Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 215
Healthy volunteers: no

Brief summary:
The purpose of this trial is to test if treatment with the trial drug, tralokinumab, can affect the body's immune response to vaccines. The trial will also evaluate the efficacy of tralokinumab when it is given concomitantly with vaccines.

The trial includes a screening period of 2 to 6 weeks, a treatment period of 16 weeks (Weeks 0 to 16), and a 14-week off-treatment follow-up period for the assessment of safety (Weeks 16 to 30). Eligible subjects may transfer to an open-label, long-term trial at Week 16 or later.

Detailed description:
Subjects with atopic dermatitis (AD) will be treated with either tralokinumab or dummy treatment (placebo) for 16 weeks. All subjects will receive 2 vaccines at Week 12. The vaccines are:

1. Tetanus (lockjaw), diphtheria (infection of the nose and throat), and pertussis (whooping cough) vaccine. This combination vaccine is also known as the Tdap vaccine and is used to prevent these 3 diseases.
2. Meningococcal vaccine. This vaccine is used to prevent meningococcal diseases (infection of the brain and spinal cord) and blood poisoning.

The primary objective of the trial is to demonstrate non-inferiority of tralokinumab versus placebo with respect to immune responses to concomitantly administered vaccines.

The secondary objective is to evaluate efficacy of tralokinumab concomitantly administered with vaccines.

Arms:
arm 1: Week 0 to 16:

Tralokinumab will be given as subcutaneous injections.

Subjects will receive a tralokinumab loading dose at Day 0 followed by tralokinumab injection regimen A. The last administration will occur at Week 14. arm 2: Placebo (dummy treatment) will be given as subcutaneous injections.

Subjects will receive a placebo loading dose at Day 0 followed by placebo injection regimen A. The last administration will occur at Week 14.

Interventions: intervention 1: Tralokinumab intervention 2: Placebo intervention 3: Tdap vaccine intervention 4: Meningococcal vaccine
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 administration. intervention 2: Placebo contains the same excipients in the same concentration only lacking tralokinumab. intervention 3: Tetanus (lockjaw), diphtheria (infection of the nose and throat), and pertussis (whooping cough) vaccine. All subjects will receive 1 dose at Week 12. intervention 4: This vaccine is used to prevent meningococcal diseases (infection of the brain and spinal cord) and blood poisoning. All subjects will receive 1 dose at Week 12.

Protocol document:
Prot_000.pdf: 
Cover Page 
Official title: A Randomised, Double-blind, Placebo-controlled Trial to Evaluate the Effect of  
Tralokinumab on Vaccine Antibody Responses in Adults With Moderate-to-severe Atopic Dermatitis Who 
Are Candidates for Systemic Therapy 
LEO Pharma number: LP0162-1341 
NCT number: NCT03562377 
Date: 23-Apr-2018 


Clinical Trial Protocol 
LP0162-1341 
Vaccine responses in tralokinumab-treated atopic dermatitis 
ECZTRA 5 (ECZema TRAlokinumab trial no. 5) 
Phase 2 – Vaccine response trial 
A randomised, double-blind, placebo-controlled trial to evaluate the effect of tralokinumab 
on vaccine antibody responses in adults with moderate-to-severe atopic dermatitis who are 
candidates for systemic therapy  
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH-GCP 
and the applicable regulatory requirements. 
LEO Pharma A/S 
Trial ID: 
LP0162-1341 
Date: 
23-Apr-2018
EudraCT no: 
Not applicable 
Version: 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
, MSc Stat 
Biostatistics Lead, Global Clinical Operations 
, MD, PhD 
Medical Lead, Medical Sciences and Safety 
, RN, PhD 
Clinical Operations Lead, Global Clinical Operations 
Approval statement signatory investigator 
The signatory investigator approves the clinical trial protocol 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: 
Joseph F. Merola, MD, MMSc 
Signatory investigator 
Acknowledgement statement investigator(s) 
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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Table of contents 
Table of contents ....................................................................................................................... 3 
List of panels ............................................................................................................................. 7 
List of abbreviations ................................................................................................................. 8 
1 Protocol synopsis ................................................................................................................ 11 
2 Trial identification ............................................................................................................. 16 
3 Schematic of trial design ................................................................................................... 16 
4 Schedule of trial procedures ............................................................................................. 17 
5 Introduction and trial rationale ....................................................................................... 22 
5.1 Atopic dermatitis ........................................................................................................ 22 
5.2 Experience with investigational medicinal product .................................................... 22 
5.3 Trial rationale .............................................................................................................. 23 
5.4 Justification for dose ................................................................................................... 24 
5.5 Ethical considerations ................................................................................................. 24 
5.6 Benefit/risk assessment ............................................................................................... 26 
6 Trial objectives and endpoints .......................................................................................... 28 
7 Trial design ......................................................................................................................... 29 
7.1 Overall trial design ..................................................................................................... 29 
7.2 Number of subjects needed ......................................................................................... 30 
7.3 End of trial definition.................................................................................................. 30 
7.4 Software ...................................................................................................................... 31 
8 Trial population ................................................................................................................. 32 
8.1 Subject eligibility ........................................................................................................ 32 
8.2 Inclusion criteria ......................................................................................................... 32 
8.3 Exclusion criteria ........................................................................................................ 34 
8.4 Screening and screening failures ................................................................................ 37 
9 Treatments .......................................................................................................................... 39 
9.1 Description of IMP ..................................................................................................... 39 
9.1.1 
Tralokinumab and placebo ............................................................................ 39 
9.1.2 
Vaccines ......................................................................................................... 40 
9.2 Administration of IMP ................................................................................................ 41 
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9.2.1 
Administration of tralokinumab and placebo ................................................ 41 
9.2.2 
Administration of vaccines............................................................................ 42 
9.3 Treatment assignment ................................................................................................. 43 
9.3.1 
Blinding ......................................................................................................... 44 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 44 
9.4 Background treatment (emollients) ............................................................................ 45 
9.5 Rescue treatment ......................................................................................................... 45 
9.6 Concomitant medication and concurrent procedures ................................................. 46 
9.7 Prohibited medication ................................................................................................. 47 
9.8 Treatment logistics and accountability ....................................................................... 49 
9.8.1 
Labelling and packaging of trial products ..................................................... 49 
9.8.2 
Storage of trial products ................................................................................ 49 
9.8.3 
Drug accountability ....................................................................................... 50 
9.8.4 
Treatment compliance ................................................................................... 51 
9.8.5 
Trial product destruction ............................................................................... 51 
9.9 Provision for subject care following trial completion ................................................ 51 
9.10 Reporting product complaints..................................................................................... 51 
10 Discontinuation and withdrawal ...................................................................................... 53 
10.1 General principles ....................................................................................................... 53 
10.2 IMP discontinuation rules ........................................................................................... 53 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 53 
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 54 
10.3 Early termination assessments .................................................................................... 54 
10.4 Lost to follow-up ........................................................................................................ 55 
11 Trial assessments and procedures .................................................................................... 56 
11.1 Overview..................................................................................................................... 56 
11.2 Assessments performed only at screening/baseline .................................................... 57 
11.2.1 Demographics................................................................................................ 57 
11.2.2 Medical history .............................................................................................. 57 
11.2.3 Height and weight ......................................................................................... 58 
11.2.4 Body surface area involvement ..................................................................... 58 
11.2.5 Columbia-Suicide Severity Rating Scale ...................................................... 58 
11.3 Efficacy assessments .................................................................................................. 59 
11.3.1 Investigator’s Global Assessment ................................................................. 59 
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11.3.2 Eczema Area and Severity Index .................................................................. 59 
11.3.3 Scoring Atopic Dermatitis ............................................................................. 61 
11.3.4 Patient-reported outcomes ............................................................................. 62 
11.4 Safety assessments ...................................................................................................... 63 
11.4.1 Vital signs ...................................................................................................... 63 
11.4.2 Physical examination..................................................................................... 64 
11.4.3 ECG ............................................................................................................... 64 
11.4.4 Pregnancy test ............................................................................................... 65 
11.4.5 Laboratory testing ......................................................................................... 66 
11.4.6 Anti-drug antibodies measurements .............................................................. 68 
11.5 Assessment of vaccine responses ............................................................................... 69 
11.6 Pharmacokinetic assessments ..................................................................................... 69 
11.7 Pharmacodynamics and pharmacogenomics .............................................................. 69 
11.8 Other assessments ....................................................................................................... 70 
11.9 Estimate of total blood volume collected ................................................................... 70 
11.10 End of trial .................................................................................................................. 70 
11.11 Storage of biological samples ..................................................................................... 71 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 72 
13 Adverse events ................................................................................................................... 74 
13.1 Definition and classification of adverse events .......................................................... 74 
13.2 Collection of adverse event reports ............................................................................ 74 
13.3 Reporting of adverse events........................................................................................ 74 
13.4 Reporting of serious adverse events ........................................................................... 75 
13.4.1 Investigator reporting responsibilities ........................................................... 75 
13.4.2 LEO reporting responsibilities ...................................................................... 76 
13.5 Other events that require expedited reporting ............................................................ 77 
13.5.1 Pregnancy ...................................................................................................... 77 
13.6 Reporting of other events............................................................................................ 77 
13.6.1 Adverse events of special interest ................................................................. 77 
13.6.2 Overdose........................................................................................................ 79 
13.6.3 Medication error ............................................................................................ 79 
13.6.4 Misuse ........................................................................................................... 79 
13.6.5 Abuse ............................................................................................................. 79 
13.6.6 Aggravation of condition .............................................................................. 80 
13.7 Follow-up for final outcome of adverse events .......................................................... 80 
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13.8 Handling of an urgent safety measure ........................................................................ 80 
14 Statistical methods ............................................................................................................. 82 
14.1 Sample size ................................................................................................................. 82 
14.2 Trial analysis sets ........................................................................................................ 82 
14.3 Statistical analysis ....................................................................................................... 84 
14.3.1 Disposition of subjects .................................................................................. 84 
14.3.2 Demographics and other baseline characteristics.......................................... 84 
14.3.3 Exposure and treatment compliance ............................................................. 84 
14.3.4 Multiple testing procedure ............................................................................ 84 
14.3.5 Analysis of primary endpoints ...................................................................... 86 
14.3.6 Analysis of secondary endpoints ................................................................... 86 
14.3.7 Analysis of other endpoints ........................................................................... 91 
14.3.8 Analysis of safety .......................................................................................... 92 
14.3.9 Interim analysis ............................................................................................. 94 
14.3.10 General principles ......................................................................................... 94 
14.3.11 Handling of missing values ........................................................................... 95 
15 References ........................................................................................................................... 96 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 100 
Appendix 2: Classification of adverse events ..................................................................... 102 
Appendix 3: Trial governance considerations ................................................................... 105 
Appendix 3A: Regulatory and ethical considerations .............................................. 105 
Appendix 3B: Informed consent process ................................................................. 106 
Appendix 3C: Subject and data confidentiality ....................................................... 106 
Appendix 3D: Record keeping, quality control, and data handling ......................... 107 
Appendix 3E: Registration, reporting and publication policy ................................. 112 
Appendix 3F: Insurance ........................................................................................... 113 
Appendix 3G: Financial disclosure .......................................................................... 113 
Appendix 3H: Trial and site closure ........................................................................ 114 
Appendix 3I: Responsibilities .................................................................................. 115 
Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD .................................. 116 
Appendix 5: Guidance for anaphylaxis diagnosis (24) ..................................................... 117 
Appendix 6: Short version of eligibility criteria ................................................................ 118 
Appendix 7: Contact list ...................................................................................................... 121 
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Appendix 8: WHO model prescribing information for classification of topical 
corticosteroids .................................................................................................................. 122 
List of panels 
Panel 1: Trial design ................................................................................................................. 16 
Panel 2: Schedule of trial procedures ....................................................................................... 17 
Panel 3: Objectives and endpoints ........................................................................................... 28 
Panel 4: Identification of IMPs (tralokinumab and placebo) ................................................... 39 
Panel 5: Identification of IMPs (vaccines) ............................................................................... 40 
Panel 6: Prohibited medication ................................................................................................ 48 
Panel 7: Sequence of assessments and procedures ................................................................... 56 
Panel 8: Investigator’s Global Assessment .............................................................................. 59 
Panel 9: Calculation of the Eczema Area and Severity Index .................................................. 60 
Panel 10: EASI severity score scale and area score scale ........................................................ 60 
Panel 11: Clinical laboratory tests ............................................................................................ 67 
Panel 12: Adverse events of special interest ............................................................................ 78 
Panel 13: Testing procedure for primary and secondary endpoints ......................................... 85 
Panel 14: Transmission of electronic data .............................................................................. 111 
Panel 15: Classification of topical corticosteroids ................................................................. 122 
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List of abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BSA 
body surface area 
CCL22 
C-C motif chemokine 22
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
at least 50% reduction in EASI score 
EASI75 
at least 75% reduction in EASI score 
EASI90 
at least 90% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
FAS 
full analysis set 
FDA 
Unites States Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
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ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IL 
interleukin 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
LEO 
LEO Pharma A/S 
Lf 
limit of flocculation 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAB 
neutralising antibodies 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PDE-4 
phosphodiesterase 4 
PK 
pharmacokinetics 
POEM 
Patient-Oriented Eczema Measure 
Q2W 
every 2 weeks 
SAE 
serious adverse event 
SC 
subcutaneous 
SCORAD 
Scoring Atopic Dermatitis  
SCORAD50 
at least 50% reduction in SCORAD score 
SCORAD75 
at least 75% reduction in SCORAD score 
SDTM 
study data tabulation model 
SOC 
system organ class 
TCI 
topical calcineurin inhibitor 
TCS 
topical corticosteroid 
Tdap 
tetanus, diphtheria, and acellular pertussis 
Th2 
T-helper-2
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ULN 
upper limit of normal 
US 
United States of America 
UV 
ultraviolet 
WHO 
World Health Organization 
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1 Protocol synopsis 
Trial ID 
IND no. 
FDA center 
LP0162-1341 
123797 
CDER 
Title of trial 
A randomised, double-blind, placebo-controlled trial to evaluate the effect of 
tralokinumab on vaccine antibody responses in adults with moderate-to-severe 
atopic dermatitis (AD) who are candidates for systemic therapy. 
Short title of trial 
Vaccine responses in tralokinumab-treated atopic dermatitis 
Main objectives 
and endpoints 
Objectives 
Endpoints 
Primary objective 
Primary endpoints 
To demonstrate 
non-inferiority of 
tralokinumab versus placebo 
with respect to immune 
responses to concomitantly 
administered vaccines. 

Positive anti-tetanus response at
Week 16 (3-fold IgG increase compared
to Week 12 if IgG ≤1.0 IU/mL at
Week 12; or IgG ≥2.5 IU/mL if
IgG >1.0 IU/mL at Week 12)

Positive anti-meningococcal response at
Week 16 (IgG ≥3.0 mcg/mL with at
least a 3-fold increase compared to
Week 12)
Secondary objective 
Secondary endpoints 
To evaluate efficacy of 
tralokinumab concomitantly 
administered with vaccines.  

Investigator Global Assessment (IGA)
score of 0 (clear) or 1 (almost clear) at
Week 161

At least 75% reduction in Eczema Area
and Severity Index (EASI75) at
Week 162
Additional secondary 
objective 
Additional secondary endpoints 
To evaluate safety and 
tolerability of tralokinumab 
concomitantly administered 
with vaccines. 

Number of adverse events (AEs)

Presence of anti-drug antibodies
1 The IGA is an instrument used in clinical trials to rate the severity of the subject's 
global AD and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). 
2 The EASI is a validated measure used in clinical practice and clinical trials to assess 
the severity and extent of AD. The EASI is a composite index with scores ranging from 
0 to 72, with higher values indicating more severe and/or more extensive condition. 
Final collection of 
data for the 
primary endpoints 
Week 16 
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Trial design 
The trial will consist of a screening period of 2 to 6 weeks (Weeks -6/-2 to 0), a 
treatment period of 16 weeks (Weeks 0 to 16), and a 14-week off-treatment 
follow-up period for the assessment of safety (Weeks 16 to 30). Eligible 
subjects may transfer to the open-label, long-term ECZTEND trial 
(LP0162-1337) at Week 16 or later. 
Subjects will be randomised in a 1:1 ratio to receive 300 mg (2 mL) of 
tralokinumab or placebo (2 mL) every 2 weeks (Q2W) following a loading 
dose of 600 mg (4 mL) or placebo (4 mL) on Day 0. Randomisation will be 
stratified by baseline disease severity (IGA 3 or 4). 
The last administration of IMP will occur at Week 14. Subjects will each 
receive 1 dose of combined tetanus, diphtheria, and acellular pertussis (Tdap) 
vaccine and 1 dose of meningococcal vaccine given intramuscularly at 
Week 12. 
The primary endpoints will be assessed at Week 16, and the final safety 
assessment will be conducted at Week 30 for those not rolling over to the 
ECZTEND trial (LP0162-1337). 
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). 
Tdap, tetanus, diphtheria, and acellular pertussis; w, weeks. 
Main assessments 
Assessments of vaccine-specific antibody response 
Anti-tetanus response, anti-meningococcal response. 
Safety assessments 
Vital signs, physical examination, electrocardiograms, laboratory testing, 
pharmacokinetics, anti-drug antibodies, and adverse event reporting. 
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Efficacy: investigator assessments 
IGA, EASI, and Scoring Atopic Dermatitis (SCORAD). 
Efficacy: subject assessments 
4 patient-reported outcomes will be completed by the subjects at the site during 
trial visits: Dermatology Life Quality Index (DLQI), EuroQoL 5-Dimension 
Health Questionnaire 5 Level (EQ-5D-5L), Patient-Oriented Eczema Measure 
(POEM), and Hospital Anxiety and Depression Scale (HADS). 
Main criteria for 
inclusion 

Age 18 to 54 years, both included, at screening

Diagnosis of AD as defined by Hanifin and Rajka (1980) criteria for AD

History of AD for ≥1 year

Subjects who have a recent history of inadequate response to treatment
with topical medications or for whom topical treatments are otherwise
medically inadvisable

AD involvement of ≥10% body surface area at screening and baseline
according to component A of SCORAD

An EASI score of ≥12 at screening and 16 at baseline

An IGA score of ≥3 at screening and at baseline

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 

Subjects for whom administration of the meningococcal vaccine provided
in this trial is contraindicated or medically inadvisable, according to local
label of the vaccine

Subjects for whom administration of the tetanus, diphtheria, and pertussis
vaccine provided in this trial is contraindicated or medically inadvisable,
according to local label of the vaccine

Active dermatologic conditions that may confound the diagnosis of AD or
would interfere with assessment of treatment, such as scabies, cutaneous
lymphoma, or psoriasis

Use of tanning beds or phototherapy within 6 weeks prior to randomisation

Treatment with immunosuppressive/immunomodulating medications
and/or systemic corticosteroids within 4 weeks prior to randomisation

Treatment with the topical medications topical corticosteroids (TCS),
topical calcineurin inhibitor (TCI) or phosphodiesterase 4 (PDE-4)
inhibitor within 2 weeks prior to randomisation

Receipt of any vaccine (except influenza virus vaccines) within 3 months
prior to screening, any meningococcal vaccine within 1 year prior to
screening, or any tetanus-, diphtheria-, or pertussis-containing vaccine
within 5 years prior to screening

Receipt of any marketed or investigational biologic agents (e.g.,
cell-depleting agents or dupilumab) within 6 months prior to randomisation
or until lymphocyte counts return to normal, whichever is longer

History of any active skin infection within 1 week prior to randomisation

History of a clinically significant infection (systemic infection or serious
skin infection requiring parenteral treatment) within 4 weeks prior to
randomisation
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Investigational 
medicinal 
products 
Tralokinumab (human recombinant IL-13 monoclonal antibody) 
150 mg/mL solution for subcutaneous injection in an accessorised pre-filled 
syringe, 1.0 mL fill volume. Each kit contains 1 syringe. 
Placebo 
Placebo solution for  subcutaneous injection in an accessorised pre-filled 
syringe, 1.0 mL fill volume. Each kit contains 1 syringe. 
Tdap vaccine 
Combined diphtheria, tetanus, acellular pertussis (adsorbed) vaccine. 
Suspension for injection in 0.5 mL single dose pre-filled syringes. 
Meningococcal vaccine 
Meningococcal (groups A, C, Y and W-135) polysaccharide diphtheria toxoid 
conjugate vaccine. Solution for injection in 0.5 mL single dose vials. 
Duration of 
treatment 
Each subject’s trial participation will be up to 36 weeks: screening period 
(including washout, if applicable) up to 6 weeks, treatment period of 16 weeks, 
and follow-up period of 14 weeks (subjects may enter the long-term extension 
trial, ECZTEND, at any time during the safety follow-up period). 
Number of 
subjects 
A total of 200 subjects will be randomised 1:1 to tralokinumab 300 mg Q2W or 
placebo. 
Number and 
distribution of 
trial sites 
Approximately 40 sites in the US and Canada. 
Statistical 
methods 
Primary endpoints:  
The difference in response rates between treatment groups will be calculated 
using the Mantel-Haenszel estimate of the risk difference stratified by baseline 
disease severity (IGA 3 or 4) together with the 95% confidence intervals. 
Non-inferiority of tralokinumab will be demonstrated if the lower limit of the 
95% confidence interval is greater than -25%. The per protocol analysis will be 
considered the primary analysis. Analyses will be based on observed data; thus 
missing data will not be imputed. 
Secondary endpoints:  
The difference in response rates between treatment groups will be analysed 
using the Cochran-Mantel-Haenszel test stratified by baseline disease severity 
(IGA 3 or 4). The primary analysis will be based on the full analysis set. 
Subjects with missing data or subjects who receive rescue medication prior to 
Week 16 will be considered as non-responders in the analysis.  
Testing strategy 
The primary and secondary endpoints will be evaluated hierarchically in the 
order shown in Panel 13. The hypothesis relating to a specific endpoint cannot 
be rejected unless all hypotheses relating to endpoints earlier in the hierarchy 
are also rejected. For the primary endpoints a non-inferiority hypothesis will be 
tested using a non-inferiority limit of -25%. For the secondary endpoints a 
superiority hypothesis will be tested. All hypotheses will be tested at a 
one-sided 2.5% significance level. For the primary endpoints, the null 
hypothesis will be rejected if the two-sided 95% confidence interval for the 
difference in immune response rate lies entirely to the right of the 
non-inferiority limit (-25%). For the secondary endpoints, the hypotheses will 
be tested by calculating the two-sided 95% confidence intervals and p-value. 
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Signatory 
investigator 
Joseph F. Merola, MD, MMSc 
Brigham and Women’s Hospital, Boston, MA, USA 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
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2 Trial identification 
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 
Tdap, tetanus, diphtheria, and acellular pertussis; w, weeks. 
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4 Schedule of trial procedures 
Panel 2: Schedule of trial procedures 
Screening 
Treatment period 
Follow-up2,3 
Uns. 
visit6 
(if appl.) 
Early 
term.5,7
(if appl.) 
Nominal 
Week 16 
visit8 
(if appl.) 
References 
(protocol 
section) 
Visit 
11
2 
3 
4 
5 
6 
7 
8 
9 
10 
112 
124 
134 
145 
11x 
Week 
-6
-2
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
30 
16 
Visit window (days)9 
±3 
-3
NA 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
±3 
Trial population and eligibility 
Informed consent10 
X 
Appendix 
3B 
Subject eligibility 
X 
X 
8.2;8.3 
Treatments and randomisation 
Initiation of emollient 
(background treatment)11 
X 
9.4 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
9.6 
Concurrent procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
9.6 
Randomisation 
X 
9.3 
IMP (tralokinumab/placebo) 
administration, compliance  
X12 
X12 
X12 
X 
X 
X 
X13 
X 
9.2.1;9.8.4 
IMP (Tdap vaccine) 
administration, compliance 
X13 
9.2.2;9.8.4 
IMP (meningococcal vaccine) 
administration, compliance 
X13 
9.2.2;9.8.4 
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Panel 2: Schedule of trial procedures (continued) 
Screening 
Treatment period 
Follow-up2,3 
Uns. 
visit6 
(if appl.) 
Early 
term.5,7
(if appl.) 
Nominal 
Week 16 
visit8 
(if appl.) 
References 
(protocol 
section) 
Visit 
11
2 
3 
4 
5 
6 
7 
8 
9 
10 
112 
124 
134 
145 
11x 
Week 
-6
-2
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
30 
16 
Visit window (days)9 
±3 
-3
NA 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
±3 
Investigator assessments at screening/baseline only 
C-SSRS
X 
11.2.5 
Demographics 
X 
11.2.1 
Demographics (age)14 
X 
X 
11.2.1 
Medical history 
X 
11.2.2 
Height and weight 
X 
11.2.3 
Body surface area involvement 
X15 
X15 
11.2.4 
Investigator assessments of efficacy 
SCORAD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.3 
IGA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.1 
EASI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.2 
Subject assessments of efficacy 
DLQI 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.4.1 
EQ-5D-5L 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.4.2 
POEM 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.4.3 
HADS 
X 
X 
X 
X 
X 
X6 
X 
X 
11.3.4.4 
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Panel 2: Schedule of trial procedures (continued) 
Screening 
Treatment period 
Follow-up2,3 
Uns. 
visit6 
(if appl.) 
Early 
term.5,7
(if appl.) 
Nominal 
Week 16 
visit8 
(if appl.) 
References 
(protocol 
section) 
Visit 
11
2 
3 
4 
5 
6 
7 
8 
9 
10 
112 
124 
134 
145 
11x 
Week 
-6
-2
0 
2 
4 
6 
8 
10 
12 
14 
16 
20 
24 
30 
16 
Visit window (days)9 
±3 
-3
NA 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
NA 
NA 
±3 
Investigator assessments of safety 
Vital signs 
X 
X12 
X12 
X12 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
11.4.1 
Physical examination 
X 
X 
X 
X 
X 
X6 
X 
11.4.2 
ECG 
X 
X 
X 
X 
X6 
X 
11.4.3 
Chemistry, haematology, IgE 
(central laboratory)  
X16 
X 
X 
X 
X 
X 
X 
X6 
X 
11.4.5 
Serum pregnancy test; hepatitis 
B, C; HIV (central laboratory) 
X 
11.4.4; 
11.4.5 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X6 
X 
11.4.4 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
11.4.5 
Anti-drug antibodies 
X 
X 
X 
X 
X6 
X 
11.4.6 
Pharmacokinetics 
X 
X 
X 
X6 
X 
11.6 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
13 
Assessment of vaccine antibody response 
Anti-tetanus response 
X 
X 
X6,17 
X18 
X18 
11.5 
Anti-meningococcal response 
X 
X 
X6,17 
X18 
X18 
11.5 
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1)
For subjects who do not require a wash-out, 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. Similarly, for subjects who only require a 2-week wash-out, screening visits 1 and 2
will be combined (Week -2). The screening period has a maximum duration of 6 weeks.
2)
Eligible subjects may roll over to the ECZTEND trial at Week 16 or later. See also footnote no. 5.
3)
All subjects, except for those who roll over to the ECZTEND trial (LP0162-1337), will have a full 14-week off-treatment safety follow-up period. The safety
follow-up period includes 2 telephone contacts and an office visit (end-of-trial visit) at Week 30. Subjects may transfer to the ECZTEND trial at any time
during the safety follow-up period.
4)
Visit will be conducted as a telephone contact.
5)
An end-of-treatment form and end-of-trial form must be completed in the eCRF for all randomised subjects. See Section 11.10 for further details.
6)
Assessments and procedures to be performed at an unscheduled visit are left at the investigator’s discretion.
7)
Subjects who permanently discontinue IMP or withdraw from the trial will be followed up as described in Section 10.3 and will have a final safety follow-up
visit 16 weeks after last dose of IMP.
8)
Subjects who permanently discontinue IMP prior to Week 16 will also attend the nominal Week 16 visit (visit 11x).
9)
If the date of a trial visit does not conform to the clinical trial protocol, subsequent visits should be planned to maintain the visit schedule relative to baseline.
10) The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and
wash-out of disallowed medications.
11) 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).
12) For the first 3 IMP (tralokinumab/placebo) dosing visits, 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).
13) Since the 2 vaccinations will be given in the upper arms (1 vaccine in each arm), the IMP (tralokinumab/placebo) injections at Week 12 will be given at a
different anatomical site (that is, anterior thigh or abdomen).
14) Where it is not allowed to collect the subject’s full date of birth per local legislation, the subject’s age in years will also be recorded.
15) The total body surface area affected by AD will be assessed by the investigator as component A of SCORAD.
16) IgE not measured at screening.
17) Only to be considered if the unscheduled visit occurs after Week 12 (that is, after administration of the vaccines).
18) Only required if the subject permanently discontinues IMP (tralokinumab/placebo) after Week 12 (that is, after administration of the vaccines).
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Appl., applicable; C-SSRS, Columbia-Suicide Severity Rating Scale; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; ECG, 
electrocardiogram; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global 
Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; NA, not applicable; POEM, Patient Oriented Eczema Measure; SCORAD, Scoring 
Atopic Dermatitis; Tdap, tetanus, diphtheria, and acellular pertussis; term., termination; uns., unscheduled. 
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5 Introduction and trial rationale 
5.1 Atopic dermatitis  
AD is a chronic inflammatory skin disease that may affect up to 20% of children and up to 
10% of adults. In its severe form, AD is characterised by widespread skin lesions, intractable 
itch, as well as enhanced susceptibility to bacterial, viral, and fungal skin infections (1-4). AD 
is associated with a substantial patient burden that typically includes poor quality of life, sleep 
disturbance, and reductions in work productivity (5). 
AD is characterised by an activated Th2 pathway with increased skin expression of key Th2 
cytokines including 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 CCL22 and recruit more IL-13 expressing Th2 cells, 
decrease differentiation, and contribute to decreased barrier function (9). IL-13 also drives 
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. 
All of these effects together drive and exacerbate the disease phenotype. A review of the 
available preclinical literature from mouse and human ex-vivo models suggests IL-13 as a, if 
not the, central mediator of the AD skin phenotype. Indeed, there is evidence that blocking the 
IL-4 receptor (which is part of the receptor complex which also binds IL-13) with the 
monoclonal antibody dupilumab leads to clinical improvement in AD subjects (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 PK is given in the 
current version of the Investigator’s Brochure. 
In total, 14 clinical trials have been conducted with tralokinumab, with phase 3 development 
ongoing in AD. Other clinical trials with tralokinumab have been conducted in subjects with 
asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in healthy subjects. Further 
information on these trials can be found in the current version of the Investigator’s Brochure. 
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In a phase 2b trial (D2213C00001), adults with moderate-to-severe AD on a background of 
mild to moderate TCS, were treated with 3 different regimens of tralokinumab (45 mg 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 EASI at Week 12 
and the percentage of subjects achieving IGA response of 0 (clear) or 1 (almost clear) at 
Week 12. Secondary endpoints included change 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 was upper respiratory tract infection (6 [3.9%] subjects in the combined 
tralokinumab group (45 mg, 150 mg, and 300 mg) and 2 [3.9%] subjects in the placebo 
group). 
In total, more than 2,343 subjects have been treated with tralokinumab (cut off date: 
18-Aug-2017). The safety of all doses studied so far has been with an acceptable benefit-risk
profile and no major safety concerns have been identified. Possible risks associated with use 
of tralokinumab are summarised in Section 5.5. 
5.3 Trial rationale 
Tralokinumab blocks IL-13 signalling and thereby modulates the immune system to inhibit 
the inflammatory Th2 response seen in patients with AD (3, 13, 16, 17); refer also to 
Section 5.1. This immunomodulation could potentially impair the immune response and 
compromise immunity in treated patients. Since vaccination programmes are an important 
part of health maintenance and globally recommended, it is relevant to investigate if 
tralokinumab affects development of vaccination-induced immune responses (18).  
This trial will assess immunisation responses against 2 vaccines (a combined tetanus, 
diphtheria, and acellular pertussis [hereinafter ‘Tdap’] vaccine and a meningococcal [groups 
A, C, Y and W-135] polysaccharide conjugated vaccine) in adults with moderate-to-severe 
AD who are treated with tralokinumab. These 2 standard vaccines have been selected to 
enable a broader assessment of the effect of tralokinumab on immune activation. The selected 
types of vaccines are known to result in an immune response involving both T and B cells as 
well as other key cell types of the immune system. 
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5.4 Justification for dose 
The selected dose for this trial is 300 mg tralokinumab administered subcutaneously Q2W. All 
subjects randomised to receive 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 support the selection of the tralokinumab Q2W 300 mg dose; 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 this trial.  
The 300 mg Q2W dose is also used in the ongoing phase 3 trials ECZTRA 1, ECZTRA 2, and 
ECZTRA 3. 
The Tdap and the meningococcal vaccines will be given according to the local labelling, that 
is, a single intramuscular injection (0.5 mL) of each vaccine. 
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 
have to agree to use a highly effective method of contraception to prevent pregnancy during 
the clinical trial and until 16 weeks after discontinuation of treatment with the IMP. In 
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addition, all female subjects of child-bearing potential will have a pregnancy test performed 
before, during and at end-of-treatment to ensure that no foetuses are exposed to the IMP. 
In a 13-week repeated-dose nonclinical study in male cynomolgus monkeys, no adverse 
effects on male reproductive endpoints were observed (see the 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 clinical trial in adult subjects with moderate-to-severe AD who are otherwise healthy, 
the immunisation responses against 2 vaccines in subjects treated with tralokinumab will be 
compared to a placebo control group. The choice of placebo as control is appropriate for 
addressing the objectives of this trial and it will provide information regarding immunisation 
response and the efficacy and safety of tralokinumab concomitantly administered with 
vaccines. The Tdap and meningococcal vaccines to be used are standard, marketed vaccines. 
Subjects will be under supervision by a dermatologist or allergist every second week during 
the treatment period, which is more frequent than standard clinical practice. This will ensure 
that the subject’s AD is carefully monitored and treated as needed in this trial. Rescue 
treatment may be given to the subjects at the investigator’s discretion for the duration of the 
trial. If subjects receive rescue treatment with systemic corticosteroids or non-steroidal 
systemic immunosuppressive drugs, treatment with IMP will be immediately discontinued. 
Investigators should only enrol subjects they expect will be able to complete the wash-out of 
previous AD medications without experiencing intolerable worsening of their AD. Subjects 
will be informed to contact the investigator if they experience a significant worsening of their 
AD.   
Altogether, the risks associated with participating in this clinical trial are considered very low 
and outweighed by the benefit of a potential future treatment option for moderate-to-severe 
AD.  
In accordance with the current version of the ICH 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.  
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In conclusion, the trial design chosen for this vaccine response trial with tralokinumab is 
regarded as ethically justified and adherent with ethical requirements. 
5.6 Benefit/risk assessment 
There is an unmet medical need for new therapies for use in subjects with moderate-to-severe 
AD as current immunosuppressive medications, such as cyclosporine, methotrexate, and 
azathioprine, have associated long-term toxicities.  
Tralokinumab has already demonstrated efficacy in moderate-to-severe AD, and has shown an 
acceptable safety profile in AD, asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and 
in trials with healthy subjects. The evidence discussed in Section 5.2 further supports the 
hypothesis that tralokinumab may benefit individuals with AD. 
In clinical trials completed to date tralokinumab was well tolerated. A number of theoretical 
potential risks have been identified that are described in the current version of the 
Investigator’s Brochure, including hypersensitivity reactions, immune complex disease, 
severe infections, malignancies, and interference with reproductive function; measures are in 
place in this trial to protect participating subjects as follows: 

Close monitoring of subjects during the trial with trial visits every 2 weeks
during the treatment period (see the schedule of trial procedures in Section 4).

Close monitoring of subjects during the post-dosing period (at the first 3 IMP
dosing visits) as a precautionary measure against hypersensitivity reactions
(further details are given in Section 9.2).

Monitoring of subjects for clinical manifestations that may be associated with
the development of specific antibodies to tralokinumab (i.e., immune complex
disease).

Exclusion of subjects with untreated systemic helminth infestations or subjects
who have failed to respond to standard of care therapy. Neutralisation of IL-13
might theoretically cause a worsening of parasitic infestation, in particular,
prevention of expulsion of gastrointestinal worms (helminths) (20).

Exclusion of subjects with a history of tuberculosis requiring treatment within
12 months prior to the screening visit.
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
Exclusion of subjects with a history of a clinically significant infection
(defined as a systemic or serious skin infection requiring parenteral antibiotics,
antiviral, or anti-fungal medication; see Section 8.3) within 4 weeks prior to
baseline which, in the opinion of the investigator or sponsor’s medical expert,
may compromise the safety of the subject in the trial.
In conclusion, previous clinical experience with tralokinumab shows no major safety or 
tolerability concerns and appropriate measures have been instituted in this trial to protect 
subjects from possible risks that have been previously identified and to closely monitor each 
subject. The current risk/benefit ratio is favourable and supports the administration of 
tralokinumab in combination with the 2 vaccines for the purposes of achieving the objectives 
of this trial. 
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6 Trial objectives and endpoints 
Panel 3: Objectives and endpoints  
Objectives 
Endpoints 
Primary objective 
Primary endpoints 
To demonstrate non-inferiority of 
tralokinumab versus placebo with 
respect to immune responses to 
concomitantly administered 
vaccines. 

Positive anti-tetanus response at Week 16 (3-fold IgG
increase compared to Week 12 if IgG ≤1.0 IU/mL at
Week 12; or IgG ≥2.5 IU/mL if IgG >1.0 IU/mL at
Week 12)

Positive anti-meningococcal response at Week 16
(IgG ≥3.0 mcg/mL with at least a 3-fold increase
compared to Week 12)
Secondary objective 
Secondary endpoints 
To evaluate efficacy of 
tralokinumab concomitantly 
administered with vaccines.  

IGA score of 0 (clear) or 1 (almost clear) at Week 16

EASI75 at Week 16
Additional secondary objective 
Additional secondary endpoints 
To evaluate safety and tolerability 
of tralokinumab concomitantly 
administered with vaccines. 

Number of AEs

Presence of anti-drug antibodies
Other objectives 
Other endpoints 
To evaluate the efficacy of 
tralokinumab concomitantly 
administered with vaccines on 
severity and extent of AD and 
health-related quality of life. 

EASI50 at Week 16

EASI90 at Week 16

Change from baseline to Week 16 in EASI score

SCORAD75 at Week 16

SCORAD50 at Week 16

Change from baseline to Week 16 in SCORAD

Change from baseline to Week 16 in DLQI score

Change from baseline to Week 16 in EQ-5D-5L

Change from baseline to Week 16 in POEM

Change from baseline to Week 16 in HADS
AE, adverse event; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; EASI50, at 
least 50% reduction in EASI score; EASI75, at least 75% reduction in EASI score; EASI90, at least 90% 
reduction in EASI score; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 5 Level; HADS, Hospital 
Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; POEM, Patient-Oriented Eczema 
Measure; SAE, serious adverse event; SCORAD, Scoring Atopic Dermatitis; SCORAD50, at least 50% 
reduction in SCORAD score; SCORAD75, at least 75% reduction in SCORAD score. 
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7 Trial design 
7.1 Overall trial design 
Overview 
This is a randomised, double-blinded, placebo-controlled, phase 2 trial in adult subjects with 
moderate-to-severe AD. The primary objective of the trial is to demonstrate non-inferiority of 
tralokinumab versus placebo with respect to immune response to concomitantly administered 
Tdap and meningococcal vaccines. The trial will evaluate the percentage of subjects achieving 
a positive anti-tetanus response at Week 16 and a positive meningococcal response at 
Week 16.  
The trial will consist of a screening period of 2 to 6 weeks (Weeks -6/-2 to 0), a treatment 
period of 16 weeks (Weeks 0 to 16) and a 14-week off-treatment follow-up period for the 
assessment of safety (Weeks 16 to 30). The primary endpoints will be assessed at Week 16, 
and the final safety assessment will be conducted at Week 30 (end-of-trial visit). Eligible 
subjects may transfer to the open-label ECZTEND trial (LP0162-1337) at Week 16 or later. 
An overview of the different parts of the trial is provided in Panel 1. 
Screening period (Week -6 to Week 0) 
The screening period has a minimum duration of 2 weeks and a maximum duration of 
6 weeks and includes 1 or 2 screening visits. The exact duration of the screening period 
depends on the washout period defined by the exclusion criteria (Section 8.3). If a washout is 
not required, screening will be reduced to 2 weeks and only requires 1 visit (Week -2; visit 2), 
i.e., the 2 screening visits will be merged. Similarly, if only a 2-week wash-out is required,
screening visits 1 and 2 will be combined (Week -2; visit 2). All subjects will attend a 
screening visit 14 days before baseline (Week -2; visit 2). Eligibility will be assessed at the 
(first) screening visit and on Day 0 prior to randomisation. 
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. 
Treatment period (Week 0 to Week 16) 
Following the screening period, approximately 200 subjects will be randomised 1:1 to one of 
the following groups stratified by disease severity (IGA of 3 or 4): 

Tralokinumab 600 mg (4 mL) at Day 0 (hereinafter “baseline”), then 300 mg
(2 mL) Q2W.
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
Placebo (4 mL) at baseline, then placebo (2 mL) Q2W.
Subjects will each receive 1 dose of Tdap and meningococcal vaccines given intramuscularly 
at Week 12. 
The last administration of IMP will occur at Week 14. 
Safety follow-up period (Week 16 to Week 30) 
All subjects, except for those who transfer to the ECZTEND trial (LP0162-1337), will 
complete a full 14-week off-treatment follow-up period which includes 2 telephone contacts 
and an office visit at Week 30 for assessment of safety, PK, and ADA. 
Long-term extension trial 
Eligible subjects may be invited to enter an open-label, long-term extension trial conducted 
under a separate protocol (LP0162-1337, ECZTEND). Subjects who fulfil the eligibility 
criteria in the ECZTEND protocol can enter the trial at the Week 16 visit or up to 16 weeks 
after the last IMP injection in the present trial. Subjects who transfer to ECZTEND must have 
had their Week 16 visit under the current protocol (LP0162-1341). 
7.2 Number of subjects needed 
Assuming a screening failure rate of 25%, approximately 267 subjects will be screened and 
approximately 200 subjects will be randomly assigned to trial treatment. The statistical power 
considerations for this sample size (n=200) are described in Section 14.1. 
This trial will be conducted at approximately 40 sites in the US and Canada. The anticipated 
minimum number of randomised subjects per trial site is 4 and the maximum number of 
subjects per trial site is 25. 
7.3 End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the safety follow-up visit (Week 30) or if they have transferred to the 
ECZTEND trial (Section 7.1). 
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 endpoints will occur at Week 16. 
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7.4 Software 
CDISC controlled terminology version 22-Dec-2017 was used for definition of controlled 
terminology used throughout this protocol and will be used for statistical programming and 
output. SDTM version 1.4 and SDTM implementation guide version 3.2 will be used for data 
tabulations. 
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8 Trial population  
8.1 Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial, and can be expected to comply with the protocol. 
Hence, subjects are expected to complete wash-out of previous AD medications without 
experiencing intolerable worsening of AD symptoms during the screening period. 
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Panel 2. It will be recorded in the 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, as applicable.  
8.2 Inclusion criteria 
For inclusion into this trial, subjects must fulfil all of the following criteria: 
1. Written informed consent and any locally required authorisation obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations.
2. Age 18 to 54 years, both included, at screening.
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 or for whom topical
treatments are otherwise medically inadvisable (e.g., due to important side effects or
safety risks).

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.
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
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.

Important side effects or safety risks are those that outweigh the potential
treatment benefits and include intolerance to treatment, hypersensitivity
reactions, significant skin atrophy, and systemic effects, as assessed by the
investigator or by the subject’s treating physician.
6. AD involvement of ≥10% body surface area at screening and baseline (visit 3)
according to component A of SCORAD.
7. An EASI score of ≥12 at screening and 16 at baseline.
8. An IGA score of ≥3 at screening and at baseline.
9. Subjects must have applied a stable dose of emollient twice daily (or more, as needed)
for at least 14 days before randomisation.
10. Women of childbearing 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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8.3 Exclusion criteria 
Subjects must not enter the trial if any of the following exclusion criteria are fulfilled: 
1. Concurrent enrolment in another clinical trial where the subject is receiving an IMP.
2. Previous randomisation in tralokinumab trials.
3. Subjects for whom administration of the meningococcal vaccine provided in this trial
is contraindicated or medically inadvisable, according to local label of the vaccine.
4. Subjects for whom administration of the tetanus, diphtheria, and pertussis vaccine
provided in this trial is contraindicated or medically inadvisable, according to local
label of the vaccine.
5. Active dermatologic conditions that may confound the diagnosis of AD or would
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or
psoriasis.
6. Known active allergic or irritant contact dermatitis that is likely to interfere with the
assessment of severity of AD.
7. 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.
8. Treatment with the following medications within 4 weeks prior to randomisation:

Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate,
cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitors
etc.).

Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery)

Three or more bleach baths during any week within the 4 weeks.
9. Treatment with the following medications within 2 weeks prior to randomisation

TCS.

TCI.

Topical PDE-4 inhibitor.
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10. Receipt of any vaccine (except influenza virus vaccines) within 3 months prior to
screening, any meningococcal vaccine within 1 year prior to screening, or any
tetanus-, diphtheria-, or pertussis-containing vaccine within 5 years prior to screening,
documented or subject-reported.
11. Receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologic
agent, including dupilumab:

Any cell-depleting agents including but not limited to rituximab: within
6 months prior to randomisation, or until lymphocyte count returns to normal,
whichever is longer.

Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to
randomisation.
12. Receipt of any investigational non-biologic agent within 5 half-lives prior to
randomisation.
13. Receipt of blood products within 4 weeks prior to screening.
14. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or
hospitalisation during the trial period.
15. Known or suspected allergy or reaction to any component of the IMP formulations.
16. History of any active skin infection within 1 week prior to randomisation.
17. History of a clinically significant infection within 4 weeks prior to randomisation
which, in the opinion of the investigator or sponsor’s medical expert, may compromise
the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the
subject’s ability to participate in the trial. Clinically significant infections are defined
as:

a systemic infection.

a serious skin infection requiring parenteral (intravenous or intramuscular)
antibiotics, antiviral, or antifungal medication.
18. 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.
19. History of anaphylaxis following any biologic therapy.
20. History of immune complex disease.
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21. History of cancer:

Subjects who have had basal cell carcinoma, localised squamous cell
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided
that the subject is in remission and curative therapy was completed at least
12 months prior to the date informed consent was obtained.

Subjects who have had other malignancies are eligible provided that the
subject is in remission and curative therapy was completed at least 5 years
prior to the date informed consent was obtained.
22. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation
will be according to local guidelines as per local standard of care.
23. 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.
24. 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.
25. History of attempted suicide or is at significant risk of suicide (either in the opinion of
the investigator or defined as a “yes” to suicidal ideation questions no. 4 or 5 or
answering “yes” to suicidal behaviour on the Columbia-Suicide Severity Rating Scale
[C-SSRS] Screening version).
26. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic,
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological,
immunological, psychiatric, or major physical impairment that is not stable, in the
opinion of the investigator, and could:

Affect the safety of the subject throughout the trial.

Influence the findings of the trial or their interpretations.

Impede the subject’s ability to complete the entire duration of trial.
27. 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.
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28. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times
the ULN (upper limit of normal) at screening.
29. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb),
hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serology
at screening. Subjects with positive HBsAb may be randomised provided they are
hepatitis B vaccinated and have negative HBsAg and HBcAb.
30. 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.
31. Subjects who are legally institutionalised.
32. Pregnant, breastfeeding, or lactating women.
33. 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 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 
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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: 

Date of informed consent.

Demographics (date of birth, sex, ethnicity, race).

Reason for screen failure:

Failure to meet eligibility criteria.

Lost to follow-up.

Withdrawal by subject.

Other.

Date of screen failure.

Any AEs and SAEs.
In case of any SAEs, these must be followed-up as described in Section 13.7. 
Individuals who do not meet the criteria for participation in this trial (screening failures) may 
not be re-screened. However, if the reason for screening failure is administrative and not due 
to the subject failing to meet the eligibility criteria, re-screening may be permitted (this will 
require approval by the sponsor’s medical expert after thorough review of all data from the 
original screening visit in the eCRF. Individuals who are re-screened will get a new 
subject ID. 
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9 Treatments 
9.1 Description of IMP 
9.1.1 Tralokinumab and placebo 
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 syringe. Refer to Panel 4 for further details. 
Panel 4: Identification of IMPs (tralokinumab and placebo) 
Investigational 
medicinal 
product 
Dosage form and 
pack size 
Active ingredient and concentration 
Source 
Tralokinumab 
150 mg/mL solution 
for injection in an 
accessorised 
pre-filled syringe, 
1.0 mL fill volume. 
Formulated at a nominal concentration 
of 150 mg/mL in 50mM sodium 
acetate/acetic acid buffer, 85mM 
sodium chloride, 0.01% (w/v) PS-80, 
pH 5.5 solution. 
MedImmune 
Placebo 
Placebo solution for 
injection in an 
accessorised 
pre-filled syringe, 
1.0 mL fill volume. 
Placebo contains the same excipients, 
in the same concentration only lacking 
tralokinumab 
MedImmune 
The accessorised prefilled 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 prefilled syringe consists of a prefilled syringe sub-assembly (1 mL prefilled 
syringe barrel with a 1/2 inch 27 gauge thin wall staked in needle, rigid needle shield, plunger 
stopper) and a safety device. 
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9.1.2 Vaccines 
The Tdap and menigococcal vaccines will be packaged in individually numbered kits, each 
containing 1 vial or 1 pre-filled syringe. Refer to Panel 5 for further details 
Panel 5: Identification of IMPs (vaccines) 
Investigational 
medicinal 
product 
Dosage form and 
pack size 
Active ingredient and concentration 
Source 
Tdap vaccine 
Suspension for 
injection in 0.5 mL 
single-dose 
pre-filled syringes. 
Combined diphtheria, tetanus, acellular 
pertussis (adsorbed) vaccine. 
The vaccine contains diphtheria toxoid, 
tetanus toxoid, and 3 purified pertussis 
antigens (pertussis toxoid, filamentous 
haemagglutinin, and pertactin) adsorbed 
onto aluminum salts. The final vaccine is 
formulated in saline. 
Each 0.5 mL dose is formulated to 
contain 5 limit of flocculation (Lf) of 
tetanus toxoid, 2.5 Lf of diphtheria 
toxoid, 8 mcg of inactivated pertussis 
toxoid, 8 mcg of filamentous 
haemagglutinin, and 2.5 mcg of pertactin 
(69 kDa outer membrane protein). 
Commercially 
available; 
supplied by 
the CMO. 
Meningococcal 
vaccine 
Solution for 
injection in 0.5 mL 
single-dose vials. 
Meningococcal (groups A, C, Y and 
W-135) polysaccharide diphtheria toxoid 
conjugate vaccine. 
Each 0.5 mL dose of vaccine is 
formulated in sodium phosphate 
buffered isotonic sodium chloride 
solution to contain 4 mcg each of 
meningococcal A, C, Y and W-135 
polysaccharides conjugated to 
approximately 48 mcg of diphtheria 
toxoid protein carrier. 
Commercially 
available; 
supplied by 
the CMO. 
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9.2 Administration of IMP 
9.2.1 Administration of tralokinumab and placebo 
Dosing visits are shown in the schedule of trial procedures (Section 4). The last administration 
of IMP (tralokinumab/placebo) will occur at Week 14. 
The first day of dosing is considered Day 0 (visit 3). Each subject will receive 4 SC injections 
(each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total loading dose of 
600 mg tralokinumab or placebo (4.0 mL). 
At subsequent visits (Q2W) in the treatment period, each subject will receive 2 SC injections 
(each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total dose of 300 mg 
tralokinumab or placebo (2.0 mL).  
The IRT will assign the required kit numbers for each subject at each dispensing visit. 
IMP (tralokinumab/placebo) will be administered by a qualified, unblinded HCP (refer to 
Section 9.3.1 for blinding details). A minimum interval of 7 days is required between 2 dosing 
visits. IMP injections will be administered at the trial site when all assessments have been 
completed (Section 11.1). 
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.  
Although the suggested anatomical site for the tralokinumab/placebo injections at Week 12 is 
the right upper arm (refer to the injection rotation scheme described in the IMP manual), it 
should be noted that in this trial, the tralokinumab/placebo injections at Week 12 will be 
administered in one of the other allowed anatomical sites (anterior thigh or abdomen). This is 
due to the fact that the 2 vaccines administered at Week 12 must be injected intramuscularly 
in the deltoid area (Section 9.2.2). 
Further details on IMP administration are provided in an IMP manual. IMP administration 
must be carried out according to these instructions.  
After IMP administration 
For the first 3 IMP dosing visits (Day 0, Week 2, and Week 4), subjects will be monitored 
after IMP administration for immediate drug reactions for a minimum of 30 minutes with vital 
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signs taken at 30 minutes or until stable, whichever is later. Vital signs will be documented in 
the eCRF. 
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organization has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) (23). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5 (24). Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be 
immediately available at trial sites, and trial personnel should be trained to recognise and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase at the central laboratory. 
Conditions requiring IMP administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and IMP 
should not be administered until the rescheduled visit: 

The subject has an intercurrent illness, that in the opinion of the investigator
may compromise the safety of the subject in the trial (e.g., viral illnesses).

The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to
IMP administration.
If the trial visit cannot be rescheduled in order to maintain minimum of 7 days to subsequent 
dose, the sponsor’s medical expert should be contacted. 
9.2.2 Administration of vaccines 
At visit 9 (Week 12), subjects will each receive 1 dose of Tdap and meningococcal vaccines 
(refer to the schedule of trial procedures [Section 4]). The vaccines will be administered by 
trial staff on the same day the tralokinumab/placebo injections are administered; the vaccines 
will be given first, then tralokinumab/placebo will be given (see below). 
The 2 vaccines will be given intramuscularly in the deltoid muscle of the upper arms, 
1 vaccine in each arm. The injection site must be recorded in the source documents and 
recorded in the eCRF. 
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The subject will be kept under observation for 30 minutes following vaccination. After this 
observational period, the 2 tralokinumab/placebo injections will be given (Panel 7). Note that 
at Week 12, the tralokinumab/placebo injections will be given in the anterior thigh or 
abdomen. 
Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc., and medical 
equipment to treat acute anaphylactic reactions must be immediately available at trial sites, 
and trial personnel should be trained to recognise and respond to anaphylaxis according to 
local guidelines. 
Syncope can occur in association with administration of the vaccines. Procedures should be in 
place to prevent falling injury and to restore cerebral perfusion following syncope. 
For each vaccine, the IRT will assign the required kit number for each subject. 
Conditions requiring vaccine administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and IMP 
(vaccines) should not be administered until the rescheduled visit: 

The subject has an intercurrent illness, that in the opinion of the investigator
may compromise the safety of the subject in the trial (e.g., viral illnesses).

The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to
IMP administration.
If the trial visit cannot be rescheduled in order to maintain minimum of 7 days to subsequent 
dose, the sponsor’s medical expert should be contacted. 
9.3 Treatment assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised at baseline (Day 0) to receive treatment with 
either tralokinumab or placebo. Treatment assignment will be pre-planned according to a 
computer generated randomisation schedule in a 1:1 ratio (tralokinumab:placebo) stratified by 
baseline disease severity (IGA 3 or 4).  
IRT will be used to control randomisation and stratification factors, along with IMP supply 
chain and expiry tracking. 
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9.3.1 Blinding 
This is a double-blinded trial in which tralokinumab and placebo are visually distinct from 
each other. Neither the subject nor any of the investigator or LEO staff who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of the 
treatment received. The packaging and labelling of the IMPs will contain no evidence of their 
identity.  
Since tralokinumab and placebo are visually distinct and not matched for viscosity, IMP 
(tralokinumab/placebo) will be handled and administered by a qualified, unblinded HCP at the 
site who will not be involved in the management of trial subjects and who will not perform 
any of the assessments. 
In the event that the treatment allocation for a subject becomes known to the investigator or 
other study 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 CRA 
to determine whether any specific actions are required. 
The trial site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of IMP administration used to maintain the blind. 
Analysis of data per last subject’s Week 16 visit 
To support submission for marketing approval, an analysis of trial data up to and including 
visit 11 (Week 16) will be performed and will require unblinding of data. To perform this 
analysis, an analysis group consisting of a Medical Expert, a Statistician, a Statistical 
Programmer and a Medical Writer will be unblinded to individual subject treatment allocation 
following database lock for the 16-week data. All staff involved in the conduct of the trial will 
remain blinded to treatment allocation for the entire duration of the trial. This principle will be 
applied to all investigator staff and to staff employed by the sponsor except for those who are 
directly involved in the execution of the analysis.  
9.3.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
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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 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 (emollients) 
All subjects must use an additive-free, basic bland emollient twice daily (or more, as needed) 
for at least 14 days before randomisation. Subjects must continue their background emollient 
treatment throughout the trial (including safety follow-up). 
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, and escalate to systemic medications only for subjects who do not respond 
adequately after at least 14 days of topical treatment.   
Subjects who receive topical rescue treatment (TCS of any WHO class [see Appendix 8], or 
TCI) will continue treatment with IMP (tralokinumab/placebo) and will receive the vaccines. 
TCI may be used for rescue, but should be reserved for body areas where TCS is not 
advisable or on areas where continued treatment with TCS is considered unsafe. 
If a subject receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, 
etc.), IMP will be immediately discontinued (see Section 10.2.2, reasons for temporary 
discontinuation of IMP). After the treatment with these medications is completed, IMP may 
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be resumed if deemed appropriate by the investigator and sponsor’s medical expert, but not 
sooner than 5 half-lives after the last dose of systemic rescue medication.   
Investigators should make every attempt to conduct efficacy and safety assessments (for 
example disease severity scores [IGA and EASI], safety labs) immediately before 
administering any rescue treatment. An unscheduled visit may be used for this purpose, if 
necessary. 
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 30) must be recorded in the subject’s medical record and the eCRF 
along with details such as: 

Medication name.

Indication.

Start and stop date of administration (it will also be recorded if the medication
is ongoing).

Dosage information, including dose per administration, unit, and frequency.

Route of administration.

Dose form (cream, lotion, ointment, other); this is only required for topical
treatments.
Similarly, concurrent procedures must also be recorded in the subject’s medical record and the 
eCRF. The following data will be recorded: name of procedure, indication, body location 
(upper limb, lower limb, trunk, head), and start and stop date. Note: in this trial, only surgical 
procedures and procedures related to AD treatment (e.g., phototherapy or bleach baths) will 
be recorded. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
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Concomitant medication for conditions other than AD may be continued throughout the trial 
without any change in dosage whenever possible. 
The following concomitant medications related to AD treatment are permitted from screening 
through safety follow-up (Week 30): 

Oral antibiotics, antiviral, or antifungal therapy for skin infections as
appropriate.

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).

Oral anti-histamines.
9.7 Prohibited medication 
The medications listed in Panel 6 are prohibited during the trial. 
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Panel 6: Prohibited medication 
Medication 
Prohibited from 
Prohibited to 
Temporary 
discontinuation 
of IMP 
required 
Topical medications used for 
treatment of AD, including: 

TCS of any WHO class.

TCI.

PDE-4 inhibitors.
Week -2 
(2 weeks prior to 
randomisation) 
Week 16 
(end of treatment) 
No 
Use of UVA or UVB, psoralen + 
UVA (PUVA), other phototherapy, 
or tanning beds. 
Week -6 
(6 weeks prior to 
randomisation) 
Week 16 
(end of treatment) 
No 
Three or more bleach baths per 
week. 
Week -4 
(4 weeks prior to 
randomisation) 
Week 16 
(end of treatment) 
No 
Investigational agents other than 
tralokinumab. 
3 months or 5 half-lives1 
prior to randomisation 
Week 30 
(safety follow-up) 
Yes 
Immunoglobulin. 
3 months or 5 half-lives1 
prior to randomisation 
Week 30 
(safety follow-up) 
Yes 
Blood products. 
 4 weeks prior to 
screening 
Week 30 
(safety follow-up) 
Yes 
Systemic corticosteroids2 
Week -4 
(4 weeks prior to 
randomisation) 
Week 30 
(safety follow-up) 
Yes 
Systemic treatment for AD with an 
immunosuppressive or 
immunomodulating agent3. 
Week -4 
(4 weeks prior to 
randomisation) 
Week 30 
(safety follow-up) 
Yes 
Allergen immunotherapy. 
Randomisation 
Week 30 
(safety follow-up) 
Yes 
Vaccination of any kind (except 
influenza virus vaccines). 
3 months prior to 
screening 
Week 30 
(safety follow-up) 
Yes 
1)
Whichever is longer. For cell-depleting agents, the use is disallowed within 6 months of randomisation.
2)
Note: nasal and inhaled corticosteroids are allowed.
3)
Examples include cyclosporine, mycophenolate mofetil, azathioprine, methotrexate, Janus kinase inhibitors,
interferon-gamma, dupilumab, and other biologics.
AD, atopic dermatitis; IMP, investigational medicinal product; PDE-4, phosphodiesterase 4; TCI, topical 
calcineurin inhibitor; TCS, topical corticosteroid; UV, ultraviolet; WHO, World Health Organization. 
In case any prohibited treatments are used during the trial, they must be recorded as 
concomitant medication.  
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Refer to Section 9.5 for principles for use of rescue treatment and re-initiation of IMP after 
discontinuation of prohibited systemic rescue treatment. 
9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
Tralokinumab/placebo 
The IMP will be packaged in individually numbered kits, each containing 1 syringe 
(tralokinumab 150 mg or placebo). 
Primary and secondary packaging materials (syringe and outer carton, respectively) will be 
individually labelled. 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Label text will be translated into local languages, as required. The inner label 
will be in English. 
Vaccines 
The IMP will be packaged in individually numbered kits, each containing 1 vial 
(meningococcal vaccine) or 1 pre-filled syringe (Tdap vaccine). 
Primary and secondary packaging materials (vial/pre-filled syringe and outer carton, 
respectively) will be individually labelled. 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Label text will be translated into local languages, as required. The inner label 
will be in English. 
Trial sites will be provided with local labels of the vaccines. 
9.8.2 Storage of trial products  
Tralokinumab/placebo and vaccines 
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
The IMP must be stored at 2 to 8°C at the site. The temperature during storage must be 
monitored by a calibrated, stationary and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer.  
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A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately contact their CRA for further guidance: 

Temperature excursion upon receipt or during storage at the trial site.

Damaged kit upon receipt.

Damaged syringe.
Damaged IMP should be documented via IRT (refer to the IRT online manual for further 
details). Damaged IMP should not be used. 
9.8.3 Drug accountability 
Tralokinumab/placebo and vaccines 
The investigator is fully responsible for the IMPs (tralokinumab/placebo and vaccines) at the 
trial site and for maintaining adequate control of the IMPs and for documenting all 
transactions with them. 
An inventory must be kept of the IMP administered to each subject randomised in the trial. 
This inventory must be available for inspection during monitoring visits and will be checked 
by the CRA to ensure correct dispensing of the IMP. Full drug accountability will be 
performed in the IRT.  
The trial site will maintain trial kit cartons from used kits until reconciliation. The IMP must 
be fully accounted for by the CRA with the help of the unblinded HCP. Following 
reconciliation, the trial kit cartons from used kits may be discarded.  
All unused IMP supplied by the CMO on behalf of LEO will be returned to the CMO. Prior to 
their return, the IMP must be fully accounted for by the CRA with the help of site staff 
responsible for dispensing the IMP. Accountability must be documented in the IRT.  
Reporting in eCRF 
The following data will be recorded in the eCRF for tralokinumab/placebo: 

Date and time of IMP administration.

Site of IMP injection (upper arm, anterior thigh, or abdomen).
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
IMP kit numbers.
The following data will be recorded in the eCRF for the vaccines: 

Date and time of IMP administration.

Site of IMP injection (left upper arm, right upper arm, other site [will require a
comment]).

IMP kit numbers.
9.8.4 Treatment compliance 
All IMP injections (tralokinumab/placebo and vaccines) will be performed by site staff who 
will also keep the accountability records up to date. Any non-compliance (subject received 
partial dose; subject received no dose) and the reason for the non-compliace will be recorded 
in the eCRF. 
9.8.5 Trial product destruction 
Used pre-filled syringes (tralokinumab/placebo, Tdap vaccine) and meningococcal vaccine 
vials will be destroyed at the trial site provided the trial site has procedures in place for such 
IMP destruction; this requires that the trial site is able to issue a certificate of destruction. 
Trial sites which do not have such IMP destruction procedures in place will dispose used 
pre-filled syringes (tralokinumab/placebo, Tdap vaccine) in sharps bins which will be shipped 
to the CMO at the end of the trial together with used vaccine vials. 
Unused IMP (tralokinumab/placebo and vaccines), used pre-filled syringes, and used vaccine 
vials returned to the CMO will be destroyed by the CMO according to approved procedures 
and/or local requirements. 
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. 
9.10 Reporting product complaints 
Any defects or issues with the IMP (tralokinumab/placebo/vaccines) as well as any device 
deficiency (including malfunctions, use errors, and inadequate labelling) must be reported to 
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Global Pharmacovigilance, LEO on the trial specific (paper) Complaint Form within 3 days of 
first knowledge.  
Critical complaints (defined as any issue, defect, 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 Pharmacovigilance, 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 
Sections 13.3 and 13.4.  
Refer to the IRT online manual for information on how to update the kit status in the IRT. 
During the investigation of the product complaint, the device must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the device needs 
to be returned for further investigation or may be destroyed. 
Global Pharmacovigilance, 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 withdraw from the trial or permanently discontinue trial treatment 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.  
Discontinued subjects will not be replaced. 
10.2 IMP discontinuation rules 
10.2.1 Reasons for permanent discontinuation of IMP 
Subjects will be permanently discontinued from IMP in the event of: 

Anaphylactic reaction or other severe systemic reaction to IMP injection.

An AE that, in the opinion of the investigator or sponsor’s medical expert,
contraindicates further dosing.

Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the
cervix, or localised squamous or basal cell carcinoma of the skin.

Evidence of pregnancy.

Any infection that is opportunistic, such as active tuberculosis and other
infections whose nature or course may suggest an immuno-compromised
status.

Severe laboratory abnormalities:
o
ALT and/or AST values >3x ULN with total bilirubin >2x ULN
(unless elevated bilirubin is related to Gilbert-Meulengracht
Syndrome).
o
Confirmed AST and/or ALT >5x ULN (for more than 2 weeks).
Refer to Section 10.3 for details on the handling of subject discontinuation and to Panel 2 for 
assessments to be performed at an early termination visit for subjects who discontinue IMP 
permanently. 
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10.2.2 Reasons for temporary discontinuation of IMP 
IMP dosing may be temporarily suspended in the event of: 

Other intercurrent illnesses or major surgery.

An infection that requires parenteral treatment with antibiotic, antifungal,
antiviral, anti-parasitic, or anti-protozoal agents.

Treatment with some of the prohibited medications given in Panel 6
(medications requiring temporary discontinuation of IMP are highlighted in the
column ‘Temporary discontinuation of IMP required’).
IMP dosing may resume after the medication leading to suspension of IMP is discontinued. 
Refer to Section 9.5 for details regarding re-initiation of IMP after discontinuation of systemic 
rescue treatment. 
10.3 Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit and return to the trial site for 2 additional visits as indicated below (see the 
schedule of trial procedures [Section 4] for data to be collected at these 3 visits). The 
investigator will review any AEs which will be followed up according to Section 13.7, if the 
subject agrees. 
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend: 

Early termination visit.

Nominal Week 16 visit (16 weeks after randomisation).

Safety follow-up visit (16 weeks after last administration of IMP).
Refer to Section 11.10 for details on data to be recorded in the eCRF for subjects who 
permanently discontinue IMP. 
Withdrawal from trial 
Subjects who withdraw from the trial for any reason should attend an early termination visit 
as soon as possible after last administration of IMP (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. 
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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. 
Refer to Section 11.10 for details on data to be recorded in the eCRF for subjects who 
withdraw from the trial. 
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: 

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 and/or should continue in the trial.

Before a subject is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the subject (where possible,
3 telephone calls and, if necessary, a certified letter to the subject’s last known
mailing address or local equivalent methods). These contact attempts should be
documented in the subject’s medical record.

Should the subject continue to be unreachable, they will be considered to have
withdrawn from the trial with a primary reason of lost to follow-up.
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11Trial assessments and procedures 
11.1 Overview 
During this trial, subjects will attend a total of 11 or 12 scheduled visits at the trial site. The 
visits and procedures to be carried out at each visit are summarised in the schedule of trial 
procedures (Panel 2). Refer to Section 7.1 for further details on the trial design. 
Assessments and procedures at each trial visit should be performed in the order shown in 
Panel 7.  
Panel 7: Sequence of assessments and procedures 
*First component C, then component A and B; ***Week 12 only.
DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; EQ-5D-5L, EuroQoL 
5-Dimension Health Questionnaire 5-Level; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s
Global Assessment; IMP, investigational medicinal product; POEM, Patient Oriented Eczema Measure; 
SCORAD, Scoring Atopic Dermatitis. 
Patient-reported outcomes
1) DLQI
2) EQ-5D-5L
3) POEM
4) HADS
Investigator assessments
1) SCORAD*
2) IGA
3) EASI
Safety and laboratory assessments
Administration of IMP (vaccines)**
Administration of IMP 
(tralokinumab/placebo)
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Subjects participating in the trial will be under careful supervision of a dermatologist or 
allergist. Investigators must be experienced in treating AD and have documented experience 
and/or training in use of the assessments required by the protocol and must be either a 
physician, certified physician’s assistant, or advanced registered nurse practitioner. AEs must 
be assessed by medically qualified personnel (Section 13.2). 
The investigators performing the assessments must not be involved in the administration of 
IMP (tralokinumab/placebo). See Section 9.3.1 for further details.  
To reduce inter-rater variability, the same investigator should perform all the evaluations for a 
given subject throughout the entire trial period, if possible. 
During the course of the trial, subjects may need to be seen at unscheduled visits. The 
assessments to be performed at an unscheduled visit are left to the investigator’s discretion 
(could include any assessment performed at an early termination visit). Refer to the schedule 
of trial procedures (Panel 2) for assessments to be considered at an unscheduled visit. 
11.2 Assessments performed only at screening/baseline 
11.2.1 Demographics  
The following demographic data will be recorded: 

Age: date, month and year of birth. Where it is not allowed to collect the subject’s
full date of birth, only month and/or year of birth will be collected as per local
legislation. In these cases, the subject’s age in years will also be recorded.

Sex: female, male.

Race: American Indian or Alaska native, Asian (Japanese), Asian (others), black or
African American, native Hawaiian or other Pacific islander, white, other.

Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or
Latino.
11.2.2 Medical history 
Relevant past and concurrent medical history must be recorded and includes: 

Skin disease history: all past and current skin disease history including:
o
Alopecia
o
Vitiligo
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o
Herpes simplex

Atopy history:
o
Duration of AD in years
o
Previous AD treatments
o
Asthma
o
Food allergy
o
Hay fever
o
Allergic conjunctivitis
o
Atopic keratoconjunctivitis
o
Eczema herpeticum

Other medical and surgical history, including concurrent diagnoses.
Relevant medical history includes also diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
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. 
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 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 will be 
assessed according to the schedule of trial procedures (Section 4). 
11.2.5 Columbia-Suicide Severity Rating Scale 
The C-SSRS Screening version is a rater-administered instrument used to assess severity of 
suicidal ideation and suicidal behaviour through a series of simple, plain-language 
questions (25). The C-SSRS must be completed at the screening visit to check that exclusion 
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criterion no. 25 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 8). The IGA score 
will be assessed according to the schedule of trial procedures (Section 4). The assessment will 
be based on the condition of the disease at the time of evaluation and not in relation to the 
condition at a previous visit. The IGA is included in the efficacy assessment & C-SSRS 
manual. 
Panel 8: Investigator’s Global Assessment 
Score 
Disease severity 
Standard IGA scale 
IGA morphological descriptors 
0 
Clear 
No inflammatory signs of atopic 
dermatitis 
No erythema and no elevation 
(papulation/infiltration). 
1 
Almost clear 
Just perceptible erythema, and 
just perceptible 
papulation/infiltration 
Barely perceptible erythema 
and/or minimal lesion elevation 
(papulation/infiltration) that is not 
widespread. 
2 
Mild disease 
Mild erythema and mild 
papulation/infiltration 
Visibly detectable, light pink 
erythema and very slight elevation 
(papulation/infiltration). 
3 
Moderate 
disease 
Moderate erythema and 
moderate papulation/infiltration 
Dull red, clearly distinguishable 
erythema and clearly perceptible 
but not extensive elevation 
(papulation/infiltration). 
4 
Severe disease 
Severe erythema and severe 
papulation/infiltration 
Deep/dark red erythema, marked 
and extensive elevation 
(papulation/infiltration). 
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 (26). 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. 
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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 9. Briefly, the investigator will assess the severity of 4 AD disease characteristics 
(erythema, induration/papulation, excoriation, and lichenification) on the 4 body regions 
(head/neck, trunk, upper extremities, lower extremities); severity will be assessed according 
to the scale shown in Panel 10. For each body region, a severity sum score will be calculated 
which will be multiplied by an area score (Panel 10) and by a weighting factor. The EASI 
score equals the sum of the scores obtained for each body region (Panel 9). Refer to the 
efficacy assessment & C-SSRS manual for further details on these assessments. 
Panel 9: Calculation of the Eczema Area and Severity Index 
Body region 
Erythema 
Induration/ 
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.1 
Trunk 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.3 
Upper extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.2 
Lower extremities ( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.4 
The EASI score is the sum of the 4 body region scores 
(range 0-72) 
AS, area score; EASI, Eczema Area and Severity Index; SS, severity score. Modified from (27). 
Panel 10: EASI severity score scale and area score scale 
Severity score scale 
Area score scale 
0 
None/absent 
0 
0% affected area 
1 
Mild 
1 
1% to 9% affected area 
2 
Moderate 
2 
10% to 29% affected area 
3 
Severe 
3 
30% to 49% affected area 
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 
EASI, Eczema Area and Severity Index. 
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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). Refer to the efficacy assessment & C-SSRS manual for further details on these 
assessments.  
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 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, edema/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 
11.3.4.1 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 (29). 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 
according to the schedule of trial procedures in Section 4. It will be completed electronically 
on the device supplied to the trial site and is included in the investigator trial file. 
11.3.4.2 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 (30). 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 according to the schedule of trial procedures in 
Section 4. It will be completed electronically on the device supplied to the trial site and is 
included in the investigator trial file. 
11.3.4.3 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). Subjects will score how often they have experienced each symptom over the 
previous week on a 5-point categorical response scale (0 = ‘no days’; 1 = ‘1 to 2 days’; 2 = ‘3 
to 4 days’; 3 = ‘5 to 6’ days; 4 = ‘every day’). The total score is the sum of the 7 items (range 
0 to 28) and reflects disease-related morbidity; a high score is indicative of a worse disease 
severity. The POEM will be completed according to the schedule of trial procedures in 
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Section 4. It will be completed electronically on the device supplied to the trial site and is 
included in the investigator trial file. 
11.3.4.4 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 (32). 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) and is 
included in the investigator trial file. 
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 
position following at least 5 minutes of rest. 
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. 27).  
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 will 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. Clinically 
significant abnormal vital signs at the (first) screening visit will be documented as medical 
history in the eCRF. If an abnormal vital sign at any other visit than the first screening visit is 
considered by the investigator to be clinically significant, it will be reported as an AE in 
accordance with Section 13.3. Further, any clinically significant deterioration of a pre-existing 
condition as well as any new clinically significant sign, symptom or illness observed after 
screening will be reported as an AE in accordance with Section 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 
and 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. 27) 
Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s assessment of the result (‘normal’, ‘abnormal, not clinically significant’, 
‘abnormal, clinically significant’). If a physical examination was not performed, a reason 
should be given. 
Clinically significant abnormal physical examination findings at the (first) screening visit will 
be documented as medical history in the eCRF. If an abnormal physical examination finding 
at any other visit than the first screening visit is considered by the investigator to be clinically 
significant, it will be reported as an AE in accordance with Section 13.3. Further, any 
clinically significant deterioration of a pre-existing condition as well as any new clinically 
significant sign, symptom or illness observed after screening will be reported as an AE in 
accordance with Section 13.3. 
11.4.3 ECG 
A single 12-lead resting digital ECG will be recorded after the subject has been supine for at 
least 5 minutes at the visits indicated in the schedule of trial procedures (Section 4). 
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. At a minimum, date of ECG collection will be recorded in the source 
documents. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. 
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date. The investigator has the final decision on the clinical 
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significance of ECG abnormalities. If a result is abnormal at the screening visit and 
considered by the investigator to be clinically significant, it will be up to the investigator’s 
discretion if the subject should be enrolled into the trial (respecting exclusion criterion 
no. 27); 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. 
Test dummy transmissions will be undertaken prior to trial conduct to ensure that 
transmissions can be made and that date and time settings are correctly set. 
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’). If an ECG was not performed, a reason should be given. 
Clinically significant abnormal ECG findings at the (first) screening visit will be documented 
as medical history in the eCRF. If an abnormal ECG at any other visit than the first screening 
visit is considered by the investigator to be clinically significant, it will be reported as an AE 
in accordance with Section 13.3. Further, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom or illness 
observed after screening will be reported as an AE in accordance with Section 13.3. 
11.4.4 Pregnancy test 
A serum pregnancy test must be taken at the screening visit in female subjects of 
child-bearing potential as described in the schedule of trial procedures in Section 4. 
A urine pregnancy test (human chorionic gonadotropin; dipstick) must be performed at the 
trial site at baseline prior to randomisation in female subjects of child-bearing potential. The 
test must be repeated every 4 weeks as shown in the schedule of trial procedures in Section 4. 
The visit date and the outcome of the urine pregnancy test will be recorded in the eCRF 
(‘positive’, ‘negative’). 
Note that pregnant subjects must discontinue IMP immediately (Section 10.2.1). 
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11.4.5 Laboratory testing 
Samples for laboratory testing will be collected according to the schedule of trial procedures 
(Section 4). 
The following safety samples will be analysed by a central laboratory: chemistry, 
haematology, serology, and serum pregnancy (Panel 11).  
Urine samples will be tested at the trial site with a dipstick; if abnormal, a urine sample will 
be sent to the central laboratory for further analysis. 
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, destruction, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
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Panel 11: Clinical laboratory tests 
Chemistry 
Haematology 
Sodium 
Potassium 
Creatinine 
Urea nitrogen 
Calcium  
Alkaline phosphatase  
Aspartate aminotransferase  
Alanine aminotransferase  
Gamma glutamyl transferase 
Bilirubin1 
Lactate dehydrogenase  
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Triglycerides 
Glucose (non-fasting) 
Albumin 
Protein 
Tryptase2 
Erythrocytes 
Hematocrit 
Hemoglobin 
Erythrocyte mean corpuscular volume  
Erythrocyte mean corpuscular haemoglobin 
concentration  
Leukocytes  
Neutrophils   
Neutrophils/leukocytes 
Lymphocytes  
Lymphocytes/leukocytes 
Monocytes  
Monocytes/leukocytes 
Eosinophils  
Eosinophils/leukocytes 
Basophils  
Basophils/leukocytes 
Thrombocytes  
Serology 
Hepatitis B virus surface antigen4
Hepatitis B virus surface antibody4 
Hepatitis B virus core antibody4 
Hepatitis C virus antibody4 
HIV-1 antibody4
HIV-2 antibody4
Immunoglobulin E5 
Urinalysis3 
Serum pregnancy test4,6 
Protein 
Glucose 
Ketones 
Occult blood 
Leukocytes 
Nitrite 
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 (Section 9.2.1).
3)
Urine samples will be tested at the trial site (dipstick). In case of abnormal dipstick results, a urine sample
will be sent to the central laboratory for microscopic examination (leukocytes, erythrocytes, and casts).
4)
Measured at screening only.
5)
Not measured at screening.
6)
Only female subjects of child-bearing potential.
HDL, high density lipoprotein; HIV, human immunodeficiency virus; LDL, low density lipoprotein.
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The investigator must evaluate all results outside the reference range (‘clinically significant’ 
or ‘not clinically significant’) and sign and date. The signed and dated version will be filed 
with the investigator’s trial documentation. Clinically significant abnormal tests at baseline 
(Week 0) or later must be repeated to confirm the abnormality. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be enrolled into the trial (respecting 
exclusion criteria no. 27, 28, and 29). 
Reporting in eCRF 
At each visit, the site staff will record the following in the eCRF: Date and time of blood 
sample (or that a blood sample was not taken) and the investigator’s assessment of the results 
(‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’). In 
addition, the site staff will record in the eCRF if a urine sample was taken and the 
investigator’s assessment of the result (‘normal’, ‘abnormal’). 
Clinically significant abnormal laboratory findings at the (first) screening visit will be 
documented as medical history in the eCRF. If an abnormal laboratory finding at any other 
visit than the first screening visit is considered by the investigator to be clinically significant, 
it will be reported as an AE in accordance with Section 13.3. Further, any clinically significant 
deterioration of a pre-existing condition as well as any new clinically significant sign, 
symptom or illness observed after screening will be reported as an AE in accordance with 
Section 13.3. 
11.4.6 Anti-drug antibodies measurements 
Blood samples will be collected for determination of anti-tralokinumab antibody levels at 
pre-determined time points according to the schedule of trial procedures (Section 4).  
It will be recorded in the eCRF if the ADA sample was taken; if not, a reason will be 
provided. 
Collection, handling and shipment instructions for ADA blood samples are provided in a 
separate laboratory manual. 
Serum samples for determination of presence or absence of ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titre determination and will be analysed for the presence of neutralising 
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antibodies (nAB). Details of the analytical method used will be described in the ADA 
bioanalytical report. 
11.5 Assessment of vaccine responses 
Blood samples for assessment of vaccine-specific serum antibody responses will be collected 
at the time points specified in the schedule of trial procedures (Section 4). 
Collection, handling and shipment instructions for these blood samples are provided in a 
laboratory manual. 
The antibody response to Tdap vaccine will be assessed by measuring serum anti-tetanus IgG 
by an immunoassay. The antibody response to meningococcal vaccine will be assessed by 
measuring serum anti-meningococcal IgG by an immunoassay. 
Reports of serum antibody responses will be provided by the laboratory to the trial sites at the 
end of the trial. The investigator must sign and date these reports. 
Reporting in eCRF 
It will be recorded in the eCRF if the blood samples to assess vaccine response were taken; if 
not, a reason will be provided. 
11.6 Pharmacokinetic assessments 
Blood samples for PK assessments must 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. 
11.7 Pharmacodynamics and pharmacogenomics 
Not applicable. 
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11.8 Other assessments 
Not applicable. 
11.9 Estimate of total blood volume collected 
Blood samples will be drawn for chemistry, haematology, serology, PK, ADA, and 
vaccine-specific serum antibody responses. The total volume of blood to be drawn is 
approximately 150 mL which is less than the volume of blood drawn during a blood donation 
(approximately 500 mL). 
11.10 
End of trial 
An end-of-treatment form and an end-of-trial form will be compled in the eCRF for all 
randomised subjects, including subjects who permanently discontinue IMP and subjects who 
withdraw from trial (see Section 10.3 for early termination assessments). 
End-of-treatment form 
An end-of-treatment form will be completed when the subject has had their last 
administration of IMP. The following data will be recorded on this form: 

Date of last administration of IMP (tralokinumab/placebo).

Has the subject completed the treatment period (yes/no). If no, the primary
reason for permanent discontinuation of IMP must be recorded (lack of
efficacy, AE, withdrawal by subject, lost to follow-up, death, other).
The primary reason for permanent discontinuation of IMP must also be recorded in the 
medical records.  
End-of-trial form 
An end-of-trial form will be completed when the subject has had their last visit. The following 
data will be collected: 

Did the subject complete the trial (yes/no).

Has the subject been transferred to LP0162-1337 (yes/no). If yes, the site will
record the last visit the subject attended, including phone calls (Week 16,
Week 20, Week 24, Week 30, unscheduled visit).

Did the subject attend the nominal Week 16 visit (yes/no). If no, the primary
reason for not attending the visit must be recorded (lack of efficacy, AE,
withdrawal by subject, lost to follow-up, death, other).
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
Did the subject attend the safety follow-up visit (yes/no). If no, the primary
reason for not attending the visit must be recorded (lack of efficacy, AE,
withdrawal by subject, lost to follow-up, death, transferred to LP0162-1337,
other).

Date of last contact.

Primary reason for withdrawal from trial (lack of efficacy, adverse event,
withdrawal by subject, lost to follow-up, death, other).
11.11 
Storage of biological samples 
The samples analysed by the central laboratory (Panel 11) will be destroyed after analysis. 
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 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.  
Samples collected to assess the vaccine-specific antibody response will be retained for as long 
as the quality of the material permits evaluation but for no longer than 12 months after 
completion of the CTR. 
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12 Scientific rationale for trial design and appropriateness of assessments 
This trial will assess immunisation responses against 2 different vaccines (a combined 
diphtheria, tetanus, and acellular pertussis vaccine and a meningococcal vaccine) in adults 
with moderate-to-severe AD who are treated with tralokinumab, to ensure a broad assessment 
of immune competence in subjects treated with tralokinumab. 
Since concomitant administration of vaccines may affect the efficacy of tralokinumab in 
patients with AD, a placebo-controlled parallel group design has been chosen to evaluate the 
efficacy and safety of Q2W tralokinumab concomitantly administered with vaccines in the 
target patient population. 
The vaccines will be given after 12 weeks of tralokinumab/placebo treatment to ensure that 
the trial drug effect has reached near-steady state levels when the vaccines are administered. 
The vaccine responses will be analysed at Week 16 when the tralokinumab/placebo treatment 
schedule is complete. This allows an evaluation of the vaccine responses 4 weeks after 
vaccination which is the time span used to evaluate efficacy of these vaccine 
products (33, 34). 
The trial will evaluate the percentage of subjects achieving a positive anti-tetanus response at 
Week 16 (defined as a 3-fold IgG increase compared to Week 12 if IgG ≤1.0 IU/mL at 
Week 12; or IgG ≥2.5 IU/mL if IgG >1.0 IU/mL at Week 12) and a positive 
anti-meningococcal response at Week 16 (defined as IgG ≥3.0 mcg/mL with at least a 3-fold 
increase compared to Week 12). These response criteria were developed based on the criteria 
for positive vaccine response in the assays used for determining anti-tetanus and 
anti-meningococcal IgG concentrations. The anti-tetanus response definition takes into 
account that some subjects may have high pre-vaccination anti-tetanus IgG levels and may 
therefore not be able to elicit the same increase in anti-tetanus IgG levels as those with low 
pre-vaccination levels. 
The results should be generalisable to an adult population with AD. The age limit of 54 years 
is chosen to ensure that no subjects older than the meningococcal vaccine age limit of 
55 years are included. 
Subjects who do not achieve or lose clinical response will not be excluded from further 
participation in the trial. This approach has been chosen to increase the likelihood that 
subjects from the placebo arm will stay in the trial until administration of the vaccines 
(Week 12) and evaluation of the vaccine responses (Week 16). Subjects who complete the 
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Week 16 visit may be invited for the open-label, long-term extension trial conducted under a 
separate clinical trial protocol (ECZTEND). 
The clinical efficacy of tralokinumab treatment will be assessed by IGA, EASI, and 
SCORAD. IGA is a key instrument used in clinical trials to rate the severity of the subject’s 
global AD. EASI is a validated measure used in clinical practice and clinical trials to assess 
the severity and extent of AD (26). SCORAD is a validated tool to assess the extent and 
severity of AD lesions and subjective symptoms (28). 
The efficacy endpoints IGA score of 0 or 1 and EASI75 are recognised as important endpoints 
in clinical trials in AD by regulators in the US and EU, respectively.  
Data on antibodies against tralokinumab (ADAs) will be collected and the potential for 
immunogenicity will be evaluated until 16 weeks after the last dose of tralokinumab, to 
ensure adequate washout (approximately 5 times the half-life). The serum samples for 
determination of presence or absence ADA will be analysed using a validated bioanalytical 
method. 
Safety will be assessed using standard clinical methods of subject evaluations, such as AE 
monitoring, ECG, vital sign and clinical laboratory measurements. 
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13 Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1. 
Classification of AEs in terms of severity, causality and outcome is defined in Appendix 2. A 
causality assessment will be made for both tralokinumab/placebo and each of the vaccines. 
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 per Section 7.3). 
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 11.4.5 for principles for data entry in the eCRF. 
13.3 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event (it will 
also be recorded if the event is ongoing). In addition, it will be recorded if the AE started prior 
to first dose of IMP (tralokinumab/placebo); it will also be recorded if the AE started prior to 
administration of the vaccines. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 2. 
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Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded (dose not changed, dose reduced, dose increased, drug interrupted, drug withdrawn, 
not applicable, unknown). 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
13.4 Reporting of serious adverse events 
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. 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 IMP (tralokinumab/placebo), IMP (vaccines), IMP device, 
or 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 
Pharmacovigilance at LEO using the e-mail address or fax number below: 
Global Pharmacovigilance 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 Pharmacovigilance 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) of SAEs, as required by current applicable 
legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial (defined as per Section 7.3) should 
not be routinely sought or collected. However, such events should be reported to Global 
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Pharmacovigilance at LEO (see contact details above) if the investigator becomes aware of 
them. 
13.4.2 LEO reporting responsibilities 
Global Pharmacovigilance at LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference safety information documents for this clinical trial are:  

For the IMP (tralokinumab/placebo), the Investigator’s Brochure, edition 17
and subsequent updates must be used.

For the IMP (Tdap and meningococcal vaccines), the latest version of the
approved labelling in the US must be used.
Global Pharmacovigilance at LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IRB(s) will be notified of SAEs according to the current applicable legislation for the 
concerned countries.  
For all countries except the US, the following reporting requirements apply: all SAEs which 
are assessed as causally related to the IMP(s) by either the investigator or LEO (ICH E2A 
Guideline), and which are unexpected (Suspected, Unexpected Serious Adverse Reactions 
[SUSARs]), are subject to expedited reporting to regulatory authorities and IRB(s) 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. 
For the US, the following reporting requirements apply: all SAEs which are assessed as 
causally related to the IMPs by LEO (Guidance for Industry and Investigators - Safety 
Reporting Requirements for INDs and BA/BE Studies; Guidance for Clinical Investigators, 
Sponsors, and IRBs: Adverse Event Reporting to IRBs – Improving Human Subject 
Protection) and which are unexpected (Serious and Unexpected Suspected Adverse Reactions 
[IND safety report]) are subject to expedited reporting to regulatory authorities and IRB(s). 
Investigators will be notified of the evolving safety profile of the IMP on an ongoing basis. 
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13.5 Other events that require expedited reporting 
13.5.1 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 
Pharmacovigilance at LEO. Contact details are given in Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3). 
13.6 Reporting of other events 
13.6.1 Adverse events of special interest 
The events listed in Panel 12 are considered AESIs in this trial and will require additional 
details to be recorded in the eCRF. LEO may also request that the investigator forward test 
results, if applicable. An AESI may be serious (requiring expedited reporting, Section 13.4) or 
non-serious. 
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Panel 12: Adverse events of special interest 
Adverse event of special interest 
Additional information to be provided 
Eczema herpeticum 
Skin findings: 

Lesion type (papules, vesicles, crusts, eroded
pits, other).

Disseminated / localised.

Location (face, scalp, back, chest, upper
limb, lower limb, genitals).

Present in an area with visible eczema / no
visible eczema / present in areas with and
without eczema.

Monomorphic / polymorphic.
Confirmation of herpes simplex virus (not confirmed, 
PCR, viral culture, Tzanck, other) 
Malignancies diagnosed after 
randomisation, excluding basal cell 
carcinoma, localised squamous cell 
carcinoma of the skin, and 
carcinoma in situ of the cervix 

Histology report available

Oncology assessment available

Treatments (surgery, radiation,
chemotherapy, other)
Skin infections requiring systemic 
treatment 

Location (face, scalp, back, chest, upper
limb, lower limb, genitals)

Outcome of pathogenic skin swab (positive,
negative, not performed)
Conjunctivitis 

Aetiology (viral, bacterial, allergic,
unknown)

Bacterial culture outcome (for events with
bacterial aetiology)

Diagnosis confirmed by ophthalmologist
Keratoconjunctivitis 

Aetiology (infectious,  non-infectious, other,
unknown)

Bacterial culture outcome (for events with
bacterial aetiology)

Diagnosis confirmed by ophthalmologist
Keratitis 

Aetiology (infectious,  non-infectious, other,
unknown)

Bacterial culture outcome (for events with
bacterial aetiology)

Diagnosis of herpes simplex keratitis (for
events with viral aetiology)

Diagnosis confirmed by ophthalmologist
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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’ must be recorded on the AE form of the eCRF. In addition, AEs 
originating from overdose must be recorded as separate events. If an AE originating from an 
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 judgment 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 recorded on the AE form in the eCRF. In addition, AEs 
originating from a medication error must be recorded as separate events. If an 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 recorded on the AE form in the eCRF. In addition AEs originating 
from misuse must be recorded as separate events. If an 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. 
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The term ‘abuse’ must be recorded on the AE form in the eCRF. In addition, AEs originating 
from abuse must be recorded as separate events. 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 in accordance with Section 13.3. If the AE 
originating from aggravation of condition qualifies as an SAE, expedited reporting is required 
(Section 13.4). 
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 study or safety follow-up periods, for example chronic illnesses, the final 
outcome should be reported as ‘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. 
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.” (35). 
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. 
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 
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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 
A total of 200 subjects will be randomised 1:1 to tralokinumab or placebo to ensure that a 
sufficient number of subjects complete the trial and fulfil the definition of the per protocol set 
which is considered the primary analysis set for establishing non-inferiority between 
tralokinumab and placebo with regard to immune responses to vaccines.  
With 200 subjects in the FAS and 160 subjects anticipated in the per protocol set, the trial will 
provide 98% power to establish non-inferiority with regard to positive anti-tetanus response 
based on a one-sided significance level of 2.5%, assuming a response rate of 80% in both 
arms and a non-inferiority margin of -25%. Assuming a positive anti-meningococcal response 
rate of 80% in both arms, an IGA 0/1 response rate of 30% (tralokinumab) versus 10% 
(placebo), and an EASI75 response rate of 40% (tralokinumab) versus 15% (placebo), the 
trial will provide approximately 89% power for rejecting all 4 hypotheses related to the 
primary and secondary endpoints with each hypothesis tested at a one-sided 2.5% significance 
level. This evaluation is assuming no correlation between the primary and secondary 
endpoints.  
To our knowledge there is no established margin in the literature for showing non-inferiority 
with regard to immune responses to vaccines and the sample size of previously conducted 
trials with similar objective varies. In a similar type of trial with dupilumab versus placebo in 
adults with moderate-to-severe atopic dermatitis (36), a total of 194 subjects was randomised 
(1:1) to assess vaccine response but no non-inferiority margin was pre-specified. By contrast, 
in a trial with ixekizumab versus placebo in healthy subjects, a total of 84 subjects were 
randomised (1:1) and a non-inferiority margin of -40% was pre-specified (ClinicalTrials.gov 
NCT02543918). Similarly, a non-inferiority margin of -40% was pre-specified in a trial with 
secukinumab versus placebo in healthy subjects (37). 
On the basis of knowledge from previous trials, the proposed sample size and non-inferiority 
margin of -25% is considered appropriate to assess the primary objective of the trial.  
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomised to treatment are included in the FAS and will be analysed for efficacy 
up to Week 16. Exclusions from the FAS can be considered in special cases as described in 
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ICH E9, Section 5.2.1, Full Analysis Set. If it is decided to exclude a randomised subject from 
the FAS, a justification addressing ICH E9 will be given. 
A per protocol analysis set will be defined by excluding subjects from the FAS for whom any 
of the following conditions apply:  

Receive no treatment with the IMP (vaccines).

Provide no vaccine data at Week 16.

Are known to have taken the wrong IMP throughout the treatment period.

Do not fulfil the inclusion criteria no. 3, 6, 7, 8.

Meet exclusion criterion related to receipt of other vaccines (that is, exclusion
criterion no. 10).

Initiate systemic rescue treatment prior to Week 10 and who are still treated
with or exposed to systemic rescue treatment at Week 10 (that is, Week 10
[visit 8] occurs within 5 half-lives after the last dose of systemic rescue
medication).

Initiate systemic rescue treatment at Week 10 or later.

Have missed more than 2 doses of tralokinumab/placebo before vaccine
administration.

Have missed any of the last 2 doses of tralokinumab/placebo before vaccine
administration (that is, Weeks 8 and 10).
The per protocol analysis set will be used as primary analysis set for the vaccine antibody 
responses at Week 16 (primary endpoints; Panel 13). For the secondary endpoints (IGA 0/1 
and EASI75 at Week 16), the FAS analysis will be considered primary. 
A safety analysis set will be defined by excluding subjects from the FAS who received no 
treatment with IMP.  
Based on the above-mentioned rules, the inclusion/exclusion of subjects or subject data from 
the trial analysis sets will be documented in the statistical analysis plan update before 
breaking the randomisation code. 
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14.3 Statistical analysis 
14.3.1 Disposition of subjects 
For all randomised subjects the reasons for permanent discontinuation of IMP and for leaving 
the trial will be presented by treatment group.  
14.3.2 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects and the per protocol analysis set. The presentations will be overall and 
by treatment group. Presentations of age, sex, ethnicity, and race will also be given by 
baseline disease severity (IGA 3 or 4). 
Demographics include age, sex, race, and ethnicity. Other baseline characteristics include vital 
signs (including height, weight, body mass index), duration of AD, concurrent diagnoses 
(from medical history and indications for concomitant medication), concomitant medication, 
and previous AD treatments.  
14.3.3 Exposure and treatment compliance 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group. 
Adherence 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. 
Adherence will be presented for the safety analysis set for each treatment group.  
14.3.4 Multiple testing procedure 
The primary and secondary endpoints will be evaluated hierarchically in the order shown in 
Panel 13. 
The hypothesis relating to a specific endpoint cannot be rejected unless all hypotheses relating 
to endpoints earlier in the hierarchy are also rejected.  
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Panel 13: Testing procedure for primary and secondary endpoints 
EASI, Eczema Area and Severity Index; EASI75, at least 75% reduction in EASI score; IGA, Investigator’s 
Global Assessment. 
Non-inferiority hypothesis to be tested for the primary endpoints:  H0: tralo-placebo  -25% 
versus H1:tralo -placebo > -25%, 
Superiority hypothesis to be tested for the secondary endpoints:  H0: tralo-placebo  0% versus 
H1:tralo -placebo > 0%,  
where tralo and placebo denotes the response rate with tralokinumab and placebo, respectively. 
All hypotheses will be tested at a one-sided 2.5% significance level. For the non-inferiority 
hypotheses, the null hypothesis will be rejected if the two-sided 95% CI for the difference in 
immune response rate lies entirely to the right of the non-inferiority limit (-25%). For the 
superiority hypotheses, a two-sided 95% CI for the difference in response rates and a 
corresponding two-sided p-value will be calculated; the null hypothesis will be rejected if the 
p-value is smaller than 5% and the point estimate is in favour of the alternative hypothesis
(that is, greater than 0). 
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14.3.5 Analysis of primary endpoints 
Positive anti-tetanus response at Week 16 (3-fold IgG increase compared to Week 12 if 
IgG ≤1.0 IU/mL at Week 12; or IgG ≥2.5 IU/mL if IgG >1.0 IU/mL at Week 12) and positive 
anti-meningococcal response at Week 16 (IgG ≥3.0 mcg/mL with at least a 3-fold increase 
compared to Week 12) are binary endpoints. The difference in response rates between 
treatment groups will be calculated using the Mantel-Haenszel estimate of the risk difference 
stratified by baseline disease severity (IGA 3 or 4) together with the 95% CI. Non-inferiority 
of tralokinumab will be demonstrated if the lower limit of the 95% CI is greater than -25%. 
The primary endpoints will be analysed for FAS and the per protocol set; the per protocol 
analysis will be considered the primary analysis. Analyses will be based on observed data; 
hence, missing data will not be imputed. 
14.3.6 Analysis of secondary endpoints 
14.3.6.1 Overview of estimand framework 
Three estimands addressing different aspects of the trial objectives will be defined: 

Primary estimand: ‘composite’.

Secondary estimand: ‘hypothetical’.

Tertiary estimand: ‘treatment policy’.
The applied estimands incorporate 2 main types of events that influence how the treatment 
effects are estimated: 

Initiation of rescue medication: Some of the estimands use the initiation of rescue
medication as an event that modifies the applied value of an endpoint, e.g. by defining a
subject receiving rescue medication as a non-responder.

Permanent discontinuation of IMP: This event occurs when a subject is permanently
withdrawn from the treatment or the trial as described in Section 10.3. This can either
happen at his/her own initiative or at the investigator’s discretion. The event also includes
the possibility of a subject being lost to follow-up. The timing of the event is defined as
the date of the early termination visit for withdrawn subjects or – in the case of a subject
lost to follow-up – the date of the last known visit to the clinic. As for the rescue
medication, the event type is used to modify an applied endpoint value.
All analyses will be based on the FAS unless otherwise specified. 
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14.3.6.2 Primary estimand: ‘composite’ 
The primary estimand for the first 2 secondary endpoints will be: 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
achieved without rescue medication, regardless of treatment discontinuation.
The primary estimand assesses the expected difference in response rates (defined as response 
obtained without initiation of any rescue medication) after 16 weeks, resulting from initiation 
of a treatment regimen with tralokinumab compared to a treatment regimen with placebo.  
Primary analysis for the primary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Subjects who prior to the Week 16 visit have 
received rescue medication will be considered non-responders, reflecting an assumption that 
initiation of rescue medication indicates failure of the randomised treatment to achieve 
response, and that a (possible) observed positive response after initiation of rescue medication 
is not attributable to the randomised treatment. Missing data for subjects who did not attend 
the Week 16 visit and where rescue medication has not been used prior to Week 16, will be 
imputed as non-responders.  
The difference in response rates between treatment groups will be analysed using the 
Cochran-Mantel-Haenszel test stratified by baseline disease severity (IGA 3 or 4). The 
treatment estimate and the corresponding 95% CI will be presented. The null hypothesis of no 
difference in response rates between tralokinumab and placebo will be tested against the 
2-sided alternative that there is a difference.
Sensitivity analyses for the primary estimand 
Two sensitivity analyses are specified for the primary estimand. In both cases the same 
Cochran-Mantel-Haenszel test as used for the primary analysis will be applied including 
stratification by baseline disease severity. 
The purpose of the analyses is to assess the robustness of results of the primary analysis with 
respect to the retrieved data at Week 16 and assumptions regarding missing Week 16 data.  
Sensitivity analysis 1: All subjects who have permanently discontinued IMP prior to Week 16 
will be imputed as non-responders, even if no rescue medication has been used. This is to 
reflect a situation where retrieved efficacy data and concomitant medications could be 
registered less accurately for subjects who have discontinued treatment.  
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Sensitivity analysis 2: Rather than imputing all subjects who do not attend the Week 16 visit 
and where rescue medication has not been used as non-responders, the following approach 
will be applied. If subjects have withdrawn due to an AE or due to lack of efficacy, they are 
still considered non-responders. Data missing for other reasons will be imputed using LOCF, 
hereby assuming that the last value is a more reliable estimate of the missing response (than a 
non-response). 
Supplementary analysis 
The primary analysis of the primary estimand is repeated based on the per protocol analysis 
set. 
14.3.6.3 Secondary estimand: ‘hypothetical’ 
The secondary estimand for the first 2 secondary endpoints will be: 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
if all subjects adhered to the treatment regimen in the sense that they did not
discontinue IMP permanently and no rescue medication was made available
before Week 16.
The secondary estimand assesses the expected difference in response rates achieved when 
adhering to the treatment regimen tralokinumab with no rescue medication as compared to a 
treatment regimen with placebo with no rescue medication.  
Primary analysis of the secondary estimand 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be applied in the analysis.  
IGA 0/1 responder imputation  
Imputation of missing binary IGA 0/1 data at Week 16 will be done using multiple 
imputations of the underlying 5-point IGA values within the 2 groups defined according to 
randomised treatment arm assuming that data is missing at random within each arm. 
1. In each group, intermittent missing values will be imputed using LOCF to obtain a
monotone missing data pattern.
2. An ordinal logistic regression model assuming proportional odds will be fitted to the
IGA value at Week 2. The model will include baseline disease severity (IGA 3 or 4) as
factor. 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=13827641).
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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 baseline disease severity (IGA 3 or 4)
together with the IGA value at Week 2 as factors. The estimated parameters, and their
variances, will be used to impute missing values at Week 4.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the IGA values from the 2 preceding visits will
be included as factors in addition to baseline disease severity. The missing binary IGA 
0/1 response at Week 16 will be derived from the corresponding underlying imputed
IGA value.
EASI75 responder imputation 
Imputation of missing binary EASI75 data at Week 16 will be done using multiple 
imputations of the underlying 72-point EASI values within the 2 groups defined according to 
randomised treatment arm assuming that data is missing at random within each arm.  
1. Intermittent missing values will be imputed in each group using a Markov Chain
Monte Carlo method to obtain a monotone missing data pattern and 100 copies of the
dataset will be generated (seed=45624941).
2. An ANCOVA model is fitted to the EASI value at Week 2. The model will include
effects of baseline EASI as a covariate, and baseline disease severity (IGA 3 or 4) as a
factor. The estimated parameters, and their variances, will be used to impute missing
EASI values at Week 2. 100 copies of the dataset will be generated (seed=11109941).
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 baseline disease
severity (IGA 3 or 4) as a factor together with the EASI value at Week 2 as covariate.
The estimated parameters, and their variances, will be used to impute missing values
at Week 4.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the EASI values from the preceding 2 visits
will be included as covariates in addition to baseline EASI as a covariate and baseline
disease severity as a factor. The missing binary EASI75 response at Week 16 will be
derived from the corresponding underlying imputed EASI value.
Analysis of Week 16 response 
For each of the 100 complete data sets, the difference in response rates (either the IGA 0/1 or 
the EASI75) between treatment groups will be analysed using the Cochran-Mantel-Haenszel 
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test stratified by baseline disease severity (IGA 3 or 4). The estimates and standard errors 
from the 100 analyses will be pooled to one estimated treatment difference and associated 
standard error using Rubin’s rule to draw inference. From these pooled estimates, the 95% CI 
for the treatment difference will be calculated.  
Sensitivity analysis for the secondary estimand 
Rather than assuming that observations are missing at random within each treatment arm, it is 
assumed that missing data from subjects who discontinue IMP permanently/receive rescue 
medication in the tralokinumab arm will resemble missing data from subjects from the 
placebo arm who do not discontinue IMP permanently/receive rescue medication. The 
underlying assumption is that the effect of tralokinumab following rescue medication or 
permanent treatment discontinuation is similar to the effect of placebo. It should be noticed 
that this assumption is pronouncedly conservative in favour of placebo as it tends to minimise 
the differences between arms.  
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab arm as well as the placebo arm will be imputed from 
observed data in the placebo arm (using a so-called copy-reference approach). With this 
exemption, the stepwise multiple imputation procedure and subsequent analysis will be 
conducted in the same way as specified for the primary analysis of the secondary estimand. 
14.3.6.4 Tertiary estimand: ‘treatment policy’ 
The tertiary estimand for the first 2 secondary endpoints will be: 

Treatment difference in response rate after 16 weeks between tralokinumab
and placebo, regardless of rescue medication and treatment discontinuation.
The tertiary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab and additional rescue medication as 
compared to a treatment regimen with placebo and additional rescue medication.  
Primary analysis for the tertiary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued treatment prior to 
Week 16 will be included in the analysis.  
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment arm and whether or not subjects have 
permanently discontinued IMP prior to Week 16. Within a given treatment arm, retrieved data 
from discontinued subjects will be used to impute missing data for other discontinued 
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subjects. Similarly, the available data from not discontinued subjects will be used to impute 
data for such patients where the Week 16 value is missing.  
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way as specified for the primary analysis of the secondary estimand. 
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16 will be too small to facilitate the same imputation model as mentioned above. 
Consequently, an imputation model with only baseline effects (IGA as a factor and EASI as a 
covariate [only for EASI75]) will be applied for discontinued subjects. Some factors may 
have to be omitted, depending on the observed data, e.g. if retrieved subjects all have the 
same baseline severity. 
The imputed datasets will be analysed in the same way as specified for the primary analysis of 
the secondary estimand. 
Sensitivity analyses for the tertiary estimand 
Rather than imputing Week 16 data as described in the primary analysis of the tertiary 
estimand, missing observations will be imputed as non-responders. The assumption reflects 
that discontinued subjects without retrieved data at Week 16 are more likely to be 
non-responders than resembling discontinued subjects with retrieved data at Week 16. 
14.3.7 Analysis of other endpoints 
To support the secondary endpoints, EASI50 at Week 16, EASI90 at Week 16, SCORAD75 at 
Week 16, and SCORAD50 at Week 16 will be analysed and presented for the FAS. These 
4 endpoints will be analysed as described for the primary analysis of the primary estimand for 
the secondary efficacy endpoints. 
The change from baseline to Week 16 in EASI, SCORAD, DLQI, EQ-5D-5L, POEM, and 
HADS will be analysed using a repeated measurements model on the post baseline responses 
up to Week 16 with an unstructured covariance matrix, Kenward-Roger approximation to 
estimate denominator degrees of freedom, and the mean modelled as follows (shown for 
change from baseline in SCORAD): 
Change from baseline in SCORAD 
= treatment × visit + baseline SCORAD × visit + baseline IGA 
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This model assumes that data is missing at random within each treatment arm. The estimates 
will be presented with nominal p-values and 95% CI at each visit. Data collected after 
permanent discontinuation of IMP or after initiation of rescue medication will not be included 
in the analysis. All analyses will be based on the FAS. 
14.3.8 Analysis of safety 
The analyses of safety will be based on the safety analysis sets. 
14.3.8.1 Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred terms and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised, however, all AEs recorded during the course of 
the trial will be included in the subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP or if started before the first use of IMP 
(applicable if subject had a wash-out) and worsened in severity thereafter. The tabulations 
described in the following will only include the treatment-emergent events. In each of the 
tabulations, AEs will be defined by MedDRA preferred terms within primary SOC. 
An overall summary of the number of treatment-emergent AEs, number (percentage) of 
subjects with any treatment-emergent AEs, SAEs, deaths, premature discontinuations from the 
trial due to AEs, treatment-related AEs and severe AEs will be presented. 
The number of AEs and the number of subjects experiencing each type of AE will be 
tabulated by treatment group. The percentage of subjects with AEs 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 (tralokinumab/placebo) 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). 
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The causal relationship to IMP (each vaccine) 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 and a narrative for each will be given. AEs 
leading to withdrawal from trial will be listed.  
14.3.8.2 Vital signs 
The change in vital signs (blood pressure, heart rate, body temperature) from baseline to each 
visit will be summarised by visit and treatment group as mean, standard deviation, median, 
minimum and maximum values for the safety analysis set. 
14.3.8.3 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit and treatment group as mean, standard deviation, median, minimum and 
maximum values for the safety analysis set. 
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at end of treatment. Subjects with 
laboratory parameters outside the reference range will be listed. 
14.3.8.4 Pharmacokinetics 
 All the PK samples in the trial are trough samples. The Ctrough concentration will be listed by 
treatment group and descriptive statistics will be provided.  
Ctrough values from subjects with positive ADA/nAb will be compared to values from subject 
with negative ADA/nAb if data permits.  
The PK data will be merged with those from other clinical trials with tralokinumab for a 
population-based meta-analysis. Results of the meta-analysis will be presented in a separate 
pharmacometrics report outside of the CTR. 
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14.3.8.5 Anti-drug antibodies 
ADA status (positive versus negative) at each visit will be summarised by treatment group. If 
considered relevant, descriptive statistics including number of subjects, mean, standard 
deviation, median, and range of the actual ADA titres by treatment group and visit will be 
provided. The ADA status across the trial for each subject (positive versus negative) will also 
be classified and summarised by treatment group.  
The association of ADA status across the trial (positive versus negative) with AEs/SAEs may 
be evaluated. In addition, the association of ADA titres (≥ median titre in positive subjects 
versus < median titre) with AE/SAEs may be evaluated for ADA-positive treated subjects 
only. The ADA-positive subjects across the trial may also be divided into persistent positive 
versus transient positive. A subject will be considered as persistent positive if he/she has 
positive ADA for at least 2 consecutive visits with ADA assessment. Otherwise, the subject 
will be considered as transient ADA positive. The associations between ADA and AE/SAEs 
may be summarised for both persistent positive subjects versus transient positives subjects.  
For subjects who develop ADA, the IGA score and change in EASI at end of treatment will be 
listed.  
Evaluations of nAB will be conducted on those serum samples that test positive for ADA. The 
test sample is deemed positive or negative for the presence of nAb to tralokinumab relative to 
a pre-determined (in assay validation), statistically derived cut point.  
For ADA, all subjects with titre information will be listed. 
14.3.9 Interim analysis 
No interim analysis is planned. 
14.3.10 
General principles 
All hypotheses will be tested at a one-sided 2.5% significance level. This will be done by 
calculating the two-sided 95% CIs and p-value (note that for the non-inferiority hypotheses a 
different approach will be used). 
An observed-cases approach will be used for tabulations of data by visit (i.e., involving only 
those subjects who attended each specific visit). 
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Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation, minimum and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan update will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan update and/or in 
the CTR dependent on the type of deviation.  
14.3.11 
Handling of missing values 
Procedures for handling of missing values are included under the sections describing the 
individual analyses. 
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15 References 
1. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and
other health and demographic factors: a US population-based study. J Allergy Clin
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2. Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A population
based survey of eczema prevalence in the United States. Dermatitis. 2007;18(2):82-91.
3. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-1494.
4. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023)1109-1122.
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is associated with a decrement in health-related quality of life. Int J Dermatol.
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6. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in
lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295(11):459-464.
7. Omori-Miyake M, Yamashita M, Tsunemi Y, Kawashima M, Yagi J. In vitro assessment of
IL-4- or IL-13-mediated changes in the structural components of keratinocytes in mice
and humans. J Invest Dermatol. 2014;134(5):1342-1350.
8. Aleksza M, Lukács A, Antal-Szalmás P, Hunyadi J, Szegedi A. Increased frequency of
intracellular interleukin (IL)-13 and IL-10, but not IL-4, expressing CD4+ and CD8+
peripheral T cells of patients with atopic dermatitis. Br J Dermatol. 2002;147(6):1135-
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9. Purwar R, Werfel T, Wittmann M. IL-13-stimulated human keratinocytes preferentially
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2006;126(5):1043-1051.
10. Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T. TRPAA1-dependent pruritus in
IL-13-induced chronic atopic dermatitis. J Immunol. 2013;191(11):5371-5382.
11. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of
interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest
Dermatol. 2009;129:742-751.
12. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two
phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016 Dec
15;375(24):2335-2348.
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13. May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. Preclinical
development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe
uncontrolled asthma. Br J Pharmacol. 2012;166(1):177-193.
14. Thom G, Minter R. Optimization of CAT-354, a therapeutic antibody directed against
interleukin-13, using ribosome display. Methods Mol Biol. 2012;805:393-401.
15. Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME. Inhibition of
human interleukin-13-induced respiratory and oesophageal inflammation by anti-human
interleukin-13 antibody (CAT-354). Clin Exp Allergy. 2005;35(8):1096-1103.
16. Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin
Immunol. 2003;111(4):677-690.
17. Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of
atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune
response genes. J Immunol. 2003;171(6):3262-3269.
18. Looney RJ, Diamond B, Holers VM, Levesque M, Moreland L, Nahm M, et al.
Guidelines for assessing immunocompetency in clinical trials for autoimmune diseases.
Clin Immunol. 2007;123(3):235-243.
19. Moffat GJ, Davies R, Kwon G, Retter MW, Chellman GJ, Kanapuram S, et al.
Investigation of maternal and fetal exposure to an IgG2 monoclonal antibody following
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Reprod Toxicol. 2014;48:132-137.
20. Bancroft AJ, Artis D, Donaldson DD, Sypek JP, Grencis RK. Gastrointestinal nematode
expulsion in IL-4 knockout mice is IL-13 dependent.
Eur J Immunol. 2000;30(7):2083-2091.
21. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol.
1980;92(Suppl):44-47.
22. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement:
updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.
23. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised
nomenclature for allergy for global use: report of the Nomenclature Review Committee of
the World Allergy Organization, October 2003.
J Allergy Clin Immunol. 2004;113(5):832-836.
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24. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et
al. Second symposium on the definition and management of anaphylaxis: Summary
report - Second National Institute of Allergy and Infectious Diseases/Food Allergy and
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397.
25. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;
164(7):1035-1043.
26. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and
severity index (EASI): assessment of reliability in atopic dermatitis.
Exp Dermatol. 2001;10(1):11-18.
27. Harmonising Outcome Measures for Eczema (HOME). EASI scoring table for aged 8 and
over [homepage on the Internet]. Available from:
http://www.nottingham.ac.uk/homeforeczema/index.aspx [cited 21-Nov-2016].
28. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the
SCORAD index. Consensus report of the European task force on atopic dermatitis.
Dermatology. 1993;186(1):23-31.
29. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
30. Greiner W, Weijnen T, Nieuwenhuizen M, Oppe S, Badia X, Busschbach J, et al. A single
European currency for EQ-5D health states. Results from a six-country study. Eur J Health
Econ. 2003;4(3):222-231.
31. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development
and initial validation of a new tool for measuring atopic eczema severity from the patients’ 
perspective. Arch Dermatol. 2004;140(12):1513-1519.
32. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand.
1983;67(6):361-370.
33. Menactra® Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria
Toxoid Conjugate Vaccine [package insert]. Swiftwater, Pennsylvania, US: Sanofi
Pasteur, Inc. 2017 [version 0.18 dated 16-Sep-2016; cited 14-Feb-2018]. Available from
the US FDA’s website.
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34. Boostrix® (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine,
Adsorbed). [package insert]. Research Triangel Park, North Carolina: GlaxoSmithKline
[cited 14-Feb-2018]. Available from the US FDA’s website.
35. European Parliament and Council of The European Union. Directive 2001/20/EC of
4 April 2001 on the approximation of the laws, regulations and administrative provisions
of the Member States relating to the implementation of good clinical practice in the
conduct of clinical trials on medicinal products for human use [2001], article 10.
36. Blauvelt A, Simpson E, Wu R, Akinlade B, Graham N, Pirozzi G, et al. The effect of
dupilumab on vaccine antibody responses in adults with moderate-to-severe atopic
dermatitis; a randomized, double-blind, placebo-controlled trial. Allergy.
2016;71(Suppl.102):95. DOI: 10.1111/all.12971.
37. Chioato A, Noseda E, Stevens M, Gaitatzis N, Kleinschmidt A, Picaud H. Treatment with
the interleukin-17A-blocking antibody secukinumab does not interfere with the efficacy of
influenza and meningococcal vaccinations in healthy subjects: results of an open-label,
parallel-group, randomized single-center study.
Clin Vaccine Immunol. 2012;19(10):1597-1602.
38. World Medical Association 2013. Declaration of Helsinki – ethical principles for medical
research involving human subjects. 7th (Fortaleza) amendment.
39. International Ethical Guidelines for Health-related Research Involving Humans, Fourth
Edition. Geneva. Council for International Organizations of Medical Sciences (CIOMS);
2016.
40. International Council for Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use (ICH) 2016. Integrated addendum to ICH E6(R1): Guideline for good
clinical practice E6(R2).
41. World Health Organization. WHO model prescribing information: drugs used in skin
diseases. Geneva. 1997.
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Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)). 
This definition includes: 

Accidental injuries.

Events related to trial procedures.

Reasons for any unfavourable and unplanned change in medication (drug
and/or dose).

Clinically significant worsening of pre-existing conditions.

Reasons for admission to hospital or surgical procedures unless these were
planned before the subject consented to trial participation.

AEs commonly observed and AEs anticipated based on the pharmacological
effect of the IMP.

Any laboratory abnormality assessed as clinically significant by the
investigator (see Section 11.4.5).
Serious adverse event definition 
An SAE is any untoward medical occurrence that 

Results in death.

Is life-threatening.
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
Requires inpatient hospitalisation or prolongation of existing hospitalisation.
Planned hospitalisation or planned prolonged hospitalisation do not fulfil the
criteria for being an SAE but should be documented in the subject’s medical
record.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.
or 

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 broncospasm, blood dyscrasias and convulsions
that do not result in hospitalisation, development of drug dependency or drug
abuse.
Adverse events of special interest are described in Section 13.6.1. 
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Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP (tralokinumab/placebo) should be 
described in terms of probable, possible, or not related according to the investigator’s clinical 
judgement. The categories are defined below. Similarly, the causal relationship to each of the 
vaccines should be evaluated using the categories defined below (that is, probably related, 
possibly related, or not related). 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
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Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Does not reappear or worsen upon re-challenge. 
Does not follow a known pattern of response to the IMP. 
Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
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Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing. 
Recovered/   
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
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 study or safety 
follow-up periods, for example chronic illnesses, the final outcome should be reported as ‘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: 

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).

Current version of applicable International Council for Harmonisation (ICH) Good
Clinical Practice (GCP) Guidelines (40).

EU’s General Data Protection Regulation 2016/679 of 27 April 2016.

Applicable laws and regulations.
The appropriate regulatory authorities must be notified of/approve the clinical trial as 
required.  
Any documents that the IRB may need to fulfil its responsibilities (such as the trial protocol, 
protocol amendments, Investigator’s Brochure, subject information leaflet, ICFs, or 
advertisements) will be submitted to the IRB. These documents must be reviewed and 
approved by the IRB before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 

Providing written summaries of the status of the trial to the IRB annually or more
frequently in accordance with the requirements, policies, and procedures established
by the IRB.

Notifying the local IRB of SAEs or other significant safety findings as required by
IRB procedures.

Providing oversight of the conduct of the trial at the trial site and adhering 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 (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 required. 
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.  
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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.   
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 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, etc.) which shall be collected as part of 
the clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO and third parties acting on behalf of LEO. 
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing and transfer of personal data in the 
clinical trial. In certain cases an agreement on transfer of personal data may also be required. 
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy, 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. 
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Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 

Date(s) of conducting the informed consent process, including date of
provision of subject information.

A statement from the investigator to verify that each of the eligibility criteria
are met and documented.

Subject ID.

The fact that the subject is participating in a clinical trial in AD including
treatment with tralokinumab or placebo for 30 weeks.

Other relevant medical information.
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to 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). 
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Protocol compliance 
Protocol deviations will be documented and notified to the investigator. LEO will assess all 
protocol deviations and decide if any of these deviations must be reported to the regulatory 
authorities as a serious breach of GCP and the protocol, as required by local legislation. 
Protocol deviations will be included in the CTR. 
Sponsor audits, IRB 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. Audits and inspections may take place during or 
after the trial. The investigator and the site staff as well as LEO staff have an obligation to 
cooperate and assist in audits and inspections. This includes giving auditors and inspectors 
direct access to all source documents and other documents at the trial site relevant to the 
clinical trial. This includes permission to examine, verify and reproduce any records and 
reports that are important to the evaluation of the trial. If the trial site is contacted for an 
inspection by competent authorities, LEO must be notified immediately. 
Risk assessment 
In this trial, overall risks have been assessed to ensure subject safety. 
Risk reduction activities for the primary endpoints include: 

Sourcing the vaccines to all participating trial sites.

Monitoring vaccine storage during the trial.

Ensuring accountability for each vaccine given to subjects.

Providing trial sites with a laboratory manual which explains how to collect
and process blood samples.

Using validated methods and a central laboratory to assess vaccine responses.
To ensure consistent data with respect to investigator assessment of efficacy (IGA, EASI and 
SCORAD), all investigators will receive training.  
Throughout the trial, data quality review meetings will be held to ensure that data collection 
can be improved and mistakes prevented. During monitoring visits to the trial sites, CRAs 
will verify that investigators work according to the protocol. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO or designee (e.g., laboratory data). The investigator or staff authorised by the 
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investigator will enter subject data into an eCRF. 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. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the Clinical Trial Agreement. Queries for discrepant 
data will be generated automatically by the system upon entry or manually by the CRA, 
sponsor’s medical expert, or the data manager. All queries will be raised electronically within 
the electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
An ePRO solution will be used to capture patient-reported data (data from questionnaires 
completed at the trial site). By the use of an ePRO, data will be available immediately after 
data entry and available for monitors and site personnel, including the investigator, with read 
access only. The ePRO system is a separate application from the eCRF and data captured 
from the eCRF and the ePRO will be stored on different 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. 
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Panel 14: Transmission of electronic data 
CTR, clinical trial report; ECG, electrocardiogram; eCRF, electronic case report form; ePRO, 
electronic patient-reported outcome. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (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. 
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For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs and ePRO data for all screened and randomised subjects 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. 
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 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, 
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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 
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 Consolidated Standards of Reporting Trials 
(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. 
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Appendix 3H: Trial and site closure 
Premature termination of trial or trial site 
LEO, the investigator, the IRBs 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 IRBs and provide a 
detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit-risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO or investigator may include but are not 
limited to: 

Failure of the investigator to comply with the protocol, the requirements of the
IRB or local health authorities, LEO’s procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO will undertake arrangements for the 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
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Appendix 3I: Responsibilities 
The 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 
From Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92 
(Suppl):44-47. 
Major Features: must have 3 or more of the following: 

Pruritus

Typical morphology and distribution:
o
Flexural lichenification or linearity in adults
o
Facial and extensor involvement in infants and children

Chronic or chronically-relapsing dermatitis

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Features: should have 3 or more of the following: 

Xerosis

Ichthyosis, palmar hyperlinearity, or keratosis pilaris

Immediate (type 1) skin-test reactivity

Raised serum IgE

Early age of onset

Tendency toward cutaneous infections (especially S. aureus and herpes simplex) or
impaired cell-mediated immunity

Tendency toward non-specific hand or foot dermatitis

Nipple eczema

Cheilitis

Recurrent conjunctivitis

Dennie-Morgan infraorbital fold

Keratoconus

Anterior subcapsular cataracts

Orbital darkening

Facial pallor or facial erythema

Pityriasis alba

Anterior neck folds

Itch when sweating

Intolerance to wool and lipid solvents

Perifollicular accentuation

Food intolerance

Course influenced by environmental or emotional factors

White dermographism or delayed blanch
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Appendix 5: Guidance for anaphylaxis diagnosis (24) 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a serious allergic 
reaction that is rapid in onset and may cause death. They recognize 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 (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING: 

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg,
hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen
lips-tongue-uvula)

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)

Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope,
incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that patient (minutes to several hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease in
systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that
person’s baseline
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Appendix 6: Short version of eligibility criteria 
This appendix provides a short form (maximum 200 characters) of each of the eligibility 
criteria to be used when data are submitted to the FDA. 
No. 
Inclusion criteria 
1 
Written informed consent has been obtained prior to any protocol-related procedures 
2 
Age 18 to 54 years, both included, at screening 
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 inadequate response to treatment with topical medications within 1 year 
before the screening visit or 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 
An EASI score of 12 (or more) at screening and 16 (or more) at baseline 
8 
An IGA score of 3 or more at screening and at baseline 
9 
Subjects must have applied a stable dose of emollient twice daily (or more, as 
needed) for at least 14 days before randomisation 
10 
Women of childbearing 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 
No. 
Exclusion criteria 
1 
Concurrent enrolment in another clinical trial where the subject is receiving an IMP 
2 
Previous randomisation in tralokinumab trials 
3 
Subjects for whom administration of the meningococcal vaccine provided in this trial 
is contraindicated or medically inadvisable, according to local label of the vaccine 
4 
Subjects for whom administration of the tetanus, diphtheria, and pertussis vaccine 
provided in this trial is contraindicated or medically inadvisable, according to local 
label of the vaccine 
5 
Active dermatologic conditions that may confound the diagnosis of AD or would 
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or 
psoriasis 
6 
Known active allergic or irritant contact dermatitis that is likely to interfere with the 
assessment of severity of AD 
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No. 
Exclusion criteria 
7 
Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA), within 6 weeks 
prior to randomisation 
8 
Treatment with immunomodulating medications, systemic corticosteroids, or 3 or 
more bleach baths during any week within 4 weeks prior to randomisation  
9 
Treatment with the topical medications TCS, TCI or PDE-4 inhibitor within 2 weeks 
prior to randomisation 
10 
Receipt of any vaccine within 3 months prior to screening, any meningococcal 
vaccine within 1 year prior to screening, or any tetanus-containing vaccine within 
5 years prior to screening  
11 
Receipt of any marketed or investigational biologic agents (e.g., cell-depleting agents 
or dupilumab) within 6 months prior to randomisation or until cell counts return to 
normal, whichever is longer 
12 
Receipt of any investigational non-biologic agent within 5 half-lives prior to 
randomisation 
13 
Receipt of blood products within 4 weeks prior to screening 
14 
Major surgery within 8 weeks prior to screening, or planned in-patient surgery or 
hospitalisation during the trial period 
15 
Known or suspected allergy or reaction to any component of the IMP formulation 
16 
History of any active skin infection within 1 week prior to randomisation 
17 
History of a clinically significant infection (systemic infection or serious skin 
infection requiring parenteral treatment) within 4 weeks prior to randomisation 
18 
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 
19 
History of anaphylaxis following any biological therapy 
20 
History of immune complex disease 
21 
History of cancer 
22 
Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation 
will be according to local guidelines as per local standard of care 
23 
History of any known primary immunodeficiency disorder including a positive HIV 
test at screening, or the subject taking antiretroviral medications  
24 
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 
25 
History of attempted suicide or at significant risk of suicide (either in the opinion of 
the investigator or on the C-SSRS) 
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No. 
Exclusion criteria 
26 
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 
27 
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 
28 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 2.0 times 
the ULN (upper limit of normal) or more at screening 
29 
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 
30 
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 
31 
Subjects who are legally institutionalised 
32 
Pregnant, breastfeeding, or lactating women 
33 
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, sponsor’s medical expert, 
vendors used in the trial, and national coordinating investigators 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 
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Appendix 8: WHO model prescribing information for classification of 
topical corticosteroids 
Hydrocortisone and betamethasone are examples of low- and high-potency TCS. TCS have 
been ranked in terms of potency into 4 groups consisting of 7 classes. Class I TCS are the 
most potent and Class VII TCS are the least potent (Panel 15). Efficacy and side-effects are 
greatest with the Class I ultra-high-potency preparations which should only be used for 
limited time periods (2-3 weeks).  
Representative preparations by group are listed in the table below according to the WHO 
model prescribing information for drugs used in skin diseases (41). These groups may vary 
depending on the formulation and concentration and should be considered approximate. In 
general, ointments are more potent than creams or lotions. Potency is also increased when 
TCS are used under occlusive dressings or in intertriginous areas. 
Panel 15: Classification of topical corticosteroids 
Potency 
Class Topical corticosteroid 
Formulation 
Ultra high 
I 
Clobetasol propionate 
Cream, 0.05% 
Diflorasone diacetate 
Ointment, 0.05% 
High 
II 
Amcinonide 
Ointment, 0.1% 
Betamethasone dipropionate 
Ointment, 0.05% 
Desoximetasone 
Cream or ointment, 0.025% 
Fluocinonide 
Cream, ointment, or gel, 0.05% 
Halcinonide 
Cream, 0.1% 
III 
Betamethasone dipropionate 
Cream, 0.05% 
Betamethasone valerate 
Ointment, 0.1% 
Diflorasone diacetate 
Cream, 0.05% 
Triamcinolone acetonide 
Ointment, 0.1% 
Moderate 
IV 
Desoximetasone 
Cream, 0.05% 
Fluocinolone acetonide 
Ointment, 0.025% 
Fludroxycortide 
Ointment, 0.05% 
Hydrocortisone valerate 
Ointment, 0.2% 
Triamcinolone acetonide 
Cream, 0.1% 
V 
Betamethasone dipropionate 
Lotion, 0.02% 
Betamethasone valerate 
Cream, 0.1% 
Fluocinolone acetonide 
Cream, 0.025% 
Fludroxycortide 
Cream, 0.05% 
Hydrocortisone butyrate 
Cream, 0.1% 
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Panel 15: Classification of topical corticosteroids (continued) 
Potency 
Class Topical corticosteroid 
Formulation 
Moderate 
V 
Hydrocortisone valerate 
Cream, 0.2% 
Triamcinolone acetonide 
Lotion, 0.1% 
Low 
VI 
Betamethasone valerate 
Lotion, 0.05% 
Desonide 
Cream, 0.05% 
Fluocinolone acetonide 
Solution, 0.01% 
VII 
Dexamethasone sodium phosphate 
Cream, 0.1% 
Hydrocortisone acetate 
Cream, 1% 
Methylprednisolone acetate 
Cream, 0.25% 
Source: WHO model prescribing information: drugs used in skin diseases (41). 
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SAP_001.pdf: 
Cover Page 
Official title: A randomised, double blind, placebo controlled trial to evaluate the effect of tralokinumab on vaccine antibody 
responses in adults with moderate-to-severe atopic dermatitis who are candidates for systemic therapy 
LEO Pharma number: LP0162-1341 
NCT number: NCT03562377 
Date: 18-Oct-2019 


Statistical analysis plan 
Vaccine responses in tralokinumab-treated atopic dermatitis 
ECZTRA 5 (ECZema TRAlokinumab trial no. 5) 
Phase 2 – Vaccine response trial 
A randomised, double-blind, placebo-controlled trial to evaluate the effect of tralokinumab 
on vaccine antibody responses in adults with moderate-to-severe atopic dermatitis who are 
candidates for systemic therapy  
LEO Pharma A/S 
Trial ID: 
LP0162-1341 
Date: 
18-OCT-2019
Version: 
FINAL 
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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. 
 
Biostatistics Lead, Medical Sciences 
 
Medical Lead, Medical Sciences 
 
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 .............................................................................................................. 5 
4 Introduction ........................................................................................................................... 7 
5 Trial analysis sets ................................................................................................................... 7 
6 Statistical analysis................................................................................................................ 10 
6.1 Baseline characteristics ................................................................................................... 10 
6.2 Disposition ....................................................................................................................... 10 
6.3 Rescue medication ........................................................................................................... 11 
6.4 Compliance ...................................................................................................................... 11 
6.5 Exposure .......................................................................................................................... 11 
6.6 Vaccine responders .......................................................................................................... 11 
6.7 Analysis of efficacy ......................................................................................................... 12 
6.8 Analysis of safety ............................................................................................................ 15 
6.8.1 
Adverse events ............................................................................................................ 15 
6.8.2 
Vital signs .................................................................................................................... 16 
6.8.3 
Electrocardiogram ....................................................................................................... 17 
6.8.4 
Laboratory data ............................................................................................................ 17 
6.8.5 
Urinalysis ..................................................................................................................... 18 
6.8.6 
Pharmacokinetics and anti-drug antibodies ................................................................. 19 
6.9 General principles ............................................................................................................ 20 
6.9.1 
Baseline value .............................................................................................................. 20 
6.9.2 
Definition of trial periods and date of permanent discontinuation of IMP ................. 20 
6.9.3 
Incomplete recordings ................................................................................................. 21 
6.9.4 
Early termination and unscheduled visits .................................................................... 22 
6.9.5 
Handling of drop-outs and missing values .................................................................. 22 
6.9.6 
Protocol deviations ...................................................................................................... 23 
7 References ........................................................................................................................... 23 
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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 
BMI 
body mass index 
BSA 
body surface area 
CI 
Confidence interval 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
At least 50% reduction in EASI score 
EASI75 
At least 75% reduction in EASI score 
EASI90 
At least 90% reduction in EASI score 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQol 5-Dimension Health Questionnaire 5 Level 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IGA 
Investigator’s Global Assessment 
IGA 0/1 
IGA response of 0 (clear) or 1 (almost clear) 
IgG 
immunoglobulin G immunoglobulin G 
IMP 
investigational medicinal product 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAB 
neutralising antibodies 
POEM 
Patient-Oriented Eczema Measure 
PYE 
patient years of exposure 
Q2W 
every 2 weeks 
QC 
quality control 
SAE 
serious adverse event 
SCORAD 
Scoring Atopic Dermatitis 
SCORAD50 
At least 50% reduction in SCORAD score 
SCORAD75 
At least 75% reduction in SCORAD score 
SOC 
system organ class 
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Tdap 
Tetanus, diphtheria and acellular pertussis 
ULN 
upper limit of normal 
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 is prepared before the unblinding of the trial and supplements the 
clinical trial protocol, which otherwise describes the originally planned statistical analyses of 
all endpoints in an intended exhaustive manner. The statistical analysis plan contains a more 
technical and detailed elaboration of some points related to the implementation of the 
statistical analysis already described in the clinical trial protocol.  
In addition, the Statistical Analysis Plan includes supplementary statistical analyses and 
aspects that are introduced after the protocol.  
Definition of vaccine response: 
1. The definition and calculation of positive meningococcal response has been specified.
New analysis for the continuous other endpoints: 
2. Analysis of a new tertiary estimand (‘composite’) for the continuous other endpoint
‘Change from baseline to Week 16 in EASI score’ is introduced. Analysis apply non-
responder imputation for subjects who receive rescue medication.
3. A repeated measurements analysis of the percentage change from baseline in EASI
score from baseline to Week 16 has been added.
The per protocol analysis set: 
4. The definition of the per protocol analysis set as stated in the protocol has been
updated with regards to handling of systemic rescue medication, baseline disease
severity related to the EASI status and visit interval between administration of the
vaccine and measurement of the vaccine response.
5 Trial analysis sets 
The trial analysis sets are defined in the protocol and the following modifications to the 
analysis sets are introduced. 
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All subjects randomised to treatment who were exposed to IMP (tralokinumab/placebo) are 
included in the full analysis set and will be analysed for efficacy up to Week 16 (Visit 11). For 
subjects not exposed to IMP (tralokinumab/placebo), the decision to withdraw can’t be biased 
by knowledge of the assigned treatment due to the blinding. This definition of the full analysis 
set implements the consideration mentioned in the protocol regarding special excluded cases 
with reference to ICH E9, Section 5.2.1. 
The safety analysis set comprises all subjects randomised to treatment who were exposed to 
IMP. The protocol further specifies to exclude subjects from the safety analysis set for whom 
no post-baseline safety data are available. However, since all subjects receive the first dose of 
IMP in connection with the Week 0 visit and are subsequently monitored for immediate drug 
reactions, all exposed subjects are considered to have post-baseline safety data available and 
no such further exclusions will be made. 
In addition to the analysis sets defined in the protocol, a safety follow-up analysis set will be 
used as the basis for evaluation of adverse events during the safety follow-up period. It 
comprises all subjects for whom date of last contact is after the date of exposure end, where 
exposure end is defined as the Week 16 visit for subjects completing the treatment period, and 
otherwise the date of permanent discontinuation of IMP (tralokinumab/placebo) for subjects 
not completing the treatment period. See also Section 6.9.2 for further details. 
For analysis of efficacy, subjects will be included ‘as randomised’. 
For analysis of safety, if a subject is mistakenly given an IMP other than that to which they 
were randomised, they will be analysed ‘as treated’, thus included in the group according to 
the therapy actually received by the subject. The below rules will be applied. 
Subjects who received at least one dose of tralokinumab will be analysed in the tralokinumab 
treatment group. Although this may dilute the AE rate in the tralokinumab treatment group 
slightly by including in the denominator subjects who only received one dose of active 
treatment, it will ensure that no significant drug reactions to tralokinumab will erroneously be 
assigned to placebo. 
The definition of the per protocol analysis set as described in the protocol has been updated to 
accept negligible deviations in baseline disease severity related to the EASI status. Thus, the 
criteria from inclusion criterion 7 have been modified to require an EASI score of ≥12 at 
screening OR ≥16 at baseline instead of requiring both criteria to be met. The rationale for 
this change is that marginal deviations in baseline disease severity is not considered to affect 
the vaccine response. 
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The criteria related to systemic rescue medication in the definition of the per protocol analysis 
set have been updated relative to the protocol text to include, not only those for the AD 
indication but all systemic immunosuppressive treatments irrespectively of indication. The 
referred criteria for excluding patients consequently become: 

Initiated systemic immunosuppressive treatment prior to Week 10 and who are still
treated with or exposed to the given treatment at Week 10 (that is, Week 10 [visit 8]
occurs within 5 half-lives after the last dose of the given systemic immunosuppressive
medication).

Initiated systemic immunosuppressive treatment at any time point from Week 10 to
Week 16.
The rationale for excluding these subjects is to ensure that subjects were not 
immunosuppressed by these treatments when the vaccinations were administered, as this 
might impact the response to the vaccination, and thereby the primary endpoints. This is 
independent of the indication for the immunosuppressive treatments and should therefore 
include all subjects treated with systemic immunosuppressants, irrespectively of the 
indication.  
In addition to the criteria specified in the protocol, subjects with Week 16 visit occurring ≥56 
days after the Week 12 visit, are not included in per protocol analysis set due to a too long 
interval between administration of the vaccine and measurement of the vaccine response, 
since this would induce a risk of a perished vaccine response.  
Systemic immunosuppressive treatment definition 
ATC2 code H02 or L04 will be used to identify administered systemic immunosuppressive 
treatments. Table 1 below presents the medications that as minimum will be identified in the 
trial (as being systemic immunosuppressive) along with the half-lives applied to evaluate the 
PP exclusion criteria. 
Medications administered in the screening period will be included in the search to ensure that 
all administered medications that could potentially be immunosuppressive at time of 
vaccination will be covered. Different routes of administration can be used for the 
medications, which will result in different half-lives.  
Table 1: Systemic immunosuppressive treatments and applied halflives 
ATC 4 
ATC 4 TERM 
Standardized Medication Name 
Route of 
Administration 
Halflife 
Hours Weeks 
5 x t½1 
H02AB 
GLUCOCORTICOIDS 
DEXAMETHASONE 
ORAL 
7.2 
0.0 
0.2 
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H02AB 
GLUCOCORTICOIDS 
DEXAMETHASONE SODIUM 
PHOSPHATE 
INTRAVENOUS 
24 
0.1 
0.7 
H02AB 
GLUCOCORTICOIDS 
DEXAMETHASONE SODIUM 
PHOSPHATE 
SUBCUTANEOUS 
336 
2.0 
10.0 
H02AB 
GLUCOCORTICOIDS 
HYDROCORTISONE SODIUM 
SUCCINATE 
INTRAVENOUS 
3 
0.0 
0.1 
H02AB 
GLUCOCORTICOIDS 
METHYLPREDNISOLONE 
ORAL 
3.5 
0.0 
0.1 
H02AB 
GLUCOCORTICOIDS 
METHYLPREDNISOLONE 
SODIUM SUCCINATE 
INTRAVENOUS 
24 
0.1 
0.7 
H02AB 
GLUCOCORTICOIDS 
PREDNISONE 
ORAL 
3 
0.0 
0.1 
H02AB 
GLUCOCORTICOIDS 
TRIAMCINOLONE ACETONIDE2 
INTRAMUSCULAR 
336 
2.0 
10.0 
H02AA 
MINERALOCORTICOIDS 
FLUDROCORTISONE ACETATE 
ORAL 
0.5 
0.0 
0.0 
L04AC 
INTERLEUKIN 
INHIBITORS 
DUPILUMAB 
SUBCUTANEOUS 
432 
2.6 
12.9 
L04AC 
INTERLEUKIN 
INHIBITORS 
DUPILUMAB 
INTRAMUSCULAR 
432 
2.6 
12.9 
L04AC 
INTERLEUKIN 
INHIBITORS 
NEMOLIZUMAB 
SUBCUTANEOUS 
432 
2.6 
12.9 
L04AX 
OTHER 
IMMUNOSUPPRESSANTS AZATHIOPRINE 
ORAL 
5 
0.1 
0.1 
L04AX 
OTHER 
IMMUNOSUPPRESSANTS METHOTREXATE 
ORAL 
15 
0.1 
0.4 
L04AA 
SELECTIVE 
IMMUNOSUPPRESSANTS BARICITINIB 
ORAL 
12.5 
0.1 
0.4 
L04AA 
SELECTIVE 
IMMUNOSUPPRESSANTS MYCOPHENOLATE SODIUM 
ORAL 
17 
0.1 
0.5 
1 5 times the halflife (t½) is presented in weeks.  
2 Intralaminar and intraarticular administration of Triamcinolone Acetonide is not considered systemic treatment 
Systemic immunosuppressive medications were prohibited during the trial, and wash-out 
criteria were specified in the exclusion criteria of the protocol accordingly. For completeness, 
medications that required wash-out will be included in the above search. 
6 Statistical analysis 
6.1 Baseline characteristics 
Baseline characteristics will be summarised and listed. 
Duration of AD in years will be calculated as (age at Week 0) minus (age at onset of AD). 
The table of concomitant medication at baseline will include medication starting before the 
first dose of IMP which does not end before the first dose of IMP. For further details, see 
Section 6.9.3. 
6.2 Disposition 
Subject disposition will be summarised and listed. 
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6.3 Rescue medication 
Rescue medication is defined by the following algorithm: Concomitant medications with 
Dermatitis atopic or Dermatitis infected as the preferred term for the indication and either 
ATC2 code H02 or D07, or ATC4 code D11AH, or preferred name Methotrexate, Ciclosporin, 
Azathioprine, Mycophenolate-mofetil, Mycophenolate-sodium, Mycophenolate-acid, or 
Dupilumab. 
According to the protocol, investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue treatment. Therefore, if 
rescue medication has start date the same day as an efficacy assessment, then the assumption 
will be that the assessment is not influenced by the rescue medication. 
The table of rescue medication will include medications taken after the first dose and before 
the Week 16 visit (or before day 7*16=112 after first dose, in case the Week 16 visit did not 
take place). 
Rescue medication will be summarised for the treatment period. In addition, a summary table 
of rescue medication by type (topical and systemic) and by overall group (corticosteroids, 
immunosuppressants, and other) will be made.  
6.4 Compliance 
Compliance will be summarised and listed. 
6.5 Exposure 
The exposure time will be defined as detailed in Section 6.9.2. Exposure time will be 
summarised and listed. 
Patient years of exposure (PYE) will be calculated as the difference between the start date and 
time and the end date and time divided by 60x60x24x365.25. 
6.6 Vaccine responders 
As stated in the protocol, a positive anti-tetanus response is defined as a 3-fold IgG increase at 
Week 16 compared to Week 12 if IgG ≤1.0 IU/mL at Week 12; or IgG ≥2.5 IU/mL if IgG >1.0 
IU/mL at Week 12. 
As stated in the protocol, a positive anti-meningococcal response is defined as at least a 3-fold 
increase in specific IgG at Week 16 compared to Week 12. 
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The anti-meningococcal response is measured in separate assays against four individual 
meningococcal serogroup antigens, including serogroup A, C, W-135 and Y. To assess the 
vaccine response against a serogroup antigen a measurable specific IgG titer against that 
antigen at both week 12 and week 16 should be available. Subjects with a visit interval 
between Week 12 and Week 16 of ≥56 days are excluded from the analysis due to a too long 
interval between administration of the vaccine and measurement of the vaccine response. 
In order to reduce the impact of missing data on the calculation of responders to the 
meningococcal vaccination the following will be applied: 

If data are available for 4 out of the four antigens, then the subject should be a
responder against at least 3 of the antigens

If data are only available for 3 out of the four antigens, then the subject should be a
responder against these 3 antigens

If data are only available for 2 out of the four antigens, then the subject should be a
responder against these 2 antigens

If data are only available for 1 out of the four antigens, then the subject should be a
responder against this 1 antigen
6.7 Analysis of efficacy 
Efficacy will be analysed as described in the clinical trial protocol. 
Sensitivity analysis 2 for the primary estimand (secondary endpoints) 
In the sensitivity analysis 2 for the primary estimand, the protocol specifies that: "If subjects 
have withdrawn due to an AE or due to lack of efficacy, they are still considered non-
responders". Such subjects will be identified based on their reason for permanent 
discontinuation of IMP. 
Primary analysis of primary estimand (continuous other endpoints) 
It is specified in the protocol that the continuous other endpoints will be analysed using a 
repeated measurements model on the post-baseline responses up to Week 16. Data collected 
after permanent discontinuation of IMP or after initiation of rescue medication will not be 
included in the analysis.  
However, some subjects may not have any post-baseline data collected before initiation of 
rescue medication. To ensure that all subjects are included in the analysis, the baseline value 
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will for these subjects be carried forward as the first post-baseline assessment, corresponding 
to imputing a change of 0 at the first post-baseline assessment. 
Tertiary (composite) estimand (continuous other endpoints) 
For the continuous other endpoint ‘Change from baseline to Week 16 in EASI score’ an 
analysis is introduced where subjects who received rescue medication are considered non-
responders. This new analysis aim to estimate the treatment effect for a ‘Composite‘ estimand 
which is currently not pre-specified in the protocol for the continuous other endpoints. Thus, a 
new tertiary ‘Composite’ estimand for the continuous other endpoints is introduced.  
Primary analysis for the tertiary (composite) estimand (continuous other endpoints): Data 
retrieved at Week 16 for subjects who have permanently discontinued IMP prior to Week 16 
will be included in the analysis. Subjects who prior to the Week 16 visit have received rescue 
medication will be considered non-responders by using worst observation carried forward 
(including the baseline value).   
Missing Week 16 data among subjects who did not use rescue medication will be imputed 
using MI (100 copies of the dataset, seed=11109941) assuming missing at random (MAR) 
within arms (based on sequential use of an ANCOVA model for Week 2, 4, 6, .. and 16). For 
subjects who dropout without any use of rescue medication, missing data at subsequent visits 
will be imputed under the assumption that the subject adheres to the randomised treatment 
regimen, i.e. the stepwise imputation model will be estimated based on available data from all 
subjects but excluding individual subject data captured after initiation of rescue medication or 
permanent discontinuation of IMP. For each of the 100 imputed datasets, the continuous other 
endpoint will be analysed using an ANCOVA model with effects of treatment, baseline 
disease severity (IGA 3 or 4), and baseline value. The estimates and standard errors from the 
100 analyses will be combined using Rubin’s rule to form a unique point estimate and 
standard error. 
Multiple imputation 
For the analysis of the secondary endpoints, multiple imputation will be carried out as 
specified in the protocol, using SAS PROC MI. For multiple imputations related to the 
treatment policy estimand and the hypothetical estimand sensitivity analyses, the seed 
11109941 will be used. The remaining seeds are specified in the protocol. 
When performing multiple imputation of continuous parameter values, imputed values at 
visits prior to Week 16 outside the relevant parameter scale shall be used as is. Values imputed 
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at Week 16 shall be truncated to the nearest upper or lower bound on the given scale. For 
example, negative imputed EASI values at Week 16 will be set to 0. 
For imputation of IGA values, the LIKELIHOOD=AUGMENT option will be used (1). 
For imputation of IGA values, it may occur that the observed data from which the imputation 
model is fitted does not contain all levels of the IGA predictors necessary for the imputation. 
For example, the imputation model for IGA values at Week 8 will be based on observed data 
from the subset of subjects with observed IGA values at both Week 6 and Week 8. If only the 
IGA values (0,1,2,3) are observed at Week 6 in this subset of subjects, the imputation model 
will not be able to predict IGA values at Week 8 for a subject with an IGA value of 4 at Week 
6. To avoid this situation, in this specific example IGA values of 3 and 4 at Week 6 will be
combined into a single category for the purpose of 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 specific imputation, according to the rules in Table 2. 
Table 2: Adjacent IGA categories combined in case of missing predictors in observed data 
IGA value(s) missing in imputation model 
IGA categories combined 
0 
(0,1) 
1 
(0,1) 
2 
(2,3) 
3 
(2,3) 
4 
(3,4) 
For the analysis of binary efficacy endpoints, it may for the tertiary (treatment policy) 
estimand not be possible to conduct a multiple imputation procedure if too few subjects have 
retrieved data, e.g. at Week 16. In such cases, the analysis may be omitted. 
Percentage change in EASI score 
In addition to the repeated measurements analysis of absolute reduction in EASI score which 
was planned in the protocol, the same analysis will be conducted for the percentage change 
from baseline in EASI scores. 
Subgroup analyses 
To access the consistency in response rate across subgroup the following subgroup analyses 
will be performed for the primary estimand: 

IGA 0/1 at Week 16 by baseline IGA
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
EASI75 at Week 16 by baseline IGA
Scoring of PROs 
POEM 
Scored according to: 
https://www.nottingham.ac.uk/research/groups/cebd/documents/methodological-
resources/poem-for-self-completion.pdf 
DLQI 
Scored according to: 
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-
index-dlqi/dlqi-instructions-for-use-and-scoring/ 
EQ-5D-
5L 
Index values calculated according to: 
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 1 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 1 
question is missing within a subscale, the subscale is considered missing.  
Missing baseline assessments 
When the baseline value is missing, endpoints concerning a change from baseline cannot be 
derived, and such subjects will be excluded from the analysis. Since the missingness of 
baseline values are unrelated to the assigned treatment, bias should not be a concern with this 
approach. 
6.8 Analysis of safety 
6.8.1 
Adverse events 
AEs will be summarised and listed. 
Assignment of AEs to periods 
An AE will be assigned to a given period (treatment period or safety follow-up) if the start 
date is after the start date and before the end date of that period (see Section 6.9.2, Table 6). 
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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.  
AEs starting on the day of exposure end (as defined in Section 6.9.2) will be assigned to the 
safety follow-up treatment period. 
For handling of incomplete start dates of AEs, see Section 6.9.3. 
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 in the Tralokinumab group. 
Other adverse events 
A MedDRA search on all reported AEs was specified to capture AEs belonging to injection 
site reactions. The MedDRA search to capture this safety area of interest was performed using 
the following HLGT levels (based on primary and secondary terms): ‘administration site 
reactions NEC’, ‘application and instillation site reactions’, and ‘injection site reactions. 
6.8.2 
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. 
Potentially clinically significant values will be defined as displayed in Table 3. 
Table 3: Potentially clinically significant vital signs values 
Protocol parameter 
SI unit 
PCS low 
PCS high 
Systolic blood pressure 
mmHg 
<90 and decrease from 
baseline ≥20 
≥180 and increase from 
baseline ≥20 
Diastolic blood pressure 
mmHg 
<50 and decrease from 
baseline ≥15 
≥105 and increase from 
baseline ≥15 
Pulse 
beats/min <50 and decrease from 
baseline ≥15 
≥120 and increase from 
baseline ≥15 
Abbrevations: PCS=potentially clinically significant. 
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6.8.3 
Electrocardiogram 
ECG data will be summarised and listed. The overall central evaluation of ECG will be 
presented using shift tables. 
6.8.4 
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 laboratory value is reported for the same visit, the latest value will be used in 
summary statistics and analyses.  
Potentially clinically significant values will be defined as displayed in Table 4. 
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Table 4: Potentially clinically significant biochemistry and haematology values 
Protocol lab parameter 
SI unit 
PCS low 
PCS high 
Biochemistry 
Sodium 
mmol/L < 129 mmol/L, 
< 125 mmol/L 
> 160 mmol/L
Potassium 
mmol/L < 3 mmol/L,  
< 2.5 mmol/L 
> 6.5 mmol/L,
> 7.5 mmol/L
Creatinine 
umol/L 
N/A 
> 1.5xULN, > 3xULN
Calcium 
mmol/L < 1.9 mmol/L 
> 3.0 mmol/L,
> 3.5 mmol/L
Alkaline phosphatase 
U/L 
N/A 
> 3xULN
Aspartate 
aminotransferase 
U/L 
N/A 
> 3xULN, > 5xULN,
> 10xULN, > 20xULN
Alanine aminotransferase 
U/L 
N/A 
> 3xULN, > 5xULN,
> 10xULN, > 20xULN
Bilirubin 
umol/L 
N/A 
> 2xULN
Cholesterol 
mmol/L N/A 
> 6.2 mmol/L
LDL cholesterol 
mmol/L N/A 
> 4.1 mmol/L,
> 4.9 mmol/L
HDL cholesterol 
mmol/L N/A 
> 1.6 mmol/L
Triglycerides 
mmol/L N/A 
> 2.3 mmol/L,
> 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 
< 1.0×109/L, 
< 0.5×109/L 
> 5.0×109/L
Monocytes, absolute count 109/L 
< 0.1×109/L 
> 0.8×109/L
Eosinophils, absolute 
count 
109/L 
N/A 
> 1.5, > 5.0
Basophils, absolute count 
109/L 
N/A 
> 0.2
Thrombocytes 
109/L 
< 100×109/L, 
< 30×109/L,  
< 10×109/L 
> 450×109/L
Abbreviations: HDL = high density lipoprotein; LDL = low density lipoprotein; N/A = not applicable; PCS = 
potentially clinically significant; ULN = upper limit of normal (i.e., upper limit of normal reference range). 
6.8.5 
Urinalysis 
Urinalysis data will be summarised and listed. 
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Potentially clinically significant values will be defined as displayed in Table 5. 
Table 5: Potentially clinically significant urinalysis values 
Protocol lab parameter 
(ACM lab parameter) 
SI unit 
PCS low 
PCS high 
Erythrocytes 
/HPF 
N/A 
> 3, >10, >25, >30
Leucocytes 
/HPF 
N/A 
> 10
Casts (hyaline casts) 
/LPF 
N/A 
> 2
Casts (WBC casts) 
/LPF 
N/A 
Few, moderate, many 
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 
Abbreviations: ACM = ACM Global Laboratories; HPF = high power field; LPF = low power field; N/A = not 
applicable; PCS = potentially clinically significant; RBC = red blood cells; ULN = upper limit of normal 
(i.e., upper limit of normal reference range); WBC = white blood cells. 
6.8.6 
Pharmacokinetics and anti-drug antibodies 
Pharmacokinetics and ADA data will be summarised and listed. 
The ADA status will be categorised as follows: 

Positive
1. Pre-existing: ADA-positive at baseline, no post-baseline ADA response ≥ 4-fold
over baseline titre level, and at least 1 non-missing post-baseline ADA assessment.
2. Treatment-boosted: ADA-positive at baseline and at least 1 post-baseline ADA
response ≥ 4-fold over baseline titre level.
3. Treatment-emergent: ADA negative or missing at baseline and at least 1 positive
post-baseline ADA response.

Negative
1. ADA negative or missing at baseline, all post-baseline ADA assessments negative.

No post-baseline ADA assessment.
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6.9 General principles 
6.9.1 
Baseline value 
Unless otherwise specified, the baseline value is defined as the latest pre-dose assessment. 
6.9.2 
Definition of trial periods and date of permanent discontinuation 
of IMP 
Date of permanent discontinuation of IMP (tralokinumab/placebo) 
Defined for subjects who have a reason for permanent discontinuation of IMP 
(tralokinumab/placebo) recorded.  
Defined as the latest of date of early termination visit (if existing) or date of onset of latest AE 
leading to withdrawal of trial product, otherwise date of the last visit, excluding safety follow-
up and nominal Week 16 visits.  
Exposure start  
Date and time of first dose. 
Exposure end  
Date of Week 16 visit (if existing) at time 23:59:00, otherwise date of permanent 
discontinuation of IMP (tralokinumab/placebo) at time 23:59:00. 
Trial periods 
The time from exposure start to exposure end will be assigned to the treatment period and 
remaining time after exposure end will be assigned to the safety follow-up period as shown in 
Table 6 (ADaM variable APHASE). The ADaM variable APERIODC will indicate the latest 
treatment at any given time point, thus not including a follow-up period (Table 7).  
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 
period1
Exposure end 
(plus 1 second) 
Date of safety follow-up visit (if existing) at time 
23:59:00 
else 
Date of last contact at time 23:59:00 
1) Only applicable if date of last contact is not equal to date of exposure end.
Table 7: Start and end time of trial periods (ADaM variable APERIODC) 
APERIODC Start of period 
End of period (only if start date exists) 
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Treatment 
period 
Exposure start 
Date of last contact at time 23:59:00 
6.9.3 
Incomplete recordings 
Adverse events 
If the AE start day is missing, but AE start month and year are not missing, the following rules 
apply: 

If the year and month of the AE start is before the year and month of the exposure
start, or if the AE end date is complete and before the exposure start, the AE will not
be considered treatment-emergent.

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.

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 safety follow-up period accordingly.
If the AE start month is missing, but AE start year is not missing, the following rules apply: 

If the year of the AE start is before the year of the exposure start, or if the AE end
month is not missing and before the month of the exposure start, or if the AE has a
complete end date which is before the exposure start date, the AE will not be
considered treatment-emergent.

If the year of the AE start is the same as the year of the exposure start, the AE will be
considered treatment-emergent and assigned to the treatment period, unless the AE
end month is not missing and before the month of the exposure start or the AE has a
complete end date which is before the exposure start date.

If the year of the AE start is after the year of exposure start, it will be assumed that the
AE started on the 01 January and the AE will be assigned to the treatment or safety
follow-up period accordingly.
Concomitant medication 
For incomplete start dates of concomitant medication, the following rules apply: 

If a medication start day is missing, but start month and year are not missing, it will be
assumed that the start day is the first day of the month. If the medication start day and
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month are 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 are missing, it will be assumed 
that the medication was started before trial start, and the date will appear as missing in 
the data. 
For incomplete end dates of concomitant medication, the following rules apply: 

If a medication end day is missing, but end month and year are not missing, it will be
assumed that the end day is the last day of the month. If the medication end day and
month are 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 are missing, it will be
assumed that the medication was ongoing at the end of the trial, and the date will
appear as missing in the data.
6.9.4 
Early termination and unscheduled visits 
When no data are available from a certain scheduled post-baseline visit for a particular 
subject, data from early termination visits and unscheduled visits have the potential to replace 
data from that particular scheduled visit in data summaries, provided the data are collected 
between 6 days before and 7 days after the planned time point for the scheduled visit, as 
displayed below.  
Visit (target day) 
Visit window (day is date of assessment 
minus date of first dose) 
Week 2 (Day 14) 
Day 8 to 21 
Week x (Day 7*x) (where x= 4, 6, ..., 16) 
Day 7*x-6 to 7*x+7 
Safety follow-up 
106-119 days after last dose
When both unscheduled and early termination visits exist within the given visit window, the 
early termination visit will be selected for analysis. When no early termination visit and 
several unscheduled visits exist, the unscheduled visit closest to the target day will be selected 
for analysis. If the difference is a tie, the latest unscheduled visit will be selected. 
6.9.5 
Handling of drop-outs and missing values 
Missing values will be handled as described in the clinical trial protocol. 
Week 16 last observation carried forward 
As specified in the protocol, a sensitivity analysis of the secondary endpoints will impute 
Week 16 missing values using LOCF. The LOCF value will be defined as the last assessment 
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obtained up to and including Day 7*16+7=119 after the first dose, i.e. the last assessment 
before or within the window for mapping an early termination visit to Week 16.  
6.9.6 
Protocol deviations 
Only major protocol deviations will be summarised and listed. 
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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