Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 106
Healthy volunteers: no

Brief summary:
Primary objective:

To evaluate the efficacy of tralokinumab in combination with topical corticosteroids (TCS) compared with placebo in combination with TCS in treating moderate-to-severe atopic dermatitis (AD).

Secondary objectives:

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

To assess the safety of tralokinumab in combination with TCS when used to treat moderate-to-severe AD for 16 weeks.

Detailed description:

Arms:
arm 1: Week 0 to Week 16: Tralokinumab will be given as subcutaneous injections. Participants will receive tralokinumab loading dose on Day 0 followed by multiple tralokinumab injections. The last administration will occur at Week 14. Topical corticosteroids (TCS) will be administered as needed. arm 2: Week 0 to Week 16: Placebo will be given as subcutaneous injections. Participants will receive placebo loading dose on Day 0 followed by multiple placebo injections. The last administration will occur at Week 14. Topical corticosteroids (TCS) will be administered as needed.

Interventions: intervention 1: Tralokinumab intervention 2: Placebo intervention 3: Topical corticosteroids (TCS)
Intervention descriptions: intervention 1: Tralokinumab is a human recombinant monoclonal antibody of the immunoglobulin G4 subclass that specifically binds to human interleukin-13 (IL-13) and blocks the interaction with 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: TCS administered as needed.

Protocol document:
Prot_002.pdf: 
Cover Page 
Study title: Tralokinumab in combination with topical corticosteroids in Japanese subjects with 
moderate-to-severe atopic dermatitis ECZTRA 8 (ECZema TRAlokinumab trial no. 8) 
LEO Pharma number: LP0162-1343 
NCT number: NCT04587453 
Date: 20-Jul-2020 
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Clinical Trial Protocol 
LP0162-1343 
Tralokinumab in combination with topical corticosteroids in Japanese subjects with 
moderate-to-severe atopic dermatitis 
ECZTRA 8 (ECZema TRAlokinumab trial no. 8) 
Phase 3 – efficacy and safety trial 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and 
safety of tralokinumab in combination with topical corticosteroids in Japanese subjects with 
moderate-to-severe atopic dermatitis who are candidates for systemic therapy 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0162-1343 
Date: 
20-Jul-2020
EudraCT no: 
Not applicable 
Version: 
1.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within eTMF LEO Pharma are considered to be a legally binding 
equivalent of traditional handwritten signatures. The following persons have approved this 
clinical trial protocol by using electronic signatures as presented on the last page of this 
document: 
, MSc Stat 
Biostatistics lead, Medical Sciences 
, MD, PhD 
Medical lead, Medical Sciences 
, RN, PhD 
Clinical operations lead, Global Clinical Operations 
, MD 
Vice president, Medical Sciences 
Norito Katoh, MD, PhD 
Signatory investigator 
Acknowledgement statement investigators 
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 ............................................................................................................................. 8 
List of abbreviations ................................................................................................................. 9 
1 Protocol synopsis ................................................................................................................ 12 
2 Trial identification ............................................................................................................. 17 
3 Schematic of trial design ................................................................................................... 17 
4 Schedule of trial procedures ............................................................................................. 18 
5 Introduction and trial rationale ....................................................................................... 22 
5.1 Atopic dermatitis ........................................................................................................ 22 
5.2 Experience with investigational medicinal product .................................................... 23 
5.3 Trial rationale .............................................................................................................. 25 
5.4 Ethical considerations ................................................................................................. 26 
5.5 Benefit/risk assessment ............................................................................................... 27 
6 Trial objectives, endpoints, and estimands ...................................................................... 29 
7 Trial design ......................................................................................................................... 32 
7.1 Overall trial design ..................................................................................................... 32 
7.2 Number of subjects needed ......................................................................................... 34 
7.3 End of trial definition.................................................................................................. 34 
8 Trial population ................................................................................................................. 35 
8.1 Subject eligibility ........................................................................................................ 35 
8.2 Inclusion criteria ......................................................................................................... 35 
8.3 Exclusion criteria ........................................................................................................ 37 
8.4 Screening and screening failures ................................................................................ 40 
9 Treatments .......................................................................................................................... 42 
9.1 Trial product description ............................................................................................. 42 
9.1.1 
Investigational medicinal products (tralokinumab and placebo) .................. 42 
9.1.2 
Auxiliary medicinal product (TCS)............................................................... 42 
9.2 Administration of trial products.................................................................................. 43 
9.2.1 
Administration of IMP .................................................................................. 43 
9.2.2 
Administration of AxMP (TCS) .................................................................... 44 
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9.3 Treatment assignment (randomisation) ...................................................................... 45 
9.3.1 
Blinding ......................................................................................................... 45 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 46 
9.4 Background treatment (emollients) ............................................................................ 46 
9.5 Rescue treatment ......................................................................................................... 47 
9.6 Concomitant medications and concurrent procedures ................................................ 48 
9.7 Prohibited medications and procedures ...................................................................... 48 
9.8 Treatment logistics and accountability ....................................................................... 50 
9.8.1 
Labelling and packaging of trial products ..................................................... 50 
9.8.2 
Storage of trial products ................................................................................ 50 
9.8.3 
Drug accountability ....................................................................................... 51 
9.8.4 
Treatment compliance ................................................................................... 53 
9.8.5 
Trial product destruction ............................................................................... 53 
9.9 Provision for subject care following trial completion ................................................ 53 
9.10 Reporting product complaints..................................................................................... 53 
10 Discontinuation and withdrawal ...................................................................................... 55 
10.1 General principles ....................................................................................................... 55 
10.2 Reasons for discontinuation of IMP ........................................................................... 55 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 55 
10.2.2 Reasons for temporary discontinuation of IMP ............................................ 56 
10.3 Early termination assessments .................................................................................... 57 
10.4 Lost to follow-up ........................................................................................................ 58 
11 Trial assessments and procedures .................................................................................... 59 
11.1 Overview..................................................................................................................... 59 
11.2 Assessments performed only at screening and/or baseline ........................................ 60 
11.2.1 Columbia-Suicide Severity Rating Scale ...................................................... 60 
11.2.2 Demographics................................................................................................ 61 
11.2.3 Medical and surgical history ......................................................................... 61 
11.2.4 Height and weight ......................................................................................... 62 
11.2.5 Body surface area involvement ..................................................................... 62 
11.3 Efficacy assessments .................................................................................................. 62 
11.3.1 Investigator’s Global Assessment ................................................................. 62 
11.3.2 Eczema Area and Severity Index .................................................................. 63 
11.3.3 Scoring Atopic Dermatitis ............................................................................. 64 
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11.3.4 Patient-reported outcomes ............................................................................. 66 
11.4 Safety assessments ...................................................................................................... 67 
11.4.1 Vital signs ...................................................................................................... 67 
11.4.2 Physical examination..................................................................................... 68 
11.4.3 ECG ............................................................................................................... 69 
11.4.4 Laboratory testing: chemistry, haematology, serology, urinalysis, 
pregnancy test ................................................................................................ 70 
11.4.5 Anti-drug antibody measurements ................................................................ 73 
11.5 Pharmacokinetic assessments ..................................................................................... 73 
11.6 Pharmacodynamics assessments ................................................................................. 73 
11.7 Other assessments ....................................................................................................... 73 
11.7.1 Photography (selected trial sites) .................................................................. 73 
11.8 End of trial .................................................................................................................. 74 
11.9 Estimate of total blood volume collected ................................................................... 75 
11.10 Storage of biological samples ..................................................................................... 75 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 76 
12.1 Scientific rationale for trial design ............................................................................. 76 
12.2 Appropriateness of assessments ................................................................................. 77 
13 Adverse events ................................................................................................................... 78 
13.1 Definition and classification of adverse events .......................................................... 78 
13.2 Collection of adverse event reports ............................................................................ 78 
13.3 Reporting of adverse events........................................................................................ 78 
13.4 Reporting of serious adverse events ........................................................................... 79 
13.4.1 Investigator reporting responsibilities ........................................................... 79 
13.4.2 LEO Pharma reporting responsibilities ......................................................... 80 
13.5 Other events that require expedited reporting ............................................................ 80 
13.5.1 Pregnancy ...................................................................................................... 80 
13.6 Reporting of other events............................................................................................ 81 
13.6.1 Adverse events of special interest ................................................................. 81 
13.6.2 Overdose........................................................................................................ 82 
13.6.3 Medication error ............................................................................................ 83 
13.6.4 Misuse ........................................................................................................... 83 
13.6.5 Abuse ............................................................................................................. 83 
13.6.6 Aggravation of condition .............................................................................. 84 
13.7 Follow-up for final outcome of adverse events .......................................................... 84 
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13.8 Handling of an urgent safety measure ........................................................................ 84 
14 Statistical methods ............................................................................................................. 86 
14.1 Sample size ................................................................................................................. 86 
14.2 Trial analysis sets ........................................................................................................ 86 
14.3 Statistical analysis ....................................................................................................... 86 
14.3.1 Disposition of subjects .................................................................................. 86 
14.3.2 Demographics and other baseline characteristics.......................................... 86 
14.3.3 Exposure and treatment compliance ............................................................. 87 
14.3.4 Rescue treatment ........................................................................................... 87 
14.3.5 Testing strategy ............................................................................................. 88 
14.3.6 Analysis of primary efficacy endpoints ........................................................ 88 
14.3.7 Analysis of key secondary efficacy endpoints .............................................. 92 
14.3.8 Analysis of secondary endpoints ................................................................... 95 
14.3.9 Analysis of other endpoints ........................................................................... 96 
14.3.10 Analysis of patient-reported outcomes .......................................................... 97 
14.3.11 Exploratory analyses ..................................................................................... 97 
14.3.12 Analysis of safety .......................................................................................... 98 
14.3.13 Pharmacokinetic analysis .............................................................................. 99 
14.3.14 Anti-drug antibodies ...................................................................................... 99 
14.3.15 Interim analysis ........................................................................................... 101 
14.3.16 General principles ....................................................................................... 101 
14.3.17 Handling of missing values ......................................................................... 101 
15 References ......................................................................................................................... 102 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 107 
Appendix 2: Classification of adverse events ..................................................................... 109 
Appendix 3: Trial governance considerations ................................................................... 112 
Appendix 3A: Regulatory and ethical considerations .............................................. 112 
Appendix 3B: Informed consent process ................................................................. 112 
Appendix 3C: Subject and data confidentiality ....................................................... 113 
Appendix 3D: Record keeping, quality control, and data handling ......................... 115 
Appendix 3E: Registration, reporting, and publication policy ................................ 118 
Appendix 3F: Insurance ........................................................................................... 120 
Appendix 3G: Financial disclosure .......................................................................... 120 
Appendix 3H: Trial and trial site closure ................................................................. 120 
Appendix 3I: Responsibilities .................................................................................. 121 
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Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD (21) .......................... 122 
Appendix 5: Guidance for anaphylaxis diagnosis (24) ..................................................... 123 
Appendix 6: TCS classification list ..................................................................................... 124 
Appendix 7: Short version of eligibility criteria ................................................................ 125 
Appendix 8: Contact list ...................................................................................................... 127 
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List of panels 
Panel 1: Trial design ................................................................................................................. 17 
Panel 2: Schedule of trial procedures ....................................................................................... 18 
Panel 3: Objectives and endpoints ........................................................................................... 29 
Panel 4: Identification of investigational medicinal products .................................................. 42 
Panel 5: Sequence of assessments ............................................................................................ 59 
Panel 6: Investigator’s Global Assessment .............................................................................. 63 
Panel 7: Calculation of EASI ................................................................................................... 64 
Panel 8: EASI severity score scale and area score scale .......................................................... 64 
Panel 9: Clinical laboratory tests .............................................................................................. 71 
Panel 10: Adverse events of special interest ............................................................................ 82 
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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 
anti-HCV 
hepatitis C virus antibody 
AST 
aspartate aminotransferase 
AxMP 
auxiliary medicinal product 
BP 
blood pressure 
BSA 
body surface area 
Ctrough 
trough concentration: lowest concentration reached by a drug before the 
next does is administered 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CMO 
contract manufacturing organisation 
CONSORT 
Consolidated Standards of Reporting Trials 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
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 
ECZTEND 
tralokinumab phase 3 long-term extension trial (LP0162-1337) in subjects 
with AD who participated in ECZTRA trials 
ECZTRA 8 
ECZema TRAlokinumab trial no. 8 
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eDiary 
electronic diary 
ePRO 
electronic patient-reported outcome 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HCP 
healthcare professional 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IGA 0/1 
IGA score of 0 (clear) or 1 (almost clear) 
IgE 
immunoglobulin E 
IgG4 
immunoglobulin G4 
IL-13 
interleukin-13 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IRT 
interactive response technology 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
JAK 
Janus kinase 
JP 
Japan 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBUVB 
narrow band ultraviolet B 
NRS 
numeric rating scale 
PDE-4 
phosphodiesterase-4 
PEF 
peak expiratory flow 
PK 
pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
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POEM 
Patient-Oriented Eczema Measure 
PT 
(MedDRA) preferred term 
PUVA 
psoralen + ultraviolet A 
Q2W 
every second week 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SCORAD 
Scoring Atopic Dermatitis 
SD 
standard deviation 
SDTM 
Standard Data Tabulation Model 
SmPC 
summary of product characteristics 
SOC 
(MedDRA) system organ class 
TCI 
topical calcineurin inhibitor(s) 
TCS 
topical corticosteroid(s) 
Th2 
T-helper-2
ULN 
upper level of normal 
UVA1 
ultraviolet A1 
UVB 
ultraviolet B 
WHO 
World Health Organization 
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The trial consists of a screening period (Week -6/-2 to Week 0), a treatment 
period (Week 0 to Week 16), and a safety follow-up period (Week 16 to 
Week 20). 
The screening period has a minimum duration of 2 weeks and a maximum 
duration of 6 weeks. The exact duration of the screening period depends on the 
length of required washout of AD treatment as defined by the exclusion 
criteria. If no washout is required or if only a 2-week washout period is 
required, the screening period is reduced to 2 weeks and only 1 screening visit 
at Week -2 is required. 
Following the screening period, eligible subjects will be randomised at baseline 
(Week 0) to treatment with either tralokinumab or placebo and initiate 
administration of the investigational medicinal product (IMP). The IMP will be 
administered every second week during the treatment period, and the last IMP 
administration (relating to this protocol) will occur at Week 14. 
Subjects in both treatment groups will also receive an AxMP, i.e. TCS. At 
baseline (Week 0), the subjects will be allowed to initiate treatment once daily 
with the supplied TCS on areas with active lesions of AD and continue this 
treatment, as needed, throughout the treatment period. The TCS use will be 
monitored throughout the trial. 
All subjects must use an emollient twice daily (or more, as needed) for at least 
14 days prior to randomisation and will continue this background treatment 
throughout the trial (including the safety follow-up). On lesional skin, 
emollients should only be applied at a time when TCS is not applied; on 
TCS-untreated areas, the emollients may be applied at all times. 
Subjects who during the treatment period or safety follow-up experience 
intolerable AD symptoms can be treated with rescue treatment according to 
investigators discretion and will thus not be deprived from effective therapy. 
Subjects who complete the 16-week treatment period (relating to this protocol) 
may enter a long-term extension trial (ECZTEND). All subjects completing the 
treatment period, except for those who enter the long-term extension trial, will 
have safety follow-up assessments 6 weeks after last IMP administration. 
The primary and secondary endpoints will be assessed at Week 16, and the 
final safety assessments will be conducted at Week 20. 
Main assessments 
Efficacy assessments related to primary and secondary endpoints: 
•
IGA, EASI, and SCORAD (investigator assessments).
•
DLQI, Worst Daily Pruritus NRS, Eczema-related Sleep NRS, and
POEM (patient-reported assessments).
Key safety assessments: 
•
AEs and ADA.
Main criteria for 
inclusion 
•
Japanese subject aged 18 years and above.
•
Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria
for AD.
•
History of AD for ≥1 year.
•
A recent history (within 1 year before screening) of inadequate
response to treatment with topical medication.
•
AD involvement of ≥10% body surface area (BSA) at screening and at
baseline according to component A of SCORAD.
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•
An EASI score of ≥12 at screening and ≥16 at baseline.
•
An IGA score of ≥3 at screening and at baseline.
•
A Worst Daily Pruritus NRS average score of ≥4 during the week prior
to baseline.
•
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 TCS are medically inadvisable e.g. due to important
side effects or safety risks in the opinion of the investigator.
•
Active dermatologic conditions that may confound the diagnosis of AD
or would interfere with assessment of treatment.
•
Use of tanning beds or phototherapy within 6 weeks prior to
randomisation.
•
Treatment with systemic immunosuppressive/immunomodulating
drugs and/or systemic corticosteroids within 4 weeks prior or
randomisation.
•
Treatment with TCS, topical calcineurin inhibitors (TCI), topical
phosphodiesterase-4 (PDE-4) inhibitors, or topical Janus kinase (JAK)
inhibitors within 2 weeks prior to randomisation.
•
Receipt of any marketed biological therapy (i.e. immunoglobulin,
anti-immunoglobulin E [anti-IgE]) including dupilumab or
investigational biologic agents 3-6 months prior to randomisation.
•
Active skin infections within 1 week prior to randomisation.
•
Clinically significant infection within 4 weeks prior to randomisation.
•
A helminth parasitic infection within 6 months prior to the date
informed consent is obtained.
•
Tuberculosis requiring treatment within the 12 months prior to
screening.
•
Known primary immunodeficiency disorder.
Investigational 
medicinal product 
(IMP) 
IMP - tralokinumab 
•
Active substance: tralokinumab.
•
Dosage form: solution for injection in an accessorised pre-filled
syringe, 1.0 mL fill volume.
•
Concentration: 150 mg/mL.
•
Dose: 600 mg initial loading dose, then 300 mg every second week.
•
Method of administration: subcutaneous.
IMP - placebo 
•
Placebo contains the same excipients in the same concentration only
lacking tralokinumab.
Auxiliary 
medicinal product 
(AxMP) 
AxMP - TCS 
•
Active substance: mometasone furoate.
•
Dosage form: cream.
•
Concentration: 0.1%.
•
Method of administration: topical.
Duration of trial 
participation 
The trial duration for an individual subject is up to 26 weeks: 
•
Screening period: 2 to 6 weeks.
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•
Treatment period: 16 weeks.
•
Safety follow-up period: 4 weeks.
Number of 
subjects 
Approximately 100 subjects will be randomised in a 1:1 ratio to 
tralokinumab+TCS or placebo+TCS. 
Number and 
distribution of 
trial sites 
Approximately 35 sites in Japan. 
Statistical 
methods 
Primary endpoints 
The difference in response rates between treatment groups will be calculated by 
the Mantel-Haenszel method stratified by baseline disease severity. Subjects 
with missing data or subjects who receive rescue medication prior to Week 16 
visit will be considered as non-responders in the analysis. 
Key secondary endpoints 
The change from baseline to Week 16 in SCORAD will be analysed using an  
analysis of covariance (ANCOVA) model on the post-baseline responses up to 
Week 16. Subjects who receive rescue medication will be considered 
non-responders in the analysis. Missing Week 16 data among subjects who did 
not use rescue medication will be imputed using multiple imputation.  
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 from 
baseline to Week 16 is a binary endpoint, and as such it will be analysed as 
described for the primary endpoints. 
Change from baseline to Week 16 in DLQI will be analysed the same way as 
change in SCORAD. 
Secondary endpoints 
EASI90 and EASI50 are binary endpoints and will be analysed as described for 
the primary endpoints. 
Percentage change from baseline to Week 16 in EASI score and change from 
baseline to Week 16 in Worst Daily Pruritus NRS (weekly average), 
Eczema-related Sleep NRS (weekly average), and POEM score will be 
analysed using a repeated measurements model on the post-baseline responses 
up to Week 16. 
Signatory 
investigator 
Norito Katoh, MD, PhD, Department of dermatology, Director,  
University hospital, Kyoto Prefectural University of Medicine  
465, Kajii-cho, Kawaramachi-Hirokoji Kamigyo-ku, Kyoto 602-8566 Japan. 
Sponsor 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark. 
LEO Pharma K.K., 1-105 Kanda-Jinbocho, Chiyoda-ku, Tokyo 101-0051, 
Japan is the sponsor of the clinical trial in Japan on behalf of LEO Pharma A/S. 
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2 Trial identification 
Trial ID: LP0162-1343 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 Schematic of trial design 
The trial design is illustrated in Panel 1. 
Panel 1: Trial design 
Abbreviations: AD, atopic dermatitis; TCS, topical corticosteroids; w, weeks. 
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c)
An end of treatment form and end of trial form must be completed in the eCRF for all randomised subjects (Section 11.8). Subjects who complete the 16-week
treatment period may enter the long-term extension trial (ECZTEND). All subjects completing the treatment period, except for those who enter the ECZTEND
trial, will have final safety follow-up assessments 6 weeks after last IMP administration.
d)
Assessments to be performed at unscheduled visits will be at the discretion of the investigator.
e)
Subjects who permanently discontinue IMP or withdraw from the trial will be followed up as described in Section 10.
f)
Subjects who discontinue IMP treatment <5 weeks prior to the planned Week 16 visit will be asked to return to the trial site both at Week 16 for the nominal
Week 16 visit and 6 weeks after last IMP administration for the safety follow-up visit. Subjects who discontinue IMP treatment ≥5 weeks prior to the planned
Week 16 visit will be asked to return to the trial site only at Week 16 for the nominal Week 16 visit, which also includes all planned safety follow-up
assessments (Section 10.3).
g)
The informed consent form must be signed prior to performing any protocol-related procedures, including but not limited to screening evaluations and washout
of disallowed medications. Screening evaluations may start at a later date than the informed consent form was signed. Additional informed consent is required
for the photography component of the trial.
h)
In case medical history is incomplete at screening, missing data will be retrieved prior to randomisation.
i)
The eDiary includes: Eczema-related Sleep NRS, Worst Daily Pruritus NRS, and Patient Days of Topical Treatment Use. Subjects will complete the eDiary
daily in the morning from Week -2 to Week 16, except for the Patient Days of Topical Treatment Use, which will be completed daily from Week 0 to Week 16.
j)
After the first 3 IMP administrations, all subjects will be monitored for a minimum of 30 minutes with vital signs taken at 30 minutes or until stable, whichever
is later.
k)
Urine samples will be tested with a dipstick at the trial site. A urine sample will be sent to the central laboratory for further analysis only if considered required
by the investigator based on the dipstick results (Section 11.4.4).
l)
At selected sites only.
m) 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 the safety follow-up period).
Abbreviations: ADA, anti-drug antibodies; appl., applicable; AxMP, auxiliary medicinal product; BSA, body surface area; C-SSRS, Columbia-Suicide
Severity Rating Scale; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; ECG, electrocardiogram; eCRF, electronic case report
form; eDiary, electronic diary; HRQoL, health-related quality of life; HIV, human immunodeficiency virus; IGA, Investigator’s Global Assessment;
IgE, immunoglobulin E; IMP, investigational medicinal product; NRS, numeric rating scale; PK, pharmacokinetics; POEM, Patient-Oriented Eczema Measure;
SCORAD, Scoring Atopic Dermatitis; TCS, topical corticosteroids.
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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 (1, 2). The prevalence varies between regions: in a web-based survey using a 
modified UK Working Party definition of AD, the 1-year prevalence of AD in adults was 
reported to be 4.3% in Japan, 8.1% in Canada, 9.4% in Europe, and 11.9% in the US (1). In its 
moderate and severe form, AD is characterised by widespread skin lesions, intractable itch, as 
well as enhanced susceptibility to bacterial, viral, and fungal skin infections. AD is associated 
with a substantial patient burden that typically includes poor quality of life and sleep 
disturbances (3). 
AD is characterised by an activated T-helper-2 (Th2) pathway with interleukin-13 (IL-13) as 
the dominant cytokine in the skin (4-6). The expression of IL-13 is increased in lesional skin 
compared with non-lesional skin, the proportion of CD4+ and CD8+ cells expressing IL-13 is 
upregulated in AD patients compared with individuals without AD, and there is a correlation 
between IL-13 expressing skin-homing T-cells and disease severity (7, 8). 
IL-13 acts on keratinocytes to release chemokines that recruit more IL-13 expressing 
Th2 cells, decrease differentiation, and contribute to decreased skin barrier function (9). IL-13 
also drives immunoglobulin E (IgE) production and contributes to mast cell activation and, 
once allergen cross-links IgE on the cell surface, drives histamine release, induces itch, alters 
the skin microbiome, and stimulates skin fibrosis (10-12). 
These effects together drive and exacerbate the disease phenotype. Data from the dose-finding 
trial (D2213C00001) have confirmed IL-13 as a valid target in AD (13). The biomarker 
sub-study of phase 3 trial, LP0162-1325, also confirmed the importance of IL-13 in the 
pathophysiology of AD. Analyses of serum and skin samples showed that IL-13 expression 
was correlated with expression of other inflammatory markers, skin colonisation with 
Staphylococcus aureus, and clinical disease severity.  
Compared with placebo, tralokinumab had a normalising effect on key aspects of AD, 
including markers of skin barrier integrity, epidermal proliferation, and epidermal 
differentiation. Furthermore, a broad anti-inflammatory effect was observed in subjects 
receiving tralokinumab, demonstrated by reduction of a range of inflammatory markers in 
both serum and skin. Skin colonisation with Staphylococcus aureus was also strongly 
suppressed in subjects receiving tralokinumab compared with subjects receiving placebo. 
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5.2 Experience with investigational medicinal product 
Tralokinumab is a human recombinant monoclonal antibody of the immunoglobulin G4 
(IgG4) subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 
receptors (14-16). A compilation of clinical and nonclinical data on tralokinumab including 
pharmacokinetics (PK) is given in the current version of the investigator’s brochure. 
Based on a data lock point of 17-Sep-2019, the use of tralokinumab has been evaluated in 
22 complete clinical trials across 4 different indications (AD, asthma, ulcerative colitis, and 
idiopathic pulmonary fibrosis), including 4281 subjects who have received at least 1 dose of 
tralokinumab (3054 patient-years of exposure). The majority of the tralokinumab exposure 
was from the trials within AD (1426 patient-years of exposure) and asthma 
(1508 patient-years of exposure).  
LEO Pharma is currently conducting a clinical development programme with tralokinumab in 
AD comprising 5 complete trials and 4 ongoing trials. The completed pivotal trials and the 
trials following was based on the dose-finding trial (D2213C00001), which was a 
phase 2b trial evaluating the efficacy of tralokinumab 45 mg+TCS, 150 mg+TCS, and 
300 mg+TCS vs placebo+TCS. Based on the results from the trial, the dose of 300 mg 
tralokinumab was chosen for the phase 3 programme. 
The other 4 completed trials include LP0162-1325 and LP0162-1326 (similar tralokinumab 
monotherapy phase 3 trials of 52 weeks where superiority of tralokinumab was tested vs 
placebo at Week 16), LP0162-1339 (a combination therapy phase 3 trial of 32 weeks where 
superiority of tralokinumab+TCS was tested vs placebo+TCS at Week 16), and LP0162-1341 
(a phase 2 vaccine response trial evaluating the effect of tralokinumab vs placebo on vaccine 
antibody responses). 
In these 4 completed trials, IGA, EASI, Worst Daily Pruritus NRS, SCORAD, and DLQI 
were included as the main assessments supporting the multiplicity-adjusted primary and 
secondary efficacy endpoints. The efficacy of tralokinumab as monotherapy in subjects with 
moderate-to-severe AD was demonstrated in the replicate confirmatory phase 3 trials 
(LP0162-1325 and LP0162-1326) with statistically significant results for all primary and 
multiplicity-adjusted secondary endpoints at Week 16. Likewise, the efficacy of tralokinumab 
in combination with TCS was consistently demonstrated by statistically significant results on 
all primary and multiplicity-adjusted secondary endpoints at Week 16 in the 
LP0162-1339 trial. Non-inferiority of tralokinumab vs placebo with respect to immune 
responses to concomitantly administered non-live vaccines was demonstrated in the 
LP0162-1341 trial. 
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The safety evaluation of tralokinumab in AD focuses primarily on results from the 
5 completed trials in AD (i.e. the AD pool). During the initial treatment period in the AD pool, 
the overall frequencies of AEs were similar for tralokinumab (66%) and placebo (67%). Most 
AEs were mild or moderate for both tralokinumab and placebo, and severe AEs occurred at a 
lower frequency for tralokinumab (4.6%) than for placebo (6.3%). The frequencies of AEs 
leading to permanent discontinuation of IMP were low and similar for tralokinumab (2.3%) 
and placebo (2.8%). The majority of AEs were classified as recovered/resolved for both 
tralokinumab (60%) and placebo (62%). 
The following AEs were reported in ≥5% of subjects in any treatment group (tralokinumab vs 
placebo): dermatitis atopic (15% vs 26%), viral upper respiratory tract infection (16% vs 
12%), upper respiratory tract infection (5.6% vs 4.8%), and conjunctivitis (5.4% vs 1.9%). 
Subgroup analyses of AEs reported in the 2 monotherapy trials (i.e. monotherapy pool) 
showed that the overall incidence of AEs was comparable or lower for tralokinumab every 
second week (Q2W) vs placebo for all the geographic regions included in these trials (Asia, 
Australia, Europe, and North America). Across regions, the AE profiles were overall similar 
to that observed for the total population, although with a tendency to lower overall incidence 
of AEs in North America compared with Asia, Australia, and Europe independent of treatment 
group. 
During the initial treatment period in the AD pool, the frequency of serious adverse events 
(SAEs) was lower for tralokinumab (2.1%) than for placebo (2.8%). The majority of SAEs in 
both treatment groups were severe events, with similar frequencies for tralokinumab (1.5%) 
and placebo (1.7%). The frequencies of SAEs leading to permanent discontinuation of IMP 
were low and similar for tralokinumab (0.6%) and placebo (0.8%). The outcome of the 
majority of SAEs were recovered/resolved for both tralokinumab (32 of 38 events) and 
placebo (16 of 22 events). 
During prolonged treatment with tralokinumab with or without TCS from 16 up to 52 weeks, 
the safety profile was consistent with the initial 16-week treatment period based on overall 
frequencies of AEs, SAEs, severe AEs, and AEs leading to permanent discontinuation of IMP 
as well as the patterns of event types within each of these AE categories. 
Tralokinumab-treated subjects had a greater mean initial increase from baseline in eosinophil 
count compared with subjects treated with placebo. However, the increase in the 
tralokinumab-treated subjects was transient, and mean eosinophil counts returned to baseline 
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during continued treatment. No other clinically significant biochemistry parameters were 
identified from the completed phase 3 trials. 
Data from the trials with tralokinumab in AD showed that the incidence rate of ADA and 
neutralising antibodies after 16 weeks of treatment was low and similar for tralokinumab and 
placebo, confirming the low immunogenicity of tralokinumab.  
Overall, there were no indications that treatment with tralokinumab was associated with a 
higher risk of the following safety areas: skin infections requiring systemic treatment, eczema 
herpeticum, severe and serious infections (including any clinical endoparasitosis, 
opportunistic infections, and tuberculous infections), malignancies, anaphylaxis, serious 
allergic reactions, and immune complex disease. However, AEs of conjunctivitis, keratitis, 
and injection site reactions were more frequent with tralokinumab than placebo. 
Thus, tralokinumab has a favourable safety profile, without any important risks identified in 
the clinical trials conducted to date. 
5.3 Trial rationale 
Treatment recommendations for AD include topical therapies, the main being TCS. Both TCS 
and TCI have limited efficacy in patients with moderate-to-severe disease. For these patients, 
therapies with topicals combined with systemic immunosuppressants or biologics are 
recommended (17, 18). 
In the 2 multi-national phase 3 trials (LP0162-1325 and LP0162-1326), tralokinumab was 
safe and efficacious in treating adult subjects with moderate-to-severe AD in a monotherapy 
setting. Japanese subjects participated in one of these trials (LP0162-1325) and results from 
the ‘treatment policy’ estimand, allowing for TCS used as rescue medication, showed efficacy 
of tralokinumab in combination with TCS compared with placebo in combination with TCS in 
Japanese subjects. In addition, the uncontrolled open-label treatment arm, where optional TCS 
was allowed, showed that treatment with tralokinumab in combination with TCS is safe and 
efficacious in Japanese subjects. This is in line with the results from the multi-national 
phase 3 trial LP0162-1339 investigating tralokinumab in combination with TCS where no 
Japanese subjects participated. Previously, only the dose-finding trial (D2213C00001) has 
investigated tralokinumab in combination with proactively administered TCS in Japanese 
subjects, and the results for the Japanese subjects were generally consistent with those in the 
overall population. 
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The primary objective of this phase 3 trial (LP0162-1343) is to evaluate tralokinumab in 
combination with TCS in Japanese subjects by using a similar design (initial 16 weeks only) 
as the LP0162-1339 trial to facilitate an evaluation of similarity in efficacy and safety as 
compared with the LP0162-1339 trial. This trial will be a prospective, randomised, 
double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and safety of 
tralokinumab in combination with TCS in Japanese subjects with moderate-to-severe AD, 
who are candidates for systemic therapy. This trial will evaluate both the percentage of 
subjects achieving an IGA score of 0 (clear) or 1 (almost clear) (IGA 0/1) at Week 16 and the 
percentage of subjects achieving at least 75% reduction in EASI score (EASI75) at Week 16. 
In addition, secondary endpoints addressing symptom scores and extent of AD, itch-related 
sleep loss, itch severity, and HRQoL measures related to AD are also included. 
5.4 Ethical considerations 
No children or other vulnerable subjects incapable of giving informed consent will be 
enrolled in this trial. Furthermore, women who are pregnant, breastfeeding, or trying to 
become pregnant will not be enrolled in this trial. Women of childbearing potential must agree 
to use a highly effective method of contraception to prevent pregnancy during the trial and 
until 16 weeks after discontinuation of treatment with the IMP. In addition, all female subjects 
of childbearing potential will have a pregnancy test performed before, during, and at 
end-of-treatment to ensure that no foetuses are exposed to the IMP. 
In a 13-week repeated-dose nonclinical study in male cynomolgus monkeys, no adverse 
effects on male reproductive endpoints were observed (investigator’s brochure). Coupled with 
the negligible exposure risk for drugs and antibodies by way of semen to achieve meaningful 
pharmacological levels in a pregnant woman or in the conceptus (19), it is not considered 
necessary to impose restrictions on fathering a child or sperm donation in clinical trials with 
tralokinumab. 
In this clinical trial, the efficacy of tralokinumab in combination with TCS will be evaluated 
in adult subjects with moderate-to-severe AD. Tralokinumab in combination with TCS will be 
compared with a placebo+TCS control group. Subjects who during the treatment period or 
safety follow-up experience intolerable AD symptoms can be treated with rescue treatment 
according to the investigators discretion and thus will not be deprived from effective therapy. 
After the 16-week treatment period, subjects can continue in a long-term extension trial 
provided that they are eligible. 
In accordance with the current version of the ICH GCP guidelines, qualified medical 
personnel employed by LEO Pharma will be readily available to advise on trial-related 
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medical questions. Medical monitoring will be performed throughout the trial and safety data 
will be reviewed regularly by medically qualified staff at LEO Pharma to ensure that prompt 
action is taken, if needed, to maximise trial subject safety. 
5.5 Benefit/risk assessment 
With more than 4200 subjects exposed to tralokinumab in the completed trials as discussed in 
Section 5.2, the benefit/risk ratio is considered favourable and supports the administration of 
tralokinumab in combination with TCS therapy for the purposes of achieving the objectives of 
this trial.  
Based on the extensive clinical experience, a reassuring safety profile of tralokinumab has 
been observed in AD, asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in trials 
with healthy subjects. No safety concerns have been identified with the use of tralokinumab, 
and tralokinumab was well-tolerated. Generally, the AE profile for tralokinumab has been 
comparable to that for placebo in controlled clinical trials, the adverse drug reactions 
observed were non-serious and mild or moderate in severity, and ADA were detected in only 
few subjects exposed to tralokinumab for up to 1 year. 
Appropriate measures have been instituted in this trial to protect subjects from potential risks 
and to closely monitor each subject, such as: 
•
Close monitoring of subjects during the trial with trial visits every 2 weeks during the
treatment period as described in the schedule of trial procedures (Section 4).
•
Close monitoring of subjects during the post-dosing period (at the first 3 IMP
administration visits in the treatment period) as a precautionary measure against
hypersensitivity reactions (Section 9.2.1).
•
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 screening.
•
Exclusion of subjects with a history of a clinically significant infection (defined as a
systemic or serious skin infection requiring parenteral antibiotics, antiviral, or
antifungal medication) within 4 weeks prior to randomisation (Section 8.3), which, in
the opinion of the investigator or sponsor’s medical expert, may compromise the
safety of the subject in the trial.
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Altogether, the risks associated with participating in this trial are considered very low and 
outweighed by the benefit of a potential more user-friendly future treatment option for 
moderate-to-severe AD. 
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The primary estimand for the primary endpoints will incorporate the ‘composite’ strategy: 
•
Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks,
achieved without rescue medication, regardless of treatment discontinuation.
The secondary estimand for the primary endpoints incorporates the ‘treatment policy’ 
strategy: 
•
Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks,
regardless of rescue medication and discontinuation of IMP.
The binary key secondary endpoint (reduction of Worst Daily Pruritus NRS ≥4 from baseline 
to Week 16) will be evaluated using the same primary and secondary estimands as described 
for the primary endpoints. 
The primary estimand for the continuous key secondary endpoints will be based on the 
‘composite’ strategy: 
•
Treatment difference in the change from baseline to Week 16 in SCORAD and DLQI,
achieved without rescue medication, regardless of discontinuation of IMP.
The secondary estimand for the continuous key secondary endpoints will implement the 
‘hypothetical’ strategy: 
•
Treatment difference in the change from baseline to Week 16 in SCORAD and DLQI,
if all subjects adhered to the treatment regimen in the sense that they did not
discontinue IMP prematurely and no rescue medication was used before Week 16.
The analyses of all endpoints and estimands are described in Section 14.3. 
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7 Trial design 
7.1 Overall trial design 
This is a randomised, double-blind, placebo-controlled, parallel-group, multi-site, phase 3 
clinical trial in adult Japanese subjects with moderate-to-severe AD who are candidates for 
systemic therapy. The trial consists of a screening period, a treatment period, and a safety 
follow-up period as described below. The primary endpoints will be assessed at Week 16, and 
the final safety assessments will be conducted at Week 20. A scheme of the trial design is 
provided in Panel 1. A schedule of all trial visits and procedures is provided in Section 4 and 
all trial-related assessments are described in Section 11. The trial design will support a 
comparison of tralokinumab in combination with TCS to placebo in combination with TCS 
during a treatment period of 16 weeks. 
Screening period (Week -6/-2 to Week 0) 
The screening period has a minimum duration of 2 weeks and a maximum duration of 
6 weeks and includes 1 or 2 screening visits. The exact duration of the screening period for 
the individual subject depends on the length of required washout of AD treatment; the 
washout periods, as specified in the exclusion criteria (Section 8.3), are:  
•
6 weeks prior to randomisation for tanning beds or phototherapy.
•
4 weeks prior to randomisation for systemic immunosuppressive/immunomodulating
drugs, systemic corticosteroid use, or 3 or more bleach baths during any week within
the 4 weeks.
•
2 weeks prior to randomisation for TCS, TCI, topical PDE-4 inhibitors, and
topical JAK inhibitors.
If no washout is needed or if a 2-week washout is required, the screening period will be 
reduced to 2 weeks and the 2 screening visits will be merged to only 1 screening visit at 
Week -2 (Visit 2). 
All subjects will attend the screening visit scheduled at Week -2 where they will receive 
electronic diary (eDiary) training and start the eDiary (Section 11.3.4). Data entered into the 
eDiary during this 2-week period, including the data collected at baseline (Week 0; Visit 3), 
will be used to calculate baseline values of the patient-reported outcomes. 
All subjects must use an emollient twice daily (or more, as needed) for at least 14 days before 
randomisation and will continue this emollient treatment throughout the trial (including the 
safety follow-up). Subjects will initiate emollient treatment no later than the Week -2 visit. On 
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lesional skin, emollients should only be applied at a time when TCS is not applied; on 
TCS-untreated areas, the emollients may be applied at all times. The emollient treatment is 
further described in Section 9.4.  
Eligibility will be assessed both at the (first) screening visit and prior to randomisation at 
baseline (Week 0; Visit 3) as described in Section 8. 
Treatment period (Week 0 to Week 16) 
Following the screening period, eligible subjects will be randomly assigned to one of the 
following treatment groups: 
•
Tralokinumab 600 mg (4 mL) at baseline, then 300 mg (2 mL) Q2W + TCS.
•
Placebo (4 mL) at baseline, then placebo (2 mL) Q2W + TCS.
The IMPs, tralokinumab and placebo, are described in Section 9.1.1 and the treatment 
assignment is described in Section 9.3. The IMP will be administered by subcutaneous (SC) 
injections every second week throughout the treatment period as described in Section 9.2. The 
last dose of IMP will be administered at Week 14. 
Subjects in both treatment groups will also be supplied with an AxMP, i.e. a TCS cream 
(mometasone furoate) as described in Section 9.1.2. The subjects will apply a thin film of the 
supplied TCS once daily on areas with active lesions as needed and as described in 
Section 9.2.2. Lower potency TCS or TCI may be prescribed if needed on body areas where 
the supplied TCS is not advisable or on areas where continued treatment with TCS is 
considered unsafe. Topical therapy should be discontinued when control is achieved; 
discontinuation should preferably be gradual. The safety and appropriateness of continued or 
repeated courses of TCS therapy will be monitored and supervised by the site staff. 
Subjects who during the treatment period or safety follow-up experience intolerable AD 
symptoms can be treated with rescue treatment according to investigators discretion as 
described in Section 9.5. 
Subjects, who complete the 16-week treatment period, may be invited to enter a long-term 
extension trial conducted under a separate protocol (ECZTEND). 
Safety follow-up period (Week 16 to Week 20) 
After the treatment period, all subjects who do not enter the long-term extension trial will 
complete an off-treatment follow-up period for assessment of safety, PK, and ADA.  
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All subjects completing the treatment period, except for those who enter the long-term 
extension trial, will have safety follow-up assessments 6 weeks after last IMP administration. 
Subjects who permanently discontinue IMP or withdraw from the trial will be followed up as 
described in Section 10. 
7.2 Number of subjects needed 
Assuming a screening failure rate of 15%, approximately 118 subjects will be screened and 
approximately 100 subjects will be randomly assigned in a 1:1 ratio to receive either 
tralokinumab+TCS or placebo+TCS throughout the treatment period. The randomisation will 
be handled in an interactive response technology (IRT) system to ensure blinding in the trial 
(see Section 9.3). 
The statistical considerations for this sample size are described in Section 14.1. 
This trial will be conducted at approximately 35 sites in Japan. The anticipated minimum 
number of randomised subjects per trial site is 3 and the maximum number of subjects is 15. 
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 20). Subjects entering the long-term extension 
trial (ECZTEND) will also be considered as completers of this trial. 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
Final collection of data for the primary endpoints occurs at Week 16. 
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8 Trial population 
8.1 Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol.  
The subject’s eligibility for the trial must be verified according to the inclusion and exclusion 
criteria at visits specified in Panel 2. It will be recorded in the electronic case report form 
(eCRF) if the subject has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the trial 
will be ensured and described in submission documentation to regulatory authorities and 
institutional review boards (IRBs)/independent ethics committees (IECs), as applicable.  
8.2 Inclusion criteria 
The subjects must fulfil all of the following criteria to be eligible for the trial: 
1. Signed and dated informed consent has been obtained prior to any protocol-related
procedures. The subject’s legally authorised representative must sign the informed
consent if the subject is below 20 years of age.
2. Japanese subject aged 18 years and above.
3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (21)
(Appendix 4).
4. History of AD for ≥1 year.
5. Subjects who have a recent history (within 1 year before screening) of inadequate
response to treatment with topical medication.
•
Inadequate response is defined as failure to achieve and maintain remission or
a low disease activity state (comparable to IGA 0 [clear] to IGA 2 [mild])
despite treatment with a daily regimen of TCS of medium or 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
strongest TCS), whichever is shorter.
•
Subjects with documented systemic treatment for AD in the past year are
considered as inadequate responders to topical treatment and are potentially
eligible for treatment with tralokinumab after appropriate washout.
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6. AD involvement of ≥10% body surface area (BSA) at screening and baseline
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. A Worst Daily Pruritus NRS average score of ≥4 during the week prior to baseline.
•
Worst Daily Pruritus NRS score at baseline will be calculated from daily
assessments of worst itch severity (Worst Daily Pruritus NRS) during the
7 days immediately preceding randomisation (Day -6 to Day 0). Worst Daily
Pruritus NRS scores must be reported for a minimum of 4 out of the 7 days to
calculate the baseline average score. For subjects who do not fulfil this
requirement, randomisation should be postponed until this requirement is met,
but without exceeding the 6 weeks’ maximum duration for screening.
10. Subjects must have applied a stable dose of emollient twice daily (or more, as needed)
for at least 14 days before randomisation.
11. Women of childbearing potential must use a highly effective* form of birth control
throughout the trial and for at least 16 weeks (5 half-lives) after last administration of
IMP.
*A highly effective method of birth control is defined as one which results in a low
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), combined (oestrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), sexual 
abstinence (when this is in line with the preferred and usual life style of the subject 
and not just being without a current partner), same-sex partner, or 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 woman is defined as not being of childbearing 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 are not eligible for the trial if they fulfil any of the following criteria: 
1. Subjects for whom TCS are medically inadvisable e.g. due to important side effects or
safety risks (including intolerance to treatment, hypersensitivity reactions, significant
skin atrophy, systemic effects etc.) in the opinion of the investigator.
2. Concurrent enrolment in another interventional clinical trial.
3. Previous randomisation in a tralokinumab clinical trial.
4. Active dermatologic conditions that may confound the diagnosis of AD or would
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or
psoriasis.
5. Known active allergic or irritant contact dermatitis that is likely to interfere with the
assessment of severity of AD.
6. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB],
ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen+ultraviolet A [PUVA]) within
6 weeks prior to randomisation.
7. Treatment with the following medications within 4 weeks prior to randomisation:
•
Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate,
cyclosporin A, azathioprine, mycophenolate mofetil, JAK inhibitors).
•
Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).
•
Three or more bleach baths during any week within the 4 weeks.
8. Treatment with the following medications within 2 weeks prior to randomisation:
•
TCS.
•
TCI.
•
Topical PDE-4 inhibitors.
•
Topical JAK inhibitors.
9. Receipt of live attenuated vaccines within 30 days prior to randomisation and during
the trial including the safety follow-up period.
•
Receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed,
provided they are not administered within 5 days before/after any trial visit.
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10. Receipt of any marketed biological therapy (i.e. immunoglobulin, anti-IgE) including
dupilumab or investigational biologic agents:
•
Any cell-depleting agents including but not limited to rituximab: within
6 months prior to randomisation, or until lymphocyte count returns to normal,
whichever is longer.
•
Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to
randomisation.
11. Receipt of any investigational non-biologic agent within 5 half-lives prior to
randomisation.
12. Receipt of blood products within 4 weeks prior to screening.
13. Major surgery within 8 weeks prior to screening or planned in-patient surgery or
hospitalisation during the trial period.
14. Known or suspected allergy or reaction to any component(s) of the IMP or AxMP
formulation.
15. History of any active skin infection within 1 week prior to randomisation.
16. History of a clinically significant infection within 4 weeks prior to randomisation
which, in the opinion of the investigator or sponsor’s medical expert, may compromise
the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the
subject’s ability to participate in the trial. Clinically significant infections are defined
as:
•
A systemic infection.
•
A serious skin infection requiring parenteral (intravenous or intramuscular)
antibiotics, antiviral, or antifungal medication.
17. A helminth parasitic infection within 6 months prior to the date informed consent is
obtained that has not been treated with, or has failed to respond to, standard of care
therapy.
18. History of anaphylaxis following any biological therapy.
19. History of immune complex disease.
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20. History of cancer:
•
Subjects who have had basal cell carcinoma, localised squamous cell
carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided
that the subject is in remission and curative therapy was completed at least
12 months prior to the date informed consent was obtained.
•
Subjects who have had other malignancies are eligible provided that the
subject is in remission and curative therapy was completed at least 5 years
prior to the date informed consent was obtained.
21. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation
will be according to local guidelines as per local standard of care.
22. History of any known primary immunodeficiency disorder including a positive human
immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral
medications as determined by medical history and/or subject’s verbal report.
23. History of chronic alcohol or drug abuse within 12 months prior to screening, or any
condition associated with poor compliance as judged by the investigator.
24. History of attempted suicide or at significant risk of suicide (either in the opinion of
the investigator or defined as a ‘yes’ to suicidal ideation questions no. 4 or 5 or
answering ‘yes’ to suicidal behaviour on the Columbia-Suicide Severity Rating Scale
[C-SSRS] screening version).
25. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic,
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological,
immunological, psychiatric, or major physical impairment that is not stable, in the
opinion of the investigator, and could:
•
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 the trial.
26. Any clinically significant abnormal findings in physical examination, vital signs,
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the
screening period, which in the opinion of the investigator may put the subject at risk
because of his/her participation in the trial, or may influence the results of the trial or
the subject’s ability to complete the entire duration of the trial.
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27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times
the upper limit of normal (ULN) at screening.
28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb),
hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (anti-HCV) serology
at screening. Subjects with positive HBsAb may be randomised provided they have
negative HBsAg, HBcAb, and HCV serology.
29. Subjects who are not willing to abstain from donating blood and/or plasma from the
time of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.
30. Subjects who are legally institutionalised.
31. Pregnant, breastfeeding, or lactating women.
32. Employees of the trial site or any other individuals directly involved with the planning
or conduct of the trial, or immediate family members of such individuals.
8.4 Screening and screening failures 
Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by the central IRT system and the 
screening evaluations to assess eligibility criteria may begin. The date of first screening 
activity could be on the same day or a later date than the informed consent was signed. The 
subject ID will be used to identify the subject during the screening process and throughout 
trial participation. 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 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. In addition, 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 Pharma. 
Screening failures 
Screening failures are defined as subjects who consent to participate in the trial but do not 
meet one or more criteria required for participation in a trial and are not subsequently 
randomly assigned to trial treatment. A minimal set of screening failure information is 
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required to ensure transparent reporting of screening failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements (22) and to respond to 
queries from regulatory authorities. As a minimum, the following data will be collected in the 
eCRF for screening failure subjects: 
•
Date of informed consent(s).
•
Demographics (year of birth/age, sex, race, ethnicity).
•
Reason for screen failure.
o
Failure to meet eligibility criteria (specify criteria).
o
Lost to follow-up.
o
Withdrawal by subject.
o
Other (specify reason).
•
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 Trial product description 
9.1.1 Investigational medicinal products (tralokinumab and placebo) 
Both tralokinumab and placebo is presented as a liquid formulation in accessorised pre-filled 
syringes for SC injection. Tralokinumab and placebo will be packaged in individually 
numbered kits, each containing 1 accessorised pre-filled syringe. Further details are provided 
in Panel 4. The administration of IMPs (tralokinumab and placebo) is described in 
Section 9.2.1. 
Panel 4: Identification of investigational medicinal products 
Investigational 
medicinal product 
Dosage form 
Active ingredient and 
concentration 
Pack size 
Source 
Tralokinumab 
Solution for 
injection. 
Tralokinumab, formulated 
at a nominal concentration 
of 150 mg/mL in 50 mM 
sodium acetate/acetic acid 
buffer, 85 mM sodium 
chloride, 0.01% (w/v) 
PS-80, pH 5.5 solution. 
1 accessorised 
pre-filled 
syringea, 
1.0 mL fill 
volume. 
MedImmue 
Placebo 
Solution for 
injection. 
Placebo contains the same 
excipients, in the same 
concentration only lacking 
tralokinumab. 
1 accessorised 
pre-filled 
syringea, 
1.0 mL fill 
volume. 
MedImmune 
a)
The accessorised pre-filled syringe is a single-use, disposable system that is designed to administer the
labelled dose of the system to the SC space during 1 injection and automatically provide a safety
mechanism to reduce the occurrence of accidental needle sticks during disposal of the system. The
accessorised pre-filled syringe consists of a pre-filled syringe sub-assembly (1 mL pre-filled syringe barrel
with a 1/2 inch (12.7 mm) 27 gauge thin wall staked-in needle, rigid needle shield, plunger stopper), and a
safety device.
9.1.2 Auxiliary medicinal product (TCS) 
Each subject will be prescribed an AxMP through the trial; the subjects will receive a TCS 
cream (JP class: Very Strong). The AxMP (TCS) will be provided as mometasone furoate, 
0.1% cream in kit sizes of approximately 180-225 g every second week according to the 
schedule of trial procedures (Section 4). If needed, additional AxMP kit(s) may be dispensed 
to the subject at a scheduled or unscheduled visit at the investigator’s discretion. The amount 
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of additional AxMP dispensed must be recorded in the eCRF. The administration of AxMP 
(TCS) is described in Section 9.2.2. 
9.2 Administration of trial products 
9.2.1 Administration of IMP 
IMP administration visits are shown in the schedule of trial procedures (Section 4). The IRT 
will assign the required IMP kit number for each subject at each IMP administration visit. 
The first day of IMP administration is considered Day 0 (Week 0; Visit 3), where each subject 
will receive 4 SC injections (each 1.0 mL) of 150 mg tralokinumab or placebo to receive a 
total loading dose of 600 mg tralokinumab or placebo. 
At subsequent visits in the treatment period, each subject will receive 2 SC injections (each 
1.0 mL) of 150 mg tralokinumab or placebo every 2 weeks to receive a total dose of 300 mg 
tralokinumab Q2W or placebo Q2W. The last IMP administration will occur at Week 14. 
The IMP will be administered by a qualified, unblinded healthcare professional (HCP); see 
Section 9.3.1 for blinding details. A minimum interval of 7 days is required between 
2 administration visits. 
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 and in the eCRF at each IMP administration visit (Section 9.8.4). 
Further details on IMP administration are provided in a trial product handling manual. The 
IMP administration must be carried out according to these instructions. 
LEO Pharma does not have any specific treatment recommendations in relation to overdose. 
The investigator will use clinical judgement to treat any overdose, if necessary. See 
Section 13.6.2 for further details regarding overdose. 
Monitoring after IMP administration 
For the first 3 IMP administration visits (i.e. Weeks 0, 2, and 4), each subject will be 
monitored after the IMP administration for immediate drug reactions for a minimum of 
30 minutes with vital signs taken at 30 minutes or until stable, whichever is later. Vital signs 
will be documented in the eCRF (Section 11.4.1). 
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organization has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
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(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) (23). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 5 (24). Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be 
immediately available at the trial sites, and trial personnel should be trained to recognise and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase at the central laboratory (Section 11.4.4). 
Conditions requiring rescheduling of IMP administration 
The investigator should reschedule the visit, and IMP should not be administered until the 
rescheduled visit, if any of the following occur: 
•
The subject has an intercurrent illness that, in the opinion of the investigator, may
compromise the safety of the subject in the trial (e.g. viral illnesses).
•
The subject is febrile (defined as ≥38°C) within 72 hours prior to IMP administration.
If the visit cannot be rescheduled to maintain a minimum of 7 days to subsequent dose, the 
sponsor’s medical expert should be contacted. 
9.2.2 Administration of AxMP (TCS) 
The IRT will assign the required AxMP (TCS) kit number for each subject at each AxMP 
dispensing visit. The AxMP dispensing visits are shown in the schedule of trial procedures 
(Section 4). The subject must return used and unused AxMP (TCS tubes) at each subsequent 
trial visit to assess the amount of TCS used. The subjects must be instructed by the site staff 
on the importance of returning all used and unused TCS tubes. The site staff will return used 
and unused TCS tubes to the contract manufacturing organisation (CMO). The returned TCS 
tubes will be weighed at the CMO. 
Each subject will be instructed to apply a thin film of the dispensed AxMP (TCS) once daily 
on active lesions of AD, as needed. The TCS should be discontinued when control is 
achieved; discontinuation should preferably be gradual, and the maximum duration of a 
treatment course should not exceed 3 weeks. The safety and appropriateness of continued or 
repeated courses of TCS therapy will be monitored and supervised by site staff.  
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The AxMP (TCS) should be the only TCS product applied to the body during this period. 
Lower potency TCS or TCI may be used at the investigator’s discretion on areas of the body 
where use of the supplied AxMP (TCS) is not advisable such as areas of thin skin (face, skin 
fold areas, genital areas, etc.) or on areas where continued treatment is considered unsafe. The 
low potency TCS and TCI will not be provided by LEO Pharma and will not be weighed but 
must be registered in the eCRF as concomitant medications (Section 9.6).  
The supplied AxMP (TCS) is only for use on active lesions of AD and not for use in other 
indications. 
9.3 Treatment assignment (randomisation) 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised centrally at baseline (Week 0; Visit 3) to receive 
treatment with either tralokinumab+TCS or placebo+TCS. 
The treatment assignment will be pre-planned according to a computer-generated 
randomisation schedule in a 1:1 ratio stratified by baseline disease severity (moderate 
[IGA score 3] / severe [IGA score 4]). 
The IRT will be used to control randomisation and stratification factor, along with IMP supply 
chain and expiry tracking, and for dispensing and return of AxMP (TCS). 
9.3.1 Blinding 
This is a double-blinded trial in which the IMPs (tralokinumab and placebo) are visually 
distinct from each other. Since tralokinumab and placebo are visually distinct from each other 
and not matched for viscosity, the IMP will be handled and administered by a qualified, 
unblinded HCP (trained site staff) at the trial site who will neither be involved in the 
management of the trial subjects nor perform any of the trial assessments. 
The packaging and labelling of the IMPs will contain no evidence of their identity. The IMP is 
packed in identical boxes, with non-sequential kit numbers to ensure that unblinding does not 
occur during shipment and handling of the IMP.  
The subjects, investigators involved in the treatment or clinical evaluation, and LEO Pharma 
staff involved in monitoring of the trial subjects will not be aware of the treatment received. 
If the treatment assignment for a subject becomes known to the investigator or other site staff 
involved in the management of trial subjects, LEO Pharma must be notified immediately. 
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Should an issue arise with the IMP (e.g. damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g. a 
malfunction during IMP administration]), the unblinded HCP at the site will contact the 
clinical research associate (CRA) to determine whether any specific actions are required. 
The trial site will maintain a written plan detailing which staff members are blinded/unblinded 
and the process of IMP administration used to maintain the blind. 
9.3.2 Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, other HCPs who are not members of the trial staff, or authorised 
LEO Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
IRT. For a requester who is not a member of the trial staff and who does not have access to the 
IRT (e.g. a physician at an emergency room), a local contact number for the emergency 
unblinding contract research organisation (CRO) is provided on the subject card (see 
Appendix 3B) to be used if the investigator or delegated site staff cannot be reached. The 
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 emollient as a background treatment twice daily (or more, as needed) 
for at least 14 days before randomisation. The background treatment should preferably be an 
additive free, basic bland emollient. On days where site visits take place, the subjects should 
preferably postpone application of emollient to after the end of the visit, since the dryness of 
the skin must be assessed as part of the efficacy assessments. 
On lesional skin, emollients should only be applied at times when TCS is not applied 
(i.e. emollients and TCS should not be used on the same areas at the same time of the day); on 
TCS-untreated areas, the emollients may be applied at all times. 
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The subjects must continue their background emollient treatment throughout the trial 
(including the safety follow-up period). 
It will be recorded in the eCRF if background treatment (emollient) has been used as 
described since last visit; if not, a reason should be provided. 
9.5 Rescue treatment 
If medically necessary (i.e. to control intolerable AD symptoms), rescue treatment for AD 
may be provided to the subjects at the discretion of the investigator. If possible, investigators 
should attempt to limit the first step of rescue treatment to topical medications (i.e. highest 
potency TCS) and escalate to systemic medications only for subjects who do not respond 
adequately after at least 14 days of topical treatment. The subjects will be monitored for signs 
of local or systemic TCS toxicity and the safety and appropriateness of continued use will be 
supervised by site staff. 
Subjects who receive topical rescue treatment (highest potency TCS, JP class > Very Strong) 
will continue IMP treatment. 
If a subject receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (methotrexate, mycophenolate mofetil, azathioprine, etc.), IMP will 
be immediately discontinued (see Section 10.2.2). After the treatment with these medications 
is completed, IMP may be resumed if deemed appropriate by the investigator, but not sooner 
than 5 half-lives after the last dose of systemic rescue treatment. The use of biological rescue 
treatment, including use of dupilumab, will be disallowed for the entire trial duration. 
Investigators should make every attempt to conduct efficacy and safety assessments (at least 
disease severity scores [IGA and EASI], concomitant medications/procedures, and AEs) 
immediately before administering any rescue treatment. An unscheduled visit may be used for 
this purpose, if necessary. 
In the primary efficacy analyses, subjects who receive highest potency TCS (JP class > Very 
Strong) or systemic rescue treatment during the treatment period will be considered as 
non-responders. 
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9.6 Concomitant medications and concurrent procedures 
Any medication or vaccine that the subject receives from 3 months prior to screening through 
the safety follow-up period 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, unit, and frequency.
•
Route of administration.
Similarly, concurrent procedures must also be recorded in the subject’s medical record and the 
eCRF. Note: in this trial, only surgical procedures and procedures related to AD treatment 
(e.g. phototherapy or bleach baths) will be recorded. The following details will be recorded: 
procedure name, body location, indication, and start and stop date (it will also be recorded if 
the procedure is ongoing). 
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. 
In addition, the following concomitant medications related to AD treatment are permitted 
from screening through the safety follow-up period (Week 20): 
•
Oral antibiotics, antiviral, or antifungal therapy for skin infections as appropriate.
•
Stable doses of an emollient (see Section 9.4; subjects must apply such emollients
twice daily [or more, as needed] for at least 14 days before baseline and throughout
trial participation).
•
Oral antihistamines.
9.7 Prohibited medications and procedures 
The medications and procedures listed below are prohibited during the trial from 
randomisation (Week 0). Medications and procedures disallowed prior to randomisation are 
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covered by the exclusion criteria (see Section 8.3). In case any prohibited treatments are used 
during the trial, they must be recorded in the eCRF as concomitant medication. 
From randomisation through end of treatment (Week 16): 
•
PDE-4 inhibitors.
•
TCS of highest potency (JP class > Very Strong).
•
Topical JAK inhibitors.
•
Use of UVA or UVB, psoralen+UVA (PUVA), other phototherapy, or tanning beds.
•
3 or more bleach baths per week.
From randomisation through safety follow-up (Week 20): 
•
Investigational agents other than tralokinumab.
•
Systemic corticosteroids (nasal, ophthalmic and inhaled corticosteroids are allowed).
•
Systemic treatment with an immunosuppressive/immunomodulating agent (examples
include: cyclosporine A, mycophenolate mofetil, azathioprine, methotrexate, JAK
inhibitors, interferon-gamma, dupilumab, or other biologics).
•
Allergen immunotherapy.
•
Live (attenuated) vaccine.
•
Immunoglobulins.
•
Blood products.
Some of the above mentioned prohibited medications can be used during the treatment period 
(Week 0 to Week 16) provided the indication is rescue treatment for AD. Please refer to 
Section 9.5 for details regarding rescue treatment. 
The sponsor’s medical expert will determine whether IMP discontinuation is required. 
Please note that receipt of inactive/killed vaccines (e.g. inactive influenza) is allowed, 
provided they are not administered within 5 days before/after any trial visit. 
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9.8 Treatment logistics and accountability 
9.8.1 Labelling and packaging of trial products 
9.8.1.1 Labelling and packaging of IMP 
The IMP will be packaged in individually numbered kits, each containing 1 pre-filled 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 (25), local regulations and trial 
requirements. Label text will be translated into local languages, as required. 
9.8.1.2 Labelling and packaging of AxMP (TCS) 
The AxMP will be packaged in individually numbered kits that contain tubes of TCS cream 
with a total weight of approximately 180-225 g. 
Primary and secondary packaging materials (tube and outer kit carton, respectively) will be 
individually labelled. 
The labelling of AxMP will be in accordance with Annex 13 (25), local regulations, and trial 
requirements. Label text will be translated into local languages, as required. 
9.8.2 Storage of trial products 
9.8.2.1 Storage of IMP 
All LEO Pharma supplied IMPs must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed. 
The IMP must be stored at 2 to 8°C at the trial site. The temperature during storage will be 
monitored by a calibrated, stationary, and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer. A temperature log must be kept to 
document the storage within the right temperature interval. Storage facilities should be 
checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
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Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately contact their CRA for further guidance: 
•
Temperature excursion upon receipt or during storage at the trial site.
•
Damaged kit upon receipt.
•
Damaged syringe/cartridge.
Damaged IMP should be documented in the IRT and reported as a product complaint to 
LEO Pharma K.K. (Section 9.10). Damaged IMP may not be used. 
9.8.2.2 Storage of AxMP (TCS) 
All LEO Pharma supplied AxMP (TCS) must be stored in a secure and restricted area under 
the conditions specified on the label and remain in the original container until dispensed. 
The AxMP must be stored at the trial site according to the approved label for mometasone 
furoate. The temperature during storage at the trial site will be monitored by a calibrated, 
stationary, and continuously monitoring system. Minimum requirement is a calibrated 
min/max thermometer. A temperature log must be kept to document the storage within the 
right temperature interval. Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected AxMP 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 AxMP should be documented in the IRT and reported as a product complaint to 
LEO Pharma K.K. (Section 9.10). Damaged AxMP may not be used. 
9.8.3 Drug accountability 
9.8.3.1 IMP accountability 
The head of institute is fully responsible for the IMPs at the trial site and for maintaining 
adequate control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
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Documentation of drug accountability must be kept of the IMPs administered to each 
individual subject randomised in the trial. This documentation must be available during 
monitoring visits and will be checked by the CRA to verify correct dispensing of the IMPs. 
Drug accountability information will be recorded in IRT system. The IRT system will also 
maintain the inventory status of all IMPs at the trial site. 
All unused IMPs (including packaging material) supplied by the CMO on behalf of 
LEO Pharma will be returned to the CMO. Prior to their return, the IMPs must be fully 
accounted for by the CRA with the help of site staff responsible for dispensing and 
administering the IMPs. Accountability must be documented on drug accountability forms 
and in the IRT. The IMP returned to the CMO will be reconciled with the individual drug 
accountability forms. 
Refer to the trial product handling manual for more information about drug accountability and 
for information on return of trial products. 
9.8.3.2 AxMP (TCS) accountability 
The head of institute is fully responsible for the AxMP (TCS) at the trial site and for 
maintaining adequate control of the AxMP and for documenting all transactions with them. 
Dispensing of AxMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
The subjects will return the AxMP (used, partly used, and unused TCS tubes [including 
packaging material]) at the visits specified in the schedule of trial procedures (Section 4). 
Returned AxMP can be stored at room temperature and must be stored separately from 
non-allocated AxMP. 
Documentation of drug accountability must be kept of the AxMP dispensed to each individual 
subject randomised in the trial. This documentation must be available during monitoring visits 
and will be checked by the CRA to verify correct dispensing and return of the AxMP. Drug 
accountability information will be recorded in IRT system. The IRT system will also maintain 
the inventory status of all AxMP at the trial site. 
All used and unused AxMP (including packaging material) supplied by the CMO on behalf of 
LEO Pharma will be returned to the CMO. Prior to their return, the AxMP must be fully 
accounted for by the CRA with the help of site staff responsible for dispensing the AxMP. 
Accountability must be documented on drug accountability forms and in the IRT. 
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Refer to the trial product handling manual for more information about drug accountability and 
information on returning trial products. 
All AxMP (TCS tubes) returned to the CMO will be weighed to determine the amount of TCS 
used by the subjects and will be reconciled with the individual drug accountability forms. The 
detailed procedure for weighing of AxMP (TCS tubes) and subsequent transfer of tube weight 
data to the clinical database will be documented. 
9.8.4 Treatment compliance 
IMP injections will be performed by site staff who will also hand out AxMP (TCS) for 
self-administration and keep the accountability records up to date. IMP administration along 
with reasons for any non-compliance will be recorded in the eCRF. 
9.8.5 Trial product destruction 
Used syringes will be destroyed at the trial sites. 
Unused IMP as well as used and unused AxMP (TCS) returned to the CMO will be destroyed 
by the CMO according to approved procedures and/or local requirements. 
Please refer to the trial product handling manual regarding details for destruction of trial 
products. 
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 as 
described in Section 7.1 may be offered participation in that trial. 
9.10  Reporting product complaints 
Any defects or issues with the IMP as well as any IMP device deficiency (including 
malfunctions, use errors, and inadequate labelling) must be reported to Pharmacovigilance at 
LEO Pharma K.K. on the trial-specific (paper) complaint form within 3 days of first 
knowledge.  
Critical complaints (defined as any defect, issue, or IMP 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 Pharmacovigilance, LEO Pharma K.K. within 24 hours.  
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Complaint forms should contain a detailed description of the defect, issue, or IMP 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 IMP device deficiency will be reported by the investigator as described 
in Sections 13.3 and 13.4. Similarly, any defects or issues with the AxMP (TCS) must also be 
reported to Pharmacovigilance at LEO Pharma K.K. using the same complaint procedure as 
for the IMP and IMP device. 
Refer to the IRT training material for information on how to update the kit status in the IRT. 
During the investigation of the product complaint, the IMP device must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the IMP device 
needs to be returned for further investigation or may be destroyed. 
Pharmacovigilance, LEO Pharma K.K., contact information for reporting product complaints: 
Fax number: +81 3 4243 3311 
E-mail address: clinical_trial_jp@leo-pharma.com
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10 Discontinuation and withdrawal 
10.1  General principles 
A subject may withdraw from the trial (prior to first dose or during the treatment period) or 
permanently discontinue trial treatment at any time if the subject, the investigator, or 
LEO Pharma considers that it is not in the subject’s best interest to continue. 
In order to obtain the most representative efficacy evaluation of tralokinumab, it is of 
importance to assess the efficacy status of each subject at the planned primary endpoints visit 
(nominal Week 16 visit), irrespective of whether the subject has discontinued IMP or not. 
Therefore, permanent discontinuation of IMP is evaluated as a separate occurrence that does 
not necessitate that the subject also withdraws from subsequent selected trial activities 
(including the safety follow-up visit). 
Permanent discontinuation of IMP and withdrawal from the trial are considered to occur in the 
following circumstances: 
•
Permanent discontinuation of IMP occurs when all further IMP administration is
actively stopped by decision of the subject or investigator. This also involves when
the subject is lost to follow-up. The subject will continue to participate in selected
trial visit activities as outlined in Section 10.3.
•
Withdrawal from trial occurs when participation in trial activities is stopped
before the planned safety follow-up visit at Week 20. This may happen either at the
time of permanent discontinuation of IMP or later.
Subjects who permanently discontinue IMP and/or withdraw from the trial will not be 
replaced. 
10.2  Reasons for discontinuation of IMP 
10.2.1  Reasons for permanent discontinuation of IMP 
Subjects will permanently discontinue 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.
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•
Evidence of pregnancy.
•
Any infection that is opportunistic, such as active tuberculosis and other infections
whose nature or course may suggest an immuno-compromised status.
•
Severe laboratory abnormalities:
o
ALT and/or AST values >3×ULN with total bilirubin >2×ULN (unless
elevated bilirubin is related to Gilbert-Meulengracht Syndrome).
o
Confirmed AST and/or ALT >5×ULN (for more than 2 weeks).
Data to be recorded in the eCRF 
The primary reason for permanent discontinuation of IMP must be recorded in the medical 
records and on the end of treatment form in the eCRF where the following options are 
available: 
•
Adverse event (a specification must be provided).
•
Death.
•
Lost to follow-up.
•
Lack of efficacy.
•
Withdrawal by subject.
•
Pregnancy.
•
Other (a specification must be provided).
10.2.2  Reasons for temporary discontinuation of IMP 
IMP administration may be temporarily suspended in the event of: 
•
Other intercurrent illnesses or major surgery.
•
An infection that requires parental treatment with antibiotic, antifungal, antiviral,
anti-parasitic, or anti-protozoal agents.
IMP administration should be temporarily suspended in the event of: 
•
Treatment with systemic corticosteroids or non-steroidal
immunosuppressive/immunomodulating medications (e.g. cyclosporine,
methotrexate, azathioprine, mycophenolate mofetil, JAK inhibitors, dupilumab or
other biologics).
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After the treatment with any of the medications mentioned in this section, IMP may be 
resumed if deemed appropriate by the investigator, but not sooner than 5 half-lives after the 
last dose of systemic therapy. 
10.3  Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend: 
•
Early termination visit (as soon as possible after last IMP administration).
•
Nominal Week 16 visit (16 weeks after randomisation).*
•
Safety follow-up visit (6 weeks after last IMP administration).*
*If a subject permanently discontinues IMP dosing ≥5 weeks before the planned
Week 16 visit, then only the nominal Week 16 visit (16 weeks after randomisation) 
will be conducted. At this visit, the relevant safety information will be collected, since 
all assessments planned at the safety follow-up visit are part of the assessments 
performed at the nominal Week 16 visit. 
Subjects who permanently discontinuing IMP <5 weeks before the planned Week 16 
visit should have both the nominal Week 16 visit and the safety follow-up visit 
conducted. 
See the schedule of trial procedures (Section 4) for assessments to be done at these visits. The 
investigator will review any AEs which will be followed up according to Section 13.7, if the 
subject agrees. 
Withdrawal from trial 
Randomised 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. 
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 subject’s medical record and eCRF. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.8. 
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10.4  Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject. 
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
•
The trial site must attempt to contact the subject and reschedule the missed visit as
soon as possible and counsel the subject on the importance of maintaining the
assigned visit schedule and ascertain whether or not the subject wishes to continue
in the trial.
•
Before a subject is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the subject. These contact attempts should
be documented in the subject’s medical record. Should the subject continue to be
unreachable, they will be considered to have withdrawn from the trial with a
primary reason of lost to follow-up.
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11 Trial assessments and procedures 
11.1  Overview 
There are up to 12 scheduled visits at the trial site during the trial. Evaluations to be done at 
each visit are shown in the schedule of trial procedures in Section 4 and the trial design is 
described in Section 7.1. Assessments and procedures should be performed in the order shown 
in Panel 5 at the screening and baseline visits. The photographs can be taken following the 
most appropriate order at each selected trial site. The order of assessments may be changed 
after the baseline visit to perform safety and laboratory assessments before the investigator 
assessments, but after the patient-reported outcomes. The assessments should preferably be 
performed in the same order for all subjects at the trial site.  
Panel 5: Sequence of assessments 
a) Performed only by adequately trained investigators.
b) First component C, then component A and B.
Abbreviations: ADA, anti-drug antibodies; AxMP, auxiliary medicinal product; DLQI, Dermatology 
Life Quality Index; EASI, Eczema Area and Severity Index; IGA, Investigator’s Global Assessment; 
IMP, investigational medicinal product; PK, pharmacokinetics; POEM, Patient-Oriented Eczema 
Measure; SCORAD, Scoring Atopic Dermatitis; TCS, topical corticosteroids. 
Patient-reported outcomes
1. DLQI
2. POEM
Investigator assessmentsa
1. SCORADb
2. IGA
3. EASI
Safety and laboratory assessments 
(including ADA and PK)
Administration of IMP 
(tralokinumab or placebo)
Dispensing of AxMP 
(TCS)
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Subjects participating in the trial will be under careful supervision of a qualified principal 
investigator. 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 
dermatologists. 
To reduce inter-rater variability, the same investigator should preferably perform all the 
efficacy evaluations (SCORAD, IGA, and EASI) for a given subject throughout the entire 
trial period. 
The investigators performing the assessments must not be involved in the administration of 
IMP (Section 9.3.1). 
AEs must be assessed by medically qualified personnel (Section 13.2). 
Subjects may also need to be seen at unscheduled visits during the trial; the assessments to be 
performed at an unscheduled visit are left at the investigator’s discretion (Section 4). In case a 
subject withdraws from the trial or permanently discontinue IMP prematurely, refer to 
Section 10 for details and Section 4 for assessments/procedures. 
11.2  Assessments performed only at screening and/or baseline 
Assessments performed only at screening (Week -6/Week -2) and/or baseline (Week 0) 
include: assessment of eligibility criteria (including review of scores on the C-SSRS screening 
version), demographics, medical history, height and weight, and BSA affected by AD. These 
are described in further detail in Sections 11.2.1 to 11.2.5. 
Laboratory tests performed only at screening/baseline include serology (hepatitis B and C, 
and HIV) and serum pregnancy test (Section 11.4.4). 
11.2.1  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 
(26). The C-SSRS must be completed at screening to check that exclusion criterion no. 24 
does not apply. Further details on the assessment according to the C-SSRS are included in the 
efficacy assessment & C-SSRS manual. 
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11.2.2  Demographics 
The following demographic data will be recorded: 
•
Year of birth.
•
Age.
•
Sex (determined by the investigator): female, male.
Sex (female, male) refers to biological differences: chromosomes, hormonal,
profiles, internal and external sex organs. Gender is a social criterion, e.g. feminine,
masculine, and will not be captured.
•
Confirmation of race and ethnic origin.
11.2.3  Medical and surgical history 
Relevant past and concurrent medical/surgical history must be recorded and includes: 
•
All past and current skin disease history, including but not limited to:
o
Alopecia.
o
Vitiligo.
o
Herpes simplex.
For each condition or diagnosis, the start date and stop date will be recorded (it 
will also be recorded if the diagnosis is ongoing). 
•
Atopy history, including:
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.
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For each condition, diagnosis, or surgical procedure, the start date and stop date will be 
recorded (it will also be recorded if the condition, diagnosis, or surgical procedure is 
ongoing). 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
11.2.4  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. 
11.2.5  Body surface area involvement 
The total BSA affected by AD will be assessed by the investigator for each section of the body 
as component A of SCORAD (Section 11.3.3) and will be reported as a percentage of all 
major body sections combined. The following body regions will be assessed (brackets show 
the highest possible score for each region): head and neck (9%), anterior trunk (18%), 
back (18%), upper limbs (18%), lower limbs (36%), and genitals (1%). The total BSA score 
will be assessed according to the schedule of procedures in Section 4. 
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 disease) (Panel 6). 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. Whenever possible, the IGA should be assessed by 
the same investigator at each visit to reduce inter-rater variability. The disease severity 
assessment score will be recorded in the eCRF. 
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Panel 6: Investigator’s Global Assessment 
Score 
Disease 
severity 
Standard IGA scale 
IGA morphological descriptors 
0 
Clear 
No inflammatory signs of 
atopic dermatitis. 
No erythema and no elevation 
(papulation/infiltration). 
1 
Almost 
clear 
Just perceptible erythema, 
and just perceptible 
papulation/infiltration. 
Barely perceptible erythema and/or minimal 
lesion elevation (papulation/infiltration) that is 
not widespread. 
2 
Mild 
disease 
Mild erythema and mild 
papulation/infiltration. 
Visibly detectable, light pink erythema and 
very slight elevation (papulation/infiltration). 
3 
Moderate 
disease 
Moderate erythema and 
moderate 
papulation/infiltration. 
Dull red, clearly distinguishable erythema and 
clearly perceptible but not extensive elevation 
(papulation/infiltration). 
4 
Severe 
disease 
Severe erythema and severe 
papulation/infiltration. 
Deep/dark red erythema, marked and extensive 
elevation (papulation/infiltration). 
11.3.2  Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (27). The EASI score will be assessed according to the schedule of 
trial procedures (Section 4). The assessment will be based on the condition of the disease at 
the time of evaluation and not in relation to the condition at a previous visit. Whenever 
possible, the EASI score should be assessed by the same investigator at each visit to reduce 
inter-rater variability. 
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 7. Briefly, the investigator will assess the severity of 4 AD disease characteristics 
(erythema, induration/papulation, excoriation, and lichenification) on the 4 body regions 
(head/neck, trunk, upper extremities, lower extremities); severity will be assessed according 
to the scale shown in Panel 8. For each body region, a severity sum score will be calculated, 
which will be multiplied by an area score (Panel 8) and by a weighting factor. The EASI score 
equals the sum of the scores obtained for each body region (Panel 7). 
The body region, severity of the disease characteristics (erythema, induration/papulation, 
excoriation, and lichenification), and the area score will be recorded in the eCRF. 
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Panel 7: Calculation of EASI 
Body region 
Erythema 
Induration/ 
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.1 
Trunk 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.3 
Upper extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.2 
Lower extremities ( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.4 
The EASI score is the sum of the 4 body region scores 
(range 0-72) 
Abbreviations: AS, area score; EASI, Eczema Area and Severity Index; SS, severity score. 
Modified from (28). 
Panel 8: EASI severity score scale and area score scale 
Severity score scale 
Area score scale 
0 
None/absent 
0 
0% affected area 
1 
Mild 
1 
1% to 9% affected area 
2 
Moderate 
2 
10% to 29% affected area 
3 
Severe 
3 
30% to 49% affected area 
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 
Abbreviations: EASI, Eczema Area and Severity Index. 
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 (29). 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). 
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The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit. Whenever possible, SCORAD should be 
assessed by the same investigator at each visit to reduce inter-rater variability. 
The assessment consists of 3 components: A = extent, B = intensity, and C = subjective 
symptoms. 
Extent (A) 
The extent of AD is assessed as a percentage of each defined body area and reported as the 
sum of all areas (maximum score = 100%). 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, oedema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) is assessed by the investigator on an average 
representative area using the following scale: 
0 
= 
None/absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Note: dryness is evaluated on uninvolved areas. 
The sum of intensity score of the 6 symptoms will be reported (maximum score = 18). 
Subjective symptoms (C) 
A subjective assessment of the average itch and sleeplessness over the last 3 days/nights is 
recorded for each symptom by the subject on a visual analogue scale, where 0 is no itching (or 
no trouble sleeping) and 10 is unbearable itching (or lot of trouble sleeping), with a maximum 
possible score of 20. 
The SCORAD is calculated as: A/5+7B/2+C. 
The extent and intensity of disease will be reported in the eCRF. 
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11.3.4  Patient-reported outcomes 
The following patient-reported outcomes will be assessed using an eDiary device: 
•
Eczema-related Sleep NRS (Section 11.3.4.1).
•
Worst Daily Pruritus NRS (Section 11.3.4.2).
•
Patient Days of Topical Treatment Use (Section 11.3.4.3).
At screening, the subjects will receive the eDiary device and eDiary training. The subjects 
must complete the eDiary in the morning each day as specified in the schedule of trial 
procedures (Section 4), and compliance with the eDiary completion will be reviewed by the 
trial site staff throughout the trial. The eDiary should be returned to the trial site as outlined in 
the schedule of trial procedures (Section 4). 
In addition, the following patient-reported outcomes will be completed by the subjects at the 
trial site: 
•
DLQI (Section 11.3.4.4).
•
POEM (Section 11.3.4.5).
An electronic device will be supplied to each trial site in which the subjects can complete the 
DLQI and POEM. 
Each subject must make individual assessments relating to their perception of their disease 
and quality of life. These will be performed independently of the investigator and trial site 
staff, and prior to the investigator performing his/her efficacy assessments. 
11.3.4.1  Eczema-related Sleep numeric rating scale 
Subjects will rate how much their eczema interfered with their sleep over the last night using 
an 11-point NRS (Eczema-related Sleep NRS) with 0 indicating that it ‘did not interfere’ and 
10 indicating that it ‘completely interfered’. Subjects will complete the Eczema-related Sleep 
NRS as part of the eDiary each day in the morning from Week -2 until Week 16. 
11.3.4.2  Worst Daily Pruritus numeric rating scale 
Subjects will assess their worst itch severity over the past 24 hours using an 11-point NRS 
(Worst Daily Pruritus NRS) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Worst Daily Pruritus NRS as part of the eDiary each 
day in the morning from Week -2 until Week 16. 
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11.3.4.3  Patient Days of Topical Treatment Use 
Subjects will assess their use of topical AD treatment over the past 24 hours using a response 
scale (‘yes’, ‘no’). Subjects will complete the Patient Days of Topical Treatment Use as part 
of the eDiary each day in the morning from baseline (Week 0) until Week 16. 
11.3.4.4  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 (30). 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 (range: 0 to 30); a high score is indicative of a poor health-related quality of life. The 
DLQI will be completed at the trial site according to the schedule of trial procedures 
(Section 4). 
11.3.4.5  Patient-Oriented Eczema Measure 
The POEM is a validated questionnaire used to assess disease symptoms in atopic eczema 
patients in both clinical practice and clinical trials (31). The tool consists of 7 items each 
addressing a specific symptom (itching, sleep, bleeding, weeping, cracking, flaking, and 
dryness). Subjects will score how often they have experienced each symptom over the 
previous week on a 5-point categorical response scale (0 = ‘no days’; 1 = ‘1 to 2 days’; 
2 = ‘3 to 4 days’; 3 = ‘5 to 6 days’; 4 = ‘every day’). The total score is the sum of the 7 items 
(range: 0 to 28) and reflects disease-related morbidity; a high score is indicative of a worse 
disease severity. The POEM will be completed at the trial site according to the schedule of 
trial procedures (Section 4). 
11.4  Safety assessments 
11.4.1  Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the schedule of trial procedures (Section 4). Vital signs will be measured in a supine or 
sitting position following at least 5 minutes of rest.  
For the first 3 IMP administration visits (i.e. at Weeks 0, 2, and 4), the subjects will be 
monitored after each IMP administration for immediate drug reactions for a minimum of 
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30 minutes with vital signs taken at 30 minutes or until stable, whichever is later 
(Section 9.2.1). 
If an abnormal vital sign at screening is considered to be clinically significant by the 
investigator, it will be at the discretion of the investigator if the subject should be randomised 
into the trial (respecting exclusion criterion no. 26). 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine or sitting 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 and the second measurement should be recorded 
in the eCRF. If the third measurement confirms the first measurement (abnormal), the second 
measurement will be considered false and the first measurement should be recorded in the 
eCRF. 
Reporting in eCRF 
The vital signs (and the time they were measured, when applicable) will be recorded in the 
eCRF; if vital signs were not assessed, a reason should be given. Clinically significant 
abnormal vital signs at the screening visit will be documented as medical history in the eCRF. 
At subsequent visits, any clinically significant deterioration of a pre-existing condition as well 
as any new clinically significant sign, symptom, or illness will be reported as an AE in 
accordance with Section 13.3. 
11.4.2  Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin 
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 
screening, the subject must not be randomised into the trial (respecting exclusion 
criterion no. 26). 
Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
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clinically significant’); if a physical examination was not performed, a reason should be 
given. 
If the only abnormal finding resulting from the physical examination is AD, the physical 
examination should be stated as ‘normal’. 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness will 
be reported as an AE in accordance with Section 13.3. 
11.4.3  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, the investigators will record the result of the immediate safety 
evaluation and the date of ECG collection 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 ECG results (‘normal’, ‘abnormal, not clinically 
significant’, or ‘abnormal, clinically significant’) and sign and date. The investigator has the 
final decision on the clinical significance of ECG abnormalities. 
If a result is abnormal at screening and considered by the investigator to be clinically 
significant, it will be up to the investigator’s discretion if the subject should be randomised 
into the trial (respecting exclusion criterion no. 26); if such a subject is randomised, 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. 
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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 findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition as well as any new clinically significant sign, symptom, or illness will 
be reported as an AE in accordance with Section 13.3. 
11.4.4  Laboratory testing: chemistry, haematology, serology, urinalysis, 
pregnancy test 
11.4.4.1  Overview 
Blood samples for chemistry, haematology, serology, and serum pregnancy test as well as 
urine samples for dipstick/urinalysis (if applicable) and urine pregnancy tests will be collected 
according to the schedule of trial procedures (Section 4). An overview of the individual 
laboratory parameters assessed in this trial is provided in Panel 9. 
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
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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 evaluation. The signed and dated version 
will be filed with the investigator’s trial documentation. In case of clinically significant 
abnormal results (at randomisation and onwards), appropriate action, as judged by the 
investigator, must be taken. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial 
(respecting exclusion criteria no. 26, 27, and 28). 
Tests performed at the trial site 
Urine samples will be tested with a dipstick at the trial site according to the schedule of trial 
procedures (Section 4). The investigator should evaluate the result of the dipstick and in case 
of abnormality, it will be at the investigator’s discretion to decide whether a urine sample will 
be sent to the central laboratory for urinalysis. 
Women of childbearing potential will have a urine pregnancy test performed at the trial site at 
baseline prior to randomisation. The test will be repeated every 4 weeks as shown in the 
schedule of trial procedures in Section 4. 
Reporting in eCRF 
It will be recorded in the eCRF if a blood sample was taken; if not, a reason should be 
provided. The investigator’s assessment of the results (‘normal’, ‘abnormal, not clinically 
significant’, ‘abnormal, clinically significant’) will also be recorded in the eCRF. 
Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition will be reported as an AE. Any new clinically significant sign, 
symptom, or illness will be reported as an AE in accordance with Section 13.3. 
Site staff will record in the eCRF if a urine dipstick was performed and whether urinalysis is 
required for further assessment, as judged by the investigator; if the urine sample was not 
tested with a dipstick, a reason will be provided. In case urinalysis is performed, the 
investigator’s assessment of the results (‘normal’, ‘abnormal, not clinically significant, 
‘abnormal, clinically significant’) will be recorded in the eCRF. 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was performed, if not, a reason should be provided. Also, the date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
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11.4.5  Anti-drug antibody measurements 
Blood samples will be collected to determine levels of ADA at pre-determined time points 
according to the schedule of trial procedures (Section 4). It will be recorded in the eCRF if an 
ADA blood sample was taken; if not, a reason will be provided. 
Collection, handling, and shipment instructions for ADA blood samples are provided in a 
laboratory manual. 
Serum samples for determination of presence or absence of ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo endpoint titre determination and will be analysed for the presence of neutralising 
antibodies. Details of the analytical method used will be described in a bioanalytical report. 
11.5  Pharmacokinetic assessments 
Blood samples for PK assessments will be collected at the time points specified in the 
schedule of trial procedures (Section 4). It will be recorded in the eCRF if the PK sample was 
taken; if not, a reason will be provided. 
Collection, handling, and shipment instructions for PK blood samples are provided in a 
laboratory manual. 
Serum samples for determination of tralokinumab concentrations will be analysed by a 
laboratory using a validated bioanalytical method. Details of the analytical method used will 
be described in a bioanalytical report. 
11.6  Pharmacodynamics assessments 
Not applicable. 
11.7  Other assessments 
11.7.1  Photography (selected trial sites) 
At selected trial sites, subjects will be asked to participate in a photography component of the 
trial, which involves digital photography assessments to show disease progression over time. 
Participation in this photography component requires that the subject provides informed 
consent. 
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Digital colour photographs will be taken of the disease area and a representative lesion 
according to the schedule of trial procedures (Section 4). It will be recorded in the eCRF if the 
photo(s) was taken; if not, a comment should be provided. 
The trial sites will use their own equipment to take the photographs. Instructions for 
photography will be provided to the trial sites in a photography manual. Photography 
standards and procedures are provided to the trial sites by a central photography vendor. 
The photographs will have no other subject identifier than the subject ID and will be 
transmitted electronically to the central photography vendor using a secure file transfer 
protocol. The photographs will be included in the clinical database, but will not be evaluated 
or discussed in the clinical trial report (CTR). 
Printed copies of the photographs must be included as part of the individual subject source 
documentation. 
LEO Pharma may at its discretion use the photographs in publications, posters, and similar 
types of information material or media targeting patients and HCPs. The photographs may 
also be part of training material used for training and educational purposes. Steps will be 
taken to ensure that the identity of the subject is protected to the extent possible.  
11.8  End of trial 
End of treatment form 
An end of treatment form will be completed in the eCRF for all randomised subjects when 
they have had their last IMP administration. This form will also be completed for subjects 
who permanently discontinue IMP and subjects who withdraw from trial (Section 10.3). 
The following data will be collected on the end of treatment form: 
•
Date of last IMP administration.
•
Did the subject permanently discontinue IMP before Week 16; if yes, the primary
reason for permanent discontinuation of IMP must be recorded (AE, death, lost to
follow-up, withdrawal by subject, lack of efficacy, pregnancy, or other).
If ‘AE’ or ‘other’ is selected, a specification must be provided.
End of trial form 
An end of trial form must be completed in the eCRF for all randomised subjects. The end of 
trial form will be completed when the subject has had their last visit (that is, the safety 
follow-up visit, early termination visit, or nominal Week 16 visit). 
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The following data will be collected on the end of trial form: 
•
Date of last contact.
•
Did the subject attend the safety follow-up visit; if not, the primary reason for not
attending the safety follow-up visit must be recorded (AE, death, lost to follow-up,
withdrawal by subject, transferred to the long-term extension trial [ECZTEND], safety
follow-up assessments done at the nominal Week 16 visit, pregnancy, or other). If ‘AE’ 
or ‘other’ is selected, a specification must be provided.
•
For subjects who permanently discontinued IMP before Week 16, it will be recorded if
the subject attended the nominal Week 16 visit; if not, the primary reason for not
attending the nominal Week 16 visit must be recorded (AE, death, lost to follow-up,
withdrawal by subject, pregnancy, other). If ‘AE’ or ‘other’ is selected, a specification
must be provided.
•
Has the subject been transferred to the long-term extension trial (ECZTEND); if yes,
the last visit the subject attended in this trial (LP0162-1343) will be specified.
11.9  Estimate of total blood volume collected 
Blood samples will be drawn for chemistry, haematology, serology, PK, ADA, and pregnancy 
test (if applicable). The total volume of blood to be drawn is approximately 100 mL. If 
additional blood samples are required, the amount of blood drawn may be more than this 
stated value; however, the total volume of blood drawn will be less than that taken during a 
blood donation (approximately 400 mL). 
11.10  Storage of biological samples 
Samples analysed by the central laboratory (Panel 9) 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 10 years after marketing authorisation. 
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12 Scientific rationale for trial design and appropriateness of assessments 
12.1  Scientific rationale for trial design 
This is a prospective, randomised, double-blind, placebo-controlled, phase 3 trial designed to 
evaluate the efficacy and safety of tralokinumab in combination with TCS in Japanese 
subjects with moderate-to-severe AD, who are candidates for systemic therapy. A similar 
design as the multi-national trial LP0162-1339 (the initial 16 weeks only) has been chosen to 
facilitate an evaluation of similarity in efficacy and safety of tralokinumab in combination 
with TCS as compared with the LP0162-1339 trial. No Japanese subjects participated in the 
LP0162-1339 trial, but efficacy and safety of Japanese subjects were evaluated in the 
multi-national trial LP0162-1325 (with tralokinumab as monotherapy). In the LP0162-1325 
trial, tralokinumab was shown to be safe and efficacious in treating Japanese subjects with 
moderate-to-severe AD, in particular also in a setting where use of TCS was analysed as being 
adjunct/combination treatment (‘treatment policy’ estimand) as in the current trial. 
The trial endpoints have been selected to evaluate the efficacy of tralokinumab in improving 
the severity and extent of AD including both objective signs of disease and subjective 
symptoms (e.g. itch) as well as HRQoL. The primary efficacy endpoints (IGA 0/1 and 
EASI75) are recognised as important endpoints in clinical trials in AD by regulators in the 
US, EU, and Japan. 
The planned trial design is considered appropriate for evaluating the objectives of the trial, as 
the double-blind condition regarding subject’s treatment (tralokinumab or placebo) is 
maintained and a possible observer bias regarding treatment effects is minimised. The 
stratification by baseline disease severity in this multi-site trial will provide a strong basis for 
generalisation of the findings to the target patient population. Further, the trial population will 
comprise both men and women to explore effects between sexes and across the adult age 
range. 
A placebo-controlled parallel-group design has been chosen to evaluate the efficacy and 
safety of tralokinumab in combination with TCS in Japanese subjects. This allows an 
evaluation of similarity to the treatment effect observed in the LP0162-1339 trial, hereby 
adding to the knowledge needed for positioning tralokinumab in the AD treatment pathway in 
Japan. 
The most important inclusion criterion for the trial is an established diagnosis of AD (as 
defined by the Hanifin and Rajka 1980 criteria for AD) (21) at screening and a history of AD 
for at least 1 year to ensure correct diagnosis and rule out differential diagnosis. A prerequisite 
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for inclusion into the trial is a documented history of topical AD treatment failure (due to 
inadequate response) to ensure that the subject is candidate for systemic treatment. Subjects 
for whom topical treatment with TCS are medically inadvisable may not be included as TCS 
will be administered in this trial. 
The dose selected for the tralokinumab phase 3 development programme is 300 mg Q2W 
administered subcutaneously. All subjects randomised to treatment with tralokinumab will 
first get a loading dose of 600 mg tralokinumab. The administration of this loading dose 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. 
12.2  Appropriateness of assessments 
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 (32). EASI is a validated measure used in clinical practice and clinical trials to 
assess the severity and extent of AD (27). SCORAD is a validated tool to assess the extent 
and severity of AD lesions and subjective symptoms (29). 
Two validated patient-reported questionnaires (DLQI and POEM) and an eDiary (Worst Daily 
Pruritus NRS, and Eczema-related Sleep NRS) have been included to assess the efficacy of 
tralokinumab on symptoms and HRQoL. 
Safety will be assessed using standard clinical methods of subject evaluations, such as AE 
monitoring, vital signs, physical examinations, ECG, and clinical laboratory measurements. 
Data on ADA (antibodies against tralokinumab) will be collected and the potential for 
immunogenicity will be evaluated. The blood samples for determination of presence or 
absence of ADA will analysed a using a validated bioanalytical method. 
Blood concentrations of tralokinumab will be analysed using a validated bioanalytical method 
and standard PK parameters will be derived to evaluate tralokinumab exposure. 
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13 Adverse events 
13.1  Definition and classification of adverse events 
AEs and SAEs are defined in Appendix 1. 
Classification of AEs in terms of severity, causality and outcome is defined in Appendix 2. 
13.2  Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the informed consent form until completion of the trial (defined as the safety follow-up visit 
6 weeks after last IMP injection) [Sections 7.3 and 10.3]). For subjects entering the long-term 
extension trial (ECZTEND), any (S)AE with onset before the final visit in LP0162-1343 
should be reported in LP0162-1343. If ongoing, the (S)AE will also be recorded as medical 
history in ECZTEND. 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
for example: “How have you felt since I saw you last?” No specific symptoms should be 
asked for. It is important that the investigator also observes the subject for any changes not 
reported by the subject and records these changes. 
Refer to Sections 11.4.1 to 11.4.4 for principles for data entry in the eCRF. 
13.3  Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event (if the 
event is ongoing it will also be recorded). In addition, it must be recorded whether the AE 
started on the same day as the IMP administration (i.e. before or after dosing). 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. For events not considered related to IMP, the causal relationship to 
the use of AxMP should be evaluated using the same definitions as for the IMP. 
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Action taken with trial treatment: any action taken with IMP or AxMP as a consequence of the 
AE must be recorded (dose not changed, dose reduced, dose increased, drug interrupted, drug 
withdrawn, not applicable, unknown). 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
Withdrawn from trial due to this AE: it must be recorded whether the AE led to withdrawal 
from the trial.  
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 Pharma K.K. 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, AxMP, or trial procedure, the action 
taken, the outcome to date, and a narrative description of the course of the event. 
By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE report. 
The completed SAE form must be faxed or scanned and e-mailed to Pharmacovigilance at 
LEO Pharma K.K. using the e-mail address or fax number below: 
Pharmacovigilance at LEO Pharma K.K. 
E-mail address: clinical_trial_jp@leo-pharma.com
Fax number: +81 3 4243 3311 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
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Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma K.K. upon 
request by fax or e-mail (see contact details above). 
The investigator must notify the local IRB(s)/IEC(s) of SAEs, as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial, including post-treatment follow-up 
(i.e. after the last safety follow-up visit at Week 20), should not be routinely sought or 
recorded. 
13.4.2  LEO Pharma reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether or not an SAE is expected. 
The relevant reference safety information documents for this clinical trial are: 
•
For the IMP, the investigator’s brochure section 7.2, edition 19 and subsequent updates
must be used.
•
For AxMP (mometasone furoate, 0.1% cream), the latest version of the summary of
product characteristics (SmPC) must be used.
Pharmacovigilance at LEO Pharma K.K. will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
country.  
The IRBs/IECs will be notified of SAEs according to the current applicable legislation for the 
concerned country.  
All SAEs which are assessed as causally related to the IMP(s) by either the investigator or 
LEO Pharma (33), and which are unexpected (Suspected, Unexpected Serious Adverse 
Reactions [SUSARs]), are subject to expedited reporting to regulatory authorities, IECs/IRBs 
according to the current applicable legislation for the concerned country. Investigators will be 
notified of the evolving safety profile of the IMP on an ongoing basis. 
13.5  Other events that require expedited reporting 
13.5.1  Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma K.K. within 24 hours of first knowledge using the 
(paper) pregnancy form (part I). All pregnancies must be followed up until delivery or 
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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 Pharmacovigilance 
at LEO Pharma K.K. 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 10 are considered AEs of special interest (AESIs) in this trial and 
will require additional details to be recorded in the eCRF. LEO Pharma may request that the 
investigator forward test results, as appropriate. An AESI may be serious (requiring expedited 
reporting, Section 13.4) or non-serious. 
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Panel 10: Adverse events of special interest 
AESI 
Additional data to be recorded in the eCRF (if available1) 
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).
Malignancy 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 infection requiring systemic 
treatment 
•
Location (face, scalp, back, chest, upper limb, lower limb,
genitals).
•
Outcome of pathogenic 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.
1)
The additional data to be recorded in the eCRF are not a requirement, but are to be reported by the
investigator, if available, for example as part of standard clinical practice.
Abbreviations: AESI, adverse event of special interest; eCRF, electronic case report form;
PCR, polymerase chain reaction.
13.6.2  Overdose 
An overdose is defined as a subject receiving a quantity of IMP which is in excess of that 
specified in this protocol. An overdose is either accidental or intentional. 
The term ‘overdose’ including a specification of why it occurred (accidental or intentional) 
must be recorded on the AE form of the eCRF. In addition, AEs originating from overdose 
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must be recorded as separate events. If the AE originating from the overdose qualifies as an 
SAE, expedited reporting is required (Section 13.4). 
If the overdose is accidental and due to a device deficiency, the device deficiency must be 
reported as a product complaint as described in Section 9.10. 
LEO Pharma does not recommend specific treatment for an overdose. The investigator will 
use clinical judgement to treat any overdose if necessary. 
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 
3 categories: wrong medication, wrong dose (including strength, form, concentration, 
amount), wrong route of administration. 
The medication error category must be documented on the AE form in the eCRF. In addition, 
AEs originating from a medication error must be recorded as separate events. If the AE 
originating from the medication error qualifies as an SAE, expedited reporting is required 
(Section 13.4). 
If the medication error is due to a device deficiency, the device deficiency must be reported as 
a product complaint as described in Section 9.10. 
13.6.4  Misuse 
Misuse refers to situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
The term ‘misuse’ must be recorded on the AE form in the eCRF. In addition, AEs originating 
from misuse must be recorded as separate events. If the AE originating from misuse qualifies 
as an SAE, expedited reporting is required (Section 13.4). 
13.6.5  Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term ‘abuse’ must be 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). 
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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 (S)AE in accordance with Sections 13.3 and 
13.4. As AD is a fluctuating disease, consider to only report an AE if the aggravation/ 
exacerbation exceeds normal disease fluctuation or if lesions appear in a body area which is 
normally not affected by AD. 
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 possibly or probably related to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. SAEs must be 
followed up until a final outcome has been established, that is, the follow-up may continue 
beyond the end of the clinical trial. For SAEs which have stabilised and from which the 
subject cannot be expected to recover during the trial or the safety follow-up periods, for 
example chronic or stabilised conditions, the final outcome at the investigator’s discretion 
should be reported as ‘recovering/resolving’ or ‘not recovered/not resolved’. In addition, a 
statement detailing why the subject cannot be expected to recover during the trial e.g. 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.” (34). 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IRBs/IECs. 
The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
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halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
14.1  Sample size 
Approximately 100 subjects will be randomised 1:1 to tralokinumab+TCS or placebo+TCS to 
facilitate an evaluation of similarity with the treatment effect observed in the LP0162-1339 
trial. 
Randomisation will be stratified by baseline disease severity (IGA 3 or 4). 
14.2  Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects who are randomised to treatment and exposed to IMP (tralokinumab/placebo) 
will be included in the full analysis set and will be analysed for efficacy up to Week 16. 
A safety analysis set will be defined as all randomised subjects who receive IMP. 
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the analysis set definition document before breaking the 
randomisation code. 
14.3  Statistical analysis 
14.3.1  Disposition of subjects 
The reasons for permanent discontinuation of IMP or withdrawal from trial will be presented 
for all randomised subjects by last visit attended and 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 by treatment group. Presentations of age, sex, race, ethnicity, 
baseline disease severity, and Worst Daily Pruritus NRS weekly average at baseline 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. 
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14.3.3  Exposure and treatment compliance 
The duration of exposure to treatment will be calculated as the number of days from date of 
first application of IMP to the date of last application of IMP, both days included. 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment group. Treatment compliance will be presented for the safety analysis set per 
treatment group as the percentages of missed applications/doses. 
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. 
14.3.4  Rescue treatment 
Rescue treatment will be defined by the following algorithm: 
Concomitant medications with ‘Dermatitis atopic’ or ‘Dermatitis infected’ as the preferred 
term (PT) for the indication, and either of the following: 
•
ATC2 code: H02.
•
Preferred name: methotrexate, ciclosporin, azathioprine, mycophenolate-mofetil,
mychophenolate-acid, mycophenolate-sodium, dupilumab, crisaborole, alitretinoin, or
delgocitinib.
•
ATC4 code: D07AD, D07BD, D07CD, or D07XD.
•
Confirmed rescue treatment (by investigator) in reported term for the indication, and
ATC4 code: D07AB, D07BB, D07CB, D07XB, D07AC, D07BC, D07CC, or D07XC.
As described in Section 9.5, investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue treatment. Therefore, if 
rescue medication has start date the same day as an efficacy assessment, then it is assumed 
that the assessment is not influenced by rescue treatment. 
Rescue treatment will be summarised for the treatment period. In addition, a summary table of 
rescue treatment by type (topical and systemic) and by overall group (corticosteroids, 
immunosuppressants, and other) will be made for the treatment period 
Additionally, rescue treatment will be summarised for the treatment period by baseline disease 
severity (IGA 3 or 4). 
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In addition, the time to first use of rescue treatment will be presented using Kaplan-Meier 
plots for the treatment period. 
14.3.5  Testing strategy 
There will be no formal testing. All confidence intervals (CIs) will be presented with 
two-sided 95% degree of confidence.  
14.3.6  Analysis of primary efficacy endpoints 
Two estimands addressing different aspects of the trial objectives will be defined: 
•
Primary estimand: ‘composite’.
•
Secondary estimand: ‘treatment policy’.
The applied estimands incorporate 2 main types of events that influence how the treatment 
effects are estimated (i.e. initiation of rescue treatment and permanent discontinuation of 
IMP).  
•
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. 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 efficacy analyses will be based on the full analysis set. 
14.3.6.1  Primary estimand: ‘composite’ 
The primary estimand for the primary endpoints will be: 
•
Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
achieved without rescue medication, regardless of treatment discontinuation.
The primary estimand assesses the expected difference in response rates (defined as response 
obtained without initiation of any rescue medication) after 16 weeks, resulting from initiation 
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of a treatment regimen with tralokinumab+TCS compared to a treatment regimen with 
placebo+TCS. 
Primary analysis for the primary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Subjects who prior to the Week 16 visit have 
received rescue medication will be considered non-responders, reflecting an assumption that 
initiation of rescue medication indicates failure of the randomised treatment to achieve 
response, and that a (possible) observed positive response after initiation of rescue medication 
is not attributable to the randomised treatment. Missing data for subjects who do not attend 
the Week 16 visit and where rescue medication has not been used prior to Week 16, will be 
imputed as non-responders.  
The difference in response rates between treatment groups will be calculated by the 
Mantel-Haenszel method stratified by baseline disease severity (IGA 3 or 4). The treatment 
difference and the corresponding 95% CI will be presented.  
Sensitivity analysis  
The purpose of the analysis is to assess the robustness of results of the primary analysis with 
respect to the retrieved data at Week 16.  
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. The same Mantel-Haenszel method as used for 
the primary analysis will be applied including stratification by baseline disease severity. 
14.3.6.2  Secondary estimand: ‘treatment policy’ 
The secondary estimand for the primary endpoints will be: 
•
Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
regardless of rescue medication and discontinuation of IMP.
The secondary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab+TCS and additional rescue medication as 
compared to a treatment regimen with placebo+TCS and additional rescue medication. 
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Primary analysis for the secondary estimand 
All data used as observed at Week 16 regardless of rescue medication and discontinuation of 
IMP, thus data retrieved at Week 16 for subjects who have permanently discontinued 
treatment prior to Week 16 will be included in the analysis.  
IGA 0/1 responder imputation  
Imputation of missing binary IGA 0/1 data at Week 16 will be done using multiple 
imputations of the underlying 5-point IGA values within the 4 groups defined according to 
randomised treatment arm and whether or not subjects have permanently discontinued IMP 
prior to Week 16 assuming that data is missing at random within each arm. Within a given 
treatment arm, retrieved data from discontinued subjects will be used to impute missing data 
for other discontinued subjects. Similarly, the available data from not discontinued subjects 
will be used to impute data for such subjects where the Week 16 value is missing. 
1. In each group, intermittent missing values will be imputed using last observation
carried forward (LOCF) to obtain a monotone missing data pattern.
2. An ordinal logistic regression model assuming proportional odds will be fitted to the
IGA value at Week 2. The model will include effect of 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=16201343).
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 Weeks 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.
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
as described above. 
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) will be 
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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. 
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 4 groups defined according to 
randomised treatment arm and whether or not subjects have permanently discontinued IMP 
prior to Week 16 assuming that data is missing at random within each arm. Within a given 
treatment arm, retrieved data from discontinued subjects will be used to impute missing data 
for other discontinued subjects. Similarly, the available data from not discontinued subjects 
will be used to impute data for such subjects where the Week 16 value is missing. 
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=11101343).
2. For each of the 100 copies of the dataset, an ANCOVA model will be 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 factor. The estimated parameters, and
their variances, will be used to impute missing EASI values at Week 2
(seed=16201343).
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 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 Weeks 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 factor. The missing binary EASI75 response at Week 16 will be
derived from the corresponding underlying imputed EASI value.
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
as described above. 
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 
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covariate) 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. 
Analysis of Week 16 response 
For each of the imputed data sets, the difference in response rates (either the IGA 0/1 or the 
EASI75) between treatment groups will be calculated using the same Mantel-Haenszel 
method as used for the primary analysis of the primary estimand including stratification 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 secondary estimand 
The primary analysis of the secondary estimand assumes that discontinued subjects with 
missing data at Week 16 behave similarly to discontinued subjects with available (retrieved) 
Week 16 data.  
The robustness of this assumption is evaluated in a sensitivity analysis, applying single 
imputation to deem all subjects with missing data at Week 16 as ‘non-responders’. The same 
Mantel-Haenszel method as used for the primary analysis of the primary estimand will be 
applied including stratification by baseline disease severity. 
14.3.7  Analysis of key secondary efficacy endpoints 
The binary key secondary endpoint, reduction of Worst Daily Pruritus NRS (weekly average) 
≥4 from baseline to Week 16, will be analysed as described for the primary endpoint EASI75 
using both estimands with the modification of the ANCOVA imputation model that reduction 
of Worst Daily Pruritus NRS weekly average replaces EASI where preceding values are used 
as covariates. 
For the continuous key secondary endpoints, change from baseline to Week 16 in SCORAD 
and DLQI, 2 estimands addressing different aspects of the trial objectives will be defined: 
•
Primary estimand: ‘composite’.
•
Secondary estimand: ‘hypothetical’.
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14.3.7.1  Primary estimand for the continuous key secondary endpoints: 
‘composite’ 
The primary estimand for the continuous key secondary endpoints will be: 
•
Treatment difference in change from baseline to Week 16 in SCORAD and DLQI,
respectively, achieved without rescue medication, regardless of discontinuation of
IMP.
Primary analysis for the primary estimand - continuous key secondary endpoints 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Subjects who prior to the Week 16 visit have 
received rescue medication will be considered non-responders by using worst observation 
carried forward (including the baseline value). 
Missing Week 16 data among subjects who did not use rescue medication will be imputed 
using multiple imputations (100 copies of the dataset, seed=16201343) assuming missing at 
random within arms (based on sequential use of an ANCOVA model for Weeks 2, 4, 6, … and 
16). The stepwise imputation model will be estimated based on available data from all 
subjects but excluding individual subject data captured after initiation of rescue medication or 
permanent discontinuation of IMP. For each of the 100 imputed datasets, the continuous 
secondary endpoint will be analysed using an ANCOVA model with effects of treatment, 
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. 
Sensitivity analysis for primary estimand - continuous key secondary endpoints  
A tipping point analysis using multiple imputations will be performed with the purpose to 
assess the robustness of results of the primary analysis for the primary estimand with respect 
to the missing at random assumption regarding missing Week 16 data. The tipping analysis 
will assess how severe the departure from the missing at random assumption in the 
tralokinumab arm must be in order to impact the results. 
The tipping point analysis will be performed using the missing at random imputed Week 16 
data from primary analysis of the primary estimand. For each of the 100 already imputed 
datasets from the primary analysis, Δ will be added to the imputed values for subjects in the 
tralokinumab arm (Δ = 0 implies missing at random) and thereby the imputed values will be 
‘shifted’ by Δ. Each of the 100 modified imputed datasets will then be analysed in the same 
way as for the primary analysis for the primary estimand. The tipping point is then found as 
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the value of Δ which causes the 95% CI to change from excluding 0 to including 0 and will be 
judged from a clinical point of view. 
14.3.7.2  Secondary estimand for the continuous key secondary endpoints: 
‘hypothetical’ 
The secondary estimand for the continuous secondary endpoints will be: 
•
Treatment difference in change from baseline to Week 16 in SCORAD and DLQI,
respectively, if all subjects adhered to the treatment regimen in the sense that they did
not discontinue IMP permanently and no rescue medication was made available before
Week 16.
The secondary estimand assesses the expected benefit when adhering to the treatment regimen 
tralokinumab+TCS with no rescue medication as compared to a treatment regimen with 
placebo+TCS with no rescue medication. 
Primary analysis for the secondary estimand - continuous key secondary endpoints 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be included in the analysis. For subjects without any post-baseline data, the baseline 
value will be carried forward as the first post-baseline assessment, corresponding to imputing 
a change of 0 at the first post-baseline assessment. This is to ensure that all subjects will be 
included in the analysis. The endpoints will be analysed using a repeated measurements 
model on the post-baseline responses up to Week 16 with an unstructured covariance matrix, 
Kenward-Roger approximation to estimate denominator degrees of freedom, and the mean 
modelled as follows (shown for change from baseline in SCORAD): 
Change from baseline in SCORAD 
= treatment × visit + baseline SCORAD × visit + baseline IGA 
This model assumes that data is missing at random within each treatment arm. The estimates 
will be presented with 95% CI at each visit. The primary comparison between 
tralokinumab+TCS and placebo+TCS will be at Week 16. 
Sensitivity analysis for secondary estimand - continuous key secondary endpoints 
Rather than assuming that observations are missing at random within each treatment arm it is 
assumed that missing data from subjects who discontinue IMP/receive rescue medication in 
the tralokinumab+TCS arm will resemble data from subjects from the placebo+TCS arm who 
do not discontinue IMP/receive rescue medication. 
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Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab+TCS arm as well as the placebo+TCS arm will be imputed 
from the placebo+TCS arm (using multiple imputations in a so-called copy-reference 
approach). 
The procedure for the change from baseline in SCORAD at Week 16 is described below. The 
same procedure will be applied for the DLQI endpoint. 
1. Intermittent missing values will be imputed in each group using a Markov Chain
Monte Carlo method to obtain a monotone missing data pattern and 100 copies of the
dataset will be generated (seed=11101343).
2. For each of the 100 copies of the dataset, an ANCOVA model will be fitted to the
SCORAD value at Week 2 in the placebo+TCS group. The model will include effects
of baseline SCORAD as a covariate, and baseline disease severity (IGA 3 or 4) as
factor. The estimated parameters, and their variances, will be used to impute missing
values at Week 2 for the placebo+TCS group as well as the tralokinumab+TCS group
(seed=16201343).
3. For each of the 100 copies of the dataset, missing values at Week 4 will be imputed in
the same way as for Week 2. The imputations will be based on a similar ANCOVA
model, but with SCORAD value at Week 2 included as an additional covariate. The
parameters from the model will be estimated based on data from the placebo+TCS
group. The estimated parameters, and their variances, will be used to impute missing
values at Week 4 for both treatment groups.
4. This stepwise procedure will then be repeated sequentially for Weeks 6, 8, 10, 12, 14,
and 16 with the SCORAD values from the preceding 2 visits included as covariates in
addition to baseline SCORAD as a covariate, and baseline disease severity as factors.
For each of the 100 imputed datasets, the change from baseline in SCORAD at Week 16 will 
be analysed using an ANCOVA model with effects of treatment, baseline disease severity 
(IGA 3 or 4), and baseline SCORAD value. The estimated difference at Week 16 will be 
derived together with the associated standard error. The estimates and standard errors from the 
100 analyses are pooled to one estimate and associated standard error using Rubin’s rule to 
draw inference. From these pooled estimates, the 95% CI for the treatment difference will be 
calculated. 
14.3.8  Analysis of secondary endpoints 
The analysis of the below dichotomous secondary endpoints will be based on the primary 
analyses of the primary estimand as specified above for the primary dichotomous endpoint. 
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For the continuous secondary endpoints, the analysis will be based on the primary (MMRM) 
analyses of the secondary estimand as specified above for the key secondary continuous 
endpoint. 
The dichotomous secondary endpoints EASI90 at Week 16 and EASI50 at Week 16 will be 
analysed according to the primary analysis of the primary estimand as specified above for the 
primary endpoints. 
The percentage change from baseline to Week 16 in EASI score and the change from baseline 
to Week 16 in Worst Daily Pruritus NRS weekly average, Eczema-related Sleep NRS (weekly 
average), and POEM will be analysed according to the primary (MMRM) analysis of the 
secondary estimand for the continuous key secondary endpoints. 
14.3.9  Analysis of other endpoints 
The binary other endpoints, reduction from baseline to Week 16 of DLQI ≥4 points among 
subjects with baseline DLQI ≥4 and reduction from baseline to Week 16 of POEM score ≥4 
points in subjects with baseline POEM score ≥4, will be summarised by treatment group. 
To evaluate the efficacy related to health care resource utilisation, the amount of TCS used 
(assessed as the amount of TCS used between visits), and the cumulative amount of TCS used 
will be determined by 2-week periods. The amount of TCS used and the cumulative amount 
of TCS used will each be logarithm-transformed prior to analysis. Due to potential zero 
valued ‘amount of TCS used’, 1 will be added to the values prior to transformation. This 
transformation has in a similar trial proven the model below to fit data better compared to 
leaving the data untransformed. Data will be analysed by a repeated measurements model 
with an unstructured covariance matrix and the mean modelled as follows: 
Log(Y+1) = treatment × visit + baseline IGA 
where ‘Y’ is either the amount of TCS used or the cumulative amount of TCS used. Data 
obtained after permanent discontinuation of IMP or after initiation of rescue treatment will be 
excluded from the analyses. 
The estimated parameters will be transformed back to the original scale using the exponential 
function, thus producing estimated geometric means and estimated ratio of means which will 
be presented together with 95% CIs.  
Results obtained after initiation of rescue treatment will be excluded from the analyses. 
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In addition, TCS use (AxMP) <5 g at Week 16 will be analysed according to the primary 
analysis of the primary estimand for the primary endpoint. 
14.3.10 
 Analysis of patient-reported outcomes 
POEM and DLQI will be summarised by treatment group and visit using descriptive statistics. 
Data will be presented for the full analysis set. 
The patient-reported outcomes collected daily in the eDiary (Worst Daily Pruritus NRS, 
Eczema-related Sleep NRS, and Patient Days of Topical Treatment Use) will all be 
summarised over time by treatment group using descriptive statistics. Data will be presented 
for the full analysis set. 
The change from baseline to Week 16 in Eczema-related Sleep NRS weekly average and 
POEM will be summarised by treatment group and domain, where applicable, and analysed 
according to the primary analysis of the secondary estimand for the continuous key secondary 
endpoints. For the Eczema-related Sleep NRS score, the mean over the last 7 days prior to 
randomisation (Day -6 to Day 0) will be used as the baseline value. 
14.3.11 
Exploratory analyses 
To further support the evaluation of the primary, key secondary, and secondary endpoints, the 
same endpoints will be evaluated at each scheduled visit/assessment up to the week specified 
below: 
•
EASI75 at each scheduled assessment up to Week 14.
•
IGA 0/1 at each scheduled assessment up to Week 14.
•
Change in SCORAD from baseline to each scheduled assessment up to Week 14.
•
Change in Worst Daily Pruritus NRS (weekly average) from baseline to each
scheduled assessment up Week 15.
•
Change in DLQI score from baseline to each scheduled assessment up to Week 12.
•
Reduction of Worst Daily Pruritus NRS (weekly average) ≥4 from baseline to each
scheduled assessment up to Week 15.
•
Change in Eczema-related Sleep NRS (weekly average) from baseline to each
scheduled assessment up to Week 15.
•
Change in POEM score from baseline to each scheduled assessment up to Week 12.
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For the binary endpoints above, the treatment difference and the corresponding 95% CI will 
be presented at each scheduled visit/assessment using the same approach as applied for the 
primary analysis of the primary estimand for the primary endpoints. For continuous 
endpoints, the approach used for the primary analysis of the secondary estimand for key 
secondary endpoints will be applied. 
For the binary endpoints, the same Mantel-Haenszel method as for the Week 16 assessment 
will be applied. For the continuous endpoints, the repeated measurements model already 
described previously for the Week 16 assessments facilitates that the treatment differences and 
95% CIs can be derived for each visit/assessment in the same analysis that already will be 
made for the corresponding Week 16 assessments. 
14.3.12 
Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.12.1 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 PT 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 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 
and worsened in severity after first dose of IMP. The tabulations described in the following 
will only include the treatment-emergent events. In each of the tabulations, AEs are defined 
by MedDRA PTs within primary SOC. 
An overall summary of the number of events and the number (percentage) of subjects with 
any treatment-emergent AEs, deaths, SAEs, premature discontinuations from the trial due to 
AEs, treatment-related AEs, and severe AEs will be presented. 
The number of AEs and number of subjects with each type of AEs will be tabulated by 
treatment group. 
The severity for each type of AE will be tabulated by treatment group. 
The causal relationship to IMP for each type of AE will be tabulated by treatment group. 
Related AEs are defined as AEs for which the investigator has not described the causal 
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relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
with each type of related AE will be tabulated. 
The causal relationship to AxMP (TCS) for each type of AE will be tabulated by treatment 
group. Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to AxMP (TCS) as ‘not related’. The number of related AEs and the number of 
subjects with each type of related AE will be tabulated. 
SAEs will be evaluated separately, and a narrative will be given. 
AESIs and AEs leading to withdrawal from trial or permanent discontinuation of IMP will be 
tabulated and listed, no narratives will be given unless the events are considered as SAEs. 
14.3.12.2 Vital signs 
The change in vital signs (resting blood pressure, pulse, and body temperature) from baseline 
to each visit will be summarised by visit and treatment group as mean, standard deviation 
(SD), median, minimum, and maximum values. 
14.3.12.3 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit as mean, SD, median, minimum, and maximum values for each treatment 
group. 
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within, or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at end of treatment. Subjects with 
laboratory parameters outside the reference range will be listed. 
14.3.13 
Pharmacokinetic analysis 
All the PK samples in the trial are trough samples. The trough concentration (Ctrough) will be 
listed by treatment group and descriptive statistics will be applied. 
14.3.14 
Anti-drug antibodies 
The presence of treatment-emergent ADA from baseline to Week 16 is a secondary endpoint 
included to assess the safety and tolerability (immunogenicity) of tralokinumab in 
combination with TCS. 
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ADA status (positive versus negative) at each visit will be summarised by treatment group. If 
considered relevant, descriptive statistics including number of subjects, mean, SD, median, 
1st quartile, 3rd quartile, and range of the actual ADA titres by treatment group and visit will 
be provided. The ADA status across the trial for each subject (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 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.
•
Perishing
4. ADA positive at baseline, all post-baseline ADA assessments negative.
•
Negative
5. ADA negative or missing at baseline, all post-baseline ADA assessments negative.
•
No post-baseline ADA assessment.
For subjects who develop ADA and are considered treatment-boosted or treatment-emergent, 
the IGA score, change in EASI at end of treatment, and titre information will be listed. 
Evaluations of neutralising antibodies will be conducted on those serum samples that test 
positive for ADA. The test sample is deemed positive or negative for the presence of 
neutralising antibodies to tralokinumab relative to a pre-determined (in assay validation), 
statistically derived cut point. 
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14.3.15 
Interim analysis 
No interim analysis is planned. 
14.3.16 
General principles 
All CIs will be presented with 95% degree of confidence, unless otherwise specified. 
An observed-cases approach will be used for tabulations of data by visit (that is, involving 
only those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
SD, 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 will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analyses 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 change. 
14.3.17 
Handling of missing values 
Procedures for handling of missing values are included under the sections describing the 
individual analyses. 
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Ortega Martell JA, Platts-Mills TA, Ring J, et al. Revised nomenclature for allergy for
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Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A,
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Posner K, Brown G, Stanley B, Brent D, Yershova K, Oquendo M, Currier G, Melvin
G, Greenhill L, Shen S, Mann J. The Columbia-Suicide Severity Rating Scale: initial
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Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area
and severity index (EASI): assessment of reliability in atopic dermatitis. EASI
Evaluator Group. Exp Dermatol. 2001;10(1):11-18.
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European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31.
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Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical
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Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure:
development and initial validation of a new tool for measuring atopic eczema severity
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Futamura M, Leshem YA, Thomas KS, Nankervis H, Williams HC, Simpson EL. A
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Pharmaceuticals for Human Use. Integrated addendum to ICH E6(R1): Guideline for
good clinical practice E6(R2). 2016.
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Parlament and of the Council 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.  (Ema ed. 2001.
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medical research involving human subjects. Amended by the 64th WMA General
Assembly, Fortaleza, Brazil. 2013.
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37.
CIOMS. International Ethical Guidelines for Health-related Research Involving
Humans. Council for International Organizations of Medical Sciences. 4th. Geneva.
2016.
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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. (35) 
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 11.4.4.2).
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 
•
Results in death.
•
Is life-threatening – at risk of death at the time of the SAE (not an event that
hypothetically might have caused death if more severe).
•
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.
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•
Is a congenital anomaly/birth defect.
•
Is a medically important condition. Events that may not be immediately
life-threatening or result in death or hospitalisation but may jeopardise the subject or
may require intervention to prevent one of the other outcomes listed in the definition
above. Examples are intensive treatment in an emergency room or at home for allergic
bronchospasm, blood dyscrasias, and convulsions that do not result in hospitalisation,
development of drug dependency, or drug abuse.
Definition of adverse events of special interest 
An AESI (serious or non-serious) is an event type of scientific and medical interest specific to 
the product or development programme, for which additional monitoring may be appropriate. 
Such event might warrant further investigation in order to characterise and understand it. 
Depending on the nature of the event rapid communication by the investigator to the sponsor 
and/or from the sponsor to other parties (e.g. regulators) might also be warranted. 
AESIs 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. 
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Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probably, 
possibly, or not related according to the investigator’s clinical judgement.  
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
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. 
For events not considered related to IMP using the criteria above, the causal relationship to 
the use of AxMP should be evaluated using the same definitions as for the IMP. 
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Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing. 
Recovered/   
resolved with 
sequelae 
The event has reached a state where no further changes are expected, and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses “recovered/resolved” only if an event 
has actually stopped. According to the CDISC definition, the category “recovered/resolved” 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as “not recovered/not resolved” or 
“recovering/resolving”. 
Similarly, it should be noted that as per the above definition, LEO Pharma uses 
“recovered/resolved with sequelae” only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered “with 
sequelae”, if it has “retained pathological conditions”. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome “recovered/resolved with sequelae” 
could have been classified with the outcome “recovered/resolved” according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC.  
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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 (36) and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines (37).
•
Current version of applicable International Council for Harmonisation Good Clinical
Practice (ICH GCP) Guidelines (33).
•
EU General Data Protection Regulation 2016/679 of 27 April 2016.
•
Applicable laws and regulations.
The appropriate regulatory authority (PMDA) must be notified of the clinical trial as required. 
Any documents that the IRB/IEC may need to fulfil its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure [as applicable], subject information 
sheet, and informed consent form(s), or advertisements) will be submitted to the IRB/IEC. 
These documents must be reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be notified to regulatory authority and approved by 
IRBs/IECs, 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/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established
by the IRB/IEC.
•
Notifying the local IRB/IEC of SAEs or other significant safety findings as required
by IRB/IEC procedures.
•
Providing oversight of the conduct of the trial at the trial site and ensuring adherence
to applicable national and international legislation.
Appendix 3B: Informed consent process 
Subjects (and/or the subject’s legally authorised representative, if applicable) will receive 
written and verbal information concerning the clinical trial. This information will emphasise 
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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 (and/or 
their legally authorised representative’s signed and dated informed consent, if applicable) will 
be obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the informed consent form. 
Subjects will be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial, if required. 
A copy of the informed consent form(s) must be provided to the subject (and/or the subject’s 
legally authorised representative, if applicable). 
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IRT 
cannot be performed. 
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO Pharma and shall not be 
used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma may use any and all information, data, and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data and/or results to other investigators, regulatory 
authorities, and/or commercial partners. 
Trial subjects will be assigned a unique identifier (subject ID) by LEO Pharma. Any subject’s 
records or datasets that are transferred to LEO Phama 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 that their personal trial-related data will be used by 
LEO Pharma in accordance with local data protection law. 
Trial subjects must be informed and consent to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example race, ethnicity, age, 
sex, 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 Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial. In certain cases, an agreement on transfer of personal data 
may also be required. 
Investigators and LEO Pharma must ensure that collection, processing and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing, and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
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Appendix 3D: Record keeping, quality control, and data handling 
Source data at trial sites 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed and dated 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.
•
Subject ID.
•
The fact that the subject is participating in a clinical trial in AD including treatment
with tralokinumab or placebo for 16 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. 
A risk-based monitoring approach will be applied. 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. The level of source data verification, data checks, and visit intervals will be 
specified in the monitoring guideline.  
In addition to on-site monitoring, pre-specified trial data will undergo central monitoring as 
specified in the trial’s data review plan. 
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In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, for example, medical records, laboratory 
reports, appointment books, etc. If the electronic medical record does not have a visible audit 
trail, the investigator must provide the CRA with signed and dated printouts. In addition, 
relevant site staff should be available for discussions at monitoring visits and between 
monitoring visits (e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as LEO Pharma 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify, and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g. laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into electronic CRFs (eCRF). Data recorded in the eCRF 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRF 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 eCRF 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 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 
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will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the 
electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
An electronic PRO (ePRO) solution will be used to capture patient-reported data (data from 
questionnaires completed at the trial site and eDiary data). By the use of an ePRO, data will 
be available immediately after data entry and available for CRAs and site personnel, including 
the investigator, with reader 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 Pharma will be transmitted and handled via a 
secure file transfer protocol site. 
Transmissions of data are documented in more detail in a data flow plan which is part of the 
trial master file. 
Statistical programming standards 
CDISC controlled terminology dated 08-May-2020 (or later) was used for definition of 
controlled terminology throughout this protocol and will be used for statistical programming 
and output. Standard Data Tabulation Model (SDTM) version 1.4 and SDTM implementation 
guide version 3.2 will be used for data tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file (33). Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
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No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs and ePRO data for all screened 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 Pharma, from regulatory authorities and/or IRBs/IECs. 
Appendix 3E: Registration, reporting, and publication policy 
Trial disclosure 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO Pharma in 
accordance with our 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 and national data registries in accordance with applicable law and 
regulations after clinical trial completion or premature termination. 
LEO Pharma may also provide researchers access to anonymised patient-level data for further 
research. Publication and access will be in accordance with the Position on Public Access to 
Clinical Trials which can be found on the LEO Pharma website. Moreover, LEO Pharma may 
re-use the same patient-level data for other projects within the same purpose as the trial. 
Publications 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A multi-site 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-site publication is made public, or if no 
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multi-site publication has been submitted with the above-described deadline, the investigator 
shall have the right to publish the results from the clinical trial generated by the investigator, 
subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider 
comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
upon the request of LEO Pharma withhold the publication or presentation to allow 
LEO Pharma to protect its inventions and other intellectual property rights described in any 
such manuscripts.  
In case no multi-site publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-site publication. 
In case of publications made by the investigator after the first multi-site publication has been 
published, the above mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines (22). 
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Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the clinical trial and for 
1 year after completion of the clinical trial, or for a longer period of time if required by local 
legislation. 
Appendix 3H: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IRB/IECs or competent authorities may decide to stop the 
clinical trial, part of the trial or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IRB/IECs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO Pharma or investigator may include but 
are not limited to: 
•
Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, LEO Pharma procedures, or GCP
guidelines.
•
Inadequate recruitment of subjects by the investigator.
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Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
Appendix 3I: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement. 
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Appendix 4: Hanifin and Rajka (1980) diagnostic criteria for AD (21) 
Major Features: must have 3 or more of the following: 
•
Pruritus.
•
Typical morphology and distribution:
o
Flexural lichenification or linearity in adults.
o
Facial and extensor involvement in infants and children.
•
Chronic or chronically-relapsing dermatitis.
•
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis).
Minor Features: should have 3 or more of the following: 
•
Xerosis.
•
Ichthyosis, palmar hyperlinearity, or keratosis pilaris.
•
Immediate (type 1) skin-test reactivity.
•
Raised serum IgE.
•
Early age of onset.
•
Tendency toward cutaneous infections (especially S. aureus and herpes
simplex) or impaired cell-mediated immunity.
•
Tendency toward non-specific hand or foot dermatitis.
•
Nipple eczema.
•
Cheilitis.
•
Recurrent conjunctivitis.
•
Dennie-Morgan infraorbital fold.
•
Keratoconus.
•
Anterior subcapsular cataracts.
•
Orbital darkening.
•
Facial pallor or facial erythema.
•
Pityriasis alba.
•
Anterior neck folds.
•
Itch when sweating.
•
Intolerance to wool and lipid solvents.
•
Perifollicular accentuation.
•
Food intolerance.
•
Course influenced by environmental or emotional factors.
•
White dermographism or delayed blanch.
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Appendix 5: Guidance for anaphylaxis diagnosis (24) 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a 
serious allergic reaction that is rapid in onset and may cause death. They recognise 
3 categories of anaphylaxis, with criteria designated to capture from 80% of cases 
(category 1) to >95% of all cases of anaphylaxis (for all 3 categories). 
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (e.g. generalized hives, pruritus or flushing, swollen lips-
tongue-uvula).
AND AT LEAST ONE OF THE FOLLOWING: 
•
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced
peak expiratory flow [PEF], hypoxemia).
•
Reduced blood pressure (BP) or associated symptoms of end-organ
dysfunction (e.g. hypotonia [collapse], syncope, incontinence).
2) Two or more of the following that occur rapidly after exposure to a likely allergen for
that patient (minutes to several hours):
•
Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush,
swollen lips-tongue-uvula).
•
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced
PEF, hypoxemia).
•
Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope,
incontinence).
•
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting).
3) Reduced BP after exposure to known allergen for that patient (minutes to several
hours):
•
Infants and children: low systolic BP (age specific) or greater than 30%
decrease in systolic BP.
•
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from
that person’s baseline.
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Appendix 6: TCS classification list 
English translation of the Japanese TCS classification list, which is included in the Guideline 
for Therapy for AD from 2018: 
Group I 
Strongest 
0.05% Clobetasol propionate 
0.05% Diflorasone diacetate 
Group II 
Very Strong 
0.1% Mometasone fuorate 
0.05% Betamethasone butyrate propionate 
0.05% Fluocinonide 
0.064% Betamethasone dipropionate 
0.05% Difluprednate 
0.1% Amcinonide 
0.1% Diflucortolone valerate 
0.1% Hydrocortisone butyrate propionate 
Group III 
Strong 
0.3% Deprodone propionate 
0.1% Dexamethasone propionate 
0.12% Dexamethasone valerate 
0.12% Betamethasone valerate 
0.025% Fluocinolone acetonide 
Group IV 
Medium 
0.3% Prednisolone valerate acetate 
0.1% Triamcinolone acetonide 
0.1% Alclometasone dipropionate 
0.05% Clobetasone butyrate 
0.1% Hydrocortisone butyrate 
0.1% Dexamethasone 
Group V 
Weak 
0.5% Prednisolone 
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Appendix 7: Short version of eligibility criteria 
A short form (maximum 200 characters) version of each eligibility criteria for the trial is 
provided below. 
No. 
Inclusion criteria 
1 
Signed and dated informed consent has been obtained prior to any protocol-related procedures 
2 
Japanese subject aged 18 years and above 
3 
Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD 
4 
History of AD for 1 year or more 
5 
Subjects with a recent history within 1 year before screening of inadequate response to treatment 
with topical medication or subjects for whom topical treatments are otherwise medically inadvisable 
6 
AD involvement of 10% (or more) body surface area at screening and at baseline according to 
component A of SCORAD 
7 
EASI score of 12 or more at screening and 16 or more at baseline 
8 
IGA score of 3 or more at screening and at baseline 
9 
Worst Daily Pruritus NRS average score of 4 or more during the week prior to baseline 
10 
Subjects must have applied a stable dose of emollient twice daily (or more, as needed) for at least 
14 days before randomisation 
11 
Women of child bearing potential must use a highly effective form of birth control, confirmed by the 
investigator, throughout the trial and at least for 16 weeks after last administration of IMP 
Abbreviation: AD, atopic dermatitis; EASI, Eczema Area and Severity Score; IGA, Investigator’s Global 
Assessment; IMP, investigational medicinal product; NRS, numeric rating scale; SCORAD, Scoring Atopic 
Dermatitis.  
No. 
Exclusion criteria 
1 
Subjects for whom TCS are medically inadvisable in the opinion of the investigator 
2 
Concurrent enrolment in another interventional clinical trial 
3 
Previous randomisation in a tralokinumab clinical trial 
4 
Active dermatologic conditions that may confound the diagnosis of AD or would interfere with 
assessment of treatment, such as scabies, cutaneous lymphoma, or psoriasis 
5 
Known active allergic or irritant contact dermatitis that is likely to interfere with the assessment of 
severity of AD 
6 
Use of tanning beds or phototherapy (NBUVB, UVB, UVA1, PUVA) within 6 weeks prior to 
randomisation 
7 
Treatment with systemic immunosuppressive/immunomodulating drugs, systemic corticosteroids, or 
bleach baths within 4 weeks prior to randomisation 
8 
Treatment with TCS, TCI, topical PDE-4 inhibitors, or topical JAK inhibitors within 2 weeks prior to 
randomisation 
9 
Receipt of live attenuated vaccines within 30 days prior to randomisation and during the trial 
including the safety follow-up period 
10 
Receipt of any marketed or investigational biological agent (e.g. cell-depleting agents or dupilumab) 
within 6 months prior to randomisation or until cell counts return to normal, whichever is longer 
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11 
Receipt of any investigational non-biologic agent within 5 half-lives prior to randomisation 
12 
Receipt of blood products within 4 weeks prior to screening 
13 
Major surgery within 8 weeks prior to screening or planned in-patient surgery or hospitalisation 
during the trial period 
14 
Known or suspected allergy or reaction to any component of the IMP or AxMP formulation 
15 
History of any active skin infection within 1 week prior to randomisation 
16 
History of a clinically significant infection (systemic infection or serious skin infection requiring 
parenteral treatment) within 4 weeks prior to randomisation 
17 
A helminth parasitic infection within 6 months prior to the date informed consent is obtained that has 
not been treated with, or has failed to respond to, standard of care therapy 
18 
History of anaphylaxis following any biological therapy 
19 
History of immune complex disease 
20 
History of cancer 
21 
Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation will be 
according to local guidelines as per local standard of care 
22 
History of any known primary immunodeficiency disorder including a positive HIV test at screening, 
or the subject taking antiretroviral medications 
23 
History of chronic alcohol or drug abuse within 12 months prior to screening, or any condition 
associated with poor compliance as judged by the investigator 
24 
History of attempted suicide or at significant risk of suicide (either in the opinion of the investigator 
or on the C-SSRS) 
25 
Any disorder, which is not stable and in the investigator’s opinion could affect the safety of the 
subject, influence the findings of the trial, or impede the subject’s ability to complete the trial 
26 
Any abnormal finding, which in the investigator’s opinion may put the subject at risk, influence the 
results of the trial, or influence the subject’s ability to complete the trial 
27 
ALT or AST level 2.0 times the upper limit of normal or more at screening 
28 
Positive HBsAg, HBsAb, HBcAb, or anti-HCV serology at screening. Subjects with positive HBsAb 
may be randomised provided they have negative HBsAg, HBcAb, and HCV serology 
29 
Subjects who are not willing to abstain from donating blood and/or plasma from the time of informed 
consent and for 16 weeks (5 half-lives) after last dose of IMP 
30 
Subjects who are legally institutionalised 
31 
Pregnant, breastfeeding, or lactating women 
32 
Employees of the trial site or any other individuals directly involved with the planning or conduct of 
the trial, or immediate family members of such individuals 
Abbreviations: AD, atopic dermatitis; ALT, alanine aminotransferase; anti-HCV, hepatitis C virus antibody; 
AST, aspartate aminotransferase; AxMP, auxiliary medicinal product; C-SSRS, Columbia-Suicide Severity 
Rating Scale; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B 
surface antigen; HIV, human immunodeficiency virus; IMP, investigational medicinal product; JAK, Janus 
kinase; NBUVB, narrow band ultraviolet B; PDE-4, phosphodiesterase-4; PUVA, psoralen + ultraviolet A; 
TCI, topical calcineurin inhibitors; TCS, topical corticosteroids; UVA1, ultraviolet A1; UVB, ultraviolet B. 
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Appendix 8: Contact list 
Contact details for the clinical project manager, appointed CRA, and sponsor’s medical expert 
are provided to the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
LEO Pharma K.K. is the sponsor of the clinical trial in Japan on behalf of LEO Pharma A/S: 
LEO Pharma K.K. 
1-105 Kanda-Jinbocho
Chiyoda-ku 
Tokyo 101-0051 
Japan 
Signatory investigator 
Norito Katoh, MD, PhD 
Department of dermatology, Director 
University hospital, Kyoto Prefectural University of Medicine 
465, Kajii-cho  
Kawaramachi-Hirokoji Kamigyo-ku  
Kyoto 602-8566  
Japan 
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Electronic signatures made within Clinical Vault are considered to be a 
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Reason for signing: Approved
Approver Verdict(s)
Name: Norito Katoh
Capacity: Clinical Trial Management
Date of signature: 21-Jul-2020 07:39:08 GMT+0000
Reason for signing: Approved
Manage
r Verdict(s)
Name: 
Capacit
Date of signature: 21-Jul-2020 07:58:16 GMT+0000
Reason for signing: Approved
Manage
ver Verdict(s)
Name: 
Capacit
Date of signature: 21-Jul-2020 08:22:58 GMT+0000
Reason for signing: Approved
Manage
s)
Name: 
Capacit
Date of signature: 21-Jul-2020 14:57:55 GMT+0000
Reason for signing: Approved
Manage
Verdict(s)
Name: 
Capacit
Date of signature: 21-Jul-2020 15:49:38 GMT+0000
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SAP_001.pdf: 
Cover Page 
Study title: Tralokinumab in combination with topical corticosteroids in Japanese subjects with 
moderate-to-severe atopic dermatitis ECZTRA 8 (ECZema TRAlokinumab trial no. 8) 
LEO Pharma number: LP0162-1343 
NCT number: NCT04587453 
Date: 15-Jun-2021 


Statistical Analysis Plan 
LP0162-1343 
Tralokinumab in combination with topical corticosteroids in Japanese 
subjects with moderate-to-severe atopic dermatitis 
ECZTRA 8 (ECZema TRAlokinumab trial no. 8) 
Phase 3 – efficacy and safety trial 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and 
safety of tralokinumab in combination with topical corticosteroids in Japanese subjects with 
moderate-to-severe atopic dermatitis who are candidates for systemic therapy 
LEO Pharma A/S 
Trial ID: 
LP0162-1343 
Date: 
15-Jun-2021
Version: 
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1 
Statistical Analysis Plan Approval 
1.1 
Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
statistical analysis plan. 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
The following persons have approved this statistical analysis plan using electronic signatures 
as presented on the last page of this document. 
, MSc 
Biostatistics Lead, Medical Science 
, MD 
Medical Lead, Medical Science 
 MSc 
QC Statistician, Biostatistics 
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2 
Statistical Analysis Plan Statements 
2.1 
Compliance with Good Clinical Practice 
This statistical analysis plan is designed to comply with the standards issued by the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) (E3: Structure and Content of Clinical Study Reports, E6: Good Clinical 
Practice, and E9: Statistical Principles for Clinical Trials). 
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Table of contents 
1 
Statistical Analysis Plan Approval .................................................................................... 2 
1.1 
Approval Statement ....................................................................................................... 2 
2 
Statistical Analysis Plan Statements ................................................................................. 3 
2.1 
Compliance with Good Clinical Practice....................................................................... 3 
Table of contents ........................................................................................................................ 4 
3 
List of Abbreviations ........................................................................................................ 6 
4 
Introduction ....................................................................................................................... 7 
5 
Trial analysis sets .............................................................................................................. 7 
6 
Statistical Analysis ............................................................................................................ 8 
6.1 
Demographics and baseline characteristics ................................................................... 8 
6.2 
Disposition ..................................................................................................................... 8 
6.3 
Treatment compliance .................................................................................................... 9 
6.4 
Exposure ........................................................................................................................ 9 
6.5 
Rescue medication ......................................................................................................... 9 
6.6 
Analysis of efficacy ....................................................................................................... 9 
6.6.1 
Primary efficacy endpoints ...................................................................................... 10 
6.6.2 
Key secondary efficacy endpoints: .......................................................................... 10 
6.6.3 
Multiple imputation ................................................................................................. 11 
6.6.4 
Other endpoints and patient-reported outcomes: ..................................................... 12 
6.6.5 
Exploratory analyses ................................................................................................ 13 
6.6.6 
AxMP (TCS) accountability .................................................................................... 13 
6.7 
Analysis of Safety ........................................................................................................ 14 
6.7.1 
Adverse events ......................................................................................................... 14 
6.7.2 
Vital signs ................................................................................................................ 15 
6.7.3 
Electrocardiogram .................................................................................................... 16 
6.7.4 
Laboratory data ........................................................................................................ 16 
6.7.5 
Urinalysis ................................................................................................................. 18 
6.7.6 
Pharmacokinetics and anti-drug antibodies ............................................................. 18 
6.8 
General Principles ........................................................................................................ 18 
6.8.1 
Baseline value .......................................................................................................... 18 
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6.8.2 
Definition of trial periods and date of permanent discontinuation of IMP .............. 18 
6.8.3 
Incomplete dates ...................................................................................................... 19 
6.8.4 
Conventions regarding time of day for concomitant medication ............................ 21 
6.8.5 
Treatment and trial completers ................................................................................ 21 
6.8.6 
Early termination and unscheduled visits ................................................................ 21 
6.8.7 
Handling of dropouts and missing values ................................................................ 22 
6.8.8 
Treatment Labels ..................................................................................................... 22 
6.8.9 
Protocol deviations .................................................................................................. 22 
7 
References ....................................................................................................................... 22 
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3 
List of Abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
ADaM 
analysis data model 
AE 
adverse event 
AxMP 
auxiliary medicinal product 
BSA 
body surface area 
CRF 
case report form 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI75 
at least 75% reduction in EASI score 
ECG 
electrocardiogram 
FAS 
full analysis set 
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) 
IMP 
investigational medicinal product 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
NRS 
numeric rating scale 
POEM 
Patient Oriented Eczema Measure 
PYE 
patient years of exposure 
Q2W 
every 2 weeks 
QC 
quality control 
SAP 
statistical analysis plan 
SCORAD 
Scoring Atopic Dermatitis 
SOC 
(MedDRA) system organ class 
SOP 
standard operating procedure 
TCS 
topical corticosteroid(s) 
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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. 
New analyses: 
The analyses of the other endpoints, reduction from baseline to Week 16 of DLQI≥4 among 
subjects with baseline DLQI≥4 and reduction from baseline to Week 16 of POEM score ≥4 
points in subjects with baseline POEM score ≥4, will be analysed by applying the composite 
estimand. In addition, the same endpoints will be evaluated at each scheduled visit/assessment 
up to Week 12. 
A repeated measurements analysis of the change from baseline in EASI score from baseline to 
Week 16 has been added. 
Trial completers will be defined as stated in the protocol. Reason for not completing the trial 
will be assessed using the alternatives listed for not attending the safety follow-up visit except 
for the alternatives ‘transferred to 1337’ and ‘safety follow-up information collected at 
nominal Week 16 visit’. 
A descriptive presentation of IGA 0/1 and EASI75 at week 16 by baseline IGA have been 
added. 
5 
Trial analysis sets 
The trial analysis sets are defined in the protocol and the following modifications to the 
analysis sets are introduced. 
All subjects who are randomised to treatment and exposed to IMP will be included in the full 
analysis set (FAS) and will be analysed for efficacy up to Week 16. Exclusions from the FAS 
can be considered in special cases as described in the ICH E9 guideline, Section 5.2.1. If it is 
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decided to exclude a randomised and exposed subject from the FAS, a justification addressing 
ICH E9 will be given. 
As stated in the protocol, a safety analysis set will be defined as all randomised subjects who 
receive IMP.  
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 6.8.2 for further details. 
For analysis of efficacy, subjects will be analysed ‘as randomised’. 
For analysis of safety, subjects will be analysed ‘as treated’ according to the following rule: 
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 decisions regarding inclusion/exclusion of subjects from the trial analysis sets will be 
documented in the analysis set definition document before breaking the randomisation code. 
6 
Statistical Analysis 
6.1 
Demographics and baseline characteristics 
Demographics and 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. Also, a table of concomitant 
medication during the treatment period will be included. Concomitant medication with start 
date equal to the day of exposure end will be assigned to the safety follow-up period, see 
Section 6.8.4. For handling of incomplete dates, see Section 6.8.3. 
6.2 
Disposition 
Subject disposition will be summarised and listed. 
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6.3 
Treatment compliance 
Compliance will be summarised and listed. If a dose is received partly, e.g. only one injection, 
then this dose is treated as a compliant (non-missed) dose in the summary tables. 
In case of permanent discontinuation of IMP, only doses missed before permanent 
discontinuation of IMP will be included in the summary tables. 
6.4 
Exposure 
The exposure time will be defined as detailed in Section 6.8.2. 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. 
6.5 
Rescue medication 
Rescue treatment will be summarised and listed. Initiation of rescue treatment will be 
presented using a cumulative proportions plot over time instead of the Kaplan-Meier plot 
described in the protocol. 
The table of rescue medication will include medications taken after the first dose and before 
the (nominal) Week 16 visit (or before day 7*16=112 after first dose, in case the (nominal) 
Week 16 visit did not take place). 
6.6 
Analysis of efficacy 
Efficacy will be analysed as described in the clinical trial protocol. 
Calculation of Weekly average of pruritus NRS 
The weekly average will only be calculated if at least 4 out of the 7 weekly assessment are 
available and otherwise set to missing. In case of several entries on the same day, the worst 
observation of that day will be used.  
When calculating the baseline value for the weekly average of Worst Daily Pruritus, the daily 
assessments in the 7 days preceding the randomisation will be used, including the day of 
randomisation. 
For the treatment period, the NRS weekly average for Week 1 will be calculated based on 
scores recorded on day 1 to day 7 (where day 0 is the day of the first dose). Similarly, for 
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Weeks 2 to Week 15, the weekly average for Week x will be calculated based on scores 
recorded on day 7*x-6 to day 7*x (where day 0 is the day of first dose). 
For Week 16, the weekly average will be calculated based on the scores recorded on the day 
of the Week 16 visit and the 6 days prior to that day.  
Calculation of Weekly average of Eczema-related Sleep NRS 
Weekly averages of Eczema-related Sleep NRS will be calculated using the same rules as for 
the weekly averages of pruritus NRS. As for the Worst Daily Pruritus NRS, in case there are 
several Eczema-related Sleep NRS assessments at the same date only the worst will be used. 
6.6.1 
Primary efficacy endpoints 
Primary analysis for the secondary estimand 
As described in the protocol, imputation of missing data at Week 16 will be done using 
multiple imputations within 4 groups defined according to treatment group and whether or not 
subjects have permanently discontinued IMP prior to Week 16 assuming data is missing at 
random (MAR). Imputation within one or more groups may not be feasible if too few data is 
available. If this is the case, the primary analysis will not be conducted and will be replaced 
by the corresponding sensitivity analysis where subjects with missing data will be imputed as 
non-responders.  
6.6.2 
Key secondary efficacy endpoints: 
Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from baseline to Week 
16 will be based on subjects in the FAS with a baseline Pruritus NRS weekly average of at 
least 4. 
The binary endpoint is planned to be analysed as described for the primary endpoint EASI75 
using the two estimands. It is however expected that subjects will not fill in the eDiary when 
they have discontinued treatment, and it is considered likely, there will be no nominal Week 
16 data available for discontinued subjects. If this is the case, the primary analysis of the 
secondary estimand (‘treatment policy’) will not be performed for this endpoint. The 
corresponding sensitivity analysis for the secondary estimand, analysing subjects with 
missing Week 16 data as non-responders, while otherwise using observed data for the 
remaining subjects, will still be conducted. 
SCORAD 
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For the calculation of SCORAD, the protocol states that dryness is evaluated on uninvolved 
areas. This means that if a subject has an extent, i.e. total body surface area (BSA) affected by 
AD, of 100% then there is no area to score. In the event that dryness is missing and extent is 
100% then a dryness score of 0 (none/absent) will be imputed. 
6.6.3 
Multiple imputation 
For the analysis of the primary and key secondary endpoints, multiple imputation will be 
carried out, as specified in the protocol, using SAS PROC MI. Unless otherwise specified in 
the protocol, the seed 11109943 will be used. 
When performing multiple imputation of continuous parameter values, imputed values at 
visits prior to Week 16 outside the relevant parameter scale shall be used as is. Values imputed 
at Week 16 shall be truncated to the nearest upper or lower bound on the given scale. For 
example, negative imputed EASI values at Week 16 will be set to 0. 
For imputation of IGA values, the LIKELIHOOD=AUGMENT option will be used (1). 
For imputation of IGA values, it may occur that the observed data from which the imputation 
model is fitted does not contain all levels of the IGA predictors necessary for the imputation. 
For example, the imputation model for IGA values at Week 8 will be based on observed data 
from the subset of subjects with observed IGA values at both Week 6 and Week 8. If only the 
IGA values (0,1,2,3) are observed at Week 6 in this subset of subjects, the imputation model 
will not be able to predict IGA values at Week 8 for a subject with an IGA value of 4 at Week 
6. To avoid this situation, in this specific example IGA values of 3 and 4 at Week 6 will be
combined into a single category for the 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 1. 
Table 1: Adjacent IGA categories combined in case of missing predictors in observed data 
IGA value(s) missing in imputation model 
IGA categories combined 
0 
(0,1) 
1 
(0,1) 
2 
(2,3) 
3 
(2,3) 
4 
(3,4) 
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6.6.4 
Other endpoints and patient-reported outcomes: 
The two binary other endpoints, reduction from baseline to Week 16 of DLQI≥4 among 
subjects with baseline DLQI≥4 and reduction from baseline to Week 16 of POEM score ≥4 
points in subjects with baseline POEM score ≥4, will be analysed as described for the primary 
analysis of the primary estimand (‘composite’) for the primary efficacy endpoints. In addition, 
the same endpoints will be evaluated at each scheduled visit/assessment up to Week 12. 
Amount of TCS used 
The amount of TCS used will be calculated as specified in section 6.6.6 and analysed in two 
ways, reflecting the two consumption assumptions. The primary analysis will be using the 
most conservative assumption that all missing tubes were fully used. The second assumption 
will be used as a sensitivity analysis, reflecting the primary analysis’s extreme opposite, that 
all non-returned tubes were not used. The method used for analysis will be the one specified 
in the protocol. Additionally, descriptive histograms of both consumption assumptions will be 
produced. 
Number of days without topical treatment use 
The number of days without topical treatment use (collected as Patient Days of Topical 
Treatment Use in the eDiary) will be determined over 1-week periods from Week 0 until 
Week 16 and will be summarised over time by treatment group as specified in the protocol. 
Number of days without topical treatment use will be calculated using the same rules as for 
the Worst Daily Pruritus NRS (weekly average).  In addition, a new binary endpoint ‘5-7 days 
without topical treatment use’ will be introduced. This new endpoint will be evaluated by 
week and by treatment group as described for the primary analysis of the primary estimand 
(‘composite’) for the primary efficacy endpoints.  
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/ 
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6.6.5 
Exploratory analyses 
Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from baseline to each 
scheduled assessment up to Week 15 will be based on subjects in the FAS with a baseline 
Pruritus NRS weekly average of at least 4. 
Change from baseline in EASI score 
In addition to the repeated measurements analysis of percentage reduction from baseline in 
EASI score, which was planned in the protocol, the same analysis will be conducted for the 
absolute change from baseline in EASI scores. 
Subgroup analyses 
To assess the consistency of the number of responders for the primary composite estimand 
across subgroups, IGA 0/1 and EASI75 will be presented descriptively by baseline IGA. 
6.6.6 
AxMP (TCS) accountability 
For each subject, the weight of TCS used for a given visit interval (WGTUSED) will be 
calculated as the difference between the weight of the tubes dispensed (WGTDISP) and the 
weight of the returned tubes (WGTRET): 
•
if WGTRET ≤ WGTDISP then WGTUSED=WGTDISP-WGTRET
•
if WGTRET > WGTDISP then WGTUSED = 0.
All tubes dispensed at a visit are assumed to be returned at the subsequent visit where new 
tubes are dispensed. The amount of TCS used from these tubes will be attributed to the period 
between these two visits. 
When tubes are not returned as specified in the protocol, the following rules will be applied: 
•
If a dispensed tube is not returned at all and the subject remains in the study, two
different approaches will be applied to explore two extreme assumptions:
1. It will be assumed that the missing tube has been fully used by the subject in the
period between the date the tube was dispensed, and the date of the next
subsequent visit attended by the subject. Estimated content (100 g) for the kit
number will be used as a contribution to the WGTRET.
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2. It will be assumed that the missing tube has not been used at all by the subject in
the period between the date the tube was dispensed, and the date of the next
subsequent visit attended by the subject, i.e. contribution from the tube to the
WGTRET is set to 0.
•
In the case where tubes from the last dispensing visit are not returned due to the
subject being withdrawn from the trial, the amount of TCS used from these tubes will
not be calculated (i.e. set to missing).
If a subject does not attend a planned visit, daily usage (DAYUSE) is calculated for the period 
between the tubes being dispensed and the subsequent dispensing visit, i.e. 
DAYUSE=WGTUSED/DURATION where DURATION =ENDDATE (date of the subsequent 
dispensing visit)-STARTDATE (date of the tubes being dispensed). The amount of TCS used 
for each visit in the period (missing visit(s) and the first visit after the tubes being dispensed) 
is calculated by multiplying daily usage (DAYUSE) by the number of days between the visit 
and the previous visit. For missing visits, the planned dates according to the trial schedule will 
be used. 
6.7 
Analysis of Safety 
As specified in the protocol, the analysis of safety will be based on the safety analysis set and 
the safety follow-up analysis set. 
6.7.1 
Adverse events 
Adverse Events will be summarised and listed. The summaries will be split into the treatment 
period and the safety follow-up period. Adverse Events occurring prior to the first dose will 
only be listed. 
Assignment of AEs to periods 
An Adverse Event (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 
6.8.2, Table 4). 
For AEs with start day on the same day as the first dose was given, only AEs starting after the 
first dose was given will be considered treatment-emergent and assigned to the treatment 
period.  
AEs starting on the day of exposure end (as defined in Section 6.8.2) will be assigned to the 
treatment period.  
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For handling of incomplete start dates of AEs, see Section 6.8.3. 
Sort order of AE tables 
Generally, AE tables by system organ class and/or preferred term will primarily be sorted 
alphabetically by SOC, and the preferred terms within the SOC will be sorted by decreasing 
number of events found in any of the treatment groups. The treatment group itself will not be 
considered in the sorting.  
Other adverse events of interest 
A MedDRA search on all reported AEs will be made to capture AEs belonging to injection 
site reactions. The MedDRA search to capture this safety area of interest was performed using 
the following high-level terms (based on primary and secondary terms): ‘administration site 
reactions NEC’, ‘application and instillation site reactions’, and ‘injection site reactions’. As 
only primary terms are available in SDTM data, a list of preferred terms included within the 
high-level terms are used to account for secondary terms. The list has been reviewed prior to 
unblinding of the trial. 
6.7.2 
Vital signs 
Vital signs will be summarised and listed. 
For the summary tables of vital signs by visit, the last pre-dose vital sign assessment will be 
presented. If no dosing occurs at a visit, the last assessment recorded at the visit will be 
presented. 
For the first 3 IMP dosing visits, subjects will be monitored after IMP administration for 
immediate drug reactions for a minimum of 30 minutes with vital signs taken at every 30 
minutes or until stable, whichever is later. These measurements will be listed. 
Potentially clinically significant values will be defined as displayed in Table 2. 
Table 2: 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 
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Abbreviations: PCS=potentially clinically significant. 
6.7.3 
Electrocardiogram 
Electrocardiogram (ECG) data will be summarised and listed. The overall central evaluation 
of ECG will be presented using shift tables. 
6.7.4 
Laboratory data 
Laboratory data will be summarised and listed. 
For the laboratory values, if the value is below the lower limit of quantification, half of the 
lower limit will be used for quantitative summaries. If the value is above the upper limit of 
quantification, the upper limit value will be used.  
If more than one laboratory value is reported for the same visit and time point, the latest value 
will be used in summary statistics and analyses.  
Shift tables from baseline to highest/lowest post-baseline value in the treatment period will be 
based on laboratory ranges. The laboratory ranges are defined for fasting values.   
Shift tables for eosinophil values from baseline to end of treatment period and to 
highest/lowest post-baseline value in the treatment period will be summarised in the following 
categories: ≤0.5∙109/L, >0.5∙109/L to ≤1.5∙109/L, and >1.5∙109/L.  
Potentially clinically significant values will be defined as displayed in Table 3. 
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Table 3: Potentially clinically significant biochemistry and haematology values 
Protocol lab parameter 
SI unit 
PCS low 
PCS high 
Biochemistry 
Sodium 
mmol/L < 129 mmol/L, 
< 125 mmol/L 
> 160 mmol/L
Potassium 
mmol/L < 3 mmol/L,  
< 2.5 mmol/L 
> 6.5 mmol/L,
> 7.5 mmol/L
Creatinine 
umol/L 
N/A 
> 1.5xULN, > 3xULN
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). 
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6.7.5 
Urinalysis 
Urinalysis data will be summarised and listed. 
6.7.6 
Pharmacokinetics and anti-drug antibodies 
Pharmacokinetics and anti-drug antibodies (ADA) data will be summarised and listed. 
6.8 
General Principles 
In addition to what is stated in the protocol, the lower and upper quartiles will be used to 
summarise continuous data.   
6.8.1 
Baseline value 
Unless otherwise specified, the baseline value is defined as the latest pre-dose assessment. 
Missing baseline assessments 
When the baseline value is missing, endpoints concerning a change from baseline cannot be 
derived, and such subjects will be excluded from the analysis. Since the missingness of 
baseline values are unrelated to the assigned treatment, bias should not be a concern with this 
approach.  
6.8.2 
Definition of trial periods and date of permanent discontinuation 
of IMP 
Date of permanent discontinuation of IMP 
Defined for subjects who have a reason for permanent discontinuation of IMP recorded. 
 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 (if existing) at time 23:59:00, otherwise date of last IMP 
administration at time 23:59:00. 
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Date of last contact 
Date of very last contact found by examining all time and date information in eCRF, 
laboratory, ECG, and PRO. 
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 4 (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 5). 
Table 4: Start and end time of trial periods (ADaM variable APHASE) 
APHASE 
Start of period 
End of period (only if start date exists) 
Treatment 
period 
Exposure start 
Exposure end 
Safety 
follow-up 
period1
First day after 
exposure end  
Date of last contact at time 23:59:00 
1) Only applicable if date of last contact is not equal to date of exposure end.
Table 5: Start and end time of trial periods (ADaM variable APERIODC) 
APERIODC Start of period 
End of period (only if start date exists) 
Treatment 
period 
Exposure start 
Date of last contact at time 23:59:00 
6.8.3 
Incomplete dates 
Adverse events 
If the AE start day is missing, but AE start month and year are not missing, the following rules 
apply: 
•
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.
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•
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
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.
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Administration of IMP 
In case of incomplete time registrations of IMP dosing with dates of administration being 
available, the time of 12:00:00 will be used. 
6.8.4 
Conventions regarding time of day for concomitant medication 
Concomitant medication 
For the purpose of associating concomitant medication with trial periods, the convention will 
be that the start time of day of concomitant medications is 23:59:59, and end time is 00:00:00, 
unless the start day is equal to the end day in which case both start and end time will be 
assumed to be 23:59:59. As a consequence, rescue medication starting on the day of transfer 
between two periods will be associated with the latter period only, and rescue medication 
ending on the day of transfer between two periods will be associated with the first period only 
(unless the start day is equal to the end day).  
Unlike adverse events which are assigned to a single period based on their start date only, a 
concomitant medication can be associated with more than one period. 
6.8.5 
Treatment and trial completers 
A subject who has not permanently discontinued IMP before Week 16 will be defined as a 
treatment completer. 
Trial completers will be defined as stated in the protocol. Reason for not completing the trial 
will be assessed using the alternatives listed for not attending the safety follow-up visit except 
for the alternatives ‘transferred to 1337’ and ‘safety follow-up information collected at 
nominal Week 16 visit’. 
6.8.6 
Early termination and unscheduled visits  
When no data are available from a certain scheduled post-baseline visit for a subject, data 
from early termination visits and unscheduled visits have the potential to replace data from 
that particular scheduled visit in data summaries, provided 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 
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Date of signature: 15-Jun-2021 09:51:07
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Reason for signing: Approved
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Date of signature: 15-Jun-2021 13:25:52
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