs)
x
Administration of IMP
Subjects may also need to be seen at unscheduled visits during the course of the trial. The 
assessments performed at an unscheduled visit are left at the investigator’s discretion, except 
if the unscheduled visit involves administration of rescue treatment. In that case, the 
investigator 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 include 
any assessment performed at an early termination visit, see Panel 3 for details.
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Subjects participating in the trial will be under careful supervision of a qualified principal 
investigator (see Appendix 1.4). 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: date of birth (or only year and month of birth as applicable according to local 
legislation).
x
Sex: female; male.
x
Race: American Indian or Alaska native; Asian; black or African American; native 
Hawaiian or other Pacific islander; white; or other. If ‘other’ is selected as race, a 
further specification needs to be provided in the eCRF.
x
Ethnic origin (self-reported by the subject): Hispanic or Latino; not Hispanic or 
Latino.
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
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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 Height and weight
The subject’s height (without shoes) will be measured; the subject’s weight (in indoor 
clothing and without shoes) will be measured.
11.2.4 Body surface area involvement
The total body surface area (BSA) 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 trial procedures 
(Section 4).
11.2.5 Columbia-Suicide Severity Rating Scale
The C-SSRS is a rater-administered instrument used to assess the lifetime history and severity 
of suicidal ideation and suicidal behaviour through a series of simple, plain-language 
questions (24, 25). The C-SSRS must be completed at the screening visit to check that 
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exclusion criterion no. 24 does not apply. Further details on the assessment according to the 
C-SSRS are included in the efficacy assessment & C-SSRS manual.
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 7; 26). 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 7: 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.
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 (27). 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.
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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 8. 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 9. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 9) and by a weighting factor. The EASI score 
equals the sum of the scores obtained for each body region (Panel 8).
Panel 8: 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 (28).
Panel 9: 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
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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 (28). 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.
The sum of intensity score of the 6 symptoms will be reported (maximum score = 18).
Subjective symptoms (C)
A subjective assessment of the average itch and sleeplessness over the last 3 days/nights is 
recorded for each symptom by the subject on a visual analogue scale, where 0 is no itch (or 
sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum 
possible score of 20.
The SCORAD is calculated as: A/5+7B/2+C
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11.3.4 Patient-reported outcomes
All PROs included in this trial are included in the investigator trial file.
11.3.4.1 Eczema-related Sleep numeric rating scale
Subjects will rate how much their eczema interfered with their sleep the last night using an 
11-point NRS (0 indicating that it ‘did not interfere’ and 10 indicating that it ‘completely 
interfered’). Subjects will complete the Eczema-related Sleep NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 26.
11.3.4.2 Worst Daily Pruritus numeric rating scale
Subjects will assess their worst itch severity over the past 24 hours using an 11-point NRS 
(‘Worst Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Worst Daily Pruritus NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 26.
11.3.4.3 Patient Days of Topical Treatment Use
Subjects will assess their use of topical AD treatment over the past 24 hours using a response 
scale (‘yes’, ‘no’). Subjects will complete the Patient Days of Topical Treatment Use as part 
of an eDiary each day in the morning from baseline (Week 0 [visit 3]) until Week 26.
11.3.4.4 SF-36
The SF-36 (version 2, Acute Recall) is a 36-item general health status assessment. Subjects 
will be asked to answer each question by selecting one of 3 to 6 categorical response options. 
The instrument instructions do not state a specific recall period; however, a recall period is 
defined within most items. The acute recall version, which asks subjects about the last week, 
will be used in this trial (30).
The SF-36 (version 2) yields scores for 8 health domains (physical functioning, role physical, 
bodily pain, general health, vitality, social functioning, role emotional, and mental health) and 
2 psychometrically derived summary scores (a physical component summary and a mental 
component summary).
The SF-36 will be completed electronically on the device supplied to the trial site according 
to the schedule of trial procedures in Section 4.
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11.3.4.5 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 (31). The tool consists of 7 items each 
addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and 
dryness). Subject will score how often they have experienced each symptom over the previous 
week on a 5-point categorical response scale (0 = ‘no days’; 1 = ‘1 to 2 days’; 2 = ‘3 to 
4 days’; 3 = ‘5 to 6 days’; 4 = ‘every day’). The total score is the sum of the 7 items (range: 
0 to 28) and reflects disease-related morbidity; a high score is indicative of a worse disease 
severity. The POEM will be completed electronically on the device supplied to the trial site 
according to the schedule of trial procedures (Section 4).
11.3.4.6  Dermatology Life Quality Index
The DLQI is a validated questionnaire with content specific to those with dermatology 
conditions. It consists of 10 items addressing the subject’s perception of the impact of their 
skin disease on different aspects of their HRQoL over the last week such as dermatology-
related symptoms and feelings, daily activities, leisure, work or school, personal relationships, 
and the treatment (32). Each item is scored on a 4-point Likert scale (0 = ‘not at all/not 
relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). The total score is the sum of the 10 items 
(0 to 30); a high score is indicative of a poor HRQoL. The DLQI will be completed 
electronically on the device supplied to the trial site according to the schedule of trial 
procedures (Section 4).
11.3.4.7 EQ-5D-5L
The EQ-5D-5L is a standardised measure of health status developed by the EuroQoL group to 
provide a simple, generic measure of health for clinical and economic appraisal (33). The 
EQ-5D-5L is a self-administered questionnaire used to assess health status ‘today’ and is 
divided into 2 sections: The first section includes 5 dimensions (mobility, self-care, usual 
activity, pain/discomfort, and anxiety/depression); each dimension will be assessed by the 
subject using a 5-point scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe 
problems’, and ‘extreme problems’). The second section consists of a vertical visual analogue 
scale anchored at 0 (‘the worst health you can imagine’) and 100 (‘the best health you can 
imagine’). The EQ-5D-5L will be completed electronically on the device supplied to the trial 
site according to the schedule of trial procedures (Section 4).
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11.3.4.8 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 (34). 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 trial procedures (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 (i.e., Weeks 0, 2, and 4), subjects will be monitored after IMP 
administration for immediate drug reactions for a minimum of 30 minutes with vital signs 
taken at 30 minutes or until stable, whichever is later (Section 9.2.1).
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. 26).
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position to verify the first measurement. 
Should the repeated measurement result in a normal value, the measurement must be repeated 
once more. If the third measurement verifies the second (normal) value, the first measurement 
should be considered 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.
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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. 26).
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.
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 
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criterion no. 26); 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 10 will be performed.
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Panel 10: Clinical laboratory tests
Chemistry
Haematology
Alanine aminotransferase
Albumin
Alkaline phosphatase
Aspartate aminotransferase
Bilirubin1
Calcium
Cholesterol
Creatinine
Gamma glutamyl transferase
Glucose (non-fasting)
HDL cholesterol
Lactate dehydrogenase
LDL cholesterol
Potassium
Protein
Sodium
Triglycerides
Tryptase2
Urea nitrogen
Basophils
Basophils/leucocytes
Eosinophils
Eosinophils/leucocytes
Erythrocyte mean corpuscular haemoglobin 
concentration
Erythrocyte mean corpuscular volume
Erythrocytes
Haematocrit
Haemoglobin
Leucocytes
Lymphocytes
Lymphocytes/leucocytes
Monocytes
Monocytes/leucocytes
Neutrophils
Neutrophils/leucocytes
Thrombocytes
Urinalysis
Serology
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
Protein
Hepatitis B virus surface antigen3
Hepatitis B virus surface antibody3
Hepatitis B virus core antibody3
Hepatitis C virus antibody3
HIV-1 antibody3
HIV-2 antibody3
Immunoglobulin E4
Pregnancy test5
Choriogonadotropin beta
1)
If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured.
2)
Only measured in case of suspected anaphylaxis.
3)
Measured at screening only.
4)
Not measured at screening.
5)
Only female subjects of child-bearing potential. Measured in serum at screening only, and in urine every
4 weeks thereafter (see Section 4).
Abbreviations: HDL, high density lipoprotein; HIV, human immunodeficiency virus; LDL, low density 
lipoprotein.
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11.4.4.2 Investigator evaluation of laboratory samples
Central laboratory
Chemistry, haematology, urinalysis (if applicable), serology, and serum pregnancy tests will 
be analysed by a central laboratory which will provide results to the trial sites. The 
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. 26, 27, and 28).
A serum pregnancy test must be taken at the screening visit in female subjects of child-
bearing 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 child-bearing 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’).
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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 ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titre determination and will be analysed for the presence of neutralising 
antibodies (nAB). Details of the analytical method used will be described in the ADA 
bioanalytical report.
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  Other assessments
11.6.1 Photography
At selected trial sites, subjects will be asked to participate in a photography component 
involving digital photography assessments to show disease progression over time.
Participation in this photography component requires that the subject provides additional 
informed consent.
Digital colour photographs will be taken of the disease area and representative lesions at 4 
different time points according to the schedule of trial procedures (Section 4).
Custom photography equipment will be delivered to trial sites by the central photography 
vendor together with a photography manual. Photography standards and procedures are 
provided in the manual. The photographs will have no other subject identifier than the subject 
ID and will be transmitted electronically to the photography vendor using a secure file 
transfer protocol.
Printed copies of the photographs must be included as part of the individual subject source 
documentation.
LEO may at its discretion use the photographs in publications, posters, and similar types of 
information material or media targeting patients and HCPs. The photographs can also be part 
of training material used for training and educational purposes. Steps will be taken to ensure 
that the identity of the subject is protected to the extent possible.
11.7 Estimate of total blood volume collected
Blood samples will be drawn for haematology, biochemistry, serology, PK, and ADA. The 
total volume of blood to be drawn is approximately 160 mL, which is less than the volume of 
blood drawn during a blood donation (approximately 500 mL).
11.8  End of trial
An end-of-treatment form and an end-of-trial form will be completed in the eCRF for all 
randomised subjects, including subjects who permanently discontinue IMP and subjects who 
withdraw from the trial (see Section 10.3 for early termination assessments).
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End-of-treatment form
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).
End-of-trial form
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, AE, withdrawal by subject, lost to 
follow-up, death, other).
x
Did the subject attend the nominal Week 16 and 26 visits. If not, the primary reason 
for not attending the visit must be recorded (lack of efficacy, AE, withdrawal by 
subject, 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, AE, withdrawal by subject, 
lost to follow-up, death, other).
x
Date of last contact.
If ‘AE’ or ‘other’ is selected, a specification must be provided in the eCRF.
The end-of-trial form will be completed when the subject has had their last visit.
11.9 Storage of biological samples
PK samples will be retained for as long as the quality of the material permits evaluation but 
for no longer than 12 months after completion of the clinical trial report (CTR).
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
The trial is designed to evaluate the efficacy of tralokinumab in combination with TCS 
compared to placebo in combination with TCS in treating severe AD in subjects who are not 
adequately controlled with or have contraindications to oral CSA, a subgroup of AD patients 
that are difficult to treat because of the few approved treatment options available (35).
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 combined with TCS) are maintained and the possible observer bias 
regarding treatment effects is minimised.
By using a placebo-controlled parallel-group design for the treatment period, superiority of 
tralokinumab in combination with TCS versus placebo in combination with TCS can be 
investigated, hereby adding to the knowledge needed for positioning tralokinumab in the AD 
treatment pathway.
Stratification by prior CSA use (yes/no), country (Germany: yes/no), 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 included 
age range.
Among the key inclusion criteria for entry into the trial are a diagnosis of AD (as defined by 
the Hanifin and Rajka 1980 criteria for AD, see Appendix 4) at screening and a history of AD 
for at least one year, to ensure correct diagnosis and rule out differential diagnoses. A 
prerequisite for inclusion into the trial is also a documented history of treatment failure with 
CSA or not being a candidate for CSA.
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 (26).
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x
EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (27).
x
SCORAD is a validated tool to assess the extent and severity of AD lesions and subjective 
symptoms (28).
The efficacy endpoints EASI75 and IGA score of 0 or 1 are recognised as important endpoints 
in clinical trials in AD by European regulators.
Several validated patient-reported questionnaires (SF-36, POEM, DLQI, EQ-5D-5L, and 
HADS) have been included to assess the efficacy of tralokinumab on PROs 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.
Data on antibodies against tralokinumab (ADA) will be collected and the potential for 
immunogenicity will be evaluated until 16 weeks after the last dose of tralokinumab, to 
ensure adequate washout (approximately 5 times the half-life). The serum samples for 
determination of presence or absence of ADA will be analysed using a validated bioanalytical 
method.
Safety will be assessed using standard clinical methods of subject evaluations, such as AE 
monitoring, vital signs, ECGs, 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 final visit in 
LP0162-1346 should be reported in LP0162-1346. 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 (i.e. not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’).
The duration of the AE must be reported by the start date and stop date of the event (it will 
also be recorded if the event is ongoing). In addition, it must be recorded whether the AE 
started prior to start of IMP.
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 2.
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Action taken with trial treatment: Any action taken with IMP or AxMP 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. 
SAE criteria are also listed on the SAE form.
13.4.1 Investigator reporting responsibilities
Any SAE must be reported to LEO on the (paper) SAE Form within 24 hours of first 
knowledge. This report should contain an assessment of available information on seriousness, 
severity, causal relationship to the trial product/ trial procedure, the action taken, the outcome 
to date, and a narrative description of the course of the event.
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at LEO 
using the e-mail address or fax number below:
Global Safety at LEO
E-mail address: drug.safety@leo-pharma.com
Fax number: +45 7226 3287
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc.
Additionally, Global Safety at LEO may request further information in order to fully assess 
the SAE. The investigator must forward such information to LEO upon request by fax or e-
mail (see contact details above).
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country.
SAEs occurring after the completion of the clinical trial (i.e., after the last safety follow-up 
visit at Week 40) should not be routinely sought or collected. However, such events should be 
reported to Global Safety at LEO (see contact details above) if the investigator becomes 
aware of them.
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13.4.2 LEO reporting responsibilities
Global Safety at LEO is responsible for assessing whether or not an SAE is expected. The 
relevant reference safety information document for this clinical trial is:
x
For the IMP, the Investigator’s Brochure, current edition, must be used.
x
For the AxMP (mometasone furoate, 0.1% cream), the latest version of the approved 
summary of product characteristics (SmPC) must be used.
Global Safety at LEO 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.
All SAEs which are assessed as causally related to the IMP by either the investigator or 
LEO (ICH E2A Guideline), and which are unexpected (Suspected, Unexpected Serious 
Adverse Reactions [SUSARs]), are subject to expedited reporting to regulatory authorities 
and 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.
13.5 Other events that require expedited reporting: pregnancy
Any pregnancy occurring during the clinical trial must be reported to LEO 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 (Section 10.2.1).
13.6 Reporting of other events
13.6.1 Adverse events of special interest
The events listed in Panel 11 are considered AEs of special interest (AESIs) in this trial and 
will require additional details to be recorded in the eCRF. LEO may request that the 
investigator forward test results, as appropriate. An AESI may be serious (requiring expedited 
reporting, Section 13.4) or non-serious.
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Panel 11: 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.
x
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). 
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.
1The additional data to be recorded in the eCRF are not a requirement, but are to be reported by the investigator, 
if available, for example as part of standard clinical practice.
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 
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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).
LEO does not recommend specific treatment for an overdose. The investigator will use 
clinical judgement to treat any overdose if necessary.
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 a 
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 cannot 
be expected to recover during the trial or the safety follow-up periods, for example chronic or 
stabilised conditions, ‘not recovered’ should be reported as a final outcome. 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.” (36).
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 – by contacting the clinical project manager 
or medical expert – of this change in the clinical trial procedure or of the temporary halt 
providing full details of the information and the decision-making process leading to the 
implementation of the urgent safety measure.
LEO must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation.
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14 Statistical methods
14.1 Sample size
With a significance level of 5%, a sample size of 250 subjects will provide 99% power for 
detecting a treatment difference for the primary endpoint, assuming an EASI75 response rate 
at Week 16 of 40% vs 15% for tralokinumab+TCS and placebo+TCS, respectively. Assuming 
a response rate of 30% vs 15% in reduction of Worst Daily Pruritus NRS (weekly average) 
score of at least 4 from baseline to Week 16 for tralokinumab+TCS and placebo+TCS, 
respectively, the trial will provide at least 80% power for rejecting the hypotheses related to 
the primary endpoint and the secondary endpoint evaluating pruritus at Week 16.
14.2 Trial analysis sets
All screened subjects will be accounted for in the CTR.
All subjects randomised to treatment and exposed to the IMP will be included in the full 
analysis set (FAS) and will be analysed for efficacy. Exclusions from the FAS can be 
considered in special cases as described in the ICH E9 guideline, Section 5.2.1 (37). If it is 
decided to exclude a randomised subject from the FAS, a justification addressing ICH E9 will 
be given.
The following safety analysis sets are applied:
x
‘safety analysis set’ for all subjects exposed to IMP within the treatment period.
x
‘safety follow-up analysis set’ for all subjects exposed to IMP within the safety 
follow-up period.
The decisions regarding inclusion/exclusion of subjects from the trial analysis sets will be 
documented in the analysis set definition document before breaking the randomisation code.
14.3 Statistical analysis
14.3.1 Aspects related to the COVID-19 pandemic
As the implications of the COVID-19 pandemic will, extraordinarily, influence trial events 
and data in manners not foreseen by the protocol, this section is introduced to elaborate on the 
COVID-19 pandemic related aspects that may require special handling depending on the 
original research question.
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x
Permanent discontinuation of IMP due to the COVID-19 pandemic:
In general, permanent discontinuation of IMP can be interpreted as lack of efficacy of IMP 
and is therefore in some of the pre-specified analyses in the original protocol used to 
conclude non-response of the relevant subject. This interpretation is not appropriate when 
permanent discontinuation of IMP is caused by an external circumstance related to the 
COVID-19 pandemic.
The causal relationship to the COVID-19 pandemic will be documented in the eCRF. The 
handling of permanent discontinuation of IMP will depend on whether it is due to the 
COVID-19 pandemic or not. The date of this event will be the date of permanent 
discontinuation of IMP.
x
Use of rescue treatment due to unavailability of IMP related to the COVID-19 
pandemic:
Analogous to the handling of permanent discontinuation of IMP, interpretation of rescue 
treatment as lack of efficacy of IMP is not appropriate if rescue treatment is administered 
to compensate for unavailability of IMP due to the COVID-19 pandemic. It is therefore 
likewise relevant to determine whether this is the case.
The collection of concomitant medication does not allow for directly linking rescue 
treatment to the COVID-19 pandemic. Instead, rescue treatment will be attributed to the 
COVID-19 pandemic if it is administered while IMP dosing is missing due to the 
COVID-19 pandemic or if it is given after permanent discontinuation of IMP due to the 
COVID-19 pandemic (these underlying conditions may both be fulfilled).
Hence, rescue treatment will be attributed to the COVID-19 pandemic if it is administered 
in a time period where IMP is unavailable due to the COVID-19 pandemic. Such periods 
can be one of the following:
1. From the date of a conducted scheduled visit without IMP dosing due to the 
COVID-19 pandemic until the date of the next administered dose.
2. From 3 days prior to the planned date of a scheduled visit which is not conducted due 
to the COVID-19 pandemic until the date of the next administered dose.
3. From the date of permanent discontinuation of IMP due to the COVID-19 pandemic.
The date of this event will be the date of the administration of rescue treatment.
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x
Prolonged interruption of IMP dosing due to the COVID-19 pandemic:
A temporary pause in dosing due to the COVID-19 pandemic may influence the 
interpretation of the subsequent outcome for the subject, and the event will therefore be 
reported.
At the first occurrence, for which a subject misses IMP doses in one of the 4 following 
scenarios, the subject will be defined as having a prolonged interruption of IMP due to the 
COVID-19 pandemic:
1. 3 consecutive missed IMP doses, for which at least one of them is due to the 
COVID-19 pandemic.
2. 2 consecutive missed IMP doses, for which at least one of them is due to the 
COVID-19 pandemic and the third consecutive IMP dose is delayed for more than 7 
days beyond the planned date of the IMP dosing.
3. Week 22 and Week 24 IMP doses and the Week 26 visit are missed, for which at least 
one of them is due to the COVID-19 pandemic.
4. Week 22 and Week 24 IMP doses are missed, for which at least one of them is due to 
the COVID-19 pandemic, and the Week 26 visit is delayed for more than 7 days 
beyond the planned date. 
In scenarios 1 and 3, the start date of the event will be the planned date of the third 
consecutive missed IMP dose or the Week 26 visit. In scenarios 2 and 4, the start date of 
the event will be the planned date of the third consecutive IMP dose +7 days or the 
Week 26 visit + 7 days.
x
Missing data due to the COVID-19 pandemic:
The collection of data at planned visits allows to report if data is missing due to the 
COVID-19 pandemic, either due to the subject being prohibited from vising the sites or 
the visit being performed via telephone/video, thereby only allowing for a subset of data 
to be collected.
In the context of some of the efficacy analyses, data recorded missing due to the COVID-
19 pandemic will be handled differently from data missing for other reasons. As an 
example, it may not be reasonable to impute missing binary responder values as a non-
response if the missingness is due to the COVID-19 pandemic.
It should be noted that a subject may have missing data due to the COVID-19 pandemic, 
even though the subject may not have discontinued IMP permanently or temporarily due 
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to the COVID-19 pandemic. This could e.g. be the case if the subject continue treatment 
with tralokinumab via home-use (Appendix 8).
x
Infection with COVID-19:
Infection with COVID-19 as an AE may give rise to one of the scenarios described above 
but will not be handled differently from other types of AEs.
14.3.2 Disposition of subjects
For all randomised subjects the reasons for permanent discontinuation of IMP and for 
withdrawal from the trial will be presented by treatment group.
Permanent discontinuation of IMP due to the COVID-19 pandemic will be added to the list of 
reasons and identified based on the information documented in the eCRF.
14.3.3 Demographics and other baseline characteristics
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects. The presentations will be overall and by treatment group. 
Demographics (age, sex, race, and ethnicity) and baseline disease characteristics (IGA, EASI, 
SCORAD, DLQI, and Worst Daily Pruritus NRS score) will be presented by the stratification 
factors: prior CSA use (yes/no), country (Germany: yes/no), and baseline disease severity 
(IGA 3 or 4).
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 medications, and previous AD treatments.
14.3.4 Exposure and treatment compliance
Exposure
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group.
Treatment compliance
Compliance to treatment regimen will be recorded in the eCRF. If any complications or 
deviations in administration are observed, these will be described as protocol deviations. 
Treatment compliance will be presented for the total missed IMP doses, missed IMP doses not 
due to the COVID-19 pandemic, and the missed IMP doses due to the COVID-19 pandemic 
for the safety analysis set for each treatment group.
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14.3.5 Rescue treatment
Rescue treatment will be defined by the following algorithm:
Concomitant medications with ‘Dermatitis atopic’ or ‘Dermatitis infected’ as the preferred 
term (PT) for the indication, and either of the following:
x
ATC2 code H02
x
Preferred name Methotrexate, Methotrexate sodium, Ciclosporin, Azathioprine, 
Mycophenolate-mofetil, Mychophenolate-acid, Mycophenolate-sodium, Dupilumab, 
Crisaborole, or Alitretinoin
x
ATC4 code D07AD or D07BD or D07CD or D07XD
x
Confirmed rescue treatment (by investigator) in reported term for the indication, and 
ATC4 code D07AB or D07BB or D07CB or D07XB or D07AC or D07BC or D07CC 
or D07XC
As described in Section 9.5, investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue treatment. Therefore, if 
rescue treatment has start date the same day as an efficacy assessment, then it is assumed that 
the assessment is not influenced by rescue treatment.
Rescue treatment will be summarised for the entire treatment period as well as for the period 
up until the Week 16 visit (actual or nominal). Rescue treatment will also be summarised for 
the periods prior to and after the start of the COVID-19 pandemic, within the treatment 
period. The start date(s) of the COVID-19 pandemic will be decided prior to unblinding in the 
statistical analysis plan, possibly reflecting on when trial procedures were disrupted on a 
national level.
Additionally, rescue treatment will be summarised for the entire treatment period by the 
variables: prior CSA use (yes/no), country (Germany: yes/no), and baseline disease severity 
(IGA 3 or 4).
A summary table of rescue treatment by type (topical and systemic) and by overall group 
(corticosteroids, immunosuppressants, and other) will be made for the entire treatment period 
as well as for the period up until the Week 16 visit (actual or nominal).
In addition, the time to first use of rescue treatment will be presented using Kaplan-Meier 
plots for the whole treatment period.
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14.3.6 Testing strategy
The primary and secondary endpoints will be evaluated hierarchically in the order shown in 
Panel 12. The hypothesis relating to a specific endpoint cannot be rejected unless all 
hypotheses relating to endpoints earlier in the hierarchy are also rejected at the 5% 
significance level. Hypothesis testing will be based on the primary analysis of the primary 
estimand for each associated endpoint.
Panel 12: Testing hierarchy for primary and secondary endpoints
Abbreviations: α = statistical significance level; DLQI = Dermatology Life Quality Index; EASI75 = at least 
75% reduction in Eczema Area and Severity Index score; IGA = Investigator’s Global Assessment; 
NRS = numeric rating scale; SCORAD = SCOring Atopic Dermatitis.
14.3.7 Intercurrent events
The applied estimands incorporate the following 3 main subject-specific intercurrent events 
that influence how the treatment effects are estimated.
x
Initiation of rescue treatment:
Some of the estimands use the initiation of rescue treatment 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 
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as described in Section 10.3. This can be at the subject’s own initiative, at the 
investigator’s discretion, or if the subject is 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 is used to modify an applied endpoint value.
x
Subject-onset of the COVID-19 pandemic:
This event is introduced to mitigate the external influence that the occurrence of the 
COVID-19 pandemic could have on the compliance of a subject with planned trial 
procedures and on the resulting interpretation of the trial.
The event reflects the first occasion when the COVID-19 pandemic prevents a subject 
from complying with the protocol in a substantial manner. As described in Section 14.3.1, 
the circumstances arising from the COVID-19 pandemic might for example prevent a 
subject from receiving IMP or from conducting visits to the site, whereby planned 
assessments and procedures could become missing.
For a given subject, this event is defined as the first occurrence of either of the 3 
underlying COVID-19 pandemic-related scenarios defined in Section 14.3.1:
o
Permanent discontinuation of IMP due to the COVID-19 pandemic.
o
Use of rescue treatment due to unavailability of IMP related to the COVID-19 
pandemic.
o
Prolonged interruption of IMP dosing due to the COVID-19 pandemic.
As for the other 2 intercurrent events (initiation of rescue treatment and permanent 
discontinuation of IMP), collected and/or missing data following the start of the event will 
be handled differently from other data in especially the ‘COVID-19 modified composite’ 
estimand.
In addition to the above-mentioned 3 intercurrent events, the COVID-19 pandemic makes it 
appropriate to introduce an attribute of individual data points that influences their handling in 
some of the estimands:
x
Missing data due to the COVID-19 pandemic:
This attribute is related to a missing data point (assessment) that is accounted for in a 
given estimand analysis. It is assigned to each data point that is missing due to the 
COVID-19 pandemic as outlined in section 14.3.1.
An overview of how the applied estimands handle the intercurrent events and missing data is 
presented below (Panel 13).
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Panel 13: Handling of intercurrent events and missing data in the primary analysis of estimands
Binary endpoints
Continuous endpoints
First prior 
intercurrent 
event
Missing or 
observed data
COVID-19
modified 
composite
Composite
treatment 
policy
hypothetical
hypothetical 
treatment 
policy 
COVID-19
modified 
composite
Rescue
treatment
Missing data
Non-response
Non-response
Event 
ignored1
MI
Not used
Event 
ignored1
WOCF
Observed data
Non-response
Non-response
Event 
ignored1
MI
Not used
Event 
ignored1
WOCF
Permanent 
discontinuation 
of IMP
Missing data
Non-response
Non-response
MI –
discontinued 
MI
Not used
MI –
discontinued
WOCF
Observed data
Non-response
Non-response
Used
MI
Not used
Used
WOCF
Subject-onset 
of the 
COVID-19
pandemic
Missing data
MI
Event 
ignored2
MI – not 
discontinued
MI
Not used
MI – not 
discontinued
MI
Observed data
MI
Event 
ignored2
MI – not 
discontinued
MI
Not used
MI – not 
discontinued
MI
No prior 
intercurrent 
event
Missing data not 
due to the 
COVID-19
pandemic
Non-response
Non-response
MI – not 
discontinued
MI 
Not used
MI – not 
discontinued
MI
Missing data due 
to the COVID-19
pandemic
MI
Non-response
MI – not 
discontinued
MI
Not used
MI – not 
discontinued
MI
Observed data
Used
Used
Used
Used
Used
Used
Used
Abbreviations: COVID-19 = Coronavirus Disease 2019; IMP = investigational medicinal product; MI = multiple imputation; MI – discontinued = MI method 
using only retrieved data at Week 16 / Week 26 from discontinued subjects; MI – not discontinued = stepwise MI method using data from not discontinued 
subjects.; WOCF = Worst observation carried forward.
1) Rescue treatment is ignored as an intercurrent event in the treatment policy estimands.
2) Subject-onset of the COVID-19 pandemic is ignored as an intercurrent event in the composite estimand.
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14.3.8 Analysis of primary efficacy endpoint
4 estimands addressing different aspects of the trial objectives will be defined for the primary 
efficacy endpoint (Panel 13):
x
Primary estimand: ‘COVID-19 modified composite’
x
Secondary estimand: ‘composite’
x
Tertiary estimand: ‘treatment policy’
x
Quaternary estimand: ‘hypothetical’
All analyses will be based on the FAS.
14.3.8.1 Primary estimand: ‘COVID-19 modified composite’
The primary estimand for the primary endpoint will be:
x
Treatment difference in response rates of EASI75 after 16 weeks achieved without 
rescue treatment and treatment discontinuation, as if the COVID-19 pandemic did not 
happen
The primary estimand assesses the expected difference in response rates (defined as response 
obtained without initiation of any rescue treatment and/or permanent discontinuation of IMP) 
after 16 weeks, resulting from initiation of a treatment regimen with tralokinumab+TCS 
compared to a treatment regimen with placebo+TCS.
Primary analysis for the primary estimand 
Subjects who prior to the Week 16 visit have received rescue treatment or permanently 
discontinued IMP, without subject-onset of the COVID-19 pandemic, will be considered 
non-responders at all visits after the relevant event occurs (Panel 13).
The non-responder imputation reflects an assumption that such initiation of rescue treatment 
and permanent discontinuation of IMP indicates failure of the randomised treatment to 
achieve response. Furthermore, this reflects that a (possible) observed positive response after 
initiation of rescue treatment or permanent discontinuation of IMP is not attributable to the 
randomised treatment.
Any missing or collected data from subjects who have subject-onset of the COVID-19 
pandemic as their first prior intercurrent event will not be used, but instead imputed assuming 
missing at random (MAR) following the start of subject-onset of the COVID-19 pandemic.
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Data missing prior to any intercurrent event will be handled as non-response, unless data is 
missing due to the COVID-19 pandemic, in which case it will be imputed assuming MAR.
The procedure for imputing values according to the rules described will be implemented in a 
2-step procedure, where all missing or ignored data (irrespectively of reason) initially will be 
imputed using MAR based on available data from all subjects. The non-responder imputation 
of data not affected by the COVID-19 pandemic will be handled subsequently.
The initial MAR imputation will be implemented using the same multiple stepwise imputation 
method as specified in Section 14.3.8.4 for the primary analysis of the hypothetical binary 
estimand. The multiple imputation (MI) procedure sequentially builds 100 complete data sets 
by stepwise use of an ANCOVA model from Week 2 to Week 16 assuming MAR within 
treatment groups.
When building the 100 complete data sets, available data from all subjects will be used, 
excluding individual subject data captured after initiation of rescue treatment, permanent 
discontinuation of IMP, or subject-onset of the COVID-19 pandemic.
Once the 100 complete data sets have been generated by MI, non-responder imputation of 
relevant data points not affected by the COVID-19 pandemic will be applied according to the 
rules described above.
For each of the resulting 100 complete data sets, the difference in response rates between 
treatment groups will be analysed using the Mantel-Haenszel risk difference stratified by prior 
CSA use (yes/no) and baseline disease severity (IGA 3 or 4). The estimates and standard 
errors from the 100 analyses will be pooled to one estimated treatment difference and 
associated standard error using Rubin’s rule to draw inference. From these pooled estimates, 
the 95% CI for the treatment difference will be calculated.
Sensitivity analysis for the primary estimand 
A tipping-point analysis will be performed with the purpose of assessing the robustness of 
results of the primary analysis (for the primary estimand) with respect to the MAR 
assumption for missing data due to the COVID-19 pandemic.
The tipping-point analysis will only test the MAR assumption among subjects in the 
tralokinumab+TCS group who had missing data imputed at the Week 16 visit due to 
subject-onset of the COVID-19 pandemic or data missing due to the COVID-19 pandemic. 
The tipping-point analysis will assess how severe the departure from the MAR assumption in 
the tralokinumab+TCS group has to be in order to impact the results (i.e. to change the 
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conclusion of the primary analysis of the primary estimand) from significant to non-
significant.
The tipping-point analysis will be performed using the MAR imputed Week 16 data from the 
primary analysis of the estimand. For each of the 100 imputed datasets, a quantity Δ will be 
added to all imputed Week 16 values for subjects in the tralokinumab+TCS group who have 
had subject-onset of the COVID-19 pandemic prior to Week 16 or have data missing due to 
the COVID-19 pandemic at Week 16, thereby causing the imputed values to be ‘shifted’ by Δ 
(Δ = 0 implies MAR).
Δ will be defined from the min to the max of the analysed score (i.e. EASI). Each of the 100 
modified imputed datasets will then be analysed in the same way as for the primary analysis 
for the primary estimand. The tipping-point is then found as the value of Δ which changes the 
conclusion (of the primary analysis) from significant to non-significant. Tipping-points will 
be judged from a clinical point of view.
The analysis will use the same method as the primary analysis of the primary estimand.
14.3.8.2 Secondary estimand: ‘composite’
The secondary estimand for the primary endpoint will be:
x
Treatment difference in response rates of EASI75 after 16 weeks achieved without 
either rescue treatment or treatment discontinuation, as if the COVID-19 pandemic did 
not happen
The secondary estimand assesses the expected difference in response rates (defined as 
response obtained without initiation of any rescue treatment or permanent discontinuation of 
IMP) after 16 weeks, resulting from initiation of a treatment regimen with tralokinumab+TCS 
compared to a treatment regimen with placebo+TCS. Essentially, this estimand will not take 
into account whether or not rescue treatment or permanent discontinuation of IMP occur due 
to the COVID-19 pandemic, and any subject-onset of the COVID-19 pandemic will be 
ignored in the analysis.
Primary analysis for the secondary estimand 
Subjects who prior to the Week 16 visit have received rescue treatment or permanently 
discontinued IMP will be considered non-responders, reflecting an assumption that initiation 
of rescue treatment or permanently discontinued IMP indicates failure of the randomised 
treatment to achieve response. It is also assumed that a (possible) observed positive response 
after initiation of rescue treatment or permanently discontinued IMP is not attributable to the 
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randomised treatment. Missing data for subjects who do not attend the Week 16 visit and 
where rescue treatment or permanently discontinued IMP has not been used prior to Week 16, 
will be imputed as non-responders (Panel 13).
The difference in response rates between treatment groups will be analysed using the 
Cochran-Mantel-Haenszel test stratified by prior CSA use (yes/no) and baseline disease 
severity (IGA 3 or 4). The treatment estimate and the corresponding 95% CI will be 
presented.
Sensitivity analyses for the secondary estimand 
The purpose of the sensitivity analysis is to assess the robustness of results of the primary 
analysis for the secondary estimand with respect to the assumption regarding any missing 
Week 16 data, among subjects who did not use any rescue treatment or permanently 
discontinued IMP.
A tipping-point analysis using MI will be performed. The procedure will be as follows: 
subjects in the tralokinumab +TCS group with missing Week 16 data will per default be 
considered non-responders, while missing Week 16 data for subjects in the placebo+TCS 
group who did not use rescue treatment or permanently discontinued IMP will be imputed 
from a Bernoulli distribution with parameter p (ranging from 0 to 1). By varying the 
parameter p, different percentages of subjects in the placebo+TCS group will be assumed to 
be responders (deviating from the default 0% of the primary analysis of the secondary 
estimand). The tipping-point is then found as the value of p which changes the conclusion of 
the primary analysis from significant to non-significant. Tipping-points will be judged from a 
clinical point of view.
The MI procedure will include the following steps for each value of p:
x
100 copies of the dataset will be generated (seed=11109946) and missing Week 16 
data will be imputed for subjects in the placebo+TCS group from a Bernoulli 
distribution with parameter p.
x
For each of the 100 complete data sets, the difference in response rates will be 
analysed as specified for the primary estimand. 
14.3.8.3 Tertiary estimand: ‘treatment policy’
The tertiary estimand for the primary endpoint will be:
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x
Treatment difference in response rate of EASI75 after 16 weeks between 
tralokinumab+TCS and placebo+TCS regardless of rescue treatment and IMP 
discontinuation, as if the COVID-19 pandemic did not happen
The tertiary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab+TCS and rescue treatment as compared to 
a treatment regimen with placebo+TCS and rescue treatment.
Primary analysis for the tertiary estimand 
Data retrieved at Week 16 for subjects who prior to Week 16 have permanently discontinued 
IMP for other reasons than the COVID-19 pandemic will be included in the analysis.
For subjects who have subject-onset of the COVID-19 pandemic prior to Week 16 and prior 
to any permanent discontinuation of IMP not due to the COVID-19 pandemic, any observed 
data from these subjects will be ignored and treated as missing in the same manner as missing 
data from not discontinued subjects in the analysis (Panel 13).
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment group and whether or not subjects have 
permanently discontinued IMP prior to Week 16. Within a given treatment group, 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/treated as missing.
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way, using the same seeds, as specified for the primary analysis of the quaternary 
‘hypothetical’ estimand described in Section 14.3.8.4.
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, a separate imputation model at Week 16 with only prior CSA use (yes/no) and 
baseline disease effects (IGA as a factor and EASI as a covariate) will be applied for 
discontinued subjects. Some factors may have to be omitted, depending on the observed data, 
e.g. if all subjects have the same baseline disease severity. In that case the preferred order of 
elimination of the effects from the imputation model will be: prior CSA use and baseline 
disease effects (seed=12576546).
The imputed datasets will be analysed in the same way as specified for the primary analysis of 
the quaternary ‘hypothetical’ estimand in Section 14.3.8.4.
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Sensitivity analyses for the tertiary estimand 
Rather than imputing Week 16 data as described in the primary analysis of the tertiary 
estimand, missing observations not caused by subject-onset of the COVID-19 pandemic or 
not missing due to the COVID-19 pandemic, 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. Missing observations due to either subject-onset of the COVID-19 pandemic or missing 
due to the COVID-19 pandemic, will be imputed as described in the primary analysis of the 
tertiary estimand.
In case the number of discontinued subjects attending the nominal Week 16 visit is too low to 
fit the imputation model in the primary analysis of the tertiary estimand, the sensitivity 
analysis will become the primary analysis of the tertiary ‘treatment policy’ estimand.
14.3.8.4 Quaternary estimand: ‘hypothetical’
The quaternary estimand for the primary endpoint will be:
x
Treatment difference in response rates of EASI75 after 16 weeks if all subjects 
adhered to the treatment regimen in the sense that they did not discontinue IMP 
permanently, no rescue treatment was made available, and as if the COVID-19 
pandemic did not happen before Week 16.
The quaternary estimand assesses the expected difference in response rates achieved when 
adhering to the treatment regimen tralokinumab+TCS with no rescue treatment or subject-
onset of the COVID-19 pandemic as compared to a treatment regimen with placebo+TCS 
with no rescue treatment or subject-onset of the COVID-19 pandemic.
Primary analysis of the quaternary estimand 
Data collected after permanent discontinuation of IMP, after initiation of rescue treatment, or 
after subject-onset of the COVID-19 pandemic will not be applied in the analysis (Panel 13).
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 2 groups defined according to 
randomised treatment group assuming that data is MAR within each group.
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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=12456746).
2. For each of the 100 copies of the dataset, an analysis of covariance (ANCOVA) model 
is fitted to the EASI value at Week 2. The model will include effects of baseline EASI 
as a covariate, and prior CSA use (yes/no), 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 (seed=12576546).
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 prior CSA use, 
country, 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 the remaining visits 
starting with Week 6 until Week 16. The only modification is that the EASI values 
from the preceding 2 visits will be included as covariates in addition to baseline EASI, 
and prior CSA use 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 between treatment 
groups will be analysed using the Mantel-Haenszel risk difference stratified by prior CSA use 
(yes/no) and baseline disease severity (IGA 3 or 4). The estimates and standard errors from 
the 100 analyses will be pooled to one estimated treatment difference and associated standard 
error using Rubin’s rule to draw inference. From these pooled estimates, the 95% CI for the 
treatment difference will be calculated.
Sensitivity analysis for the quaternary estimand 
Rather than assuming that observations are MAR within each treatment group, it is assumed 
that missing data from subjects who had any of the intercurrent events in the 
tralokinumab+TCS group will resemble missing data from subjects from the placebo+TCS 
group who had none of the intercurrent events. The underlying assumption is that the effect of 
tralokinumab following rescue treatment, permanent treatment discontinuation, or subject-
onset of the COVID-19 pandemic is similar to the effect of placebo. It should be noticed that 
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this assumption is pronouncedly conservative in favour of placebo as it tends to minimise the 
differences between treatment groups.
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab+TCS group as well as the placebo+TCS group will be 
imputed from observed data in the placebo+TCS group (using a so-called copy-reference 
approach). With this exemption, the stepwise MI procedure and subsequent analysis will be 
conducted in the same way as specified for the primary analysis of the quaternary estimand.
14.3.9 Analysis of secondary endpoints
The secondary endpoints evaluate the impact of 16 and 26 weeks of treatment on (i) itch, 
(ii) severity and extent of AD, and (iii) HRQoL. The corresponding endpoints are (i) reduction 
(yes/no) of Worst Daily Pruritus NRS average score for the past week (hereinafter ‘Worst 
Daily Pruritus NRS weekly average’) of at least 4 from baseline to Week 16/ Week 26, (ii) the 
change from baseline to Week 16/ Week 26 in SCORAD, the (iii) change from baseline to 
Week 16/ Week 26 in DLQI score, (ii) IGA score of 0 (clear) or 1 (almost clear) at Week 16/ 
Week 26, (ii) EASI75 at Week 26. Worst Daily Pruritus NRS over the last week prior to 
baseline (Day -6 to 0) will be used to calculate the baseline itch (see also inclusion criterion 
no. 9).
EASI75 at Week 26 is a binary endpoint and it will be analysed as described for the primary 
endpoint (EASI75 at Week 16) using all 4 estimands with the modification that the imputation 
algorithm will be applied until Week 26.
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 from baseline to 
Week 16/ Week 26 is a binary endpoint, and it will be analysed as described for the primary 
endpoint (EASI75 at Week 16) using all 4 estimands with the modification of the ANCOVA 
imputation model that reduction of Worst Daily Pruritus NRS weekly average replaces EASI 
where preceding values are used as covariates. Only subjects with an average Worst Daily 
Pruritus NRS score of 4 or above at baseline will be included in these analyses.
For each of the binary secondary endpoints, tipping-point analyses using the method 
described for the tipping-point analyses of the binary primary endpoint (EASI75 at Week 16) 
will be added as sensitivity analyses for the primary estimand.
Subgroup analysis of binary endpoints
Subgroup analyses will be applied for the primary analyses of the primary and tertiary 
estimands for the groups: sex, prior CSA use (yes/no), baseline disease severity (IGA 3 or 4), 
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country (Germany: yes/no), and baseline age (≤65 years, >65 years). Interaction between 
subgroups and treatment effect will be tested using a conditional logistic regression. The 
conditional logistic regression model will implement a test of the treatment-by-subgroup 
interaction while adjusting for the same strata used in the corresponding analyses. The model 
used for the test of interaction will be:
Y = treatment + subgroup + treatment*subgroup
The stratification variables used will be the same as the ones used in the corresponding 
analyses and will be specified as strata to the conditional logistic regression model. If a 
stratification variable (prior CSA use [yes/no] or baseline disease severity [IGA 3 or 4]) is the 
subject of a subgroup analysis, then the variable will be omitted from the stratification for that 
analysis. The p-value of the interaction term between treatment and the subgroup will be 
reported as the interaction test outcome. Subgroup analyses will be performed for the 
following endpoints:
x
EASI75 at Week 16
x
EASI75 at Week 26
x
Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from baseline to 
Week 16.
x
Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from baseline to 
Week 26
x
IGA score of 0 or 1 at Week 16
x
IGA score of 0 or 1 at Week 26
The binary endpoint IGA 0/1 will be analysed as described for the primary endpoint using all 
4 estimands with the modification that the following imputation algorithm will be used for the 
primary, tertiary, and quaternary estimands.
IGA 0/1 responder imputation 
Imputation of missing binary IGA 0/1 data at Week 16 and Week 26 will be done using 
multiple imputations of the underlying 5-point IGA values within the 2 groups defined 
according to randomised treatment group assuming that data is MAR within each group.
1. In each group, intermittent missing values will be imputed using last observation 
carried forward (LOCF) to obtain a monotone missing data pattern.
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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 prior CSA use (yes/no) 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=37649846).
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 prior CSA use, and baseline disease severity 
together with the IGA value at Week 2 as factors. The estimated parameters, and their 
variances, will be used to impute missing values at Week 4.
4. This stepwise procedure will then be repeated sequentially for the remaining visits 
starting with Week 6 until Week 16 (or until Week 26 for the Week 26 endpoint) with 
the modification that only the IGA values from the 2 preceding visits will be included 
as factors in addition to prior CSA use, and baseline disease severity. The missing 
binary IGA 0/1 response at Week 16/ Week 26 will be derived from the corresponding 
underlying imputed IGA value.
The changes from baseline to Week 16/ Week 26 in SCORAD and DLQI scores, respectively, 
are continuous endpoints and will be analysed using 3 estimands addressing different aspects 
of the trial objectives (Panel 13):
x
Primary estimand: ‘hypothetical’
x
Secondary estimand: ‘treatment policy’
x
Tertiary estimand: ‘COVID-19 modified composite’
All analyses will be based on the FAS.
14.3.9.1 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/ Week 26 in SCORAD and 
DLQI scores, respectively, if all subjects adhered to the treatment regimen in the sense 
that they did not discontinue IMP permanently, no rescue treatment was made 
available, and as if the COVID-19 pandemic did not happen before Week 16/ Week 
26.
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The primary estimand assesses the expected benefit when adhering to the treatment regimen 
tralokinumab+TCS with no rescue treatment or subject-onset of the COVID-19 pandemic as 
compared to a treatment regimen with placebo+TCS with no rescue treatment or subject-onset 
of the COVID-19 pandemic.
Primary analysis of the primary estimand (continuous secondary endpoints) 
Data collected after permanent discontinuation of IMP, after initiation of rescue treatment, or 
after subject-onset of the COVID-19 pandemic will not be included in the analysis (Panel 13).
The endpoints will be analysed using a repeated measurements model on the post-baseline 
responses up to Week 26 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 + prior CSA use + country + baseline IGA
This model assumes that data is MAR within each treatment group. The estimates will be 
presented with nominal p-values and 95% CI at each visit. The comparisons between 
tralokinumab+TCS and placebo+TCS will be at Week 16 and Week 26.
Sensitivity analysis for the primary estimand (continuous secondary endpoints) 
Rather than assuming that observations are MAR within each treatment group it is assumed 
that missing data from subjects who had any of the intercurrent events in the 
tralokinumab+TCS group will resemble data from subjects from the placebo+TCS group who 
had none of the intercurrent events. Imputation of missing data at Week 16/ Week26 will be 
done using a pattern mixture model where missing data in the tralokinumab+TCS group as 
well as the placebo+TCS group will be imputed from the placebo+TCS group (using a so-
called copy-reference approach). The procedure for the change from baseline in SCORAD at 
Week 16/ Week 26 is described below. The same procedure will be applied for the DLQI 
endpoint.
1. Intermittent missing values will be imputed in each group using a Markov Chain 
Monte Carlo method to obtain a monotone missing data pattern, and 100 copies of the 
dataset will be generated (seed=14563746).
2. For each of the 100 copies of the dataset, an ANCOVA model will be fitted to the 
SCORAD value at Week 2 in the placebo+TCS group. The model will include effects 
of baseline SCORAD as a covariate with prior CSA use (yes/no), country 
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(Germany: yes/no), baseline disease severity (IGA 3 or 4) as factors. The estimated 
parameters, and their variances, will be used to impute missing values at Week 2 for 
the placebo+TCS group as well as the tralokinumab+TCS group (seed=65749346).
3. For each of the 100 copies of the dataset, missing values at Week 4 will be imputed in 
the same way as for Week 2. The imputations will be based on a similar ANCOVA 
model, but with SCORAD value at Week 2 included as an additional covariate. The 
parameters from the model will be estimated based on data from the placebo+TCS 
group. The estimated parameters, and their variances, will be used to impute missing 
values at Week 4 for both treatment groups.
4. This stepwise procedure will then be repeated sequentially for the remaining visits 
starting with Week 6 until Week 16 (or Week 26 for the Week 26 endpoint) with the 
SCORAD values from the preceding 2 visits included as covariates in addition to 
baseline SCORAD as a covariate, prior CSA use, country, and baseline disease 
severity as factors.
For each of the 100 imputed dataset, the change from baseline in SCORAD at Week 16/ 
Week 26 will be analysed using an ANCOVA model with effects of treatment, prior CSA use, 
country, baseline disease severity, and baseline SCORAD value as factors. The estimated 
difference at Week 16/ Week 26 will be derived together with the associated standard error. 
The estimates and standard errors from the 100 analyses are pooled to one estimate and 
associated standard error using Rubin’s rule to draw inference. From these pooled estimates, 
the 95% CI for the treatment difference will be calculated.
14.3.9.2 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/ Week 26 in SCORAD and 
DLQI scores, respectively, between tralokinumab+TCS and placebo+TCS regardless 
of rescue treatment use and treatment discontinuation, as if the COVID-19 pandemic 
did not happen.
The secondary estimand assesses the average difference in change from baseline in SCORAD 
and DLQI at Week 16/ Week 26, resulting from initiation of a treatment regimen with 
tralokinumab+TCS and rescue treatment as compared to a treatment regimen with 
placebo+TCS and rescue treatment.
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Primary analyses for the secondary estimand (continuous secondary endpoints) 
Data retrieved at Week 16/ Week 26 for subjects who prior to Week 16/Week 26 have 
permanently discontinued IMP for other reasons than the COVID-19 pandemic will be 
included in the analysis.
For subjects who have subject-onset of the COVID-19 pandemic prior to Week 16/ Week 26 
and prior to any permanent discontinuation of IMP not due to the COVID-19 pandemic, any 
observed data from these subjects will be ignored and treated as missing in the same manner 
as missing data from not discontinued subjects in the analysis (Panel 13).
Missing Week 16/ Week 26 data will be imputed using multiple imputations assuming that 
data is MAR within the groups used for imputation.
Imputation of missing data at Week 16/ Week 26 will be done using multiple imputations 
within 4 groups defined according to randomised treatment group and whether or not subjects 
have discontinued treatment prior to Week 16/ Week 26. Within a given treatment group, 
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/ Week 26 value is missing/treated as 
missing.
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way, using the same seeds, as specified for the imputation of the underlying EASI 
values in the primary analysis of the quaternary estimand for the binary endpoints (see 
Section 14.3.8.4).
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16/ Week 26 will be too small to facilitate the same imputation model as mentioned just 
above. Consequently, an imputation model with prior CSA use (yes/no), country 
(Germany: yes/no), and baseline disease severity (IGA 3 or 4) as factors and baseline 
SCORAD/DLQI as a covariate will be applied for discontinued subjects. Some factors may 
have to be omitted, depending on the observed data, e.g. all subjects have the same baseline 
disease severity. In that case, the preferred order of elimination of the effects from the 
imputation model will be: country, prior CSA use, baseline disease severity, and baseline 
SCORAD/DLQI (seed=12576546).
Each of the 100 imputed datasets will be analysed as described in the sensitivity analyses for 
the primary estimand for the continuous secondary endpoints (see Section 14.3.9.1).
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Sensitivity analyses for the secondary estimand (continuous secondary endpoints) 
Rather than assuming that observations are MAR, it is assumed that missing data from 
subjects in the tralokinumab+TCS group who have/have not discontinued treatment prior to 
Week 16/ Week 26 will resemble data from subjects from the placebo+TCS group who 
have/have not discontinued treatment prior to Week 16/ Week 26.
Imputation of missing data at Week 16/ Week 26 will be done using a pattern mixture model 
where missing data in the tralokinumab+TCS group as well as the placebo+TCS group will be 
imputed from the placebo+TCS group (copy-reference approach). With this exemption, the 
MI 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 (Section 14.3.9.2).
14.3.9.3 Tertiary estimand for the continuous secondary endpoints: 
‘COVID-19 modified composite’
The primary estimand for the continuous tertiary endpoint will be:
x
Treatment difference in change from baseline to Week 16/Week 26 in SCORAD and 
DLQI scores, respectively, without rescue treatment and treatment discontinuation, as 
if the COVID-19 pandemic did not happen
The continuous tertiary estimand assesses the expected treatment difference (obtained without 
initiation of any rescue treatment and/or permanent discontinuation of IMP) after 16/ 26 
weeks, resulting from initiation of a treatment regimen with tralokinumab+TCS compared to 
a treatment regimen with placebo+TCS.
Primary analysis for the tertiary estimand (continuous secondary endpoints) 
Data retrieved at Week 16/ Week 26, depending on the endpoint, for subjects who have 
received rescue treatment or permanently discontinued IMP prior to the visit, without subject-
onset of the COVID-19 pandemic, will be considered non-responders by using worst 
observation carried forward (including the baseline value) (Panel 13).
Any missing or collected data from subject who have subject-onset of the COVID-19 
pandemic as their first prior intercurrent event will not be used, but instead be imputed 
assuming MAR following the start of subject-onset of the COVID-19 pandemic.
Any data missing at the relevant visit from subjects without prior rescue treatment, permanent 
discontinuation of IMP, or subject-onset of the COVID-19 pandemic will be imputed 
assuming MAR.
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The procedure for imputing values according to the rules described above will follow the 
same imputation procedure described in the primary analysis of the binary primary estimand.  
However, any data missing at the relevant visit from subjects without a prior intercurrent 
event will not be imputed as a ‘non-responder’ after the imputation step, but will be imputed 
assuming MAR.
For each of the resulting 100 imputed datasets, this primary analysis will be analysed using an 
ANCOVA model with effects of treatment, prior CSA use (yes/no), country (Germany: 
yes/no) and baseline disease severity (IGA 3 or 4) as factors. The estimates and standard 
errors from the 100 analyses are pooled to one estimate and associated standard error using 
Rubin’s rule to draw inference. From these pooled estimates, the 95% CI for the treatment 
difference will be calculated.
14.3.9.4 Subgroup analysis of continuous endpoints
Subgroup analyses will be performed for the SCORAD and DLQI endpoints at Week 16 and 
Week 26 for the following groups: sex, prior CSA use, baseline disease severity (IGA 3 or 4), 
country, age (≤65 years, >65 years) for the primary analysis of primary and secondary 
estimands. For the primary estimand the following repeated measurements model with an 
unstructured covariance matrix and Kenward-Roger approximation of degrees of freedom will 
be applied (presented for subgroup sex).
Change from baseline in SCORAD
= sex × treatment × visit + baseline SCORAD × visit + CSA use +country + baseline IGA.
The interaction between sex and treatment effect will be tested at Week 16 and Week 26.
14.3.10
Analysis of other endpoints
All binary endpoints listed under ‘Other endpoints’ (Panel 4) will be analysed as for the 
primary analysis of the primary and secondary estimands for the primary endpoint and 
presented for the FAS at Week 16 and Week 26.
All continuous endpoints listed under ‘Other endpoints’ (Panel 4) will be analysed as for the 
primary analysis of the primary and secondary estimands for the continuous secondary 
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. For the Worst Daily Pruritus NRS and 
Eczema-related Sleep NRS scores, it is expected that subjects will return their eDiaries upon 
permanent discontinuation of IMP, and no data is available after that point. Thus, analysis 
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using the primary analysis of the secondary continuous estimand will not be possible in the 
‘Other endpoints’ with Worst Daily Pruritus NRS or Eczema-related Sleep NRS scores.
To evaluate the efficacy related to health care resource utilisation, the amount of TCS used 
(assessed as the amount of TCS used between visits) will be determined over 2-week periods, 
and the number of days without topical treatment use (collected as Patient Days of Topical 
Treatment Use in the eDiary) will be determined over 1-week periods. The amount of TCS 
used and the number of days without topical treatment use will each be analysed using a 
repeated measurements model with an unstructured covariance matrix and the mean modelled 
as follows:
Y = treatment × [visit/week] + prior CSA use + country + baseline IGA
where ‘Y’ is either the amount of TCS used or the number of days without topical treatment 
use. Data obtained after permanent discontinuation of IMP, after initiation of rescue treatment, 
or after subject-onset of the COVID-19 pandemic will be excluded from the analyses.
14.3.11
Analysis of exploratory supporting endpoints
There will be performed longitudinal analyses by visit/week of all primary, secondary and 
‘Other’ efficacy endpoints, as specified in Panel 4.
For the binary endpoints, the analyses will use the primary analysis of the primary estimand 
for each scheduled visit/week in the treatment period where an assessment is planned 
according to Panel 2. The variables used for stratification (prior CSA use [yes/no] and 
baseline disease severity [IGA 3 or 4]) will be the same as the ones used for the primary 
analysis of the primary estimand.
For the continuous endpoints, a repeated measurements model using the same method 
described in the primary analysis of the primary estimand of the continuous secondary 
endpoints. The estimates and differences will be presented with 95% CIs, and nominal 
p-values for each scheduled visit/week in the treatment period where an assessment is planned 
according to Panel 2.
14.3.12
Analysis of patient-reported outcomes
The PROs (POEM, DLQI, EQ-5D-5L [index and VAS scores], SF-36, and HADS) will be 
summarised by treatment group and visit using descriptive statistics based on the FAS.
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The PROs collected in the eDiaries on a daily basis (Worst Daily Pruritus NRS, Eczema-
related Sleep NRS) will all be summarised over time by treatment group using descriptive 
statistics based on the FAS.
To investigate a possible early onset of itch relief, a reduction in Worst Daily Pruritus NRS 
weekly average of at least 4 from baseline to Week 2 will be summarised by treatment group 
and analysed as described for the primary analysis of the primary estimand for the primary 
endpoint.
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 Weeks 16 and 26 will be summarised by 
treatment group and analysed as described for the primary analysis of the primary estimand 
for the primary endpoint.
The change from baseline to Weeks 16 and 26 in Eczema-related Sleep NRS weekly average, 
HADS, POEM, SF-36, and the EQ-5D-5L scores will be summarised by treatment group and 
domain, where applicable.
14.3.13
Analysis of safety
The analyses of safety will be based on the safety analysis set and the safety follow-up 
analysis set.
14.3.13.1
Adverse events
To assess the safety of tralokinumab in combination with TCS when used to treat severe AD 
for 26 weeks, the frequency of AEs and SAEs are included as additional secondary endpoints.
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred terms (PTs) and primary 
system organ class (SOC).
Treatment-emergent AEs will be summarised, however, all AEs recorded during the course of 
the trial will be included in the subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP. The tabulations described in the 
following will only include the treatment-emergent events. In each of the tabulations, AEs 
will be defined by MedDRA PTs within primary SOC.
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An overall summary of treatment-emergent AEs (the number of AEs, the number and 
percentage of subjects with an AE, and the event rate of AEs), deaths, SAEs, permanent 
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 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 and AxMP (TCS) for each type of AE will be tabulated by treatment group.
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
experiencing each type of related AE will be tabulated. The percentage of subjects with 
related AEs will be compared between treatment groups by a chi-square test or Fisher’s exact 
test (if expected cell count <5).
SAEs and AESIs will be evaluated separately. A narrative for each SAE will be given. AESIs 
and AEs leading to withdrawal from trial or permanent discontinuation of IMP will be 
tabulated and listed.
Due to the COVID-19 pandemic and the implementation of home-use (self-injection) with 
telephone/video follow-up, overall safety monitoring could be impacted. To assess this, all 
AEs collected prior to and after the start of the COVID-19 pandemic will, in addition to being 
presented together, be presented separately for the overall summary of AEs and for all the AEs 
by SOC and PT.
14.3.13.2
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, 1st 
quartile, 3rd quartile, minimum, and maximum values for the safety analysis set. Vital signs 
will be listed for the safety follow-up analysis set.
14.3.13.3
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, 1st quartile, 3rd 
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quartile, minimum, and maximum values for the safety analysis set. Laboratory parameters 
will be listed for the safety follow-up 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.
14.3.13.4
Anti-drug antibodies
The frequency of ADA is a secondary endpoint included to assess the safety and tolerability 
(immunogenicity) of tralokinumab in combination with TCS.
ADA status at each visit will be summarised by treatment group. If considered relevant, 
descriptive statistics including number of subjects, mean, standard deviation, median, 1st 
quartile, 3rd quartile, and range of the actual ADA titres by treatment group and visit will be 
provided. The ADA status across the trial for each subject will also be classified and 
summarised by treatment group.
The association of ADA status across the trial 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 status will be categorised as follows:
x
Positive
1. Pre-existing: ADA positive at baseline, no post-baseline ADA response ≥ 4-fold over 
baseline titre level, and at least 1 non-missing post-baseline ADA assessment.
2. Treatment-boosted: ADA positive at baseline and at least 1 post-baseline ADA 
response ≥ 4-fold over baseline titre level.
3. Treatment-emergent: ADA negative or missing at baseline and at least 1 positive post-
baseline ADA response.
x
Perishing
4. ADA positive at baseline, all post-baseline ADA assessments negative.
x
Negative
5. ADA negative or missing at baseline, all post-baseline ADA assessments negative.
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x
No post-baseline ADA assessment.
For subjects who develop ADA and are considered treatment-boosted or treatment-emergent, 
the IGA score, change in EASI at end of treatment, and titre information will be listed.
Evaluations of nAB will be conducted on those serum samples that test positive for ADA. The 
test sample is deemed positive or negative for the presence of nAB to tralokinumab relative to 
a pre-determined (in assay validation) statistically derived cut point.
14.3.14
Pharmacokinetics
All the PK samples in the trial are trough samples. The trough concentration (Ctrough) will be 
listed by treatment group and descriptive statistics will be applied. Ctrough values from subjects 
with positive ADA/nAB will be compared to values from subjects with negative ADA/nAB if 
data permits.
14.3.15
Interim analysis
No interim analysis is planned.
14.3.16
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).
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, 1st quartile, 3rd quartile, 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 and the analysis set definition document 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, and/or in the 
CTR dependent on the type of deviation.
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14.3.17
Handling of missing values
Procedures for handling of missing values are included under the sections describing the 
individual analyses.
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2006;117(2):391–397.
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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 in-patient hospitalisation or prolongation of existing hospitalisation. Elective 
hospitalisation or elective prolonged hospitalisation do not fulfil the criteria for being an 
SAE but should be documented in the subject’s medical record.
x
Results in persistent or significant disability/incapacity.
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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.
AEs 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
x
Follows a reasonable temporal sequence from administration of the IMP.
x
Could not be reasonably explained by the subject’s clinical state, 
environmental, or toxic factors or other therapies administered to the subject.
x
Follows a known pattern of response to the IMP.
x
Disappears or decreases on cessation or reduction in dose of the IMP.
x
Reappears or worsens upon re-challenge.
Possibly 
related
x
Follows a reasonable temporal sequence from the administration of the IMP.
x
Could also be reasonably explained by the subject’s clinical state, 
environmental, or toxic factors or other therapies administered to the subject.
x
Follows a known pattern of response to the IMP.
Not 
related
x
Does not follow a reasonable temporal sequence from administration of the 
IMP.
x
Is better explained by other factors like the subject’s clinical state, 
environmental, or toxic factors or other therapies administered to the subject.
x
Does not reappear or worsen upon re-challenge.
x
Does not follow a known pattern of response to the IMP.
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For events not considered related to IMP using the criteria above, the causal relationship to 
the use of AxMP should be evaluated using the same definitions as for the IMP.
Outcome
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below.
Recovered/
resolved
x
The event has stopped. The stop date of the event must be recorded.
Recovering/
resolving
x
The subject is clearly recovering from an event. The event is not yet completely 
resolved. 
Not 
recovered/
not resolved
x
Event is still ongoing. 
Recovered/
resolved
with 
sequelae
x
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.
x
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified.
Fatal
x
The subject has died as a consequence of the event. Date of death is recorded as 
stop date for the AE.
Unknown
x
Unknown to investigator, e.g. subject lost to follow-up.
Note that as per the above definition, LEO 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 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 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 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 ‘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. 
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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 (38) and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines (39).
x
Current version of applicable International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guidelines (40).
x
EU’s General Data Protection Regulation 2016/679 of 27 April 2016.
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, informed 
consent forms, 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 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 will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting.
The subject’s signed and dated informed consent to participate in the clinical trial will 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.
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if applicable. A copy of the ICF(s) must be provided to the subject.
Subject card
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the 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 and shall not be used by the 
investigator for purposes other than this clinical trial.
The investigator agrees that LEO may use any and all information, data, and results from this 
clinical trial in connection with the development of the IMPs and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners.
Trial subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records 
or datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.
Trial subjects must be informed and consent to that their personal trial-related data will be 
used by LEO in accordance with local data protection law.
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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 and third parties acting on behalf of LEO.
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing, and transfer of personal data in the 
clinical trial. In certain cases, an agreement on transfer of personal data may also be required.
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy, including but not 
limited to the EU General Data Privacy Regulation.
Subjects must be asked to consent to the collection, processing and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities.
LEO has obtained the necessary authorisations for the processing of personal data collected in 
the trial.
Appendix 3D: Record keeping, quality control, and data handling 
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.
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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 
groups of tralokinumab+TCS or placebo+TCS for 26 weeks.
x
Other relevant medical information.
Trial monitoring
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to 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 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 or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
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during or after the trial. The investigator and the site staff as well as LEO staff have an 
obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant 
to the clinical trial. This includes permission to examine, verify and reproduce any records 
and reports that are important to the evaluation of the trial.
If the trial site is contacted for an inspection by competent authorities, LEO must be notified 
immediately.
Risk assessment
In this trial, the risks to critical trial processes and data have been evaluated.
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, 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 or 
designee electronically (e.g. laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into electronic CRFs (eCRFs). Data recorded in the eCRFs 
will be accessible to the trial site and LEO personnel immediately after entry. The eCRFs 
must be maintained in an up-to-date state by the trial site at all times.
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRFs used. This signature information will be kept in the audit trail 
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.
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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 electronic 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 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 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 14.
Panel 14: Transmission of electronic data
Abbreviations: CTR, clinical trial report; ECG, electrocardiogram; eCRF, electronic case report form; ePRO, 
electronic patient-reported outcome.
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Archiving of trial documentation
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (40). Essential trial documents must be stored 
until LEO informs the investigator that the documents are no longer to be retained, or longer 
if required by local regulations.
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities).
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period.
No 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 in accordance with 
LEO’s Position on Public Access to Clinical Trial Information no later than 12 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 may also 
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provide researchers access to anonymised patient level data for further research. Publication 
and access will be in accordance with LEO’s Position on Public Access to Clinical Trials 
which can be found on LEO’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 
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 a copy of all such manuscripts and/or presentations. LEO 
shall have rights to review and comment. The investigator shall consider LEO’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 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 withhold the publication or 
presentation to allow LEO 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, LEO and the writing group may also delay 
the publication or presentation if the manuscript is deemed to harm the ongoing multi-centre 
publication.
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed.
Any publication must comply with Good Publication Practice (GPP3) standards.
LEO complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO complies with the positions of the International 
Federation of Pharmaceutical Manufacturers & Associations (IFPMA), European Federation 
of Pharmaceutical Industries and Associations (EFPIA), Japan Pharmaceutical Manufacturers 
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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 also follows the CONSORT reporting guidelines (22).
Appendix 3F: Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations.
Appendix 3G: Financial disclosure 
Investigators will provide LEO with sufficient, accurate financial information as requested to 
allow LEO to submit complete and accurate financial certification or disclosure statements to 
the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation.
Appendix 3H: Trial and site closure 
Premature termination of trial or trial site
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the clinical 
trial, part of the trial or a trial site at any time, but agreement on procedures to be followed 
must be obtained.
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO must promptly inform IRB/IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed.
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs, and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial.
Reasons for the early closure of a trial site by LEO or investigator may include but are not 
limited to:
x
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, LEO’s procedures, or GCP guidelines.
x
Inadequate recruitment of subjects by the investigator.
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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 will undertake arrangements for the 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed.
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record.
Appendix 3I: 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
Source: Hanifin and Rajka, 1980 (21)
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
Source: Sampson et al., 2006 (41)
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network (FAAN) Guidance for Anaphylaxis Diagnosis 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., dyspnoea, 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., dyspnoea, 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
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: 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 18 years and above
3
Diagnosis of AD as defined by Hanifin and Rajka 1980 criteria for AD
4
History of AD for 1 year or more
5
Subjects with a history within 1 year prior to screening of inadequate response to treatment 
with topical medications or subjects for whom topical treatments are otherwise medically 
inadvisable
6
AD involvement of 10% (or more) body surface area at screening and baseline (visit 3) 
according to component A of SCORAD
7
EASI score of 20 (or more) at screening and baseline
8
An IGA score of 3 or more at screening and at baseline
9
A Worst Daily Pruritus numeric rating scale average score of 4 or more during the week prior 
to baseline
10
Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at 
least 14 days before randomisation
11
Women of child-bearing potential must use a highly effective form of birth control, confirmed 
by the investigator, throughout the trial and at least for 16 weeks after last administration of 
IMP
12
Documented history of either no previous CSA exposure and not currently a candidate for 
CSA treatment OR previous exposure to CSA in which case CSA treatment should not be 
continued or restarted
No.
Exclusion criteria
1
Subjects for whom TCSs are medically inadvisable in the opinion of the investigator
2
Concurrent enrolment in another interventional clinical trial 
3
Previous randomisation in a tralokinumab trial
4
Active dermatologic conditions that may confound the diagnosis of AD or would interfere 
with assessment of treatment, such as scabies, cutaneous lymphoma, or psoriasis
5
Known active allergic or irritant contact dermatitis that is likely to interfere with the 
assessment of severity of AD
6
Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA), within 6 weeks prior 
to randomisation
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7
Treatment with immunomodulatory medications or bleach baths within 4 weeks prior to 
randomisation
8
Treatment with 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
Receipt of any investigational non-biologic agent within 5 half-lives prior to randomisation
12
Receipt of blood products within 4 weeks prior to screening
13
Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period
14
Known or suspected hypersensitivity to any component of the IMP or AxMP formulation
15
History of any active skin infection within 1 week prior to randomisation
16
History of a clinically significant infection (systemic infection or serious skin infection 
requiring parenteral treatment) within 4 weeks prior to randomisation
17
A helminth parasitic infection within 6 months prior to the date informed consent is obtained 
that has not been treated with, or has failed to respond to, standard of care therapy
18
History of anaphylaxis following any biological therapy
19
History of immune complex disease
20
History of cancer
21
Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation will be 
according to local guidelines as per local standard of care
22
History of any known primary immunodeficiency disorder including a positive HIV test at 
screening, or the subject taking antiretroviral medications
23
History of chronic alcohol or drug abuse within 12 months prior to screening, or any 
condition associated with poor compliance as judged by the investigator
24
History of attempted suicide or at significant risk of suicide (either in the opinion of the 
investigator or on the C-SSRS)
25
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
26
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
27
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 2.0 times the 
ULN (upper limit of normal) or more at screening
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28
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
29
Subjects who are not willing to abstain from donating blood and/or plasma from the time of 
informed consent and for 16 weeks (5 half-lives) after last dose of IMP
30
Subjects who are legally institutionalised
31
Pregnant, breastfeeding, or lactating women
32
Employees of the trial site or any other individuals directly involved with the planning or
conduct of the trial, or immediate family members of such individuals
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Appendix 7: 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’ 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
Signatory investigator
Prof. Dr. med 
, Germany
phone: +49 
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Appendix 8: Clinical Trial Protocol Addendum COVID-19
1 Rationale for clinical trial protocol addendum
The current COVID-19 pandemic warrants many subjects in the ECZTRA 7 trial to stay at 
home to comply with authority issued preventive measures. This make visits to the sites 
challenging, and in some cases impossible. To follow authorities restrictions and to safeguard 
the subjects in ECZTRA 7 as well as providing continued therapy to secure the scientific 
integrity, this clinical trial protocol addendum is installed to provide an opportunity for 
subjects to continue treatment with tralokinumab via home-use (self-injection).
No safety issues have been observed in subjects who applied home-use of IMP after training 
by site staff in previous or ongoing clinical trials with tralokinumab. Therefore, no safety 
issues are expected regarding home-use of IMP in ECZTRA 7.
2 GCP statement
Normal GCP procedures are followed for this protocol addendum. Subjects will be verbally 
informed and verbally consent to providing contact details (name, address, and telephone 
number) for shipping purposes.
3 eCRF recording
It must be recorded in the eCRF if the visit was conducted as a home-visit.
If the subject is reached by telephone/video contact and collection of AEs, concomitant 
medication and pregnancy test result (if applicable) are assessed, “Visit date” must be 
documented in the eCRF. All other assessments should be marked “Not done”. The log line 
“If not done, specify reason” must be answered with “COVID-19”. In addition, in the 
“Comments log”, one log line per visit should be entered with “COVID-19” – as reason for 
only partly performed assessments at the visit.
If no contact can be established between site and subject at a given visit, this must be recorded 
as a missed visit in the eCRF (“Not done”). The log line “If not done, specify reason” must be 
answered with “COVID-19”.
4 Description of visit scenarios
Without compromising the safety of subjects and site personnel, it is expected that efforts are 
made to secure attendance at sites for the Week 16 and Week 26 visits, securing important 
efficacy and safety assessments for the trial. Dependant on national guidelines regarding 
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COVID-19 and subject preferences, the remaining visits can follow three different scenarios 
as described below:
1) The subject is not restricted from attending visits at the clinic and continue to follow 
all procedures specified in the protocol.
2) The subject is still able to come to the clinic, but may foresee difficulties attending 
visits to the clinic going forward. In this case the following procedures must take place 
and be document in source documentation:
a.
Subject is verbally informed using the Participant Information Sheet and 
agrees to home-use of IMP.
b. Site staff allocates IMP and TCS for subject using the EDC system (RAVE®) 
for the current visit + 2 additional visits.
c.
Subject is trained by site staff in home-use of IMP (see Section 5.1) by the 
unblinded HCP. The subject then self-injects IMP under supervision of the 
unblinded HCP. The remaining part of the visit takes place as per protocol.
d. Site staff provide the following items to the subject:
i. Participant Information Sheet for home use.
ii. Instructions for Use.
iii. Log of Drug Administration.
iv. The proper amount of IMP (see bullet c) in a cooling bag.
v. The proper amount of TCS (see bullet c).
vi. One sharp-bin container.
vii. Sanitisers: alcohol wipes, cotton balls or gauze.
viii. For female subjects of child-bearing potential: one urine pregnancy test 
kit and Urine Pregnancy Test Instruction.
e.
The following visits must be conducted via phone with collection of AEs, 
assessment of concomitant medication, and urine pregnancy test results (if 
applicable) before IMP is self-injected. The subject is reminded to complete 
the eDiary and to start using the TCS tubes allocated for the next period.
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3) Subject is not able to attend visits at the clinic:
a.
Site staff informs subject about the possibility of home-use as described in the 
Participant Information Sheet for home-use.
b. Subject is verbally informed about home-use of IMP and verbally consents to 
providing contact details (name, address, and telephone number) to the courier 
for shipping purposes.
c.
Site staff allocates IMP and TCS for subject using the EDC system (RAVE®) 
for the 3 visits. In case needed, IMP and TCS can be dispensed for one 
additional visit.
d. Site staff sends the following items by a LEO-approved courier company:
i. Participant Information Sheet for home use.
ii. Instructions for Use.
iii. Log of Drug Administration.
iv. The proper amount of IMP (see bullet c) in a cooling bag.
v. The proper amount of TCS (see bullet c).
vi. One sharp-bin container.
vii. Sanitisers: alcohol wipes, cotton balls or gauze.
viii. For female subjects of child-bearing potential: one urine pregnancy test 
kit and Urine Pregnancy Test Instruction.
e.
Site staff contacts the subject (by video-call) and ensures the following:
i. Confirms that the Participant Information Sheet has been read, 
understood, and agreed to.
ii. Subject is asked about pregnancy test outcome, concomitant 
medication use, and adverse events.
iii. Subject is being instructed in home-use of IMP.
iv. The subject self-injects IMP under supervision of the site staff.
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v. The subject is reminded to complete the eDiary and to start using the 
TCS tubes allocated for the next period.
f.
Site staff documents all of the above in the medical record at the clinic.
g. Site staff enters all available information into the EDC system (RAVE®), see 
Section 3.
5 Home-use of IMP
5.1 Subject training in self-injections of tralokinumab
Subjects will have the option to self-inject tralokinumab after adequate training by the 
investigator or delegated site staff. If the subject is a health care professional or has previous 
experience with SC-injections as judged by the investigator, training is limited to handling the 
IMP according to the Trial Product Handling Manual and procedures to be followed in case of 
an emergency.
The subject must inject tralokinumab under supervision by the trainer on one or more 
occasions such that the trainer is satisfied with the individual’s understanding and confidence 
of the procedure. The subject will also be trained in filling out the Log of Drug 
Administration.
5.2 Injections of tralokinumab
Prior to self-injection at home, the subject will receive proper training in SC injection 
technique and on procedures to be followed in case of an emergency during or following 
home-use of tralokinumab. Tralokinumab will be injected by the subject when AE 
assessments have been completed.
All IMP self-injections need to be documented in the eCRF with ‘COVID-19’ written in the 
comments log for the visit in scope.
Subjects who misses one or more doses need to be documented in the eCRF with ‘COVID-19’ 
written in the comments log for each visit in scope.
Further details on IMP-injection are provided in the Trial Product Handling Manual. Subjects 
will also receive a pamphlet with instructions for IMP home-use and a Log of Drug 
Administration.
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5.2 TCS
The use of TCS is described in the ECZTRA 7 clinical trial protocol and does not change with 
this document.
5.3 Emollients
The use of emollients is described in the ECZTRA 7 clinical trial protocol and does not 
change with this document.
6 Urine pregnancy tests
The schedule of pregnancy testing does not change with this document. However, the subjects 
need to perform the urine pregnancy test at home using the kit delivered by the site. The 
subject will also be provided with a Urine Pregnancy Test Instruction. Results should be 
communicated to the site and documented in the eCRF and source documents.
7 Supporting documents (LEO Pharma use only)
Document
eTMF ID
ECZTRA 7 Clinical Trial Protocol
000064964
Trial Product Handling Plan
000105963
Patient Information Sheet for Home-use
000296864
Instructions for IMP home-use (pamphlet)
000077966 
Log of Drug Administration
000298224
Urine Pregnancy Test Instruction
000298227
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Appendix 9: Clinical Trial Protocol Addendum no. 2 Imagine for Studies
1 Rationale for clinical trial protocol addendum
The current COVID-19 pandemic warrants many subjects in the ECZTRA 7 trial to stay at 
home to comply with authority-issued preventive measures. This makes visits to the sites 
challenging, and in some cases impossible. This clinical trial protocol addendum is installed 
for subjects who cannot come to the site for the Week 26 visit and who have provided 
informed consent for using the mobile application called ‘Imagine for Studies’ for remote 
collection of data related to efficacy of tralokinumab.
No safety issues are expected as a consequence of this clinical trial addendum.
2 GCP statement
Normal GCP procedures are followed for this protocol addendum. Subjects will be verbally 
informed and verbally consent to the site staff providing contact details (name, address, and 
telephone number) for sending the necessary information about Imagine for Studies to 
subjects via courier.
The subjects sign the Participant Information Sheet after having ample time to consider 
participation. The site staff will not sign the Participant Information Sheet.
Precautionary steps have been taken to secure the integrity of the trial and the confidentiality 
of the identity of the subjects via a controlled data transfer between two separate units of LEO 
Pharma: LEO iLab (including a team of certified dermatologists) and LEO Clinical 
Operations. In this manner, the GCP adherence described in the clinical trial protocol and the 
ICF signed at screening remains intact and unchanged.
The procedures described in this addendum are considered well-balanced and proportionate, 
taking into account the legitimate interest of trial sites in avoiding further burden in terms of 
time and staffing during the COVID-19 pandemic (1).
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3 Roles and responsibilities
The following responsibilities have been assigned to all parties involved in the processes 
described in this protocol addendum (see Table 1).
Table 1 Roles and responsibilities
Role
Responsibilities
Reference
LEO Clinical 
Operations
x
Overall responsible for the ECZTRA 7 trial conduct 
and reporting
Section 5.4
LEO iLab
x
Handles all data from the Imagine for Studies app and 
sends data without potential subject identifiers to LEO 
Clinical Operations
x
Technically responsible for the Imagine for Studies
app (including user support)
x
Provides username and password to site staff
x
Manages a team of certified dermatologists who 
evaluate the photos using remote EASI scores
Section 5.4
Site staff
x
Manages the informed consent process
x
Sends written information material to the subject
x
Provides subject login details (password and 
username) for the Imagine for Studies app
Section 4
Subject
x
Provides verbal informed consent to use the Imagine 
for Studies app
x
Signs the Participant Information Sheet and returns it 
at the next possible site visit
Section 4
x
Uses the app as instructed
Participant 
Guidance Booklet
NL-CRA
x
Submits clinical trial protocol addendum and 
supporting documents to the relevant ethical 
committees and competent authorities as per local 
regulations
x
Supports site staff with information material to the 
subjects
Section 2
4 Information to trial sites
If a subject cannot come to the site for the Week 26 visit, the site staff should initiate remote 
collection of efficacy-related outcomes using the Imagine for Studies app by following the 
steps below:
1) Site staff informs the subject about the possibility of remote collection of 
efficacy-related outcomes using the Imagine for Studies app as described in the 
Participant Information Sheet.
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2) Subject is verbally informed about the Imagine for Studies app and verbally consents 
to providing contact details (name, address, and telephone number) to the courier.
3) Site staff sends the following items by the courier:
a.
Participant Information Sheet.
b. Participant Guidance Booklet.
4) Site staff contacts the subject and ensures that the subject has had ample time to 
consider the written content in the Participant Information Sheet and the Participant 
Guidance Booklet.
a.
If verbal consent is obtained, the site staff documents this in the medical 
record.
b. Subject signs the Participant Information Sheet and returns it at the next 
possible site visit.
5) Site staff completes all remote assessments as described in the previous clinical trial 
protocol addendum (for COVID-19) and ensures that the subject is able to complete 
data collection via the Imagine for Studies app.
6) Site staff documents all of the above in the medical record at the site.
5 Remote collection of data related to efficacy of tralokinumab using the 
Imagine for Studies app
The Imagine for Studies app is a digital solution that has been developed by LEO iLab 
specifically for the ECZTRA 7 trial and provided in local language. Subjects that are not able 
to attend the Week 26 visit at the site and who have given informed consent to use the 
Imagine for Studies app can upload photos of their skin lesions from selected body areas 
(Section 5.2) as well as answering a questionnaire about the extent of AD (Section 5.3).
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5.1 Installation and login procedure
The subject downloads the Imagine for Studies app and follows the instructions provided in 
the Participant Guidance Booklet. For questions and support, please see Section 5.5. The 
screens for installation and login are presented in Figure 1 below.
Figure 1 Installation and login procedure
A.
Download of the Imagine for Studies app.
B.
Login frontpage: Username and password must be filled in here.
C.
Welcome page “Welcome to the ECZTRA 7 trial app. To be able to follow how your disease is 
progressing during the COVID-19 pandemic, we kindly ask you to take four pictures in total of four 
body areas of your eczema. After you have taken the four pictures please answer questions about how 
much eczema you have. Thank you!”.
5.2 Taking photos of the skin
Subjects will take 4 photos as described below at the time of the planned Week 26 visit before 
applying any moisturiser.
x
One photo of eczema on the head or neck
x
One photo of eczema on one arm
x
One photo of eczema on either the stomach, chest, or back
x
One photo of eczema on one leg
It is very important that the subject takes all 4 photos.
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The subject will be asked to upload a photo of normal healthy skin if there is no visible 
eczema in one of the four body areas. Furthermore, the photos are to be taken in a prioritised 
order as follows:
x
If there are multiple skin lesions of eczema in one body area, the lesion with the most 
redness should be chosen.
x
If there are multiple lesions with the same level of redness in one body area, the lesion 
with the most redness and oozing should be chosen.
If the photo is of substandard quality, LEO iLab will ask the NL-CRA to inform the site staff, 
who then contacts the subject and asks for a new photo to be upload.
Figure 2 illustrates how the subject selects one body area at a time and captures a photo of the 
skin. The Participant Guidance Booklet outlines tips and best practices for ensuring adequate 
photo quality.
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Figure 2 Taking photos of the skin
A.
Screen menu ‘Edit body areas’. The function ‘Add body area’ is selected to proceed.
B.
Screen menu ‘Choose body area’. Here, the body areas ‘Head/Neck, Arms, Trunk/Groin, or Legs’ can 
be chosen.
C.
The Imagine for Studies app requests permission to access the camera. ‘OK’ must be selected to 
proceed.
D.
A photo of the skin is taken according to the body area selection made in (B). The photo can be retaken 
or accepted (not shown).
E.
The photo assigned to the body area is saved, and a new body area can be selected by choosing ‘Add 
body area’. This takes the subject back to the menu in (B), where a new body area must be selected. The 
steps (B-E) are repeated until 4 photos, 1 for each body area, are saved.
F.
Screen with the text: “All done. It is now time to report your extent of eczema”. The subject then 
proceeds to the questionnaire by selecting ‘Report Extent of Eczema’.
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5.3 Questionnaire about the extent of atopic dermatitis
The questionnaire in the Imagine for Studies app allows the subject to evaluate the percentage 
of a selected body area that is covered by AD lesions on a scale from 0–100%. Each body 
area accounts for 100%. The subjects will be presented for the following text in the app 
provided in local language. Figure 3 shows the questionnaire with guiding illustrations of the 
relevant body parts.
Figure 3 Questionnaire about the extent of atopic dermatitis
The texts of the screens (A-G) are copied below.
A-B
Thank you for taking four photos! Now we would like to know the extent of your eczema. To 
accurately assess how much of your body is covered by eczema, and to what degree you are affected, 
we need to know the extent of eczema on your body.
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We assess the extent of your eczema, by viewing your body as four separate areas. The head and 
neck, the trunk, the arms, and the legs. Below, you will see four drawings, one of each area. For each 
area, you need to assess, and then enter, how many percentages are covered by eczema. For instance, 
if one of your arms is fully covered by eczema, from hand to shoulder, but the other arm is not, you 
should enter 50% in the arms field. That is because 50%, is half of the arms’ area. Similarly, if only 
the lower arm and hand of one of your arms is affected, you should enter 25%.
We know that many people suffering from eczema, have multiple smaller lesions, and that it might 
be difficult to sum up the area, but we ask you to try your best. A rule of thumb is that your palm 
area, including fingers will cover 10% of your head, 5% of your arms, 3% of your trunk and back, 
and 3% of your legs. So for instance, if you have an eczema lesion on your leg, that is the same size 
as your hand, but no other lesions on the legs, you would enter 3%. If you have a lesion that is only 
just covered by both of your hands, you would enter 6%. So, here is a 3-step summary (1) For each 
of the areas, you should estimate how many percentages of your body is covered by eczema. Each 
area equals 100% (2) Remember that the body parts have both a front, and a back (3) If you do not 
have eczema in an area, please input 0%. There are examples for each area in the submission fields 
below.
C
Subject ID. Do not change this value. This is your unique Subject ID. For your head and neck, please 
specify percentages of your eczema from 0-100. For example; If you do not have any eczema on 
your head, you put in “0” in the field.
D
For your arms and hands, please specify percentages of your eczema from 0-100. For example; If 
you have eczema on the back of both of your hands, but nowhere else on your arms, you should put 
in 10%, as the back of the hands equal about 10% of the area of your arms and hands.
E
For your groin, stomach, chest and back, please specify percentages of your eczema from 0-100. For 
example; If you have eczema on your stomach, but not on your chest, or your lower or upper back, 
you should put in 25%, as the stomach is about 25% of the trunk.
F
For your legs, feet, and buttocks please specify percentages of your eczema from 0-100. For 
example; If your entire left leg is covered by eczema, but the other leg is perfectly clear, you should 
put in 50%, as half of the leg area is covered by eczema. 
G
Thank you for submitting your information. We appreciate you taking part in this trial.
5.4 Data flow
The key principles for how data flows from the subject using the Imagine for Studies app to 
the reporting in the CTR are showed in Figure 4 and briefly explained below.
All data collected via the Imagine for Studies app are stored on secure (GDPR and HIPAA 
compliant) AWS servers managed by LEO iLab. The data captured will include potential 
subject identifiers, such as photos of the facial region as well as information about the extent 
of AD. Therefore, precautionary steps have been taken to ensure that LEO Clinical Operations 
at no point in time will have access to data with potential subject identifiers.
The photos will be evaluated by a team of certified dermatologists within LEO iLab who have 
no connections to LEO Clinical Operations. The outcome of the evaluation will be a remote 
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EASI score, one score for each subject. The EASI principles used to assess a remote EASI 
score is based on the HOME working group definitions (2).
The remote EASI scores and the questionnaire data will together form the data transfer that 
does not include photos (i.e. potential subject identifiers). The data transfer delivered by 
LEO iLab to the SDTM database within LEO Clinical Operations will take place before 
database lock. An ADAM dataset is then derived from the SDTM database and used for 
statistical reporting. The data generated from the Imagine for Studies app will not be part of 
the pre-specified analysis, but rather serve as a supplement to handling the missing data at 
Week 26. All data obtained from Imagine for Studies will be deleted from the LEO iLab 
secure server before finalisation of the CTR.
Figure 4 Data flow from the Imagine for Studies mobile application to final clinical trial 
report.
Abbreviations: AD = atopic dermatitis; ADAM = analysis data model; CTR = clinical trial report; 
SDTM = study data tabulation model; QE = questionnaire.
5.5 Questions and support
The subject will be asked to contact the site staff regarding questions related to the Imagine 
for Studies app. The site staff may contact LEO iLab via one of the telephone numbers listed 
in the Participant Guidance Booklet if support is needed. Translator service is available for all 
countries in scope for this ECZTRA 7 clinical trial protocol addendum.
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6 Supporting documents (LEO Pharma use only)
Document
eTMF ID
ECZTRA 7 Clinical Trial Protocol
000064964
Patient Information Sheet (Imagine for Studies)
000316466
Participant Guidance Booklet
000316469
7 References
1. EMA. European Medicines Agency. Guidance on the Management of Clinical Trials 
during the COVID-19 (Coronavirus) Pandemic. Version 3. 2020.
2. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area 
and severity index (EASI): assessment of reliability in atopic dermatitis. EASI 
Evaluator Group. Exp Dermatol. 2001;10(1):11-18.
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Appendix 10: Protocol amendment history
The protocol amendment summary of change table for the current amendment is located 
directly before the table of contents.
Amendment 2 (19-Aug-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 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 is the addition of photographs to the trial assessments. 
Furthermore, clarifications on the required qualifications of the principal investigator as well 
as on prohibited medications during the trial are provided.
Additional changes included in the amendment are also presented in the table below.
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it).
Section no. and 
name
Description of change
Brief rationale
Section 4
Schedule of trial 
procedures
Section 11.1
Overview
Section 11.6.1
Photography
Schedule of trial procedures has been 
updated to include photographs.
Photographs have been added to the list
of trial procedures.
At selected trial sites, subjects will 
be asked to participate in a 
photography component involving 
digital photography assessments 
to show disease progression over 
time.
To add a photography component 
to assessments to show disease 
progression over time.
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Section no. and 
name
Description of change
Brief rationale
Participation in this photography 
component requires that the 
subject provides additional 
informed consent.
Digital colour photographs will be 
taken of the disease area and 
representative lesions at 4 
different time points according to 
the schedule of trial procedures 
(Section 4).
Custom photography equipment 
will be delivered to trial sites by 
the central photography vendor 
together with a photography 
manual. Photography standards 
and procedures are provided in 
the manual. The photographs will 
have no other subject identifier 
than the subject ID and will be 
transmitted electronically to the 
photography vendor using a 
secure file transfer protocol.
Printed copies of the photographs 
must be included as part of the 
individual subject source 
documentation.
LEO may at its discretion use the 
photographs in publications, 
posters and similar types of 
information material or media 
targeting patients and HCPs. The 
photographs can also be part of 
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Section no. and 
name
Description of change
Brief rationale
training material used for training 
and educational purposes. Steps 
will be taken to ensure that the 
identity of the subject is protected 
to the extent possible.
Section 9.5 
Rescue treatment
Section 10.2.2 
Reasons for 
temporary 
discontinuation 
of IMP
If a subject receives rescue treatment 
with systemic corticosteroids or non-
steroidal systemic immunosuppressive 
drugs (CSA, methotrexate, 
mycophenolate mofetil, azathioprine,
dupilumab, etc.), IMP will be 
immediately discontinued (see Section 
10.2.2). 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.
Treatment with systemic corticosteroids 
or non-steroidal 
immunosuppressive/immunomodulating 
medications (e.g., CSA, 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.
To reflect that subjects have either 
failed on previous CSA treatment 
or CSA is contraindicated as per 
inclusion criterion. Therefore, CSA 
is not applicable as rescue 
treatment.
Section 9.7 
Prohibited 
medications and 
The panel with prohibited medications 
and procedures in the previous version 
of the protocol has been replaced with a 
To ensure clear instructions on 
prohibited medications and 
procedures to investigators.
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Section no. and 
name
Description of change
Brief rationale
procedures
text description. 
The content and meaning of the 
section has not been changed, only 
the presentation of information for 
increased readability.
Section 11.1 
Overview
Subjects participating in the trial will be 
under careful supervision of a qualified
principal investigator who must be 
dermatologist or allergist (see 
Appendix 1.4).
To reflect that the principal 
investigator or investigator does not 
have to be a certified dermatologist 
or allergist to conduct the trial.
Throughout
Global Pharmacovigilance has been 
changed to Global Safety.
To reflect a change of department 
name within LEO Pharma.
Throughout
Minor editorial and document 
formatting revisions.
Minor, have therefore not been 
summarised.
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Amendment 1 (13-Nov-2018)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the amendment
The main reason for the amendment is to introduce the possibility for eligible subjects in 
selected countries to participate in a long-term extension trial (conducted under a separate 
protocol [LP0162-1337, ECZTEND]) without completing the safety follow-up period in the 
present trial. Indeed, a new anti-drug antibodies (ADA) assay has been developed with 
improved tralokinumab tolerance. This means that the presence or absence of ADA can be 
determined in serum samples with tralokinumab present. Previously, this was not possible and 
therefore ADA sampling at the end of the 14-week off-treatment safety follow-up was 
originally required for the ADA evaluation. Thus, in selected countries, the new ADA assay 
will allow eligible subjects who have completed the treatment periods of the present trial to 
continue into the long-term extension trial without completing the safety follow-up period in 
the present trial. These subjects will have their safety follow-up period after end of treatment 
in the long-term extension trial.
Additional changes included in the amendment are also presented in the table below.
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it).
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Section no. and 
name
Description of change
Brief rationale
Section 1
Protocol 
synopsis
Section 4
Schedule of 
procedures
Panel 3 
(footnote 2)
Section 7.1
Overall trial 
design
Section 7.3
End of trial 
definition
Section 9.9
Provision for 
subject care 
following trial 
completion
Subjects will have a final safety 
follow-up visit 16 weeks after the 
last dose of IMP (which is also 
considered the end-of-trial visit), 
except subjects who enter the long-
term extension trial (conducted 
under a separate protocol [LP0162-
1337, ECZTEND]). The subjects 
may enter ECZTEND at any time 
during the off-treatment safety 
follow-up period. For these 
subjects, the end-of-trial visit will 
be the last visit in the present trial.
The subjects entering ECZTEND 
after completion of the end-of-
treatment visit (Week 26) will also 
be considered as trial completers. 
For all subjects assigned treatment, 
an end-of-treatment form and end-
of-trial form will be completed in 
the eCRF.
To clarify that eligible subjects 
(in selected countries) who have 
completed the treatment periods 
of the present trial may continue 
into the long-term extension trial 
(conducted under a separate 
protocol [LP0162-1337, 
ECZTEND]) without 
completing the safety follow-up 
period.
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Section no. and 
name
Description of change
Brief rationale
Section 8.3
Exclusion 
criteria
Appendix 6
Eligibility 
criteria
Known or suspected allergy or 
reaction to any component of the 
IMP or AxMP formulation.
To clarify that components of 
the AxMP is also taken into 
account. 
Section 11.1
Overview
Order of patient-reported outcomes 
(PROs) revised.
To match the order by which the 
PROs appear in the reporting 
device used by the subjects at 
the trial site.
Section 11.4.1
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 13.2
Collection of 
adverse events
AEs must be collected from time of 
first trial-related activity after the 
subject has signed the informed 
consent form (ICF) until 
completion of the clinical trial 
(defined as the safety 
follow-up visit 16 weeks after last 
injection of IMP). For subjects 
entering the long-term extension 
To clarify how (S)AEs occurring 
in subjects entering LP0162-
1337 (ECZTEND) will be 
collected if visits in LP0162-
1346 overlap with visits in 
ECZTEND.
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Section no. and 
name
Description of change
Brief rationale
trial (LP0162-1337, ECZTEND), 
any (S)AE with onset before the 
final visit in LP0162-1346 should 
be reported in LP0162-1346. If 
ongoing, the (S)AE will also be 
recorded as medical history in 
ECZTEND.
Section 13.6.1
Adverse events 
of special 
interest
Panel 12
The text in the heading of the right 
column was modified as follows:
Additional information to be 
provided (if available1)
A footnote was added:
1The additional data to be 
recorded in the eCRF are not a 
requirement, but are to be 
reported by the investigator, if 
available, for example as part of 
standard clinical practice.
To clarify that additional 
information regarding the 
adverse events (AEs) of special 
interest is to be provided only if 
available, and that it is not a 
requirement.
Section 14.3.9.1
Adverse events
SAEs and AESIs will be evaluated 
separately. and aA narrative for 
each SAE will be given. AESIs 
and AEs leading to withdrawal 
from trial or permanent 
discontinuation of IMP will be 
tabulated and listed.
Tabulation and listings are 
considered a more practical and 
informative way of presenting 
AESIs. This will enable easier 
overview of the individual cases 
as well as sorting and pooling of 
data from other trials.
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Section no. and 
name
Description of change
Brief rationale
Throughout
Minor editorial and document 
formatting revisions.
Minor, have therefore not been 
summarised.
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LEO Pharma number: LP0162-1346 
NCT number: NCT03761537 
Date: -2FW-2020 


Trial ID: LP0162-1346
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Statistical Analysis Plan 
LP0162-1346
Tralokinumab in combination with topical corticosteroids in subjects 
with severe atopic dermatitis who are not adequately controlled with or 
have contraindications to oral cyclosporine A
ECZTRA 7 (ECZema TRAlokinumab trial no. 7)
Phase 3 – efficacy and safety trial
A randomised, double-blind, placebo-controlled, parallel-group, multi-centre, phase 3 
trial investigating the efficacy, safety, and tolerability of tralokinumab administered in 
combination with topical corticosteroids to adult subjects with severe atopic dermatitis 
who are not adequately controlled with or have contraindications to oral cyclosporine A
LEO Pharma A/S
Trial ID:
LP0162-1346
Date:
21-OCT-2020
Version:
v1.0
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1 Statistical Analysis Plan Approval
1.1 Approval Statement
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan.
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control.
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document.
, MSc Stat
Biostatistics Lead, Medical Sciences
, MD
Medical Lead, Medical Sciences
, MSc Stat
QC Statistician, Biostatistics
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2 Statistical Analysis Plan Statements
2.1 Compliance with Good Clinical Practice
This Statistical Analysis Plan is designed to comply with the standards issued by the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) (E3: Structure and Content of Clinical Study Reports, E6: Good Clinical 
Practice, and E9: Statistical Principles for Clinical Trials).
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Table of Contents
1 Statistical Analysis Plan Approval......................................................................................... 2
1.1
Approval Statement........................................................................................................... 2
2 Statistical Analysis Plan Statements...................................................................................... 3
2.1
Compliance with Good Clinical Practice .......................................................................... 3
Table of Contents ....................................................................................................................... 4
3 List of Abbreviations ............................................................................................................. 6
4 Introduction ........................................................................................................................... 8
5 Trial analysis sets................................................................................................................... 9
6 Statistical analysis.................................................................................................................. 9
6.1
Aspects related to the COVID-19 pandemic..................................................................... 9
6.2
Disposition......................................................................................................................... 9
6.3
Demographics and baseline characteristics..................................................................... 10
6.4
Exposure and treatment compliance................................................................................ 10
6.4.1
Compliance.................................................................................................................. 10
6.4.2
Exposure...................................................................................................................... 10
6.5
Rescue treatment ............................................................................................................. 10
6.6
Analysis of efficacy......................................................................................................... 12
6.6.1
Intercurrent events....................................................................................................... 12
6.6.2
Analysis of the primary endpoint (EASI75 at week 16) ............................................. 12
6.6.3
Analysis of secondary endpoints................................................................................. 13
6.6.3.1
Binary secondary endpoints..................................................................................... 13
6.6.3.2
Continuous secondary endpoints ............................................................................. 14
6.6.4
Multiple imputation..................................................................................................... 15
6.6.5
Analysis of other endpoints......................................................................................... 16
6.6.6
Analysis of patient-reported outcomes........................................................................ 18
6.6.7
Analysis of exploratory supporting endpoints............................................................. 18
6.6.8
Drug accountability ..................................................................................................... 18
6.6.9
Descriptive statistics.................................................................................................... 19
6.7
Analysis of safety............................................................................................................ 20
6.7.1
Adverse Events............................................................................................................ 20
6.7.2
Vital signs.................................................................................................................... 21
6.7.3
ECG............................................................................................................................. 21
6.7.4
Laboratory data............................................................................................................ 21
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6.7.5
Urinalysis..................................................................................................................... 22
6.7.6
Pharmacokinetics and anti-drug antibodies................................................................. 23
6.8
General Principles ........................................................................................................... 24
6.8.1
Baseline value.............................................................................................................. 24
6.8.2
Definition of trial periods, date of permanent discontinuation of IMP and start of the 
COVID-19 pandemic .................................................................................................. 24
6.8.3
Incomplete dates.......................................................................................................... 27
6.8.4
Early termination and unscheduled visits.................................................................... 28
6.8.5
Technical handling of intercurrent events and missing values.................................... 29
6.8.6
Timing of intercurrent events ...................................................................................... 32
6.8.7
Rules for single imputation methods........................................................................... 32
6.8.8
Technical aspects of attributing events and missing data to the COVID-19 pandemic
..................................................................................................................................... 32
6.8.9
Treatment labels .......................................................................................................... 34
7 References ........................................................................................................................... 35
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3 List of Abbreviations
AD
Atopic dermatitis
ADA
Anti-drug antibodies
ADaM
Analysis data model
AE
Adverse event
AESI
Adverse event of special interest
ATC
Anatomical Therapeutic Chemical
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
Case Report Form
CSA
Cyclosporine A
CTR
Clinical trial report
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
EASI50
At least 50% reduction in EASI score
EASI75
At least 75% reduction in EASI score
EASI90
At least 90% reduction in EASI score
ECG
Electrocardiogram
EQ-5D-5L
EuroQoL 5-Dimension Health Questionnaire 5 Level
FAS
Full analysis set
FDA
US. Food and Drug Administration
GCP
Good Clinical Practice
HADS
Hospital Anxiety and Depression Scale
ICH
The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IGA
Investigator’s Global Assessment
IMP
Investigational medicinal product
LOCF
Last observation carried forward
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
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nAB
Neutralising antibodies
NRS
Numeric rating scale
POEM
Patient Oriented Eczema Measure
PT
Preferred term
Q2W
Every 2 weeks
QC
Quality control
SAP
Statistical Analysis Plan
SAE
Serious adverse event
SCORAD
Scoring Atopic Dermatitis
SF-36
36-Item Short Form Health Survey
TCS
Topical corticosteroid
SOC
System Organ Class
VAS
Visual analogue scale
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4 Introduction
The statistical analysis will be performed as outlined in the Clinical Trial Protocol. This 
Statistical Analysis Plan (SAP), prepared before the unblinding of the trial, contains a more 
technical and detailed elaboration of relevant points in the statistical analysis described in the 
Clinical Trial Protocol. 
Change log of major changes or additions to the protocol, made in this SAP:
1. Major eligibility criteria have been defined and a review of all critical protocol deviations 
has been formalised in accordance with ICH E9 and the protocol. From these, it will be 
possible to make exclusions to the full analysis set during a blind review of data. 
2. Further specification to the analyses of the primary and secondary endpoints, where 
applicable, in relation to when there is not enough data to facilitate MI of data using 
Rubin’s rule and the handling of such situations.
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5 Trial analysis sets
As specified in the protocol, but with some further specification of the full analysis set (FAS).
The FAS will, as specified in protocol, consist of all subjects randomised and dosed with IMP. 
But, in addition to this, exclusions can be made in accordance ICH E9 if major eligibility 
criteria have been breached or a critical protocol deviation has been identified to seriously 
impact data integrity in relation to the primary endpoint of this trial. These major eligibility 
criteria are inclusion criteria 3, 6, 7, 8, and 12, as defined in the protocol. These are selected 
due to their criticality in relation to defining the targeted population.
During the blind review of data each critical protocol deviation and any violation of the 
defined major eligibility criteria will be reviewed, and a decision will be made whether the 
subject will be removed from or kept in the FAS.
In the analysis set definition document, made prior to unblinding of the trial, documentation 
of any exclusions will be made and each critical protocol deviation will have a reason for 
excluding or not excluding the subject from the FAS.
6 Statistical analysis
6.1 Aspects related to the COVID-19 pandemic
As specified in the protocol. Technical aspects of attributing events and missing data to the 
COVID-19 pandemic is further detailed in Section 6.8.8.
6.2 Disposition
Subject disposition will be summarised as detailed in the protocol.
Additionally, reasons for not attending the nominal Week 16 and Week 26 visits will be 
summarised for randomised subjects. Not attending the nominal Week 16 and Week 26 visits 
due to the COVID-19 pandemic will be added to the list of reasons based on the information 
documented in the eCRF. Technical aspects of attributing missed visits to the COVID-19 
pandemic is further detailed in Section 6.8.8.
The number of randomised subjects and screen failures will be summarised for all screened 
subjects. Screen failures will be summarised by reason as well as overall.
For the safety follow-up visit, attendance will be summarised for all subjects included in the 
safety follow-up analysis set. Not attending the safety follow-up visit due to the COVID-19 
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pandemic will be added to the list of reasons, as for reasons for not attending the nominal 
Week 16 and Week 26 visits.
6.3 Demographics and baseline characteristics
Demographics and baseline characteristics will be summarised as specified in the protocol. 
Duration of AD in years will be calculated as (age at Week 0) minus (age at onset of AD).
The table of concomitant medication at baseline will include medication with start date before 
or at the Week 0 visit date which does not have an end date before the Week 0 visit date. For 
handling of incomplete dates, see Section 6.8.3.
In addition, any concomitant medication taken during the treatment period will be 
summarised.
In case a subject has been randomised based on a wrong value of a stratification variable, the 
correct value of the variable will always be used in descriptive statistics and analyses. 
Subject(s) who were randomised within a wrong stratum will be listed.
6.4 Exposure and treatment compliance
6.4.1 Compliance
Compliance will be summarised and listed. Technical aspects of attributing missed IMP doses 
to the COVID-19 pandemic are further detailed in Section 6.8.8.
6.4.2 Exposure
Exposure time will be summarised as detailed in the protocol with the exception that it will be 
presented using years of exposure instead of days. Definitions used for exposure time during 
the treatment period is detailed in Section 6.8.2. 
6.5 Rescue treatment
Presentation of rescue treatment and the definition of rescue treatment is as defined in the 
protocol. 
For the presentation of rescue treatment up until the Week 16 visit (actual or nominal) the 
planned date of the Week 16 visit will be used if no Week 16 visit exists (actual or nominal).
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Due to the allowance of TCS in the screening period, some subjects might during this period 
use TCS of a high enough potency to be categorised as rescue treatment ending on the day of 
randomisation. Such cases will not be categorised as rescue medication as the assumption will 
be that the use of high potency TCS will stop prior to administration of IMP. 
The global start date of the COVID-19 pandemic is defined in Section 6.8.2.
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6.6 Analysis of efficacy
As described in Section 6.3, in case a subject is randomised based on a wrong value of a 
stratification variable, the correct value of the variable will always be used in the analysis to 
reflect the actual characteristics of the subject. The variable collected at randomisation will be 
used.
6.6.1 Intercurrent events
As specified in the protocol. The timing and technical handling of intercurrent events in 
relation to analysed visits and the technical aspects of attributing events and missing data to 
the COVID-19 pandemic are further detailed in Sections 6.8.5, 6.8.6 and 6.8.8. 
6.6.2 Analysis of the primary endpoint (EASI75 at week 16)
The analysis of the primary endpoint will be as specified in the protocol, further changes or 
specifications to the analysis of the endpoint are described here. 
Primary analysis of the primary estimand (‘COVID-19 modified composite’)
In case not enough data is missing due to the COVID-19 pandemic or set to missing due to 
subject-onset of the COVID-19 pandemic (less than 2 imputed values within treatment 
groups), the primary analysis of the secondary estimand (composite) will be used instead, as it 
will not be possible to estimate the variance using Rubin’s rule for MI.
Primary analysis of the tertiary estimand (‘treatment policy’)
As stated in the protocol, it is expected that the number of observed values in the 2 treatment 
groups of discontinued subjects is too small to facilitate MI of data using Rubin’s rule. In this 
case, the primary analysis will be substituted with the sensitivity analysis. A limit of 2 or less 
observed values within each of the treatment groups of discontinued subjects will be used to 
enforce when the sensitivity analysis will become the primary analysis.
Sensitivity analysis of the tertiary estimand (‘treatment policy’)
For the 2 treatment groups within the discontinued subjects, in case not enough data (less than 
2 data points) is missing due to the COVID-19 pandemic or set to missing due to subject-
onset of the COVID-19 pandemic, the sensitivity analysis will assume any missing data to be 
non-response, as it will not be possible to estimate the variance using Rubin’s rule for MI. 
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6.6.3 Analysis of secondary endpoints
6.6.3.1 Binary secondary endpoints
The analysis of the binary secondary endpoints will be as specified in the protocol and section 
6.6.2, further changes or specifications for endpoints’ analyses are described here. 
Multiple imputation is further specified in section 6.6.4.
Calculation of Weekly average of Worst Daily pruritus NRS
The weekly average will only be calculated if at least 4 out the 7 weekly assessments are 
available and otherwise set to missing. In case of several entries on the same day the worst 
observation on that day is used.
The baseline value of the Worst Daily Pruritus NRS (weekly average) will be calculated as 
defined in the protocol based on daily assessments of the 7 days preceding randomisation 
including day of randomisation (day -6 to 0 where day 0 is the day of randomisation).
For the treatment period, the Worst Daily Pruritus NRS (weekly average) for Week 1 will be 
calculated based on scores recorded on day 1 to day 7 (where day 0 is the day of the first 
dose). Similarly, for week 2 to week 25, the weekly average for week x will be calculated 
based on scores recorded on day 7*x-6 to day 7*x (where day 0 is the day of first dose). 
Since the Week 26 visit (regular or nominal) may occur between day 179 and day 185, the 
week 26 weekly average will instead be based on the 7 days before (and including) the day of 
the week 26 visit (regular or nominal). In case no week 26 visit (regular or nominal) exists, 
the date of an unscheduled visit or early termination visit can be mapped as per Section 6.8.4 
(if existing), else the planned date will be used.
Sensitivity analyses of the primary estimand of IGA 0/1 and reduction of Worst Daily Pruritus 
NRS (weekly average) of at least 4 at Week 16 and 26
The tipping-point analyses are not considered relevant for secondary endpoints, thus the 
sensitivity analyses of the primary estimand of IGA 0/1 and reduction of Worst Daily Pruritus 
NRS (weekly average) of at least 4 at Weeks 16 and 26 will not be done.
Subgroup analyses
During the analysis of blinded data, possible convergence issues of the conditional logistic 
regression have been discovered for individual imputation datasets, but not all imputation 
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datasets at once. This might not happen when the trial is unblinded, but in the event that it 
does, the analysis methods for the test of interaction can be re-opened for individual subgroup 
analyses if this issue is discovered. If this were to occur on unblinded data, the first step will 
be to relax the convergence criterion from the standard of ͳ כ ͳͲି଼ to ͳ כ ͳͲି଺. If other 
measures are needed, it will be documented in the clinical trial report.
6.6.3.2 Continuous secondary endpoints
Primary analysis of primary continuous estimand (‘hypothetical’)
Some subjects may not have any post-baseline data collected before initiation of rescue 
medication, have permanently discontinued IMP, or having subject-onset of the COVID-19 
pandemic prior to the first post-baseline assessment. To ensure that all eligible subjects are 
included in the analysis, the baseline value will be carried forward as the first post-baseline 
assessment for these subjects, corresponding to imputing a change of 0 at the first post-
baseline assessment. Additionally, subjects might be early terminated from the trial prior to 
the first scheduled post-baseline assessment with an assessment being done at the early 
termination visit. In this case the last assessment (including the baseline assessment) done 
prior to the first scheduled post-baseline assessment will be carried forward to the first 
scheduled post-baseline assessment.
Primary analysis of the secondary continuous estimand (‘treatment policy’)
Due to the high chance of discontinued subjects opting not to attend the nominal Week 16 / 26 
visits, a general conservative rule is put in place. In case within one of the 4 groups defined is 
2 or less observed values the missing data will be imputed using the worst observation carried 
forward.
In the multiple imputation methods specified, the variables used in the imputation procedures 
will not be prior CSA use and baseline IGA, but prior CSA use, county (Germany Yes/No), 
and baseline IGA.
Sensitivity analysis of the secondary continuous estimand (‘treatment policy’)
As for the primary analysis of this estimand, the sensitivity analysis will also have the general 
rule applied if there are not enough observed data to facilitate MI of data. Since the MI in this 
sensitivity analysis applies a copy-reference approach, only the discontinued/non-
discontinued subjects randomised to placebo are applicable for this. The rule will, again, be 
that if there are 2 or less observed values at the analysed visit in the respective placebo group 
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then missing data within the group will be imputed using the worst observation carried 
forward.
In the multiple imputation methods specified, the variables used in the imputation procedures 
will not be prior CSA use and baseline IGA, but prior CSA use, county (Germany Yes/No), 
and baseline IGA.
Primary analysis of the tertiary estimand (COVID-19 modified composite)
In the multiple imputation methods specified, the variables used in the imputation procedures 
will not be prior CSA use and baseline IGA, but prior CSA use, county (Germany Yes/No), 
and baseline IGA.
SCORAD
For the calculation of SCORAD, the protocol states that dryness is evaluated on uninvolved 
areas. This means that if a subject has an extent of 100% then there is no area to score. In the 
event that dryness is missing and extent is 100% then 0 (none/absent) will be imputed instead.
6.6.4 Multiple imputation
For the analysis of the primary and secondary endpoints, multiple imputation will be carried 
out, as specified in the protocol, using SAS PROC MI. Unless otherwise specified in the 
protocol or this SAP, the seed 11109946 will be used in any multiple imputation strategies. 
When performing multiple imputation of continuous parameter values, imputed values 
outside the relevant parameter scale for visits prior to the relevant visit will be used as it is. 
Values imputed at the relevant visit will be truncated to the nearest upper or lower bound on 
the given scale. E.g., negative imputed EASI values at Week 16 will be set to 0 in an analysis 
of Week 16 data. 
Secondary endpoints IGA 0/1
For imputation of IGA values, the LIKELIHOOD=AUGMENT option will be used (1). 
For imputation of IGA values, it may occur that the observed data from which the imputation 
model is fitted does not contain all levels of the IGA predictors necessary for the imputation. 
Imputation will be performed within treatment groups at each visit. E.g. if at a visit within one 
treatment group, the IGA values (0,1,2,3) for each level have 2 or more observed values but 
the IGA value of 4 only has 1 or less, the imputation model will not be able to predict for IGA 
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values of 4 at that specific visit. I.e. categories can be combined at a visit for one group, but 
not the other. To avoid this situation, in this specific example IGA values of 3 and 4 will be 
combined into a single category prior to the imputation. In general, if this situation arises, 
IGA categories will be combined into a single category at the specific visit for the purpose of 
the imputation, according to the rules in Table 1.
Table 1: Adjacent IGA categories combined if a predictor contains 1 or less observed 
values
IGA value(s) in imputation model
IGA categories combined
0
(0,1)
1
(0,1)
2
(2,3)
3
(2,3)
4
(3,4)
6.6.5 Analysis of other endpoints
As specified in the protocol, but with the change that ‘Other’ endpoints will not be analysed 
for the secondary estimand (‘composite’), but for the tertiary estimand (‘treatment policy’), as 
originally proposed in previous versions of the protocol.
Percent change of DLQI
The analyses of percent change in DLQI at Week 16 and Week 26 have been added in support 
of the secondary endpoints.
Calculation of Weekly average of Eczema-related Sleep NRS
Weekly averages of Eczema-related Sleep NRS will be calculated using the same rules as for 
the weekly averages of pruritus NRS. As for the Worst Daily Pruritus NRS, in case there are 
several Eczema-related Sleep NRS assessments at the same date only the worst will be used.
HADS
For the analysis of the endpoint HADS-anxiety < 8 and HADS-depression < 8, the imputation 
of missing data due to the COVID-19 pandemic or set to missing due to the COVID-19 
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pandemic will be imputed within each sub-score prior to analysis using the primary analysis 
of the primary estimand.
Amount of TCS used
The amount of TCS used will be calculated as specified in section 6.6.8 and analysed in two 
ways, reflecting the two consumption assumptions. The primary analysis will be using the 
most conservative assumption that all missing tubes were fully used. The second assumption 
will be used as a sensitivity analysis, reflecting the primary analysis’s extreme opposite, that 
all non-returned tubes were not used. The method used for analysis will be the one specified 
in the protocol. Additionally, descriptive histograms of both consumption assumptions will be 
produced.
In an extra sensitivity analysis, the amount of TCS used will be log transformed. This 
transformation has in a similar trial proven to fit data better. TCS amount will be log 
transformed by adding 1 (due to potential zero values) and then taking the logarithm. The 
analysis will use the same repeated measures model with the mean modelled as follows: 
log[TCS amount used + 1] (g) = Treatment*visit + prior CSA use + country + Baseline IGA
The analysis results will be presented by back-transforming using the exponential function, 
thus producing estimated geometric means and estimated ratio of means, which will be 
presented with nominal p-values and 95% confidence intervals (CI). This sensitivity analysis 
will be done for both consumption assumptions. 
Additionally, descriptive histograms of both consumption assumptions will be produced for 
the amount of TCS.
Number of days without topical treatment use
The number of days without topical treatment use will be analysed as specified in the 
protocol. Number of days without topical treatment use will be calculated using the same 
rules as for the Worst Daily Pruritus NRS (weekly average).
Scoring of PROs 
Table 2: Scoring of PROs
POEM
Scored according to:
https://www.nottingham.ac.uk/research/groups/cebd/documents/methodological-
resources/poem-for-self-completion.pdf
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DLQI
Scored according to:
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-
index-dlqi/dlqi-instructions-for-use-and-scoring/
EQ-5D-
5L
Index values calculated according to:
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-
sets/crosswalk-index-value-calculator/
The UK value sets will be used.
HADS
The HADS consists of 14 items, 7 of which are related to anxiety and 7 related 
to depression. The maximum score is 21 for each subscale (anxiety and 
depression). 
If one question is missing within a subscale, the response to that question will 
be imputed as the mean of the remaining questions in that subscale. If more than 
one question is missing within a subscale, the subscale is considered missing. 
SF-36
Version 2, acute recall.
6.6.6 Analysis of patient-reported outcomes
As specified in the protocol.
6.6.7 Analysis of exploratory supporting endpoints
As specified in the protocol.
6.6.8 Drug accountability
For each subject, the weight of TCS used for a given visit interval (WGTUSED) will be 
calculated as the difference between the weight of the tubes dispensed (WGTDISP) and the 
weight of the returned tubes (WGTRET):
x
if WGTRET ≤ WGTDISP then WGTUSED=WGTDISP-WGTRET
x
if WGTRET > WGTDISP then WGTUSED = 0.
When tubes are not returned as specified in the protocol, the following rules will be applied:
x
If tubes are returned at the wrong visit, the amount of TCS used from these tubes will 
be assumed to be used in the period from the tubes being dispensed to being returned.
x
If a dispensed tube is not returned at all and the subject remains in the study, two 
different approaches will be applied to explore two extreme assumptions:
1. It will be assumed, conservatively, that the missing tube has been fully used by the 
subject in the period between the date the tube was dispensed, and the date of the 
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next subsequent visit attended by the subject. Estimated content (100 g) for the kit 
number will be used as a contribution to the WGTRET.
2. It will be assumed that the missing tube has not been used at all by the subject in 
the period between the date the tube was dispensed, and the date of the next 
subsequent visit attended by the subject, i.e. contribution from the tube to the 
WGTRET is set to 0.
x
In the case where tubes from the last dispensing visit are not returned due to the 
subject being withdrawn from the trial, the amount of TCS used from these tubes will 
not be calculated (i.e. set to missing). 
x
If dispensed tubes have no weighing data due to any other cause the most conservative 
estimate will be imputed, i.e. that the whole tube dispensed was used.
If a subject does not attend a planned visit, daily usage (DAYUSE) is calculated for the period 
between the tubes being dispensed and the subsequent dispensing visit, i.e. 
DAYUSE=WGTUSED/DURATION where DURATION =ENDDATE (date of the subsequent 
dispensing visit)-STARTDATE (date of the tubes being dispensed). If all tubes in the batch 
are not dispensed/returned at the same time, date of the first dispensed or last returned tube in 
the batch is used, dependent on the situation. The amount of the TCS used for each visit in the 
period (missing visit(s) and the first visit after the tubes being dispensed) is calculated by 
multiplying daily usage (DAYUSE) by the number of days between the visit and the previous 
visit.
6.6.9 Descriptive statistics
In support of all endpoints, summaries will be included for all observed scores by visit.
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6.7 Analysis of safety
As specified in the protocol, the analysis of safety will be based on the safety analysis set and 
the safety follow-up analysis set.
6.7.1 Adverse Events
Adverse events (AEs) will be summarised and listed. However, the summaries will be split 
into the two periods, the treatment period and the safety follow-up period. This is to 
differentiate the AEs based on whether or not subjects are on active treatment. 
The start date of the COVID-19 pandemic is defined in Section 6.8.2.
Assignment of AEs to periods
An AE will be assigned to a given period (treatment or safety follow-up) if the start date of 
the AE is after the start date and before or at the end date of that period (see Section 6.8.2, 
Table 6).
For AEs with start day on the same day as the first dose was given, only AEs starting after the 
first dose was given will be considered treatment emergent and assigned to the treatment 
period.
For the handling of incomplete start dates of AEs, see Section 6.8.3.
Sort order of AE tables
Generally, AE tables by system organ class and/or preferred term will be sorted by decreasing 
number of affected subjects:
x
For the treatment period, AE tables will be sorted by decreasing number of affected 
subjects in the Tralokinumab Q2W+TCS group. AEs only occurring in the Placebo+TCS 
group will be sorted last by decreasing number of affected subjects in the Placebo+TCS 
group.
x
For the safety follow-up period, AE tables will be sorted by decreasing total (whole trial 
period) number of affected subjects in the Tralokinumab Q2W+TCS group. AEs only 
occurring in the Placebo+TCS group will be sorted last by decreasing number of affected 
subjects in the Placebo+TCS group.
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6.7.2 Vital signs
Vital signs will be summarised and listed. 
For the summary tables of vital signs by visit, the last pre-dose vital sign assessment will be 
presented. If no dosing occurs at a visit, the last assessment recorded at the visit will be 
presented.
For the first 3 IMP dosing visits, subjects will be monitored after IMP administration for 
immediate drug reactions for a minimum of 30 minutes with vital signs taken every 30 
minutes or until stable, these measurements will be listed.
6.7.3 ECG 
ECG data will be summarised and listed for the treatment period. ECG data from the safety 
follow-up period will be listed. 
The overall central evaluation of ECG will be presented using shift tables for the treatment 
period.
6.7.4 Laboratory data
Laboratory data will be summarised and listed. 
For the laboratory values, if the value is below the lower limit of quantification, half of the 
lower limit will be used for quantitative summaries. If the value is above the upper limit of 
quantification, the upper limit value will be used.
If more than one laboratory value is reported for the same visit and time point, the latest value 
will be used in summary statistics and analyses.
Potentially clinically significant values will be defined as displayed in Table 3.
Table 3: Potentially clinically significant biochemistry and haematology values
Protocol Lab parameter
SI Unit
PCS low
PCS High
Biochemistry
Sodium
mmol/L
< 129 mmol/L, 
< 125 mmol/L
> 160 mmol/L
Potassium
mmol/L
< 3 mmol/L, 
< 2.5 mmol/L
> 6.5 mmol/L, 
> 7.5 mmol/L
Creatinine
umol/L
N/A
> 1.5xULN, > 3xULN
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Protocol Lab parameter
SI Unit
PCS low
PCS High
Calcium
mmol/L
< 1.9 mmol/L
> 3.0 mmol/L, 
> 3.5 mmol/L
Alkaline phosphatase 
U/L
N/A
> 3xULN
Aspartate 
aminotransferase
U/L
N/A
> 3xULN, > 5xULN, 
> 10xULN, > 20xULN
Alanine aminotransferase 
U/L
N/A
> 3xULN, > 5xULN, 
> 10xULN, > 20xULN
Bilirubin
umol/L
N/A
> 2xULN
Cholesterol
mmol/L
N/A
> 6.2 mmol/L
LDL cholesterol
mmol/L
N/A
> 4.1 mmol/L, 
> 4.9 mmol/L
HDL cholesterol
mmol/L
N/A
> 1.6 mmol/L
Triglycerides
mmol/L
N/A
> 2.3 mmol/L, 
> 5.6 mmol/L
Glucose (non-fasting)
mmol/L
< 3.9 mmol/L
>11.1 mmol/L
Haematology
Haemoglobin
g/L
<110 g/L, < 80 g/L
> 185 g/L for male, 
> 165 g/L for female
Neutrophils, absolute 
count
109/L
< 1.5 109/L, < 1.0 109/L, 
< 0.5 109/L
N/A
Lymphocytes, absolute 
count
109/L
< 1.0 x 109/L, 
< 0.5 x 109/L
> 5.0 x 109/L 
Monocytes, absolute count 109/L
< 0.1 x 109/L
> 0.8 x 109/L 
Eosinophils, absolute 
count
109/L
N/A
> 1.5, > 5.0
Basophils, absolute count
109/L
N/A
> 0.2
Thrombocytes 
109/L
< 100 x 109/L, 
< 30 x 109/L, 
< 10 x 109/L
> 450 x 109/L
PCS: potentially clinically significant; ULN: Upper limit of normal, i.e. upper limit of normal reference range.
6.7.5 Urinalysis
Urinalysis data will be presented as detailed in the protocol under ‘Clinical laboratory 
evaluation’, Section 14.3.9.3. 
Potentially clinically significant values will be defined as displayed in Table 4. 
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Table 4: Potentially clinically significant urinalysis values
Protocol lab parameter
(Central lab parameter)
SI Unit
PCS low
PCS High
Erythrocytes
/HPF
N/A
> 3, >10, >25, >50
Leucocytes
/HPF
N/A
> 10
Casts (Hyaline casts)
/LPF
N/A
> 2
Casts (WBC casts)
/LPF
N/A
Few, Moderate, Many
Casts (RBC casts)
/LPF
N/A
Few, Moderate, Many
Casts (Waxy casts)
/LPF
N/A
Few, Moderate, Many
Casts (Granular casts)
/LPF
N/A
Few, Moderate, Many
PCS: potentially clinically significant; HPF: high power field; LPF: low power field; 
6.7.6 Pharmacokinetics and anti-drug antibodies
Pharmacokinetics and anti-drug antibodies data will be summarised as detailed in the 
protocol, but for the treatment period only.
An extra summarisation will be made over ADA status across the entire trial.
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6.8 General Principles
6.8.1 Baseline value
Unless otherwise specified, the baseline value is defined as the latest pre-dose assessment.
Missing baseline assessments
When the baseline value is missing, endpoints concerning a change from baseline cannot be 
derived, and such subjects will be excluded from the analysis. Since the missingness of 
baseline values is unrelated to the assigned treatment, bias should not be a concern with this 
approach.
6.8.2 Definition of trial periods, date of permanent discontinuation of IMP 
and start of the COVID-19 pandemic
Date of permanent discontinuation of IMP
Defined for subjects who have a reason for permanent discontinuation of IMP recorded.
The latest date of either is the date of permanent discontinuation of IMP: The date of early 
termination visit (if existing) or the date of onset of latest AE leading to withdrawal of IMP (if 
existing). Otherwise, the date of the last visit, excluding safety follow-up, nominal Week 16 
visit and nominal Week 26 visit, unless the last visit is the Week 26 visit in which case the 
subsequent scheduled visit following the last administered IMP dose will be used (observed 
date (if existing) else planned date + 7 days).
Unscheduled visits can be used as the date of permanent discontinuation of IMP if the 
unscheduled visit is within the window for where subjects can be dosed. This means that only 
unscheduled visits between the baseline visit and the Week 24 visit (if existing), or the 
planned visit + 7 days will be used to account for the visit window. 
Exposure start
Date and time of first dose.
Exposure end
Date of Week 26 visit (if existing) at time 23:59:50, otherwise date of permanent 
discontinuation of IMP (if existing) at time 23:59:50, otherwise date of last IMP 
administration at time 23:59:00.
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Date of last contact
Date of very last contact found by examining all time and date information in eCRF, 
laboratory, ECG, PRO and eDiary data.
Start of the COVID-19 pandemic
The start of the COVID-19 pandemic will be set to the 1st of March 2020 at time 00:00:00 
across the whole trial. The date was decided based on the fact that at this date the trial 
procedures were most likely not impacted by the COVID-19 pandemic but still keeping it as 
close as possible to the first observed occurrence of missed procedures due to the COVID-19 
pandemic.
Trial periods
For efficacy assessments the analysis set are defined only for the treatment period which is 
listed in Table 5 (ADaM variable APERIOD). 
For safety assessments, the two analysis sets are defined by a start and end of each period 
which are listed in Table 6 (ADaM variable APHASE). 
Additionally, a sub-trial period is defined for the safety assessments considering the COVID-
19 pandemic. For this we define the start and stop for the treatment and safety follow-up 
periods prior to and after the start of the COVID-19 pandemic which are listed in 
Table 7.
Table 5: Start and end time of trial periods (ADaM variable APERIOD)
APERIOD
Start of period
End of period (only if start 
date exists) 
Treatment period
Exposure start
Date of last contact at time 
23:59:59
Table 6: Start and end time of trial periods (ADaM variable APHASE)
APHASE
Start of period
End of period (only if start 
date exists) 
Treatment period
Exposure start
Exposure end 
Safety follow-up 
period
Exposure end (plus 1 second)
Date of safety follow-up visit (if 
existing) at time 23:59:59
else
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Date of last contact at time 
23:59:59
Table 7: Start and end time of trial periods related to onset of the COVID-19 pandemic
Start of period
End of period (only if start 
date exists) 
Treatment period, 
prior to the start of 
the COVID-19 
pandemic
Exposure start if prior to the start 
of the COVID-19 pandemic
else 
Missing
Whichever comes first of: 
Exposure end 
or 
Start of the COVID-19 
pandemic
Treatment period, 
after the start of the 
COVID-19 
pandemic
Start of the COVID-19 
pandemic if between exposure 
start and exposure end
else 
Exposure start if after the start of 
the COVID-19 pandemic
else
Missing
Exposure end if after the start of 
the COVID-19 pandemic
else
Missing
Safety follow-up 
period, prior to the 
start of the COVID-
19 pandemic
Exposure end (plus 1 second) if 
prior to the start of the COVID-
19 pandemic
else 
Missing
Whichever comes first of: 
Date of safety follow-up visit (if 
existing) at time 23:59:59
else
Date of last contact at time 
23:59:59 
or 
Start of the COVID-19 
pandemic
Safety follow-up 
period, after the start 
of the COVID-19 
pandemic
Start of the COVID-19 
pandemic if between Exposure 
end (plus 1 second), and Date of 
safety follow-up visit (if 
existing) at time 23:59:59 else 
Date of last contact at time 
23:59:59
else 
Missing
Date of safety follow-up visit (if 
existing) at time 23:59:59
else
Date of last contact at time 
23:59:59, 
if after the start of the COVID-
19 pandemic
else 
Missing
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6.8.3 Incomplete dates
Adverse events
If the AE start day is missing, but AE start month and year are not missing, the following rules 
apply:
x
If the year and month of the AE start is before the year and month of the exposure 
start, or if the AE end date is complete and before the exposure start, the AE will not 
be considered treatment emergent. 
x
If the year and month of the AE start is the same as the year and month of the 
exposure start, the AE will be considered treatment emergent and assigned to the 
treatment period, unless the AE has a complete end date which is before exposure 
start.
x
If the year and month of the AE start is after the year and month of exposure start, it 
will be assumed that the AE started on the first day of the month and the AE will be 
assigned to the treatment or follow-up period accordingly.
If the AE start month is missing, but AE start year is not missing, the following rules apply:
x
If the year of the AE start is before the year of the exposure start, or if the AE end 
month and year is not missing and before the month of the exposure start and before or 
at the year of exposure start, or if the AE has a complete end date which is before the 
exposure start date, the AE will not be considered treatment emergent. 
x
If the year of the AE start is the same as the year of the exposure start, the AE will be 
considered treatment emergent and assigned to the treatment period, unless the AE end 
month and year is not missing and before the month of the exposure start and before or 
at the year of the exposure start, or the AE has a complete end date which is before the 
exposure start date.
x
If the year of the AE start is after the year of exposure start, it will be assumed that the 
AE started on the 01 January and the AE will be assigned to the treatment or follow-up 
period accordingly.
Concomitant medication
For incomplete start dates of concomitant medication, the following rules apply:
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x
If a medication start day is missing, but start month and year is not missing, it will be 
assumed that the start day is the first day of the month. If the medication start day and 
month is missing, but start year is not missing, it will be assumed that the start day is 
01 January. If the medication start day, month and year is missing, it will be assumed 
that the medication was started before study start. Time of medication will be set to 
23:59:59.
For incomplete end dates of concomitant medication, the following rules apply:
x
If a medication end day is missing, but end month and year is not missing, it will be 
assumed that the end day is the last day of the month. If the medication end day and 
month is missing, but end year is not missing, it will be assumed that the end day was 
31 December. If the medication end day, month and year is missing, it will be assumed 
that the medication was ongoing at the end of the study. Time of medication will be set 
to 00:00:00, unless the end date is equal to the start date of the concomitant 
medication where the time of the end date will be set to 23:59:59.
Administration of IMP 
In case of incomplete time registrations of IMP dosings with dates of administration being 
available, the time of 12:00:00 will be used.
6.8.4 Early termination and unscheduled visits
When no data is available from a certain scheduled post-baseline visit for a subject, data from 
early termination visits and unscheduled visits have the potential to replace data from that 
particular scheduled visit in data summaries, provided that the data is collected between 6 
days before and 7 days after the planned time point for the scheduled visit, as displayed 
below. 
Table 8: Visit days and windows
Visit (Target day)
Visit window (Day is date of assessment 
minus date of first dose)
Week 2 (Day 14)
Day 8 to 21
Week x (Day 7*x) (where x= 4, 6, ..., 26) 
Day 7*x-6 to 7*x+7
Safety follow-up
106-119 days after last dose
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When data from both unscheduled and early termination visits exist within the given visit 
window, the early termination visit will be selected for analysis. When no data from early 
termination visit and data from unscheduled visit(s) exist, within window, the unscheduled 
visit will be selected for analysis. If several unscheduled visits exist, the one closest to the 
target day will be selected for analysis. If the distance to the target day is tied, the latest 
unscheduled visit will be selected. 
6.8.5 Technical handling of intercurrent events and missing values
Intercurrent events and missing values will be handled as described in the protocol. 
This section describes the technical aspects in relation to this.
The variable DTYPE is created to indicate each special handling of data used. Observed data 
will be indicated when DTYPE is empty (DTYPE=’’). Subjects having experienced a prior 
intercurrent event or having a missing value at a visit can have inserted 5 extra data rows of 
separate DTYPEs. These data rows will be inserted dependent on the needs of the estimands 
applied. Non-responder imputation will be indicated using DTYPE=’NRI’, no value will be 
imputed but criteria/outcome values will be imputed as non-response. Worst observation 
carried forward will be indicated using DTYPE=’WOCF’, imputing the worst observation 
observed up until and including the data point. When imputing values, DTYPE=’MISSING’ 
will be used on relevant missing or set to missing data. In addition, to indicate when there is 
no observed value an extra category DTYPE=’MISSOBS’ is created. DTYPE=’LOCF’, last 
observation carried forward (including baseline observation) is used in the special case when 
no assessments exist at the first scheduled post-baseline assessment visit prior to any 
intercurrent events.
As intercurrent events are handled based on whichever of the regarded prior intercurrent 
events comes first, 3 first prior intercurrent event indicator variables are created. ICECOVIN 
indicates which of three prior intercurrent events comes first: permanent discontinuation of 
IMP not due to the COVID-19 pandemic, rescue treatment not due to the COVID-19 
pandemic, or subject-onset of the COVID-19 pandemic. ICECOVIN is used in the COVID-19 
modified composite and hypothetical estimands. ICECOMIN indicates which of either rescue 
treatment or permanent discontinuation of IMP comes first including events due to the 
COVID-19 pandemic. ICECOMIN is used in the composite estimand. ICETREIN indicates 
which of either permanent discontinuation of IMP not due to the COVID-19 pandemic or 
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subject-onset of the COVID-19 pandemic comes first. ICETREIN is used in the treatment 
policy estimands.
Missing values due to the COVID-19 pandemic will be handled using the flag MISSCVFL 
which will only be assigned onto visits with no observed data.
As a convenience, estimand flags have been created for each estimand in order to select the 
correct data rows based on the intercurrent event indicator variables and the DTYPE variable. 
How data rows are selected for the primary analysis of each estimand can be seen in Table 9.
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Table 9: Technical handling of intercurrent events and missing data in the primary analysis of the estimands
Binary endpoints
Continuous endpoints
Estimand flag
EBICOVFL
EBICOMFL
EBITREFL
EBIHYFL
ECOHYFL
ECOTREFL
ECOCOVFL
First prior intercurrent event 
indicator variable
ICECOVIN
ICECOMIN
ICETREIN
ICECOVIN
ICECOVIN
ICETREIN
ICECOVIN
First prior 
intercurrent 
event (indicator)
Missing or 
observed data
COVID-19
modified 
composite
Composite
treatment 
policy
hypothetical
hypothetical2
treatment 
policy
COVID-19
modified 
composite
Rescue treatment
(RESCNCFL or 
RESCUEFL)1
Missing data
DTYPE=NRI
DTYPE=NRI
NA
DTYPE=
MISSING
DTYPE=
MISSING
NA
DTYPE=
WOCF
Observed data
DTYPE=NRI
DTYPE=NRI
NA
DTYPE=
MISSING
DTYPE=
MISSING
NA
DTYPE=
WOCF
Permanent 
discontinuation of 
IMP
(DISCNCFL or 
DISCONFL) 1
Missing data
DTYPE=NRI
DTYPE=NRI
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
WOCF
Observed data
DTYPE=NRI
DTYPE=NRI
DTYPE=’’
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=’’
DTYPE=
WOCF
Subject-onset 
of the COVID-19
pandemic
(SOC19FL)
Missing data
DTYPE=
MISSING
NA
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
Observed data
DTYPE=
MISSING
NA
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
No prior 
intercurrent event
(‘’)
Missing data 
not due to the 
COVID-19
pandemic
DTYPE=NRI
DTYPE=NRI
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
Missing data 
due to the 
COVID-19
pandemic
DTYPE=
MISSING
DTYPE=NRI
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
DTYPE=
MISSING
Observed data
DTYPE=’’
DTYPE=’’
DTYPE=’’
DTYPE=’’
DTYPE=’’
DTYPE=’’
DTYPE=’’
Abbreviations: NA = Not applicable; COVID-19 = Coronavirus Disease 2019; IMP = investigational medicinal product; RESCNCFL = rescue treatment not due to 
the COVID-19 pandemic flag; RESCUEFL = rescue treatment flag; DISCNCFL = permanent discontinuation of IMP not due to the COVID-19 pandemic;
DISCONFL = permanent discontinuation of IMP; SOC19FL = subject-onset of the COVID-19 pandemic.
1)
Which first prior intercurrent event indicator is used is dependent on the estimand.
2)
If no post-baseline scheduled assessment exists, the last observation is carried forward (including baseline) with DTYPE=’LOCF’.
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6.8.6 Timing of intercurrent events
Actions taken based on intercurrent events will be dependent on whether or not an 
intercurrent event happens prior to a relevant visit. The rule will be that if any regarded 
intercurrent event happens prior to the date of the visit then the intercurrent event will be 
defined to be prior to the relevant visit. The following list of dates will be used in a prioritised 
manner as the date of the visit, i.e. if a date higher in the hierarchy exists that date will be 
used: 
1. Observed date of the visit. When no data is available from the scheduled visit, data
and visit date can be mapped to the visit per the rules stated in Section 6.8.4.
2. Planned date of the visit – 7 days, to account for the visit window.
In case intercurrent events occurs on the same date the following prioritise list will be used: 
rescue treatment, permanent discontinuation of IMP, and then subject-onset of the COVID-19 
pandemic.
6.8.7 Rules for single imputation methods
Worst observation carried forward (WOCF) will be defined using the worst observation ever 
recorded between the baseline visit and the analysed visit (baseline assessment included). The 
date of the analysed visit will be defined as the observed date of the visit if existing, if not 
then the date of the planned visit + 7 days, i.e. the last assessment before or within the 
window for mapping an early termination visit or unscheduled visit to a planned visit.
The LOCF value will be used in some cases but only when data is missing and is defined as 
the last assessment obtained before the observed date of the visit if existing, if not then the 
planned date of the visit + 7 days.
6.8.8 Technical aspects of attributing events and missing data to the 
COVID-19 pandemic
Definition of identifying interference by the COVID-19 pandemic in comment fields/logs
In addendum 1, it was introduced that to attribute events to the COVID-19 pandemic the 
eCRF comments fields/log had to be used to identify when trial related procedures were 
interrupted due to the COVID-19 pandemic by writing “COVID-19”. However, alternative 
ways of specifying this should be accounted for and therefore if any comment fields/logs 
contain one of the following search terms it will be treated as equal to writing “COVID-19”: 
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“COVID” and “CORONA”. Note, this will capture cases where there is written 
"CORONAVIRUS", as this would be included by the "CORONA” search term. All comments 
will be used in an uppercase format.
Permanent discontinuation of IMP due to the COVID-19 pandemic
Permanent discontinuation of IMP will be attributed to the COVID-19 pandemic if reason for 
permanent discontinuation of IMP contains a COVID-19 reference.
Missed visits due to the COVID-19 pandemic
Missed visits will be attributed to the COVID-19 pandemic if the eCRF comments log for the 
missed visit contains a COVID-19 reference.
Missed IMP doses due to the COVID-19 pandemic
Missed IMP doses can be attributed to the COVID-19 pandemic if one of the following 
occurs:
1. Missed visit due to the COVID-19 pandemic, implying that IMP dosing at that
scheduled visit then also is missed due to the COVID-19 pandemic.
2. The eCRF comments field for the administration of IMP contains a COVID-19
reference.
Use of rescue treatment due to unavailability of IMP related to the COVID-19 pandemic 
As stated in the protocol, attributing rescue treatment to the COVID-19 pandemic depends on 
either missed IMP dosing, missed visits or permanent discontinuation of IMP, due to the 
COVID-19 pandemic and thus the definition depends on the previous defined events.
Prolonged interruption of IMP due to the COVID-19 pandemic
As defined in the protocol and using the defined methods for missed IMP doses due to the 
COVID-19 pandemic and missed visits due to the COVID-19 pandemic.
Missing assessment data due to the COVID-19 pandemic
Assessment data missing will be attributed to the COVID-19 pandemic if one of the following 
occurs:
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1. The visit where the assessment is scheduled to occur is missed due to the COVID-19 
pandemic.
2. The visit where the assessment was scheduled to occur is not missing but is indicated 
to have been a telephone/video visit by having a COVID-19 reference in eCRF 
comment log implying that the assessment was not possible to do.
3. The eCRF comments field for the missing assessment data contains a COVID-19 
reference.
6.8.9 Treatment labels
Table 10: Treatment labels for the clinical trial report text and tables
Period
Label Used in Text
Label Used in Tables
Order in 
Table
Treatment
period
Tralokinumab Q2W + TCS
Tralokinumab Q2W + TCS
1
Treatment
period
Placebo + TCS
Placebo + TCS
2
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7 References 
1. White IR, Daniel R, Royston P. Avoiding bias due to perfect prediction in multiple 
imputation of incomplete categorical variables. Computational Statistics and Data 
Analysis 54 (2010): 2267-2275.
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