Conditions: Atopic Dermatitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 802
Healthy volunteers: no

Brief summary:
Primary objective:

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

Secondary objectives:

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

Maintenance objective:

To evaluate maintenance of effect with continued tralokinumab dosing up to 52 weeks compared to placebo for subjects achieving clinical response at Week 16.

Detailed description:
Subjects found eligible following the screening period were randomized 3:1 to initial treatment with tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Randomization was stratified by region (North America, Europe, and Japan) and disease severity (Investigator's Global Assessment \[IGA\] 3 or 4).

Subjects achieving a clinical response at Week 16 (defined as IGA of 0 or 1 on a 5-point scale ranging from 0 \[clear\] to 4 \[severe\], or at least 75% reduction in Eczema Area and Severity Index \[EASI\] score from baseline \[EASI75\]) continued into maintenance treatment that continued until Week 52.

Subjects randomized to tralokinumab in the initial treatment period and who achieved a clinical response at Week 16 (defined by IGA 0 or 1, or EASI75) were re-randomized 2:2:1 to one of the following Q2W maintenance regimens stratified by region (North America, Europe, and Japan) and IGA response at Week 16 (IGA 0/1 or IGA \>1):

* Tralokinumab 300 mg Q2W.
* Tralokinumab 300 mg Q4W (alternating dose administrations tralokinumab 300 mg and placebo).
* Placebo (Subjects randomized to placebo in the initial treatment period who achieved a clinical response at Week 16 \[defined by IGA 0 or 1, or EASI75\] continued to receive placebo Q2W in the maintenance treatment period).

Subjects not achieving a clinical response at Week 16 as well as those who met the criteria listed below during maintenance treatment were transferred to open-label tralokinumab 300 mg Q2W treatment with optional use of topical corticosteroid (TCS) up to Week 52.

Transfer to open-label treatment during maintenance:

Subjects with IGA=0 at Week 16: IGA of at least 2 and not achieved EASI75 over at least a 4-week period (i.e. over 3 consecutive visits).

Subjects with IGA=1 at Week 16: IGA of at least 3 and not achieved EASI75 over at least a 4-week period (i.e. over 3 consecutive visits).

Subjects with IGA \>1 at Week 16: not achieved EASI75 over at least a 4-week period (i.e. over 3 consecutive visits).

Subjects transferring to open-label treatment had the option to self-administer tralokinumab in their home after adequate training (at 3 dosing visits in the open-label period after additional consent has been obtained) by site staff at the investigator's discretion.

After completion of the maintenance treatment period (or open-label treatment), all subjects, except for those who entered the open-label long-term extension trial, continued in a 14-week off-treatment follow-up period for the assessment of safety and anti-drug antibody (ADA).

Arms:
arm 1: Week 0 to Week 16:

Two subcutaneous (SC) injections of tralokinumab as a loading dose on Day 0, followed by a SC injection of tralokinumab Q2W regimen for 16 weeks. arm 2: Week 0 to Week 16:

Two subcutaneous (SC) injections of placebo as a loading dose on Day 0 followed by a SC injection of placebo Q2W regimen for 16 weeks. arm 3: Week 16 to Week 52:

Tralokinumab responders from the initial treatment period re-randomised at Week 16 and administered tralokinumab maintenance subcutaneous injection regimen Q2W for 36 weeks. arm 4: Week 16 to Week 52:

Tralokinumab responders from the initial treatment period re-randomised at Week 16 and administered tralokinumab maintenance subcutaneous injection regimen Q4W for 36 weeks.

Subjects in this group receive alternating doses of tralokinumab SC injection and placebo SC injection every 2 weeks. arm 5: Week 16 to Week 52:

Tralokinumab responders from initial treatment period randomised at Week 16 and administered placebo subcutaneous maintenance injection for 36 weeks. arm 6: Week 16 to Week 52:

Placebo responders from the initial treatment period re-assigned at Week 16 and administered placebo maintenance subcutaneous injection regimen Q2W for 36 weeks. arm 7: Week 16 to Week 52:

Subjects receiving initial treatment with tralokinumab Q2W or placebo Q2W assigned to open-label treatment at Week 16 and administered Tralokinumab subcutaneous (SC) injection + optional TCS\* regimen Q2W.

OR

Subjects receiving maintenance treatment with tralokinumab Q2W/Q4W or placebo assigned to open-label treatment after Week 16 and administered tralokinumab SC injection + optional TCS\* regimen Q2W.

\*TCS = topical corticosteroids. arm 8: Week 52 to Week 68 \[Short term extension (Japan only)\] :

Japanese subjects who were transferred to the open-label tralokinumab Q2W arm at Week 16 continued an additional 16 weeks (Week 52 to Week 66) of open-label treatment to receive 52 weeks of active therapy.

Interventions: intervention 1: Tralokinumab intervention 2: Placebo
Intervention descriptions: intervention 1: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for subcutaneous (SC) administration intervention 2: Placebo contains the same excipients, in the same concentration only lacking tralokinumab

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: Tralokinumab monotherapy for moderate-to-severe atopic dermatitis ECZTRA 1 (ECZema TRAlokinumab trial no. 1) 
LEO Pharma number: LP0160-1325 
NCT number: NCT03131648 
Date: 14-Aug-2018 
 


Updated Clinical Trial Protocol 
LP0162-1325 
Tralokinumab monotherapy for moderate-to-severe atopic dermatitis 
ECZTRA 1 (ECZema TRAlokinumab trial no. 1)  
Phase 3 - Efficacy and safety trial 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and 
safety of tralokinumab monotherapy in 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: 
LP0162-1325 
Date: 
14-Aug-2018
EudraCT No: 
2016-004200-65 
Version: 
4.0 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 2 of 169 
1 Clinical trial protocol statement  
1.1 Approval statement LEO Pharma A/S 
The following persons have approved this clinical trial protocol by using electronic signatures 
as presented on the last page of this document: 
, MSc Stat 
Biostatistics Lead, Global Clinical Operations 
, MD, PhD 
Medical Lead, Medical Sciences and Safety 
, RN, PhD 
Clinical Operations Lead, Global Clinical Operations 
1.2 Approval statement international coordinating investigator 
The international coordinating investigator approves the clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by manually 
signing the International Coordinating Investigator Clinical Trial Protocol Approval Form, 
which is a separate document adjoined to this document. 
The following person has approved this clinical trial protocol: 
Andreas Wollenberg, Prof. Dr. med. Dr. h.c. 
International coordinating investigator 
1.3 Acknowledgement statement investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol and 
consolidated clinical trial protocol(s) comprising any subsequent amendment(s) by signing a 
Clinical Trial Protocol Acknowledgement Form or a similar document. 
eDoc-00631888 - Version
4. 0
PPD
PPD
PPD


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 3 of 169 
Protocol amendment summary of changes table 
Document history 
Date 
Type of amendment 
Amendment 3 (substantial) 
14-Aug-2018 
Global 
Amendment 2 (substantial) 
12-Dec-2017 
Global 
Amendment 1 (substantial) 
28-Aug-2017 
Global 
Original protocol 
03-Mar-2017 
Amendment 3 (14-Aug-2018) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union (33).  
Overall rationale for the amendment 
The main reason for the amendment is that a new anti-drug antibody (ADA) assay has been 
developed with improved tralokinumab tolerance. This means that the presence or absence of 
ADA can be determined in serum samples with tralokinumab present. Previously, this was not 
possible and therefore ADA sampling at the end of the 14-week off-treatment safety follow-up 
was originally required for the ADA evaluation. Thus, the new ADA assay will allow eligible 
subjects who have completed the treatment periods of trial LP0162-1325 to continue into the 
long-term extension trial (conducted under a separate protocol [LP0162-1337, ECZTEND]) 
without completing the safety follow-up period in the present trial. These subjects will have 
their safety follow-up period after end-of-treatment in the long-term extension trial. 
In addition, the amendment includes other changes, as presented in the table below. 
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it).  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 4 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 4 
Schedule of 
procedures (SoP), 
Panel 2 (footnote 3), 
Panel 3 (footnote 2) 
and Panel 4 
(footnote 2); 
Section 7.1 
Overall trial design; 
Section 7.3 
End of trial 
definition 
Subjects will have a final safety follow-up 
visit 16 weeks after the last dose of IMP 
(which is also considered end of trial visit), 
except subjects who enter the long-term 
extension trial (conducted under a separate 
protocol [LP0162-1337, ECZTEND]). The 
subjects may enter ECZTEND at any time 
during the off-treatment safety follow-up 
period. For these subjects, the end of trial 
visit will be the last visit in trial LP0162-
1325. The subjects entering ECZTEND 
after completion of the end of treatment 
visits (Week 52 or Week 68) will also be 
considered as trial completers. For all 
subjects assigned treatment, an end of 
treatment form and end of trial form will be 
completed in the eCRF. 
To clarify that eligible 
subjects who have completed 
the treatment periods of trial 
LP0162-1325 may continue 
into the long-term extension 
trial (conducted under a 
separate protocol 
[LP0162-1337, ECZTEND]) 
without completing the safety 
follow-up period. 
Section 4 
Schedule of 
procedures (SoP), 
Panel 2 (footnote 5), 
and Panel 4 
(footnote 3); 
Section 7.1 
Overall trial design; 
Section 9.2 
Administration of 
investigational 
medical products 
Subjects eligible for home-use will receive 
proper training at 3 dosing visits in the 
open-label period after additional consent 
has been obtained. 
To clarify what is considered 
proper training of the subjects 
or caregivers in home-use 
(that is 3 dosing visits during 
open-label treatment). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 5 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 9.5 
Concomitant 
medication and 
procedures; 
Section 9.7 
Rescue treatment 
In addition, the use of topical treatments 
is permitted during safety follow-up 
(from Week 52 or Week 68) at the 
investigator’s discretion. 
From Week 16 through safety follow-up 
(FU1 [Week 66] or FU2 [Week 82]) 
subjects may use mild to moderate strength 
TCS and/or TCI as needed (prn usage) on 
lesional skin at the investigator’s discretion 
(see Appendix 9 for TCS classification and 
examples). Use of such TCS and TCI 
should be recorded as concomitant 
medication. 
To clarify that the use of 
topical treatments is 
permitted during the safety 
follow-up period. 
To clarify that subjects in the 
open-label tralokinumab arm 
are allowed to use TCS as 
well as TCI. 
Section 9.9.2 
Storage of IMPs 
The IMP must be stored at 2 to 8°C at the 
site. The temperature during storage must 
be monitored by a calibrated, stationary, 
and continuously monitoring recording 
system. Minimum requirement is a 
calibrated min/max thermometer. 
To clarify that the storage of 
IMP will be monitored. 
Section 9.9.3 
Drug accountability 
Used syringes will be destroyed at the trial 
site provided the trial site has procedures in 
place for such IMP destruction; this 
requires that the trial site is able to issue a 
certificate documenting the kit number(s) 
that were destroyed. 
Trial sites which do not have such IMP 
destruction procedures in place will dispose 
used syringes in sharps bins which will be 
shipped to the contract manufacturing 
organisation (CMO) at the end of the trial. 
For more information about IMP 
accountability, please refer to the IMP 
manual. 
To clarify that a certificate of 
destruction is not required for 
used IMP. 
To also allow shipment of 
sharps bins to the CMO 
during the trial. 
Section 10.3.2.8 
EQ-5D-5L  
The second section consists of a vertical 
visual analogue scale anchored at 0 (‘the 
worst best health you can imagine’) and 
100 (‘the best worst health you can 
imagine’). 
To correct the definition of 
extremes in the vertical visual 
analogue scale. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 6 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 10.5.2 
Serum biomarkers 
The biomarker results from the small panel 
will be presented in the CTR, whereas 
results from the large panel (assessed at 
selected trial sites) will be presented in a 
separate report. 
To clarify that the results 
from the small biomarker 
panel will be included in the 
CTR. 
Section 10.5.3 
Skin biopsies 
(selected trial sites) 
Global gene expression analysis by RNA 
sequencingmicroarray. 
Overall, tThe results from the analyses of 
biopsy material will not be included in the 
CTR, except the global gene expression 
analysis which but will be presented in a 
separate report. 
To clarify that global gene 
expression analysis will be 
carried out by RNA 
sequencing and that the 
results from this analysis will 
not be included in the CTR. 
Section 11.1 
Collection of 
adverse events; 
AEs must be collected from time of first 
trial-related activity after the subject has 
signed the informed consent form until 
completion of the clinical trial (defined as 
the safety follow-up visit 16 weeks after 
last injection). For subjects entering the 
long-term extension trial (LP0162-1337, 
ECZTEND), any (S)AE with onset 
before the final visit in LP0162-1325 
should be reported in LP0162-1325. If 
ongoing, the (S)AE will also be recorded 
as medical history in ECZTEND. 
To clarify how (S)AEs 
occurring in subjects entering 
ECZTEND will be collected 
if visits in LP0162-1325 
overlap with visits in 
ECZTEND. 
Section 11.5.1 
Adverse events of 
special interest 
Panel 13 
(Footnote 1) 
The additional data to be recorded in the 
eCRF are not a requirement, but are to 
be reported by the investigator, if 
available, for example as part of 
standard clinical practice. 
To clarify that additional 
information is to be provided 
only if available and is not a 
requirement. 
Section 12.3.7 
Analysis of safety 
Adverse events of special interest (AESIs) 
will be tabulated and listed instead of being 
presented in a narrative. 
Tabulation and listings are 
considered a more practical 
and informative way of 
presenting data on AESIs. 
This will enable easier 
overview of the individual 
cases as well as sorting and 
pooling of data from several 
trials. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 7 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.3.7.5 
Anti-drug antibodies 
Evaluations of nAB will be conducted on 
those serum samples that test positive for 
ADA. The test sample is deemed positive 
or negative for the presence of nAb to 
tralokinumab relative to a pre-determined 
(in assay validation), statistically derived 
cut point. Samples positive for nAb to 
tralokinumab are then titrated to determine 
relative amounts of nAb present in each test 
sample. 
To reflect that titre 
information will not be 
available from the nAB assay. 
Appendix 1 
Protocol summary 
Updated with the changes described above, 
as applicable. 
To reflect updated text in the 
protocol. 
Appendix 7 
Country-specific 
requirements 
Section 9.9.3 Drug accountability 
Used syringes will be destroyed at the 
trial site provided the trial site has 
procedures in place for such IMP 
destruction. 
Trial sites which do not have such IMP 
destruction procedures in place will 
dispose used syringes in sharps bins 
which will be shipped to the contract 
manufacturing organisation (CMO). 
In Japan, used syringes will be destroyed 
at the trial sites. 
To clarify that used syringes 
will be destroyed at the trial 
site in Japan. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not 
been summarised. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 8 of 169 
Table of contents 
1 Clinical trial protocol statement ............................................................................................ 2 
1.1 Approval statement LEO Pharma A/S ............................................................................... 2 
1.2 Approval statement international coordinating investigator ............................................. 2 
1.3 Acknowledgement statement investigator(s) .................................................................... 2 
Protocol amendment summary of changes table ........................................................................ 3 
Table of contents ........................................................................................................................ 8 
List of panels ............................................................................................................................ 13 
List of abbreviations ................................................................................................................. 14 
2 Trial identification ............................................................................................................... 17 
3 Schematic of trial design ..................................................................................................... 17 
4 Schedule of procedures (SoP).............................................................................................. 18 
5 Introduction and rationale .................................................................................................... 30 
5.1 Atopic dermatitis ............................................................................................................. 30 
5.2 Experience with investigational medicinal product ........................................................ 30 
5.3 Trial rationale .................................................................................................................. 31 
5.4 Justification for dose ....................................................................................................... 32 
5.5 Benefit/risk assessment ................................................................................................... 33 
5.6 Ethical considerations ...................................................................................................... 34 
6 Trial objectives and endpoints ............................................................................................. 36 
6.1 Initial treatment period of Weeks 0 to 16 ........................................................................ 37 
6.2 Maintenance treatment period of Weeks 16 to 52 for responders at Week 16 ................ 39 
7 Trial design .......................................................................................................................... 40 
7.1 Overall trial design .......................................................................................................... 40 
7.2 Number of subjects needed ............................................................................................. 43 
7.3 End of trial definition ...................................................................................................... 43 
8 Trial population and withdrawal .......................................................................................... 44 
8.1 Subject eligibility ............................................................................................................ 44 
8.2 Inclusion criteria .............................................................................................................. 44 
8.3 Exclusion criteria ............................................................................................................. 46 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 9 of 169 
8.4 Screening, screening failures, and randomisation ........................................................... 49 
8.5 Discontinuation ............................................................................................................... 50 
9 Treatments ........................................................................................................................... 52 
9.1 Trial product description ................................................................................................. 52 
9.2 Administration of investigational medical products ....................................................... 53 
9.3 Treatment assignment ...................................................................................................... 55 
9.3.1 
Blinding ....................................................................................................................... 56 
9.3.2 
Emergency unblinding of individual subject treatment ............................................... 56 
9.4 Background treatment (emollients) ................................................................................. 57 
9.5 Concomitant medication and procedures ........................................................................ 57 
9.6 Prohibited medication and procedures ............................................................................ 58 
9.7 Rescue treatment ............................................................................................................. 59 
9.8 Dose modification and IMP discontinuation rules .......................................................... 60 
9.8.1 
Reasons for permanent discontinuation of IMP .......................................................... 60 
9.8.2 
Reasons for temporary discontinuation of IMP .......................................................... 61 
9.9 Treatment logistics and accountability ............................................................................ 61 
9.9.1 
Labelling and packaging of IMPs ............................................................................... 61 
9.9.2 
Storage of IMPs ........................................................................................................... 61 
9.9.3 
Drug accountability ..................................................................................................... 62 
9.9.4 
Trial product destruction ............................................................................................. 63 
9.9.5 
Treatment compliance ................................................................................................. 63 
9.10 Provision for subject care following trial completion ..................................................... 64 
9.11 Reporting product complaints ......................................................................................... 64 
10 Trial schedule and assessments ........................................................................................... 65 
10.1 Overview ......................................................................................................................... 65 
10.2 Assessments performed only at screening/baseline ........................................................ 66 
10.2.1 Columbia-Suicide Severity Rating Scale .................................................................... 66 
10.2.2 Demographics .............................................................................................................. 66 
10.2.3 Medical history ............................................................................................................ 67 
10.2.4 Height and weight ....................................................................................................... 67 
10.2.5 Body surface area involvement ................................................................................... 67 
10.3 Efficacy assessments ....................................................................................................... 68 
10.3.1 Investigator assessments .............................................................................................. 68 
10.3.1.1 Investigator’s Global Assessment ............................................................................ 68 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 10 of 169 
10.3.1.2 Eczema Area and Severity Index ............................................................................. 68 
10.3.1.3 Scoring Atopic Dermatitis ....................................................................................... 70 
10.3.2 Subject assessments ..................................................................................................... 71 
10.3.2.1 Eczema-related Sleep numeric rating scale ............................................................. 71 
10.3.2.2 Worst Daily Pruritus numeric rating scale ............................................................... 71 
10.3.2.3 Average Daily Pruritus numeric rating scale ........................................................... 71 
10.3.2.4 Patient Global Impression of Bother ....................................................................... 71 
10.3.2.5 Patient Global Impression of Severity ..................................................................... 71 
10.3.2.6 Patient-Oriented Eczema Measure .......................................................................... 72 
10.3.2.7 Dermatology Life Quality Index ............................................................................. 72 
10.3.2.8 EQ-5D-5L ................................................................................................................ 72 
10.3.2.9 SF-36........................................................................................................................ 73 
10.3.2.10 Work Productivity and Activity Impairment – General Health ............................... 73 
10.3.2.11 Hospital Anxiety and Depression Scale ................................................................... 74 
10.3.2.12 Treatment Satisfaction Questionnaire for Medicine ................................................ 74 
10.4 Safety assessments .......................................................................................................... 74 
10.4.1 Vital signs .................................................................................................................... 74 
10.4.2 Physical examination ................................................................................................... 75 
10.4.3 Digital ECG ................................................................................................................. 75 
10.4.4 Pregnancy test .............................................................................................................. 76 
10.4.5 Laboratory testing ........................................................................................................ 76 
10.4.6 Pharmacokinetic assessments ...................................................................................... 78 
10.4.7 Anti-drug antibodies measurements ............................................................................ 78 
10.5 Other assessments and photography ................................................................................ 79 
10.5.1 Skin microbiology ....................................................................................................... 79 
10.5.1.1 Background and rationale ........................................................................................ 79 
10.5.1.2 Staphylococcus aureus colonisation (all subjects) ................................................... 79 
10.5.1.3 Skin microbiome characterisation (selected trial sites) ........................................... 80 
10.5.2 Serum biomarkers ........................................................................................................ 80 
10.5.2.1 Rationale .................................................................................................................. 80 
10.5.2.2 Small biomarker panel (all subjects) ....................................................................... 81 
10.5.2.3 Large biomarker panel (selected trial sites) ............................................................. 81 
10.5.3 Skin biopsies (selected trial sites) ............................................................................... 81 
10.5.4 Storage of biological samples ...................................................................................... 82 
10.5.5 Photography (selected trial sites)................................................................................. 83 
10.6 Estimate of total blood volume collected ........................................................................ 83 
11 Adverse events ..................................................................................................................... 84 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 11 of 169 
11.1 Collection of adverse events ............................................................................................ 84 
11.2 Reporting of adverse events ............................................................................................ 84 
11.3 Reporting of serious adverse events ................................................................................ 85 
11.3.1 Investigator reporting responsibilities ......................................................................... 85 
11.3.2 LEO reporting responsibilities .................................................................................... 86 
11.4 Other events that require expedited reporting ................................................................. 86 
11.4.1 Pregnancy .................................................................................................................... 86 
11.5 Reporting of other events ................................................................................................ 87 
11.5.1 Adverse events of special interest ............................................................................... 87 
11.5.2 Overdose ...................................................................................................................... 88 
11.5.3 Medication error .......................................................................................................... 88 
11.5.4 Misuse ......................................................................................................................... 88 
11.5.5 Abuse ........................................................................................................................... 89 
11.5.6 Aggravation of condition ............................................................................................. 89 
11.6 Follow-up for final outcome of adverse events ............................................................... 89 
11.7 Handling of an urgent safety measure ............................................................................. 89 
12 Statistical methods ............................................................................................................... 91 
12.1 Sample size ...................................................................................................................... 91 
12.2 Trial analysis sets ............................................................................................................ 91 
12.3 Statistical analysis ........................................................................................................... 93 
12.3.1 Disposition of subjects ................................................................................................ 93 
12.3.2 Demographics and other baseline characteristics ........................................................ 93 
12.3.3 Exposure and treatment compliance ............................................................................ 93 
12.3.3.1 Exposure .................................................................................................................. 93 
12.3.3.2 Treatment compliance .............................................................................................. 94 
12.3.4 Multiple testing procedure ........................................................................................... 94 
12.3.5 Analysis of initial treatment ........................................................................................ 95 
12.3.5.1 Analysis of primary endpoints ................................................................................. 95 
12.3.5.1.1 Primary estimand: ‘composite’ ............................................................................ 96 
12.3.5.1.2 Secondary estimand: ‘hypothetical’ ..................................................................... 97 
12.3.5.1.3 Tertiary estimand: ‘treatment policy’ ................................................................. 100 
12.3.5.2 Analysis of secondary endpoints ........................................................................... 101 
12.3.5.2.1 Primary estimand for the continuous secondary endpoints: ‘hypothetical’ ....... 101 
12.3.5.2.2 Secondary estimand for the continuous secondary endpoints: ‘treatment policy’
 ............................................................................................................................ 103 
12.3.5.3 Analysis of additional secondary endpoints .......................................................... 105 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 12 of 169 
12.3.5.4 Analysis of other endpoints ................................................................................... 105 
12.3.5.4.1 Efficacy over time .............................................................................................. 105 
12.3.5.4.2 Patient-reported outcomes .................................................................................. 106 
12.3.5.4.3 Skin microbiology .............................................................................................. 108 
12.3.6 Analysis of maintenance treatment ........................................................................... 108 
12.3.6.1 Analysis of maintenance endpoints ....................................................................... 108 
12.3.6.2 Analysis of other maintenance endpoints .............................................................. 110 
12.3.6.2.1 Time to relapse ................................................................................................... 110 
12.3.6.2.2 Continued treatment for non IGA responders .................................................... 110 
12.3.6.2.3 Supportive maintenance ..................................................................................... 110 
12.3.7 Analysis of safety ...................................................................................................... 110 
12.3.7.1 Adverse events ....................................................................................................... 111 
12.3.7.2 Vital signs .............................................................................................................. 111 
12.3.7.3 Clinical laboratory evaluation ................................................................................ 112 
12.3.7.4 Pharmacokinetics ................................................................................................... 112 
12.3.7.5 Anti-drug antibodies .............................................................................................. 112 
12.3.8 Interim analysis ......................................................................................................... 113 
12.3.9 Analysis of data per last subject’s Week 52 visit ...................................................... 113 
12.3.10 General principles ...................................................................................................... 113 
12.3.11 Handling of missing values ....................................................................................... 114 
13 References ......................................................................................................................... 115 
Appendix 1: Protocol summary .............................................................................................. 119 
Appendix 2: Definitions of adverse events and serious adverse events ................................. 124 
Appendix 3: Classification of adverse events ........................................................................ 126 
Appendix 4: Trial governance considerations ........................................................................ 128 
Appendix 4A: Regulatory and ethical considerations ............................................................ 128 
Appendix 4B: Informed consent process ............................................................................... 128 
Appendix 4C: Subject and data confidentiality ...................................................................... 129 
Appendix 4D: Record keeping, quality control, and data handling ....................................... 130 
Appendix 4E: Registration, reporting and publication policy ................................................ 134 
Appendix 4F: Insurance ......................................................................................................... 135 
Appendix 4G: Financial disclosure ........................................................................................ 136 
Appendix 4H: Committee structure ....................................................................................... 136 
Appendix 4I: Trial and site closure ........................................................................................ 137 
Appendix 4J: Responsibilities ................................................................................................ 138 
Appendix 5: Hanifin and Rajka (1980) diagnostic criteria for AD ........................................ 139 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 13 of 169 
Appendix 6: Guidance for anaphylaxis diagnosis .................................................................. 140 
Appendix 7: Country-specific requirements .......................................................................... 142 
Appendix 8: Contact list ......................................................................................................... 146 
Appendix 9: WHO model prescribing information for classification of topical corticosteroids
 ........................................................................................................................................... 149 
Appendix 10: Protocol amendment history ............................................................................ 151 
List of panels 
Panel 1  Trial design ................................................................................................................. 17 
Panel 2  Schedule of trial procedures: screening and initial treatment period ......................... 18 
Panel 3  Schedule of trial procedures: maintenance treatment period and follow-up .............. 22 
Panel 4  Schedule of trial procedures: open-label tralokinumab and follow-up ...................... 25 
Panel 5  Schedule of trial procedures: short-term extension and follow-up (selected countries)
 .......................................................................................................................... 28 
Panel 6  Objectives and endpoints: initial treatment period ..................................................... 37 
Panel 7  Objectives and endpoints: maintenance treatment period .......................................... 39 
Panel 8  Identification of investigational medicinal products .................................................. 52 
Panel 9  Overview of schedules of procedures ........................................................................ 65 
Panel 10  Investigator’s Global Assessment ............................................................................ 68 
Panel 11  Calculation of the Eczema Area and Severity Index ................................................ 69 
Panel 12  EASI severity score scale and area score scale ........................................................ 69 
Panel 13  Central laboratory testing ......................................................................................... 77 
Panel 14  Adverse events of special interest ............................................................................ 87 
Panel 15  Testing procedure for primary, secondary, and maintenance endpoints ................... 94 
Panel 16  Transmission of electronic data .............................................................................. 133 
Panel 17  Classification of topical corticosteroids ................................................................. 149 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 14 of 169 
List of abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BSA 
body surface area 
CCL 
C-C motif chemokine
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CRA 
clinical research associate 
CRO 
contract research organisation 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
DMC 
Data Monitoring Committee 
DPP4 
dipeptidyl peptidase 4 
EASI 
Eczema Area and Severity Index 
EASI50 
At least 50% reduction in EASI score 
EASI75 
At least 75% reduction in EASI score 
EASI90 
At least 90% reduction in EASI score 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
FU 
follow-up visit 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HCP 
healthcare professional 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 15 of 169 
HQoL 
health-related quality of life 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
identification number 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IgE 
immunoglobulin E 
IL 
interleukin 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
LEO 
LEO Pharma A/S 
LOCF 
last observation carried forward 
nAB 
neutralising antibodies 
NRS 
numeric rating scale 
PDE-4 
phosphodiesterase 4 
PGI-B 
Patient Global Impression of Bother 
PGI-S 
Patient Global Impression of Severity 
PK 
pharmacokinetics 
POEM 
Patient Oriented Eczema Measure 
PRO 
patient-reported outcome 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
SAE 
serious adverse event 
SC 
subcutaneous 
SCORAD 
Scoring Atopic Dermatitis  
SCORAD50 
At least 50% reduction in SCORAD score 
SF-36 
36-Item Short Form Health Survey
SoP 
schedule of procedures 
TCI 
topical calcineurin inhibitor 
TCS 
topical corticosteroid 
Th2 
T-helper-2
TSQM 
Treatment Satisfaction Questionnaire for Medication 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 16 of 169 
ULN 
upper limit of normal 
UV 
ultraviolet 
WPAI-GH 
Work Productivity and Activity Impairment – General Health 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 17 of 169 
2 Trial identification 
EudraCT number: 2016-004200-65 
IND number: 123797 
ClinicalTrials.gov number: NCT03131648 
3 Schematic of trial design 
Panel 1  Trial design 
EASI 75, at least 75% reduction in EASI score; IGA, Investigator’s Global Assessment; No, number; rando, 
randomisation; TCS, topical corticosteroid; w, week.  
eDoc-00631888 - Version
4. 0








Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 21 of 169 
4)
Additional informed consents are required for participation in (i) the exploratory component involving microbiome skin swab, large biomarker panel, and skin
biopsy, and (ii) the photograph component (selected trial sites only).
5)
Subjects who are eligible for home-use during open-label treatment will have to provide additional informed consent before the training at the site
(Section 9.2); home-use will only commence after proper training of the subject or caregiver (at 3 dosing visits after the additional consent has been obtained)
and after 3 doses of open-label tralokinumab administered at the trial site, i.e., starting no earlier than Week 22, depending on when the subject transfers to
open-label treatment (selected countries only).
6)
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.
7)
Subjects who achieve a clinical response (IGA 0/1 or EASI75) at Week 16 will be re-randomised into the maintenance period and then receive the first
injections of maintenance treatment (Panel 3). Subjects that do not achieve clinical response at Week 16 will be transferred to open-label tralokinumab 300 mg
Q2W treatment with optional use of TCS and then receive the first injections of open-label treatment (Panel 4).
8)
For the first 3 IMP dosing visits in both the initial and open-label treatment period, subjects will be monitored after IMP administration for immediate drug
reactions for a minimum of 2 hours with vital signs taken every 30 minutes or until stable, whichever is later (Section 9.2).
9)
The eDiary consists of (i) Eczema-related Sleep NRS, (ii) Worst Daily Pruritus NRS, (iii) Average Daily Pruritus NRS, (iv) PGI-B, and (v) PGI-S. The eDiary
will be completed daily from Week -2 to Week 52.
10) IgE not assessed at screening.
11) Optional, selected trial sites only.
12) At baseline, a total of 4 skin biopsies will be taken (2 from lesional skin, 2 from non-lesional skin) at an anatomically similar site.
ADA, anti-drug antibodies; Bcg, background; BSA, body surface area; C-SSRS, Columbia-Suicide Severity Rating Scale; DLQI, Dermatology Life Quality Index; 
EASI, Eczema Area and Severity Index; EASI75, at least 75% reduction in EASI score; ECG, electrocardiogram; eDiary , electronic diary; EQ-5D-5L, EuroQoL 
5-Dimension Health Questionnaire 5 Level; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E;
IMP, investigational medicinal product; NA, not applicable; NRS, numeric rating scale; PGI-B, Patient Global Impression of Bother; PGI-S, Patient Global 
Impression of Severity; POEM, Patient Oriented Eczema Measure; Q2W, every 2 weeks; SCORAD, Scoring Atopic Dermatitis; SF-36, 36-Item Short Form Health 
Survey; TSQM, Treatment Satisfaction Questionnaire for Medication; WPAI-GH, Work Productivity and Activity Impairment – General Health. 
eDoc-00631888 - Version
4. 0






Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 24 of 169 
4)
The eDiary consists of (i) Eczema-related Sleep NRS, (ii) Worst Daily Pruritus NRS, (iii) Average Daily Pruritus NRS, (iv) PGI-B, and (v) PGI-S.
5)
Optional, selected trial sites only.
ADA, anti-drug antibodies; 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; ECG, electrocardiogram; eDiary , electronic diary; EQ-5D-5L, EuroQoL 5-Dimension Health Questionnaire 
5 Level; HADS, Hospital Anxiety and Depression Scale; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; IMP, investigational medicinal product; 
NRS, numeric rating scale; PGI-B, Patient Global Impression of Bother; PGI-S, Patient Global Impression of Severity; POEM, Patient Oriented Eczema Measure; 
Q2W, every 2 weeks; SCORAD, Scoring Atopic Dermatitis; SF-36, 36-Item Short Form Health Survey; TCS, topical corticosteroids; TSQM, Treatment 
Satisfaction Questionnaire for Medication; WPAI-GH, Work Productivity and Activity Impairment – General Health. 
eDoc-00631888 - Version
4. 0






Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 27 of 169 
ADA, anti-drug antibodies; EASI, Eczema Area and Severity Index; ECG, electrocardiogram; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; 
IMP, investigational medicinal product; SCORAD, Scoring Atopic Dermatitis. 
eDoc-00631888 - Version
4. 0




Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 29 of 169 
1)
Only subjects who join the open-label tralokinumab arm at Week 16.
2)
Assessments to be done at an early termination visit.
3)
All subjects will have a safety follow-up (FU2) 16 weeks after last administration of IMP. This is considered the end of trial visit.
4)
Not applicable for subjects self-administering tralokinumab (home-use; selected countries only; Sections 7.1 and 9.2).
ADA, anti-drug antibodies; EASI, Eczema Area and Severity Index; ECG, electrocardiogram; IGA, Investigator’s Global Assessment; IgE, immunoglobulin E; 
IMP, investigational medicinal product; SCORAD, Scoring Atopic Dermatitis. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 30 of 169 
5 Introduction and rationale 
5.1 Atopic dermatitis 
Atopic dermatitis (AD) is a chronic inflammatory skin disease that may affect up to 20% of 
children and up to 10% of adults. In its severe form, AD is characterised by widespread skin 
lesions, intractable itch, as well as enhanced susceptibility to bacterial, viral, and fungal skin 
infections (1-4). AD is associated with a substantial patient burden that typically includes poor 
quality of life, sleep disturbance, and reductions in work productivity (5). 
Treatment recommendations for AD include topical therapies, the main being topical 
corticosteroids (TCS). Unfortunately, TCS and topical calcineurin inhibitors (TCIs) have 
limited efficacy in patients with moderate-to-severe disease. TCS and non-biologic systemic 
therapies are all associated with toxicities with long-term use (6-8). 
AD is characterised by an activated T-helper-2 (Th2) pathway with increased skin expression 
of key Th2 cytokines including interleukin (IL)-13 (9, 10). The expression of IL-13 is 
increased in lesional skin compared to non-lesional skin, and the proportion of CD4+ and 
CD8+ cells expressing IL-13 is upregulated in AD patients compared to individuals without 
AD (9, 11).  
IL-13 acts on keratinocytes to release C-C motif chemokine 22 (CCL22) and recruit more 
IL-13 expressing Th2 cells, decrease differentiation, and contribute to decreased barrier 
function (12). IL-13 also drives immunoglobulin E (IgE) production and contributes to mast 
cell activation status and, once allergen cross-links IgE on the cell surface, drives histamine 
release and induces itch (13, 14). Indeed, itch is a key issue in AD, which drives significant 
mechanical damage to the skin and further facilitates allergen and pathogen entry.  
All of these effects together drive and exacerbate the disease phenotype. A review of the 
available preclinical literature from mouse and human ex vivo models suggests IL-13 as a, if 
not the, central mediator of the AD skin phenotype. Indeed, there is evidence that blocking the 
IL-4 receptor (which is part of the receptor complex which also binds IL-13) with the 
monoclonal antibody dupilumab leads to clinical improvement in AD subjects (15). 
5.2 Experience with investigational medicinal product 
Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that 
specifically binds to human IL-13 and blocks interaction with the IL-13 receptors (16-18). A 
compilation of clinical and nonclinical data on tralokinumab including pharmacokinetics (PK) 
is given in the current Investigator’s Brochure. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 31 of 169 
In total, 17 clinical trials have been conducted with tralokinumab, with phase 3 development 
ongoing in asthma and AD. Other clinical trials with tralokinumab have been conducted in 
subjects with ulcerative colitis, idiopathic pulmonary fibrosis, and in healthy subjects. Further 
information on these trials can be found in the current Investigator’s Brochure. 
In a phase 2b trial (D2213C00001), adults with moderate-to-severe AD on a background of 
mild to moderate TCS, were treated with 3 different regimens of tralokinumab (45 mg every 
second week [Q2W], 150 mg Q2W, or 300 mg Q2W) or placebo to evaluate the safety and 
efficacy over a treatment period of 12 weeks. The primary endpoints were change from 
baseline in Eczema Area and Severity Index (EASI) at Week 12 and the percentage of 
subjects achieving IGA response of 0 (clear) or 1 (almost clear) at Week 12. Secondary 
endpoints included change from baseline in EASI and Scoring Atopic Dermatitis (SCORAD) 
scores, the percentage of subjects achieving at least 50% reduction from baseline in EASI and 
SCORAD scores (EASI50 and SCORAD50). In the overall intent-to-treat phase 2b 
population, an improvement in EASI score at Week 12 was seen in the tralokinumab 300 mg 
Q2W group versus placebo. 26% of subjects achieved an IGA of 0 or 1 in the tralokinumab 
300 mg Q2W group versus 12% in the placebo group. The most commonly reported causally 
related treatment-emergent adverse event was upper respiratory tract infection (6 [3.9%] 
subjects in the combined tralokinumab group (45 mg, 150 mg, and 300 mg) and 2 [3.9%] 
subjects in the placebo group). 
In total, more than 2,343 subjects have been treated with tralokinumab (cut-off date: 
18-Aug-2017) based on actual exposure data from any completed clinical trials and the
enrolment/randomisation schemes for ongoing trials. The safety of all doses studied so far has 
been with an acceptable benefit-risk profile and no major safety concerns have been 
identified. Possible risks associated with use of tralokinumab are summarised in Section 5.5.  
5.3 Trial rationale 
The purpose of this phase 3 trial is to provide evidence of the efficacy and safety of 
tralokinumab monotherapy in the treatment of subjects with moderate-to-severe AD 
inadequately controlled with topical therapies. Such subjects would be candidates for 
systemic therapy.  
The primary objective of this trial is to demonstrate that tralokinumab provides more effective 
control of the skin manifestations of AD than placebo. The trial will evaluate the percentage 
of subjects achieving IGA response of 0 (clear) or 1 (almost clear) and the percentage of 
subjects achieving at least 75% reduction in EASI score (EASI75) at Week 16, with 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 32 of 169 
secondary endpoints addressing symptom scores and extent of AD (SCORAD), itch severity, 
and health-related quality of life (HQoL) measures related to AD.  
As AD is a chronic disease requiring long-term treatment, it is also relevant to evaluate the 
efficacy of tralokinumab as maintenance treatment. After the 16-week initial treatment period, 
the trial will evaluate 2 different treatment options for maintenance therapy (300 mg Q2W and 
300 mg every 4 weeks [Q4W]).  
As an exploratory component, the present trial will also investigate whether subjects who 
have elevated levels of biomarkers of IL-13 may be more likely to respond to an IL-13 
neutralising therapy. Periostin and dipeptidyl peptidase 4 (DPP4) were identified as key 
markers of IL-13 mediated activation in the phase 2b trial (D2213C00001). In a post-hoc 
analysis of trial D2213C00001, subjects with baseline serum DPP4 or periostin levels above 
the median were seen to derive greater benefit from tralokinumab. Further exploratory 
analyses of these biomarkers will be conducted so as to identify sub-populations where 
prospective testing may be conducted in future clinical trials. 
The trial will further characterise the benefit-risk profile of the drug and understand how best 
to position tralokinumab in the AD treatment pathway. 
5.4 Justification for dose 
The selected dose for the initial treatment period in trial is subcutaneously administered 
300 mg tralokinumab Q2W. All subjects randomised to receive treatment with tralokinumab 
will get an initial loading dose of 600 mg on Day 0 (baseline). The administration of the 
loading dose of tralokinumab will allow systemic concentrations to reach steady-state faster, 
and potentially reduce the time to onset of clinical effect. The serum concentrations of 
tralokinumab after the 600 mg loading dose will not exceed the serum tralokinumab 
concentrations at steady state for the 300 mg Q2W. 
The tralokinumab 300 mg Q2W dose was chosen based on the results of the phase 2b trial in 
subjects with moderate-to-severe AD (trial D2213C00001) described in Section 5.2. The 
subjects were treated with 3 different fixed dose regimens of tralokinumab (45, 150, or 
300 mg Q2W) or placebo to evaluate safety and efficacy over a treatment period of 12 weeks. 
In the overall intention-to-treat phase 2b population, a statistically significant improvement in 
EASI change from baseline at Week 12 was observed in the tralokinumab 300 mg group 
versus placebo; however, formal statistical significance was not demonstrated for the 
co-primary endpoint IGA. The key secondary and exploratory endpoint results from 
trial D2213C00001 also support the selection of the tralokinumab Q2W 300 mg dose for 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 33 of 169 
phase 3 development; and overall, larger numerical differences were observed for 300 mg 
tralokinumab dose than for 150 mg compared to placebo for most of the trial endpoints. 
Since the safety profile in trial D2213C00001 was acceptable in all treatment cohorts and no 
clear safety related dose-response pattern was identified, the dose of 300 mg Q2W has been 
selected for evaluation in this trial.  
In the maintenance treatment period, 1 of the treatment arms will be dosed with tralokinumab 
Q4W. This approach will allow the sponsor of the trial, LEO Pharma A/S (hereinafter 
“LEO”), to establish whether less frequent dosing of tralokinumab may be sufficient for 
long-term maintenance of efficacy. 
5.5 Benefit/risk assessment 
There is an unmet medical need for new therapies for use in subjects with moderate-to-severe 
AD as current immunosuppressive medications, such as cyclosporine, methotrexate, and 
azathioprine, have associated long-term toxicities.  
Tralokinumab has already demonstrated efficacy in both moderate-to-severe AD as well as in 
a severe asthma population in phase 2 trials, and has shown an acceptable safety profile in 
AD, asthma, ulcerative colitis, idiopathic pulmonary fibrosis, and in trials with healthy 
subjects. The evidence discussed in Section 5.2 further supports the hypothesis that 
tralokinumab may benefit individuals with AD. 
In clinical trials completed to date tralokinumab was well tolerated. A number of theoretical 
potential risks have been identified that are described in the current Investigator’s Brochure, 
including hypersensitivity reactions, immune complex disease, severe infections, 
malignancies, and interference with reproductive function; measures are in place in this trial 
to protect participating subjects as follows: 

Close monitoring of subjects during the trial with trial visits every 2 weeks
during the treatment period as described in the SoP (Section 4). Where
home-use is appropriate (open-label treatment only), trial visits will be
scheduled every 4 weeks.

Close monitoring of subjects during the post-dosing period (at the first
3 investigational medicinal product [IMP] dosing visits in initial treatment
period and in open-label treatment) as a precautionary measure against
hypersensitivity reactions (further details are given in Section 9.2).
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 34 of 169 

Monitoring of subjects for both clinical manifestations that may be associated
with the development of specific antibodies to tralokinumab (i.e., immune
complex disease).

Exclusion of subjects with untreated systemic helminth infestations or subjects
who have failed to respond to standard of care therapy (neutralisation of IL-13
might theoretically cause a worsening of parasitic infestation, in particular,
prevention of expulsion of gastrointestinal worms (helminths) [29])

Exclusion of subjects with a history of tuberculosis requiring treatment within
12 months prior to the screening visit.

Exclusion of subjects with a history of a clinically significant infection
(defined as a systemic or serious skin infection requiring parenteral antibiotics,
antiviral, or anti-fungal medication; see Section 8.3) within 4 weeks prior to
baseline which, in the opinion of the investigator or sponsor’s medical expert,
may compromise the safety of the subject in the trial.
In conclusion, previous clinical experience with tralokinumab shows no major safety or 
tolerability concerns and appropriate measures have been instituted in this trial to protect 
subjects from possible risks that have been previously identified and to closely monitor each 
subject. The current risk/benefit ratio is favourable and supports the administration of 
tralokinumab for the purposes of achieving the objectives of this trial. 
5.6 Ethical considerations 
No children or other vulnerable subjects incapable of giving informed consent will be 
enrolled in this clinical trial. Furthermore, women who are pregnant, breastfeeding, or trying 
to become pregnant will not be enrolled in this clinical trial. Women of child-bearing potential 
have to agree to use a highly effective method of contraception to prevent pregnancy during 
the clinical trial and until 16 weeks after discontinuation of treatment with the IMP. In 
addition, all female subjects of child-bearing potential will have a pregnancy test performed 
before, during and at End of Treatment to ensure that no foetuses are exposed to the IMP. 
In this clinical trial, the efficacy of tralokinumab will be evaluated in adult subjects with 
moderate-to-severe AD who are otherwise healthy. Tralokinumab treatment will be compared 
with a placebo control group. Subjects who do not achieve a clinical response (IGA 0/1 or 
EASI75) at Week 16 will be transferred to open-label tralokinumab 300 mg Q2W treatment 
with optional use of TCS. Similarly, during the maintenance treatment period, subjects who 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 35 of 169 
meet the protocol definition of transfer to open-label will be treated with open-label 
tralokinumab 300 mg Q2W with optional use of TCS. 
Altogether, the risks associated with participating in this clinical trial are considered very low 
and outweighed by the benefit of a potential future treatment option for moderate-to-severe 
AD. Moreover, 75% of the subjects will be randomised to active treatment with tralokinumab 
in the initial treatment phase and those who do not achieve a clinical response at Week 16 
(including subjects randomised to placebo) will be treated with open-label tralokinumab in the 
maintenance phase with a potential effect and benefit for the individual subject. 
In accordance with the current version of the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines, qualified medical personnel employed by LEO will 
be readily available to advise on trial-related medical questions. Medical monitoring will be 
performed throughout the trial. Safety data will be reviewed regularly by Global 
Pharmacovigilance, LEO and an independent Data Monitoring Committee (DMC; see 
Appendix 4H) to ensure that prompt action is taken, if needed, to maximise patient safety.  
In conclusion, the trial design chosen for this efficacy and safety trial on tralokinumab is 
regarded as ethically justified and adherent with ethical requirements. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 36 of 169 
6 Trial objectives and endpoints 
The initial treatment period (randomisation until Week 16) will be analysed separately from 
the maintenance treatment period (Week 16 until Week 52; subjects who responded and were 
re-randomised at Week 16). For this reason, the objectives and endpoints for the 2 treatment 
periods are listed separately in Panel 6 and Panel 7. 
eDoc-00631888 - Version
4. 0








Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 40 of 169 
7 Trial design  
7.1 Overall trial design 
Overview 
This is a phase 3 randomised, double-blinded, placebo-controlled trial in adult subjects with 
moderate-to-severe AD. The trial will consist of a screening period of 2 to 6 weeks 
(Weeks -6/-2 to 0), an initial treatment period of 16 weeks (Weeks 0 to 16) and a maintenance 
treatment period of 36 weeks (Weeks 16 to 52). The primary endpoint is assessed at Week 16, 
and the final efficacy assessment will be conducted at Week 52. A 14-week off-treatment 
follow-up period for the assessment of safety is also included (Weeks 52 to 66). Subjects not 
achieving a clinical response at Week 16 as well as those who meet certain criteria during 
maintenance treatment will be transferred to open-label tralokinumab 300 mg Q2W treatment 
with optional use of TCS up to Week 52. An overview of the different parts of the trial is 
provided in Panel 1 and Panel 9. 
Screening period (Week -6 to Week 0) 
The screening period has a minimum duration of 2 weeks and a maximum duration of 
6 weeks and includes 1 or 2 screening visits. The exact duration of the screening period 
depends on the washout period defined by the exclusion criteria (Section 8.3). If a washout is 
not required, screening will be reduced to 2 weeks and only requires 1 visit (Week -2; visit 2), 
i.e., the 2 screening visits will be merged. Similarly, if only a 2-week wash-out is required,
screening visits 1 and 2 will be combined (Week -2; visit 2). Eligibility will be assessed at the 
(first) screening visit and on Day 0 prior to randomisation. 
All subjects will attend a screening visit 14 days before baseline (Week -2; visit 2) where they 
will receive electronic diary (eDiary) training and start the eDiary. Data entered in the eDiary 
during the 2 weeks before randomisation will be used to calculate baseline values of the 
patient-reported outcomes (PROs). 
All subjects will use an emollient twice daily (or more, as needed) for at least 14 days before 
randomisation and will continue this treatment throughout the trial. Subjects will initiate 
emollient treatment no later than the Week -2 visit. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 41 of 169 
Initial treatment period (Week 0 to Week 16) 
Following the screening period, approximately 780 subjects will be randomised 3:1 to one of 
the following groups stratified by region and disease severity (IGA of 3 or 4) 

Tralokinumab 600 mg (4 mL) at Day 0 (hereinafter “baseline”), then 300 mg
(2 mL) Q2W.

Placebo (4 mL) at baseline, then placebo (2 mL) Q2W.
Maintenance treatment period (Week 16 to Week 52)  
Subjects achieving a clinical response at Week 16 will continue into maintenance treatment 
that will continue until Week 52.  
Clinical response is defined as IGA of 0 or 1, or at least 75% reduction in EASI score from 
baseline (EASI75). 
Subjects randomised to tralokinumab in the initial treatment period will be re-randomised 
2:2:1 to one of the following Q2W maintenance regimens stratified by region and IGA 
response at Week 16 (IGA 0/1 or IGA >1): 

Tralokinumab 300 mg (2 mL) (‘tralokinumab Q2W’).

Alternating dose administrations tralokinumab 300 mg (2 mL) and placebo (2 mL)
(‘tralokinumab Q4W’).

Placebo (2 mL).
Subjects randomised to placebo in the initial treatment period who achieve a clinical response 
at Week 16, defined by IGA of 0 or 1, or EASI75 will continue to receive placebo Q2W in the 
maintenance treatment period. 
Transfer to open-label treatment  
Subjects will be transferred from maintenance treatment to open-label treatment 
(tralokinumab 300 mg Q2W with optional use of TCS) if they meet the criteria listed below. 
Transfer to open-label may occur at any visit while the subject is in the maintenance treatment 
period but no earlier than Week 22. 
Subjects with IGA=0 at Week 16: 

IGA of at least 2 and not achieving EASI75 over at least a 4-week period (i.e., over
3 consecutive visits).
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 42 of 169 
Subjects with IGA=1 at Week 16: 

IGA of at least 3 and not achieving EASI75 over at least a 4-week period (i.e., over
3 consecutive visits).
Subjects with IGA >1 at Week 16: 

Not achieving EASI75 over at least a 4-week period (i.e., over 3 consecutive visits).
Subjects who are transferred to open-label treatment will continue their scheduled visit 
sequence. 
Open-label treatment (Week 16 to Week 52) 
Any subject that does not achieve the protocol defined clinical response at Week 16 will be 
treated with open-label tralokinumab 300 mg Q2W with optional use of TCS. The open-label 
treatment will extend to Week 52.  
For selected countries 
Subjects transferring to open-label treatment will have the option to self-administer 
tralokinumab – or have tralokinumab administered by a caregiver – in their home after 
adequate training by site staff at the investigator’s discretion (Section 9.2). This home-use will 
only commence after 3 doses of tralokinumab have been administered at the trial site (i.e., 
starting no earlier than Week 22, depending on when the subject transferred to open-label) as 
a safety precaution for subjects receiving their first active therapy. After proper training of the 
subject and/or the caregiver that is, at 3 or more dosing visits during open-label treatment 
after additional consent for home-use has been obtained, these subjects will only have trial 
visits every 4 weeks. For subjects where home-use is inappropriate, tralokinumab will 
continue to be administered by site staff at the trial visit. 
Short-term extension (Week 52 to Week 68) 
For selected countries 
Subjects who join the open-label tralokinumab arm at Week 16 will continue an additional 
16 weeks of open-label treatment in order to secure at least 52 weeks of active therapy.  
Safety follow-up period (Week 52 to Week 66 [or Week 68 to Week 82]) 
All subjects, except for those who enter the long-term extension trial (LP0162-1337, 
ECZTEND, see below), will complete a 14-week off-treatment follow-up period for the 
assessment of safety and ADA at Week 66 (or Week 82).  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 43 of 169 
Long-term extension trial 
Eligible subjects may be invited to enter a long-term extension trial conducted under a 
separate protocol (LP0162-1337, ECZTEND). Subjects who transfer to ECZTEND must have 
had their last visit in the treatment period (Week 52 or Week 68 [selected countries]) under 
the current protocol (LP0162-1325).  
7.2 Number of subjects needed 
Assuming a screening failure rate of 25%, approximately 1040 subjects will be screened and 
approximately 780 subjects will be randomly assigned to trial treatment in the initial 
treatment period (3:1; 585 subjects in the tralokinumab arm and 195 subjects in the placebo 
arm). At Week 16, approximately 40% of the tralokinumab treated subjects are expected to be 
re-randomised (2:2:1 to tralokinumab Q2W, tralokinumab Q4W, and placebo, respectively) 
into the maintenance treatment period; any subject who does not achieve a clinical response at 
Week 16 will be treated with open-label tralokinumab Q2W. 
The statistical power considerations for this sample size (n=780) are described in 
Section 12.1. 
This trial will be conducted at approximately 130 sites in Europe, North America, and Japan. 
The anticipated minimum number of subjects per trial site is 4 and the maximum number of 
subjects is 30. 
7.3 End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the safety follow-up visit (FU1 [Week 66] or FU2 [Week 82]). Subjects 
entering the long-term extension trial (LP0162-1337, ECZTEND) after completion of the end 
of treatment visits (Week 52 or Week 68) will also be considered as trial completers. 
The end of the trial is defined as the date of the last visit of the last subject in the trial 
globally. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 44 of 169 
8 Trial population and withdrawal 
8.1 Subject eligibility 
The investigator should only enrol subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol.  
The subject’s eligibility for the clinical trial must be checked according to the inclusion and 
exclusion criteria at visits specified in Panel 2. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in the submission documentation to regulatory 
authorities/ethics committees, as applicable.  
8.2 Inclusion criteria 
1. Written informed consent and any locally required authorisation obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations.
2. Age 18 and above.
3. Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria for AD (34;
Appendix 5).
4. Diagnosis of AD for ≥1 year.
5. Subjects who have a recent history (within 1 year before the screening visit) of
inadequate response to treatment with topical medications or for whom topical
treatments are otherwise medically inadvisable (e.g., due to important side effects or
safety risks).

Inadequate response is defined as failure to achieve and maintain remission or
a low disease activity state (comparable to IGA 0=clear to 2=mild) despite
treatment with a daily regimen of TCS of medium to higher potency (±TCI as
appropriate), applied for at least 28 days or for the maximum duration
recommended by the product prescribing information (e.g., 14 days for
super-potent TCS), whichever is shorter.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 45 of 169 

Subjects with documented systemic treatment for AD in the past year are also
considered as inadequate responders to topical treatments and are potentially
eligible for treatment with tralokinumab after appropriate washout.

Important side effects or safety risks are those that outweigh the potential
treatment benefits and include intolerance to treatment, hypersensitivity
reactions, significant skin atrophy, and systemic effects, as assessed by the
investigator or by the subject’s treating physician.
6. AD involvement of ≥10% body surface area at screening and baseline (visit 3).
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 numeric rating scale (NRS) average score of ≥4 during the
week prior to baseline.

Worst Daily Pruritus NRS at baseline will be calculated from daily assessments
of worst itch severity (Worst Daily Pruritus NRS) during the 7 days
immediately preceding randomisation (Day -6 to 0). A minimum of 4 Worst
Daily Pruritus NRS scores out of the 7 days is required to calculate the
baseline average score. For subjects who do not have at least 4 scores reported
during the 7 days immediately preceding the planned randomisation date,
randomisation should be postponed until this requirement is met, but without
exceeding the 6 weeks maximum duration for screening.
10. Subjects must have applied a stable dose of emollient twice daily (or more, as needed)
for at least 14 days before randomisation (refer to exclusion criterion no. 8 for
limitations regarding emollients).
11. Women of childbearing potential must use a highly effective* form of birth control
(confirmed by the investigator) throughout the trial and at least for 16 weeks
(5 half-lives) after last administration of IMP.
*A highly effective method of birth control is defined as one which results in a low
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), combined (oestrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 46 of 169 
associated with inhibition of ovulation (oral, injectable, implantable), sexual 
abstinence (when this is in line with the preferred and usual life style of the subject), 
vasectomised partner (given that the subject is monogamous). The subjects must have 
used the contraceptive method continuously for at least 1 month prior to the pregnancy 
test at baseline. A female is defined as not being of child-bearing potential if she is 
postmenopausal (at least 12 months with no menses without an alternative medical 
cause prior to screening), or surgically sterile (hysterectomy, bilateral salpingectomy 
or bilateral oophorectomy).  
8.3 Exclusion criteria 
1. Concurrent enrolment in another clinical trial where the subject is receiving an IMP.
2. Previous randomisation in tralokinumab trials.
3. Active dermatologic conditions that may confound the diagnosis of AD or would
interfere with assessment of treatment, such as scabies, cutaneous lymphoma, or
psoriasis.
4. Known active allergic or irritant contact dermatitis that is likely to interfere with the
assessment of severity of AD.
5. 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.
6. Treatment with the following medications within 4 weeks prior to randomisation:

Systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate,
cyclosporine, azathioprine, mycophenolate mofetil, Janus kinase inhibitors
etc.).

Systemic corticosteroid use (excludes topical, inhaled, or intranasal delivery).

Three or more bleach baths during any week within the 4 weeks.
7. Treatment with the following medications within 2 weeks prior to randomisation

TCS.

TCI.

Topical PDE-4 inhibitor.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 47 of 169 
8. Initiation of treatment of AD with prescription emollients or emollients containing
additives such as ceramide, hyaluronic acid, urea, or filaggrin degradation products
during the screening period (subjects may continue using stable doses of such
emollients if initiated before the screening visit).
9. Receipt of live attenuated vaccines 30 days prior to the date of randomisation and
during the trial including the safety follow-up period.

Receipt of inactive/killed vaccinations (e.g. inactive influenza) are allowed,
provided they are not administered within 5 days before/after any study visit.
10. Receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologic agent,
including dupilumab:

Any cell-depleting agents including but not limited to rituximab: within
6 months prior to randomisation, or until lymphocyte count returns to normal,
whichever is longer.

Other biologics: within 3 months or 5 half-lives, whichever is longer, prior to
randomisation.
11. Receipt of any investigational non-biologic agent within 5 half-lives prior to
randomisation.
12. Receipt of blood products within 4 weeks prior to screening.
13. Major surgery within 8 weeks prior to screening, or planned in-patient surgery or
hospitalisation during the trial period.
14. Known or suspected allergy or reaction to any component of the IMP formulation.
15. History of any active skin infection within 1 week prior to randomisation.
16. History of a clinically significant infection within 4 weeks prior to randomisation
which, in the opinion of the investigator or sponsor’s medical expert, may compromise
the safety of the subject in the trial, interfere with evaluation of the IMP, or reduce the
subject’s ability to participate in the trial. Clinically significant infections are defined
as:

a systemic infection.

a serious skin infection requiring parenteral (intravenous or intramuscular)
antibiotics, antiviral, or antifungal medication.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 48 of 169 
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 biologic therapy.
19. History of immune complex disease.
20. History of cancer:

Subjects who have had basal cell carcinoma, localised squamous cell
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided
that the subject is in remission and curative therapy was completed at least
12 months prior to the date informed consent was obtained.

Subjects who have had other malignancies are eligible provided that the
subject is in remission and curative therapy was completed at least 5 years
prior to the date informed consent was obtained.
21. Tuberculosis requiring treatment within the 12 months prior to screening. Evaluation
will be according to local guidelines as per local standard of care.
22. History of any known primary immunodeficiency disorder including a positive human
immunodeficiency virus (HIV) test at screening, or the subject taking antiretroviral
medications as determined by medical history and/or subject’s verbal report.
23. History of chronic alcohol or drug abuse within 12 months prior to screening, or any
condition associated with poor compliance as judged by the investigator.
24. History of attempted suicide or is at significant risk of suicide (either in the opinion of
the investigator or defined as a “yes” to suicidal ideation questions no. 4 or 5 or
answering “yes” to suicidal behaviour on the Columbia-Suicide Severity Rating Scale
[C-SSRS] Screening version).
25. Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic,
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological,
immunological, psychiatric, or major physical impairment that is not stable, in the
opinion of the investigator, and could:

Affect the safety of the subject throughout the trial.

Influence the findings of the trial or their interpretations.

Impede the subject’s ability to complete the entire duration of trial.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 49 of 169 
26. Any clinically significant abnormal findings in physical examination, vital signs,
electrocardiogram (ECG), haematology, clinical chemistry, or urinalysis during the
screening period, which in the opinion of the investigator, may put the subject at risk
because of his/her participation in the trial, or may influence the results of the trial, or
the subject’s ability to complete entire duration of the trial.
27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.0 times
the ULN (upper limit of normal) at screening.
28. Positive hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb),
hepatitis B core antibody (HBcAb) or hepatitis C virus antibody (anti-HCV) serology
at screening. Subjects with positive HBsAb may be randomised provided they are
hepatitis B vaccinated and have negative HBsAg and HBcAb.
29. Subjects who are not willing to abstain from donating blood and/or plasma from the
time of informed consent and for 16 weeks (5 half-lives) after last dose of IMP.
30. Subjects who are legally institutionalised.
31. Pregnant, breastfeeding, or lactating women.
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, screening failures, and randomisation 
Trial participation begins once written informed consent is obtained (see Appendix 4B for 
details on the informed consent process). Once informed consent is obtained, a subject 
identification number (subject ID) will be assigned by a central interactive web response 
system (IWRS) and the screening evaluations to assess eligibility criteria may begin. The 
subject ID will be used to identify the subject during the screening process and throughout 
trial participation, if applicable. A master log of all consented subjects will be maintained at 
the trial site. 
Screening failures are defined as subjects who consent to participate in the trial but are not 
subsequently randomly assigned to trial treatment. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure subjects to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements (27) 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screening failure details, eligibility criteria, and any adverse events (AEs) and 
serious AEs (SAEs). Follow-up of SAEs must be carried out according to Section 11.6. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 50 of 169 
Individuals who do not meet the criteria for participation in this trial (screening failures) may 
not be re-screened. However, if the reason for screening failure is administrative and not due 
to the subject failing to meet the eligibility criteria, re-screening may be permitted (this will 
require approval by the sponsor’s medical expert after thorough review of all data from the 
original screening visit in the electronic case report form [eCRF]). Individuals who are 
re-screened will get a new subject ID. 
The investigator will maintain a list of all randomised subjects at the trial site including each 
subject’s identity, date of enrolment and corresponding subject ID so that any subject may be 
identified if required for any reason. The list must not be copied or retained by LEO. 
Note that enrolment is defined as the period from screening to randomisation (i.e., subjects are 
not enrolled until randomised) (27). 
8.5 Discontinuation 
A subject may withdraw from trial or from treatment at any time (prior to first dose or during 
treatment period) at his/her own request. A subject may be withdrawn at any time at the 
discretion of the investigator. Discontinued subjects will not be replaced.  
Medical reasons for permanent discontinuation of IMP are given in Section 9.8.1. 
Assessments 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit and return to the trial site for 1 or 2 additional visits as indicated below 
depending on the time of discontinuation of IMP (see the SoP [Section 4] for data to be 
collected at these visits). The investigator will review any AEs which will be followed-up 
according to Section 11.6, if the subject agrees. 
Subjects who permanently discontinue IMP prior to Week 16 will be asked to attend: 

Early termination visit.

Nominal Week 16 visit (16 weeks after randomisation).

Safety follow-up visit (16 weeks after last administration of IMP).
Subjects who permanently discontinue IMP at Week 16 or after Week 16 will be asked to 
attend:  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 51 of 169 

Early termination visit.

Safety follow-up visit (16 weeks after last administration of IMP).
If a subject withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site’s trial records.  
Reason(s) for discontinuation from IMP and withdrawal from the trial must be recorded in the 
medical records and the eCRF (lack of efficacy, AE, withdrawal by subject, lost to follow-up, 
death, other). For subjects randomised to IMP but not attending any post-baseline visits, it 
will be recorded whether any safety evaluations were performed after exposure to IMP. 
Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject.  
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 

The trial site must attempt to contact the subject and reschedule the missed visit as
soon as possible and counsel the subject on the importance of maintaining the
assigned visit schedule and ascertain whether or not the subject wishes to and/or
should continue in the trial.

Before a subject is deemed lost to follow-up, the investigator or designee must make
every effort to regain contact with the subject (where possible, 3 telephone calls and, if
necessary, a certified letter to the subject’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the subject’s
medical record.

Should the subject continue to be unreachable, they will be considered to have
withdrawn from the trial with a primary reason of lost to follow-up.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 52 of 169 
9 Treatments 
9.1 Trial product description 
Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that 
specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is 
presented as a liquid formulation for subcutaneous (SC) administration. 
Tralokinumab and placebo will be packaged in individually numbered kits, each containing 
1 syringe. Refer to Panel 8 for further details. 
Panel 8  Identification of investigational medicinal products 
Investigational 
medicinal 
product 
Dosage form 
Concentration and 
formulation 
Manufacturer 
Tralokinumab 
150 mg/mL solution 
for injection in an 
accessorised pre-filled 
syringe, 1.0 mL fill 
volume. 
Formulated at a nominal 
concentration of 
150 mg/mL in 50mM 
sodium acetate/acetic 
acid buffer, 85mM 
sodium chloride, 0.01% 
(w/v) PS-80, pH 5.5 
solution. 
MedImmune 
Placebo 
Placebo solution for 
injection in an 
accessorised pre-filled 
syringe, 1.0 mL fill 
volume. 
Placebo contains the 
same excipients, in the 
same concentration only 
lacking tralokinumab 
MedImmune 
The accessorised prefilled syringe is a single use, disposable system that is designed to 
administer the labelled dose of the system to the subcutaneous space during 1 injection and 
automatically provide a safety mechanism to reduce the occurrence of accidental needle sticks 
during disposal of the system.  
The accessorised prefilled syringe consists of a prefilled syringe sub-assembly (1 mL prefilled 
syringe barrel with a 1/2 inch 27 gauge thin wall staked in needle, rigid needle shield, plunger 
stopper) and a safety device. 
No active comparators will be used in this trial. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 53 of 169 
9.2 Administration of investigational medical products 
The IWRS will assign the required kit numbers for each subject at each dispensing visit. 
The first day of dosing is considered Day 0 (visit 3). Each subject will receive 4 SC injections 
(each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total loading dose of 
600 mg tralokinumab or placebo (4.0 mL). 
At subsequent visits (Q2W) in the initial treatment period, each subject will receive 2 SC 
injections (each 1.0 mL) of 150 mg tralokinumab or placebo to receive a total dose of 300 mg 
tralokinumab or placebo.  
Subjects in the maintenance period will receive either 

Tralokinumab Q2W (2 SC injections [each 1.0 mL] of 150 mg tralokinumab).

Tralokinumab Q4W (alternating dose administrations 2 SC injections [each
1.0 mL] of 150 mg tralokinumab and placebo).

Placebo (2 SC injections [each 1.0 mL] of placebo).
Subjects who have been transferred to open-label treatment will receive 2 SC injections (each 
1.0 mL) of 150 mg tralokinumab at each dosing interval. 
Dosing visits are shown in the SoP (Section 4). The last administration of IMP under this 
protocol will occur at Week 50 (or Week 66). 
IMP will be administered by a qualified, unblinded healthcare professional (HCP; see 
Section 9.3.1 for blinding details), or by the subject or the subject’s caregiver (open-label 
treatment only; selected countries). A minimum interval of 7 days is required between 
2 dosing 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 at each treatment visit and recorded in the eCRF.  
Further details on IMP administration are provided in an IMP manual. IMP administration 
must be carried out according to these instructions. 
After IMP administration 
For the first 3 IMP dosing visits in both the initial treatment period (i.e., Weeks 0, 2, and 4) 
and in open-label treatment, subjects will be monitored after IMP administration for 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 54 of 169 
immediate drug reactions for a minimum of 2 hours with vital signs taken every 30 minutes or 
until stable, whichever is later. Vital signs will be documented in the eCRF. 
As with any antibody, allergic reactions to dose administration are possible. The World 
Allergy Organization has categorised anaphylaxis into 2 subgroups: allergic anaphylaxis 
(mediated by an immunologic mechanism) and nonallergic anaphylaxis (which has a 
nonimmunologic cause) (31). The clinical criteria for defining anaphylaxis for this trial are 
listed in Appendix 6 (35). Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions must be 
immediately available at trial sites, and trial personnel should be trained to recognise and 
respond to anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase at the central laboratory. 
Conditions requiring IMP administration rescheduling 
If any of the following should occur, the investigator should reschedule the visit and IMP 
should not be administered until the rescheduled visit: 

The subject has an intercurrent illness, that in the opinion of the investigator
may compromise the safety of the subject in the trial (e.g., viral illnesses).

The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to
IMP administration.
If the trial visit cannot be rescheduled in order to maintain minimum of 7 days to subsequent 
dose, the sponsor’s medical expert should be contacted. 
Home-use 
Subjects transferring to open-label treatment will have the option to self-administer 
tralokinumab – or have tralokinumab administered by a caregiver – in their home after 
training and at the investigator’s discretion (selected countries only). Subjects who do not 
want to self-inject may have the staff at the trial site administer all the injections at the trial 
site.  
Subjects who are found eligible for home-use will have to provide additional informed 
consent and home-use will only commence after 3 doses of tralokinumab have been 
administered at the trial site (i.e., starting no earlier than Week 22, see Section 7.1 and the SoP 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 55 of 169 
[Panel 4]). Home-use will start no later than Week 50 (this also applies for subjects in the 
short-term extension). 
Prior to self-administration at home, the individual who will be administering the injections 
(i.e., the subject and/or the caregiver) will receive proper training (that is, at 3 dosing visits 
during open-label treatment after additional consent has been obtained) in SC injection 
technique and on procedures to be followed in the event of an emergency during or following 
home-use of tralokinumab. This training will be conducted by the unblinded HCP.  
The subject and/or the caregiver must also undertake SC administration under HCP 
supervision on one or more occasions such that the HCP is satisfied with the individual’s 
understanding and confidence of the procedure. 
Subjects or their caregivers will only self-administer tralokinumab at home every 4 weeks, 
i.e., in weeks where no efficacy and safety assessments are scheduled (Panel 4 and Panel 5;
see also Section 9.9.3). Where trial visits with efficacy and safety assessments are scheduled 
(every 4 weeks), tralokinumab injections will be administered at the trial site, preferably by 
the subject or their caregiver, alternatively by the unblinded HCP, when all assessments have 
been completed.  
At each trial visit it will be recorded in the eCRF whether tralokinumab was administered by 
the subject or the unblinded HCP. 
9.3 Treatment assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria will be randomised at baseline (Day 0) to receive treatment with 
either tralokinumab or placebo in the initial treatment period. Treatment assignment will be 
pre-planned according to a computer-generated randomisation schedule in a 3:1 ratio 
(tralokinumab:placebo) stratified by region (North America, Japan, and Europe) and baseline 
disease severity (IGA 3 or 4).  
Subjects found to be eligible for maintenance treatment at Week 16 will be re-randomised to 
the maintenance treatment period in a 2:2:1 ratio (tralokinumab Q2W:tralokinumab 
Q4W:placebo) stratified by region and IGA response at Week 16 (IGA 0/1 or IGA >1).  
Subjects randomised to placebo in the initial treatment period who achieve a clinical response 
at Week 16 (IGA 0/1 or EASI75) will continue to receive placebo Q2W in the maintenance 
treatment period. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 56 of 169 
Subjects not eligible for the maintenance part of the trial will be transferred to open-label 
tralokinumab Q2W treatment. 
IWRS will be used to control randomisation and stratification factors, along with IMP supply 
chain and expiry tracking.  
9.3.1 Blinding 
This is a double-blinded trial in which tralokinumab and placebo are visually distinct from 
each other. Neither the subject nor any of the investigator or LEO staff who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of the 
treatment received. The packaging and labelling of the IMPs will contain no evidence of their 
identity.  
Since tralokinumab and placebo are visually distinct and not matched for viscosity, IMP will 
be handled and administered by a qualified, unblinded HCP at the site who will not be 
involved in the management of trial subjects and who will not perform any of the 
assessments. 
In the event that the treatment allocation for a subject becomes known to the investigator or 
other study staff involved in the management of trial subjects, LEO must be notified 
immediately.  
Should an issue arise with the IMP (e.g., damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe [e.g., a 
malfunction during IMP administration]), the unblinded HCP at the site will contact the 
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, HCPs who are not members of the trial staff, or authorised LEO 
personnel. 
Provisions are in place for 24 hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator can unblind a subject’s treatment in the 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 57 of 169 
IWRS. For a requester who is not a member of the trial staff and who does not  have access to 
the IWRS (e.g., a physician at an emergency room), a local contact number for the emergency 
unblinding contract research organisation (CRO) is provided on the subject card (see 
Appendix 4B) to be used if the investigator or delegated site staff cannot be reached. The 
requester will provide the trial ID and subject ID to the emergency unblinding CRO who will 
immediately reveal the individual treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. Should the requester wish to discuss whether unblinding 
is necessary, the emergency unblinding CRO will provide the requester with the LEO 24/7 
contact which will be diverted to the medical cover.  
9.4 Background treatment (emollients) 
All subjects must use an additive-free, basic bland emollient twice daily (or more, as needed) 
for at least 14 days before randomisation. Subjects are not allowed to start treatment with 
prescription emollients or emollients containing additives such as ceramide, hyaluronic acid, 
urea, or filaggrin, unless initiated prior to the screening visit (Section 9.6). Subjects must 
continue their background emollient treatment throughout the trial. 
9.5 Concomitant medication and procedures 
Any medication or vaccine that the subject receives from 3 months prior to screening through 
safety follow-up (FU1 [Week 66] or FU2 [Week 82]) must be recorded in the subject’s 
medical record and the eCRF along with details such as: 

Reason for use.

Dates of administration including start and stop dates.

Dosage information including dose and frequency.

For topical treatments: size of treated area (≤250 cm2 or >250 cm2).
Similarly, concomitant procedures (including body location, diagnosis, and start and stop 
date) must also be recorded in the subject’s medical record and the eCRF. Note: in this trial, 
only surgical procedures will be recorded. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.6. The 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 58 of 169 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
Concomitant medication for conditions other than AD may be continued throughout the trial 
without any change in dosage whenever possible. 
The following concomitant medications related to AD treatment are permitted from screening 
through safety follow-up (FU1 [Week 66] or FU2 [Week 82]): 

Oral antibiotics, antiviral, or antifungal therapy for skin infections as
appropriate.

Stable doses of an emollient (see Section 9.4 for allowed emollients; subjects
must apply such emollients twice daily [or more, as needed] for at least
14 days before baseline and throughout trial participation).

Oral anti-histamines.
In addition, the use of topical treatments is permitted during safety follow-up (from Week 52 
or Week 68) at the investigator’s discretion. 
9.6 Prohibited medication and procedures 
The following medications are prohibited during the trial from randomisation through 
Week 52 (or Week 68): 

TCS of any WHO class (except for subjects in open-label treatment).

Other topical medications used for the treatment of AD, such as TCI.

Use of ultraviolet A or B (UVA or UVB), psoralen + UVA (PUVA), other
phototherapy, or tanning beds.

Prescription emollients or emollients containing additives such as ceramide,
hyaluronic acid, urea, or filaggrin (unless treatment was initiated prior to
screening).

Three or more bleach baths per week.
Any prohibited topical treatments must be recorded as concomitant medication. 
The following medications are prohibited during the trial from randomisation through safety 
follow-up (FU1 [Week 66] or FU2 [Week 82]): 

Investigational agents other than tralokinumab
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 59 of 169 

Immunoglobulin or blood products

Systemic corticosteroids (nasal and inhaled corticosteroids are allowed)

Systemic treatment for AD with an immunosuppressive/ immunomodulating
agent (e.g., cyclosporine, mycophenolate mofetil, azathioprine, methotrexate,
Janus kinase inhibitors, interferon-gamma, or other biologics)

Allergen immunotherapy

Live (attenuated) vaccine
The sponsor’s medical expert must be notified if a subject receives any of these medications 
during the trial. 
9.7 Rescue treatment 
Initial treatment period and maintenance treatment period 
If medically necessary (i.e., to control intolerable AD symptoms), rescue treatment for AD 
may be provided to trial subjects at the discretion of the investigator. For the purpose of 
efficacy analysis, subjects who receive rescue treatment during the initial treatment period 
will be considered as non-responders, but they will continue IMP treatment if rescue consisted 
of topical medications.  
TCI may be used for rescue, but should be reserved for problem areas only, for example face, 
neck, intertriginous and genital areas, etc. If possible, investigators should attempt to limit the 
first step of rescue therapy to topical medications, and escalate to systemic medications only 
for subjects who do not respond adequately after at least 14 days of topical treatment.  
If a subject receives rescue treatment with systemic corticosteroids or non-steroidal systemic 
immunosuppressive drugs (cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, 
etc.), IMP will be immediately discontinued (see Section 9.8.2, reasons for temporary 
discontinuation of IMP). After the treatment with these medications is completed, IMP may 
be resumed if deemed appropriate by the investigator and sponsor’s medical expert, but not 
sooner than 5 half-lives after the last dose of systemic rescue medication.  
Investigators should make every attempt to conduct efficacy and safety assessments (for 
example disease severity scores, safety labs) immediately before administering any rescue 
treatment. An unscheduled visit may be used for this purpose, if necessary. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 60 of 169 
Open-label tralokinumab arm only 
From Week 16 through safety follow-up (FU1 [Week 66] or FU2 [Week 82]) subjects may use 
mild to moderate strength TCS and/or TCI as needed (prn usage) on lesional skin at the 
investigator’s discretion (see Appendix 9 for TCS classification and examples). Use of TCS 
and TCI should be recorded as concomitant medication. 
9.8 Dose modification and IMP discontinuation rules 
9.8.1 Reasons for permanent discontinuation of IMP 
Subjects will be permanently discontinued from IMP in the event of: 

Anaphylactic reaction or other severe systemic reaction to IMP injection.

An AE that, in the opinion of the investigator or sponsor’s medical expert,
contraindicates further dosing.

Diagnosis of a malignancy during the trial, excluding carcinoma in situ of the
cervix, or localised squamous or basal cell carcinoma of the skin.

Evidence of pregnancy.

Any infection that is opportunistic, such as active tuberculosis and other
infections whose nature or course may suggest an immuno-compromised
status.

Severe laboratory abnormalities:
o
ALT and/or AST values >3x ULN with total bilirubin >2x ULN
(unless elevated bilirubin is related to Gilbert-Meulengracht
Syndrome)
o
Confirmed AST and/or ALT >5x ULN (for more than 2 weeks)
Subjects in open-label treatment (tralokinumab 300 mg Q2W with optional use of TCS) who 
in the opinion of the subject or investigator have unacceptable treatment effect of 
tralokinumab may discontinue open-label treatment and enter the safety follow-up period. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 61 of 169 
9.8.2 Reasons for temporary discontinuation of IMP 
IMP dosing may be temporarily suspended in the event of: 

Other intercurrent illnesses or major surgery.

An infection that requires parenteral treatment with antibiotic, antifungal,
antiviral, anti-parasitic, or anti-protozoal agents.

Treatment with systemic corticosteroids or non-steroidal
immunosuppressive/immunomodulating medications (e.g., cyclosporine,
methotrexate, azathioprine, mycophenolate mofetil, Janus kinase inhibitors,
biologic agents).
IMP dosing may resume after the medication leading to suspension of IMP is discontinued. 
A decision to discontinue IMP temporarily or to reinstitute IMP treatment must be discussed 
with sponsor’s medical expert. However, the investigator may suspend trial treatment at any 
time, even without consultation with sponsor’s medical expert if the urgency of the situation 
requires immediate action and if this is determined to be in the subject’s best interest. In such 
cases, sponsor’s medical expert should be informed as soon as possible.  
9.9 Treatment logistics and accountability 
9.9.1 Labelling and packaging of IMPs 
The IMP will be packaged in individually numbered kits, each containing 1 syringe 
(tralokinumab 150 mg or placebo). 
Primary and secondary packaging materials (syringe and outer carton, respectively) will be 
individually labelled. 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Label text will be translated into local languages, as required. The inner label 
will be in English for kits used at trial sites. 
9.9.2 Storage of IMPs 
All LEO supplied IMPs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 62 of 169 
The IMP must be stored at 2 to 8°C at the site. The temperature during storage must be 
monitored by a calibrated, stationary and continuously monitoring system. Minimum 
requirement is a calibrated min/max thermometer.  
A temperature log must be kept to document the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
Storage of IMP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
Note that in the cases listed below, site staff should not use the affected IMP and should 
immediately contact their CRA for further guidance: 

Temperature excursion upon receipt or during storage at the trial site.

Damaged kit upon receipt.

Damaged syringe/cartridge.
Damaged IMP should be documented via IWRS (refer to the IWRS manual for further 
details). Damaged IMP should not be used.  
9.9.3 Drug accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
An inventory (trial medication inventory log) must be kept of the IMP administered to each 
subject randomised in the trial. The trial medication inventory log must be available for 
inspection during monitoring visits and will be checked by the CRA to ensure correct 
dispensing of the IMP.  
Full drug accountability will also be performed in the IWRS. 
Used syringes will be destroyed at the trial site provided the trial site has procedures in place 
for such IMP destruction. 
Trial sites which do not have such IMP destruction procedures in place will dispose used 
syringes in sharps bins which will be shipped to the contract manufacturing organisation 
(CMO). 
The trial site will maintain trial kit cartons from used kits until reconciliation. The IMP must 
be fully accounted for by the CRA with the help of the unblinded HCP. Accountability must 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 63 of 169 
be documented on the trial medication inventory log and in the IWRS. Following 
reconciliation, the trial kit cartons from used kits may be discarded.  
All unused IMP supplied by the CMO on behalf of LEO will be returned to the CMO. IMP 
may be returned from the trial site either to the CMO directly or via the LEO Pharma A/S 
affiliate or CRO responsible for the running of the clinical trial. The IMP returned to the CMO 
will be reconciled with the individual drug accountability forms. 
For more information about IMP accountability, please refer to the IMP manual. 
Where home-use is appropriate, the following apply: 

Subjects will only attend trial visits every 4 weeks, i.e., in weeks where
efficacy and safety assessments are scheduled (Section 9.2). At these trial
visits, subjects will be provided with IMP to be administered at home at the
next dosing interval.

Subjects will be provided with sharps bins for used syringes. Filled sharps bins
will be returned to the trial site.

Subjects will return trial kit cartons, and any unused IMP at each trial visit.

Unused IMP returned by the subjects to the trial site can be stored at room
temperature and must be stored separately from non-allocated IMP.

The trial medication inventory log will document all IMP handed out to and
returned by each subject.
9.9.4 Trial product destruction 
Unused IMP(s) as well as used syringes returned to the CMO will be destroyed by the CMO 
according to approved procedures and/or local requirements.  
9.9.5 Treatment compliance 
IMP injections will be performed by site staff who will also keep the accountability records 
up to date. Any non-compliance and the reason for it must be recorded in the eCRF. 
Where home-use is appropriate, the following apply: 
Subjects will record date and injection site for each administration in a log of drug 
administration; these data will then be transcribed into the eCRF by site staff at the next trial 
visit. If a subject is found to be non-compliant, the investigator should remind the subject of 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 64 of 169 
the importance of following the treatment instructions including taking the IMP as prescribed. 
Any non-compliance and the reason for it must be recorded in the eCRF.  
Where tralokinumab is administered by the subject at the trial site (Section 9.2), the site staff 
will record compliance data in the eCRF. 
9.10 Provision for subject care following trial completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. Subjects who qualify for the long-term extension trial (see 
Section 7.1) may be offered participation. 
9.11 Reporting product complaints 
Any defects or issues with the IMP as well as any device deficiency (including malfunctions, 
use errors, and inadequate labelling) must be reported to Global Pharmacovigilance, LEO on 
the trial-specific (paper) Complaint Form within 3 days of first knowledge.  
Critical complaints (defined as any issue, defect, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., SAE or large particles in the syringe]) must 
be reported to Global Pharmacovigilance, LEO within 24 hours.  
Complaint forms should contain a detailed description of the defect, issue, or device 
deficiency, including whether it led to an AE. (S)AEs which occur due to a defect or issue 
with the IMP or due to a device deficiency will be reported by the investigator as described in 
Sections 11.2 and 11.3. 
Refer to the IMP manual for information on how to update the kit status in the IWRS. 
During the investigation of the product complaint, the device must be stored at labelled 
conditions unless otherwise instructed; the trial site will be notified whether the device needs 
to be returned for further investigation or may be destroyed. 
Global Pharmacovigilance, LEO contact information for reporting product complaints: 
Fax number: +45 7226 3287  
E-mail address: drug.safety@leo-pharma.com
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 65 of 169 
10 Trial schedule and assessments 
10.1 Overview 
Evaluations to be done at each visit are shown in the schedule of procedures (SoP) in 
Section 4. Links to the relevant SoPs are given in Panel 9. Refer to Section 7.1 for further 
details on the trial design. 
Panel 9  Overview of schedules of procedures 
Period 
Start 
Stop 
Follow-up 
visit 
SoP 
Screening and initial treatment 
Week -61 
Week 16 
Not applicable 
Panel 2 
Maintenance treatment2 
Week 16 
Week 52 
Week 66 
Panel 3 
Open-label treatment3 
Week 16 
Week 52 
Week 66 
Panel 4 
Selected countries only: 
short-term extension4 
Week 52 
Week 68 
Week 82 
Panel 5 
1.
For subjects who do not require a wash-out, screening will start at Week -2 (Section 7.1).
2.
Subjects achieving a clinical response at Week 16 will continue into maintenance treatment that will
continue until Week 52 (Section 7.1).
3.
Any subject that does not achieve a clinical response at Week 16 will be treated with open-label
tralokinumab 300 mg Q2W with optional use of TCS. In addition, subjects who meet certain criteria during
maintenance treatment will also be transferred to open-label treatment (Section 7.1).
4.
Subjects who transfer to open-label tralokinumab treatment at Week 16 will continue an additional 16 weeks
of open-label treatment in order to secure at least 52 weeks active therapy (Section 7.1).
Q2W, every 2 weeks; SoP, schedule of procedures; TCS, topical corticosteroids. 
During the course of the trial, subjects may need to be seen at unscheduled visits. The 
assessments to be performed at an unscheduled visit are left to the investigator’s discretion 
(could include any assessment performed at an early termination visit).  
Assessments/procedures at any trial visit should be performed in the following order: 

PROs.

Investigator assessments (performed only by adequately trained investigators;
the same investigator should perform all the evaluations for a given subject
throughout the entire trial period) in the following order:
1. SCORAD component C, then component A and B.
2. IGA.
3. EASI.

Safety and laboratory assessments.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 66 of 169 

Other assessments (skin microbiology, serum biomarkers, skin biopsies,
photographs).

Administration of IMP.
Subjects participating in the trial will be under careful supervision of a dermatologist or 
allergist. Investigators must be experienced in treating AD and have documented experience 
and/or training in use of the assessments required by the protocol and must be either a 
physician, certified physician’s assistant, or advanced registered nurse practitioner. The 
investigators performing the assessments must not be involved in the administration of 
IMP (Section 9.3.1).  
10.2 Assessments performed only at screening/baseline 
Assessments performed only at the screening and/or baseline visit include: assessment of 
eligibility criteria (including review of scores on the Columbia-Suicide Severity Rating Scale 
[C-SSRS] Screening version), demographics, medical history, height and weight, and body 
surface area (BSA) affected by AD. These are described in further detail below. Laboratory 
tests include hepatitis B, hepatitis C, HIV-1, HIV-2, and serum pregnancy test (Sections 10.4.4 
and 10.4.5). 
10.2.1 Columbia-Suicide Severity Rating Scale 
The C-SSRS Screening version is a rater-administered instrument used to assess severity of 
suicidal ideation and suicidal behaviour through a series of simple, plain-language questions 
(36). The C-SSRS must be completed at screening to check that exclusion criterion no. 24 
does not apply.  
10.2.2 Demographics  
The following demographic data will be recorded: 

Month and year of birth

Sex

Race: American Indian or Alaska Native, Asian (Japanese), Asian (others),
Black or African American, Native Hawaiian or Other Pacific Islander, White,
Other

Ethnic origin (self-reported by the subject): Hispanic or Latino, not Hispanic or
Latino
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 67 of 169 
10.2.3 Medical history 
Relevant past and concurrent medical history must be recorded and includes: 

Skin disease history: all past and current skin disease history including:
o
Alopecia
o
Vitiligo
o
Herpes simplex

Atopy history:
o
Duration of AD in years
o
Previous AD treatments
o
Asthma
o
Food allergy
o
Hay fever
o
Allergic conjunctivitis
o
Atopic keratoconjunctivitis
o
Eczema herpeticum

Other medical and surgical history including concurrent diagnoses.
Relevant medical history includes also diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
10.2.4 Height and weight 
The subject’s height must be measured (without shoes) and weight must be determined (in 
indoor clothing and without shoes). 
10.2.5 Body surface area involvement 
The total BSA affected by AD will be assessed by the investigator for each section of the body 
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 SoP (Section 4).  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 68 of 169 
10.3 Efficacy assessments 
10.3.1 Investigator assessments  
10.3.1.1 Investigator’s Global Assessment 
The IGA is an instrument used in clinical trials to rate the severity of the subject’s global AD 
and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (Panel 10). The IGA score 
will be assessed according to the SoP (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. 
Panel 10  Investigator’s Global Assessment 
Score 
Disease severity 
Standard IGA scale 
IGA morphological descriptors 
0 
Clear 
No inflammatory signs of 
atopic dermatitis 
No erythema and no elevation 
(papulation/infiltration). 
1 
Almost clear 
Just perceptible erythema, and 
just perceptible 
papulation/infiltration 
Barely perceptible erythema 
and/or minimal lesion elevation 
(papulation/infiltration) that is not 
widespread. 
2 
Mild disease 
Mild erythema and mild 
papulation/infiltration 
Visibly detectable, light pink 
erythema and very slight elevation 
(papulation/infiltration). 
3 
Moderate disease 
Moderate erythema and 
moderate 
papulation/infiltration 
Dull red, clearly distinguishable 
erythema and clearly perceptible 
but not extensive elevation 
(papulation/infiltration). 
4 
Severe disease 
Severe erythema and severe 
papulation/infiltration 
Deep/dark red erythema, marked 
and extensive elevation 
(papulation/infiltration). 
10.3.1.2 Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the 
severity and extent of AD (19). The EASI score will be assessed according to the SoP 
(Section 4). The assessment will be based on the condition of the disease at the time of 
evaluation and not in relation to the condition at a previous visit. Whenever possible, the 
EASI should be assessed by the same investigator at each visit to reduce inter-rater variability. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 69 of 169 
The EASI is a composite index with scores ranging from 0 to 72, with higher values 
indicating more severe and/or more extensive condition. The index will be calculated as 
shown in Panel 11. 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 12. For each body region, a severity sum score 
will be calculated which will be multiplied by an area score (Panel 12) and by a weighting 
factor. The EASI score equals the sum of the scores obtained for each body region (Panel 11). 
Panel 11  Calculation of the Eczema Area and Severity Index 
Body region 
Erythema 
Induration/ 
papulation 
Excoriation 
Lichenification 
Area score 
Weighting factor 
Score 
Head/neck 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.1 
Trunk 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.3 
Upper extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.2 
Lower extremities 
( SS   + 
   SS   + 
   SS   + 
   SS ) 
x  AS 
x 0.4 
The EASI score is the sum of the 4 body region scores 
(range 0-72) 
AS, area score; EASI, Eczema Area and Severity Index; SS, severity score. Modified from (28). 
Panel 12  EASI severity score scale and area score scale 
Severity score scale 
Area score scale 
0 
None/absent 
0 
0% affected area 
1 
Mild 
1 
1% to 9% affected area 
2 
Moderate 
2 
10% to 29% affected area 
3 
Severe 
3 
30% to 49% affected area 
Half-points (0.5; 1.5; 2.5) may also be 
used. 
4 
50% to 69% affected area 
5 
70% to 89% affected area 
6 
90% to 100% affected area 
EASI, Eczema Area and Severity Index. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 70 of 169 
10.3.1.3 Scoring Atopic Dermatitis 
The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with 
subjective symptoms (20). The maximum total score is 103, with higher values indicating 
more severe disease. SCORAD will be assessed according to the SoP (Section 4). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit. Whenever possible, SCORAD should be 
assessed by the same investigator at each visit to reduce inter-rater variability. 
The assessment consists of 3 components: A = extent, B = intensity, and C = subjective 
symptoms 
Extent (A) 
The extent of AD is assessed as a percentage of each defined body area and reported as the 
sum of all areas (maximum score = 100%) 
Intensity (B) 
The intensity of 6 specific symptoms of AD (erythema, edema/papulation, oozing/crusting, 
excoriation, lichenification, and dryness) is assessed by the investigator on an average 
representative area using the following scale:  
0 
= 
None/absent 
1 
= 
Mild 
2 
= 
Moderate 
3 
= 
Severe 
Note: dryness is evaluated on uninvolved areas.  
The sum of intensity score of the 6 symptoms will be reported (maximum score = 18). 
Subjective symptoms (C) 
A subjective assessment of the average itch and sleeplessness over the last 3 days/nights is 
recorded for each symptom by the subject on a visual analogue scale, where 0 is no itch (or 
sleeplessness) and 10 is the worst imaginable itch (or sleeplessness), with a maximum 
possible score of 20. 
The SCORAD is calculated as: A/5+7B/2+C 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 71 of 169 
10.3.2 Subject assessments 
10.3.2.1 Eczema-related Sleep numeric rating scale 
Subjects will rate how much their eczema interfered with their sleep the last night using an 
11-point NRS (0 indicating that it ‘did not interfere’ and 10 indicating that it ‘completely
interfered’). Subjects will complete the Eczema-related Sleep NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 52. The Eczema-related Sleep NRS is 
included in the investigator trial file. 
10.3.2.2 Worst Daily Pruritus numeric rating scale 
Subjects will assess their worst itch severity over the past 24 hours using an 11-point NRS 
(‘Worst Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Worst Daily Pruritus NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 52. The Worst Daily Pruritus NRS is 
included in the investigator trial file.  
10.3.2.3 Average Daily Pruritus numeric rating scale 
Subjects will assess their average itch over the past 24 hours using an 11-point NRS 
(‘Average Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch 
imaginable’. Subjects will complete the Average Daily Pruritus NRS as part of an eDiary each 
day in the morning from Week -2 (visit 2) until Week 52. The Average Pruritus NRS is 
included in the investigator trial file. 
10.3.2.4 Patient Global Impression of Bother 
The Patient Global Impression of Bother (PGI-B) is a single item designed to capture the 
subject’s perception of how bothered they have been by their AD over the past 24 hours at the 
time of completion. A 5-point categorical response scale will be used (‘not at all’, ‘slightly’, 
‘somewhat’, ‘a lot’, ‘very much’). Subjects will complete this item as part of the eDiary each 
day in the morning from Week -2 (visit 2) until Week 52. The PGI-B is included in the 
investigator trial file. 
10.3.2.5 Patient Global Impression of Severity 
The Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 
subject’s perception of overall eczema symptom severity over the last 24 hours on a 4-point 
categorical response scale (‘no symptoms’ to ‘severe’). Subjects will complete this item as 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 72 of 169 
part of the eDiary each day in the morning from Week -2 (visit 2) until Week 52. The PGI-S is 
included in the investigator trial file. 
10.3.2.6 Patient-Oriented Eczema Measure 
The Patient-Oriented Eczema Measure (POEM) is a validated questionnaire used to assess 
disease symptoms in atopic eczema patients in both clinical practice and clinical trials (21). 
The tool consists of 7 items each addressing a specific symptom (itching, sleep, bleeding, 
weeping, cracking, flaking, and dryness). Subject will score how often they have experienced 
each symptom over the previous week on a 5-point categorical response scale (0 = ‘no days’; 
1 = ‘1 to 2 days’; 2 = ‘3 to 4 days’; 3 = ‘5 to 6’ days; 4 = ‘every day’). The total score is the 
sum of the 7 items (range 0 to 28) and reflects disease-related morbidity; a high score is 
indicative of a worse disease severity. The POEM will be completed according to the SoP in 
Section 4. It will be completed electronically on the device supplied to the trial site and is 
included in the investigator trial file. 
10.3.2.7  Dermatology Life Quality Index 
The Dermatology Life Quality Index (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 HQoL over the last 
week such as dermatology-related symptoms and feelings, daily activities, leisure, work or 
school, personal relationships, and the treatment (22). Each item is scored on a 4-point Likert 
scale (0 = ‘not at all ⁄not relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). The total score 
is the sum of the 10 items (0 to 30); a high score is indicative of a poor HQoL. The DLQI will 
be completed according to the SoP in Section 4. It will be completed electronically on the 
device supplied to the trial site and is included in the investigator trial file. 
10.3.2.8 EQ-5D-5L 
The EuroQoL 5-Dimension Health Questionnaire 5 Level (EQ-5D-5L) is a standardised 
measure of health status developed by the EuroQol group to provide a simple, generic 
measure of health for clinical and economic appraisal (23). The EQ-5D-5L is a 
self-administered questionnaire used to assess health status ‘today’ and is divided into 
2 sections: The first section includes 5 dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression); each dimension will be assessed by the subject 
using a 5-point scale (‘no problems’, ‘slight problems’, ‘moderate problems’, ‘severe 
problems’, and ‘extreme problems’). The second section consists of a vertical visual analogue 
scale anchored at 0 (‘the worst health you can imagine’) and 100 (‘the best health you can 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 73 of 169 
imagine’). The EQ-5D-5L will be completed according to the SoP in Section 4. It will be 
completed electronically on the device supplied to the trial site and is included in the 
investigator trial file. 
10.3.2.9 SF-36 
The SF-36v2 (Acute Recall) is a 36-item general health status assessment. Subjects will be 
asked to answer each question by selecting one of 3 to 6 categorical response options. The 
instrument instructions do not state a specific recall period; however, a recall period is defined 
within most items. The acute recall version, which asks subjects about the last week, will be 
used in this trial (32). 
The SF-36v2 (Acute Recall) yields scores for 8 health domains (physical functioning, role 
physical, bodily pain, general health, vitality, social functioning, role emotional, and mental 
health) and 2 psychometrically derived summary scores (a physical component summary and 
a mental component summary). 
The SF-36 will be completed according to the SoP in Section 4. It will be completed 
electronically on the device supplied to the trial site and is included in the investigator trial 
file. 
10.3.2.10 Work Productivity and Activity Impairment – General Health 
The impact of AD on the subject’s ability to work and perform regular activities will be 
assessed by Work Productivity and Activity Impairment – General Health (WPAI-GH). The 
WPAI-GH questionnaire is an instrument to measure impairments in both paid work and 
unpaid work (40). It consists of 6 items and measures absenteeism, presenteeism as well as 
the impairments in unpaid activity because of health problem during the past 7 days. The 
following 4 main outcomes can be generated from the WPAI-GH:  

Percent work time missed due to health for those who were currently
employed.

Percent impairment while working due to health for those who were currently
employed and actually worked in the past 7 days.

Percent overall work impairment due to health for those who were currently
employed.

Percent activity impairment due to health for all respondents.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 74 of 169 
The WPAI-GH will be completed electronically on the device supplied to the trial site 
according to the SoP (Section 4) and is included in the investigator trial file. 
10.3.2.11 Hospital Anxiety and Depression Scale 
The Hospital Anxiety and Depression Scale (HADS) is a Likert-scale tool widely used to 
detect states of anxiety and depression in a general hospital setting (24). The tool consists of 
14 items that assess the subject’s anxiety (7 items) and depression (7 items) during the last 
week. Each question is scored from 0 to 3, with high scores indicating a poor state. The 
HADS will be completed electronically on the device supplied to the trial site according to the 
SoP (Section 4) and is included in the investigator trial file. 
10.3.2.12 Treatment Satisfaction Questionnaire for Medicine 
The Treatment Satisfaction Questionnaire for Medicine (TSQM) v. II is a generic 
questionnaire assessing subjects’ satisfaction with the treatment (30). The tool consists of 
11 items addressing effectiveness, side effects, convenience and overall satisfaction. The 
TSQM will be completed electronically on the device supplied to the trial site according to 
the SoP (Section 4) and is included in the investigator trial file. 
10.4 Safety assessments 
10.4.1 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the SoP (Section 4). Vital signs will be measured in supine position following at least 
5 minutes rest. 
If an abnormal vital sign at screening is 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).  
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later with subjects resting in a supine position to verify the first measurement. 
Should the repeated measurement result in a normal value, the measurement must be repeated 
once more. If the third measurement verifies the second (normal) value, the first measurement 
should be considered as false. If the third measurement confirms the first measurement 
(abnormal) the second measurement will be considered as false. Only the last value measured 
and considered as correct will be recorded in the eCRF.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 75 of 169 
Clinically significant abnormal vital signs at the (first) screening visit will be documented as 
medical history in the eCRF (refer to Appendix 4D for further details). If an abnormal vital 
sign at any other visit than the first screening visit is considered by the investigator to be 
clinically significant, it will be reported as an AE in accordance with the principles for data 
entry (Appendix 4D). 
10.4.2 Physical examination 
A thorough physical examination of the subject including whole body inspection of the skin 
and auscultation of heart, lungs and abdomen; palpation of the abdominal organs and basic 
neurological status must be performed according to the SoP (Section 4). 
If an unacceptable abnormal finding is identified during the physical examination at the 
screening visit, the subject must not be randomised into the clinical trial (respecting exclusion 
criterion no. 26). 
Refer to Appendix 4D for principles for data entry into the eCRF. 
10.4.3 Digital ECG 
A single 12-lead resting digital ECG will be recorded after the subject has been supine for at 
least 5 minutes at the visits indicated in the SoP (Section 4). 
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. At a minimum, date of ECG collection will be recorded in the source 
documents.  
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. 
The investigator must evaluate all abnormal ECG results (‘clinically significant’ or ‘not 
clinically significant’) and sign and date. The investigator has the final decision on the clinical 
significance of ECG abnormalities. If a result is abnormal at the screening visit and 
considered by the investigator to be clinically significant, it will be up to the investigator’s 
discretion if the subject should be enrolled into the trial (respecting exclusion criterion 
no. 26); if such a subject is enrolled, the investigator will provide a justification in the medical 
record. Refer to Appendix 4D for principles for data entry in the eCRF.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 76 of 169 
Test dummy transmissions will be undertaken prior to trial conduct to ensure that 
transmissions can be made and that date and time settings are correctly set. 
The collection and transmission of ECG data will be described in a separate ECG manual. 
10.4.4 Pregnancy test 
A serum pregnancy test must be taken at the screening visit in female subjects of 
child-bearing potential as described in the SoP in Section 4. 
A urine pregnancy test (human chorionic gonadotropin; dipstick) must be performed at the 
trial site at baseline prior to randomisation in female subjects of child-bearing potential. The 
test must be repeated every 4 weeks as shown in the SoP in Section 4. 
Note that pregnant subjects must discontinue IMP immediately (Section 9.8.1). 
10.4.5 Laboratory testing 
The following safety samples will be analysed by a central laboratory: chemistry, 
haematology, serology, and serum pregnancy (Panel 13). Urine samples will be tested at the 
trial site with a dipstick; if abnormal, a urine sample will be sent to the central laboratory for 
further analysis. 
A laboratory manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information 
specific to this trial. 
Samples for laboratory testing will be collected according to the SoP (Section 4). 
eDoc-00631888 - Version
4. 0




Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 78 of 169 
The central laboratory will provide results in conventional units to trial sites in the US and in 
SI units to trial sites in Europe and Asia; results that are transferred to the trial database will 
be in conventional and SI units. 
Handling, storage, destruction and shipment instructions are provided in a separate laboratory 
manual. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be enrolled into the trial (respecting 
exclusion criteria no. 26, 27, and 28).  
10.4.6  Pharmacokinetic assessments 
Blood samples for PK assessments must be collected at the time points specified in the SoP 
(Section 4). Note that at Week 15, a blood sample for PK will be drawn but no assessments 
that require trial personnel will be performed. 
Collection, handling and shipment instructions for PK blood samples are provided in a 
laboratory manual.  
Serum samples for determination of tralokinumab concentrations will be analysed by a 
laboratory using a validated bioanalytical method. Details of the analytical method used will 
be described in the bioanalytical report. 
Samples will be retained for as long as the quality of the material permits evaluation but for 
no longer than 12 months after completion of the clinical trial report (CTR). 
10.4.7 Anti-drug antibodies measurements 
Blood samples will be collected for determination of anti-tralokinumab antibody levels at 
pre-determined time points according to the SoP (Section 4).  
Collection, handling and shipment instructions for ADA blood samples are provided in a 
separate laboratory manual. 
Serum samples for determination of presence or absence ADA will be analysed by a 
laboratory using a validated bioanalytical method. A tiered testing scheme will be employed, 
with the first step being screening. Samples found positive in the screening step will be tested 
in the confirmatory step. Samples confirmed positive for ADA in the confirmatory step will 
undergo ADA endpoint titre determination and will be analysed for the presence of 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 79 of 169 
neutralising antibodies (nAB). Details of the analytical method used will be described in the 
ADA bioanalytical report. 
Samples will be retained for as long as the quality of the material permits evaluation but for 
no longer than 15 years after marketing authorisation. 
10.5 Other assessments and photography 
10.5.1 Skin microbiology 
10.5.1.1 Background and rationale 
Normal skin is colonised by a wide variety of microorganisms, including fungi, viruses, and 
bacteria. The skin microbiome is complex and diverse, and varies between individuals and 
anatomical sites (37). It has been known for years that some skin diseases are associated with 
dysbiosis of the skin microbiome. AD, in particular, has long been associated with increased 
skin colonisation with S. aureus. Indeed, S. aureus colonisation has been proposed to play an 
important role in AD pathophysiology via bacterial production of specific virulence 
factors (38). Increased colonisation with S. aureus in AD is accompanied by decreased 
colonisation with many commensal bacterial species, resulting in overall decreases in 
bacterial diversity (39). Resolution of active disease in AD in response to therapy correlates 
with reduction of S. aureus colonisation and increases in microbiome diversity (39).  
A recent phase 2b trial in subjects with moderate-to-severe AD who were sampled with skin 
swabs on lesional skin showed a reduced frequency of S. aureus positive subjects following 
treatment with tralokinumab compared with placebo. A similar evaluation will be performed 
in the present trial. Since global analyses of microbiome diversity were not undertaken in the 
phase 2b tralokinumab trial, the present trial will use gene sequencing to identify specific 
strains of bacteria present on the skin and thus characterise treatment effects on the skin 
microbiome in AD subjects. 
10.5.1.2 Staphylococcus aureus colonisation (all subjects) 
Samples (skin swabs) from a representative lesion will be taken from all subjects to detect 
presence or absence of S. aureus colonisation. Samples will be collected according to the SoP 
(Section 4) and the body location will be documented in the eCRF (upper limb, lower limb, 
trunk, head). Efforts will be made to swab the same skin site (lesion) at all time-points, even if 
the lesion has cleared.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 80 of 169 
S. aureus colonisation will be determined using an RNA-based method (quantitative real-time
polymerase chain reaction). This will provide data on treatment effects on subclinical 
infections with S. aureus that is very frequent in AD patients.  
Collection, handling and shipment instructions for skin swabs are provided in a separate 
laboratory manual. 
10.5.1.3 Skin microbiome characterisation (selected trial sites) 
At selected trial sites, subjects will be asked to participate in an exploratory component 
involving skin microbiome characterisation. Participation in this exploratory component 
which also includes skin biopsies and additional serum biomarker testing requires that the 
subject provides additional informed consent. 
Skin swabs will be taken from a representative lesion. Samples will be collected according to 
the SoP (Section 4) and the same lesion will be sampled throughout the trial. The location of 
the lesion will be documented in the eCRF (upper limb, lower limb, trunk). Isolates will be 
cultured and the microbiome will be characterised using next-generation sequencing.  
Subjects should not shower, bathe, or otherwise wash the lesion where the swab will be taken 
from within 12 hours of sample collection.  
Collection, handling and shipment instructions for skin swabs are provided in a separate 
laboratory manual. 
Since subjects will also have skin biopsies taken from the lesion selected for microbiome 
characterisation, the trial will provide a unique opportunity to combine gene expression, 
histology, and microbiome data from the same lesions in AD subjects. The results will help to 
clarify the role of IL-13 pathways in regulation of the skin microbiome and may shed light on 
the role of the microbiome in the pathophysiology of AD. 
The skin microbiome results will not be included in the CTR but will be presented in a 
separate report. 
10.5.2 Serum biomarkers 
10.5.2.1 Rationale 
Serum biomarkers will be evaluated as an exploratory part of the tralokinumab phase 3 
programme to profile the molecular response and to identify subpopulations of AD patients 
with increased response to treatment. 
Collection, handling and shipment instructions for biomarker samples are provided in a 
separate laboratory manual. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 81 of 169 
The biomarker results from the small panel will be presented in the CTR, whereas results 
from the large panel (assessed at selected trial sites) will be presented in a separate report. 
10.5.2.2 Small biomarker panel (all subjects) 
All subjects will have blood samples taken for analysis of a small panel of biomarkers. The 
biomarkers to be analysed include, but are not limited to, the following: periostin, DPP4, 
CCL17 (also known as thymus and activation regulated chemokine [TARC]), IL-13, IL-17, 
IL-22, and beta-defensin 4A (DEFB4A). These samples will be taken according to the SoP 
(Section 4). LEO may only analyse samples from a subset of subjects. 
10.5.2.3 Large biomarker panel (selected trial sites) 
At selected trial sites, subjects will be asked to participate in additional biomarker testing. 
Participation in this component of the trial which also includes skin microbiome 
characterisation and skin biopsies requires that the subject provides additional informed 
consent. 
Subjects consenting to additional biomarker testing will have an extra blood sample taken to 
measure additional serum biomarkers. These samples will be taken according to the SoP 
(Section 4). To allow unbiased biomarker discovery, a large panel of biomarkers will be 
assessed. 
10.5.3 Skin biopsies (selected trial sites) 
At selected trial sites, subjects will be asked to participate in an exploratory component 
involving skin biopsies. Participation in this component of the trial which also includes skin 
microbiome characterisation and additional serum biomarker testing requires that the subject 
provides additional informed consent. 
Two 3 mm skin biopsies (1 for histology, 1 for gene expression analysis) must be taken from 
lesional skin at the time-points specified in the SoP (Section 4). At baseline, 2 skin biopsies 
will also be taken from non-lesional skin at an anatomically similar site (i.e., a total of 
4 biopsies at baseline). The lesional skin biopsies must be taken from the same lesion used for 
microbiome characterisation (Section 10.5.1.3). The body location of each site will be 
documented in the eCRF (upper limb, lower limb, trunk).  
A check of skin biopsy wound healing including removal of suture, if applicable, will be 
performed at the next trial visit (i.e., at Weeks 2, 6, and 18). 
Collection, handling and shipment instructions for skin biopsy samples are provided in a 
separate laboratory manual. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 82 of 169 
The biopsies will be analysed for expression of markers of inflammation and skin barrier 
integrity by histology/immunohistochemistry and gene expression analysis. 
The biomarkers to be analysed include, but are not limited to, the following: 
Histology/immunohistochemistry/in-situ hybridisation 

T cells (e.g., CD3+ and CD8+), dendritic cells (e.g., CD11c+, FcεR1),
monocytes/macrophages (e.g., CD68), epidermal markers (e.g., epidermal
thickness, keratin type I cytoskeletal 16, proliferation marker protein Ki-67,
protein S100-A, filaggrin, loricrin).
Gene expression analysis 

Global gene expression analysis by RNA sequencing.

Quantitative real-time polymerase chain reaction (qPCR) analysis of the
following genes: IL-1B, IFNG, IL-13, IL-31, CCL17 (TARC), CCL26, C-X-C
motif chemokine ligand 10 (CXCL10), IL-12/IL-23p19, IL-17A, CCL20,
IL-19, IL-20, IL-22, S100A9, S100A12.
Rationale for selection of biomarkers in biopsies 
The biomarkers to be analysed in the biopsies have been selected to assess the effect of IL-13 
inhibition on cell types and cytokines that play a key role in AD skin. Effective treatments of 
AD are known to reduce the number of inflammatory cells in lesional skin as well as to 
modulate epidermal markers towards a non-diseased phenotype (25). A quantitative real-time 
polymerase chain reaction analysis of markers of specific subsets of T cells (e.g., Th1, Th2, 
Th17, and Th22) will allow analysis of the mechanism of action of tralokinumab in diseased 
AD skin.  
Overall, the results from the analyses of biopsy material will be included in the CTR, except 
the global gene expression analysis which will be presented in a separate report. 
10.5.4 Storage of biological samples 
Samples collected as part of the exploratory component (microbiome characterisation, 
biomarkers, and skin biopsies) 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 unless 
specific additional consent has been obtained that allows storage for future research (see 
below). 
Biobank 
This protocol includes the collection and analysis of different biological samples. If consent is 
given by the subject, LEO will store samples collected as part of the exploratory component 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 83 of 169 
(i.e., serum samples for biomarker analysis and skin biopsies) in the biobank established by 
LEO and hosted by BioStorage Technologies, Inc. The residual biological samples will be 
used for future research performed by LEO. Donation of the samples for future research is 
voluntary and subjects must give their separate written consent to confirm donation and 
storage and the terms associated herewith. The samples will be transferred from the relevant 
laboratory to the biobank. The samples will be labelled with the trial ID, subject ID, and the 
sample date to protect the privacy of the subjects and to allow continued blinding for future 
analyses. The samples from this trial will be stored for 10 years after the end of the trial and 
will then be destroyed. 
10.5.5 Photography (selected trial sites) 
At selected trial sites, subjects will be asked to participate in a photography component 
involving digital photography assessments to show disease progression over time. 
Participation in this photography component requires that the subject provides additional 
informed consent. 
Digital colour photographs will be taken of the disease area and a representative lesion 
according to the SoP (Section 4). 
The trial sites will use their own equipment to take the photographs. Instructions for 
photography will be provided to the sites in a photography manual. Photography standards 
and procedures are provided to the trial sites by the central photography vendor.  
The photographs will have no other subject identifier than the subject ID and will be 
transmitted electronically to the photography vendor using a secure file transfer protocol. 
Printed copies of the photographs must be included as part of the individual subject source 
documentation.  
LEO may at its discretion use the photographs in publications, posters and similar types of 
information material or media targeting patients and HCPs. The photographs can also be part 
of training material used for training and educational purposes. Steps will be taken to ensure 
that the identity of the subject is protected to the extent possible. 
10.6 Estimate of total blood volume collected 
Blood samples will be drawn for safety (chemistry, haematology, serology, PK, ADA) and 
biomarkers. The total volume of blood to be withdrawn is approximately 435 mL which is 
less than the volume of blood drawn during a blood donation (approximately 500 mL).
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 84 of 169 
11Adverse events 
AEs and serious adverse events (SAEs) are defined in Appendix 2. 
Classification of AEs in terms of severity, causality and outcome are defined in Appendix 3. 
11.1 Collection of adverse events 
AEs must be collected from time of first trial-related activity after the subject has signed the 
informed consent form until completion of the clinical trial (defined as the safety 
follow-up visit 16 weeks after last injection). For subjects entering the long-term extension 
trial (LP0162-1337, ECZTEND), any (S)AE with onset before the final visit in the LP0162-
1325 trial should be reported LP0162-1325. 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 Appendix 4D for principles for data entry in the eCRF. 
11.2 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the CRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (i.e. not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’).  
The duration of the AE must be reported by the start date and stop date of the event. In 
addition, it must be recorded whether the AE started prior to start of IMP. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 3. 
Action taken with trial treatment: Any action taken with IMP as a consequence of the AE 
must be recorded (dose not changed, dose reduced, dose increased, drug interrupted, drug 
withdrawn, not applicable, unknown). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 85 of 169 
Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concomitant procedure). 
Withdrawn due to AE: it must be recorded whether the AE leads to withdrawal from the trial. 
11.3 Reporting of serious adverse events 
The criteria that define an AE as serious (i.e., an SAE) are defined in Appendix 2. 
11.3.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO on the (paper) SAE Form within 24 hours of first 
knowledge. This report should contain an assessment of available information on seriousness, 
severity, causal relationship to the IMP, comparator or trial procedure, the action taken, the 
outcome to date, and a narrative description of the course of the event. 
The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO using the e-mail address or fax number below: 
Global Pharmacovigilance, LEO 
E-mail address: drug.safety@leo-pharma.com
Fax number: +45 7226 3287 
It may be relevant for the investigator to enclose other information with the SAE form, such 
as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Pharmacovigilance, LEO may request further information in order to 
fully assess the SAE. The investigator must forward such information to LEO upon request by 
fax or e-mail (see contact details above). 
The investigator must notify the local institutional review board(s) (IRB[s])/ independent 
ethics committee(s) (IEC[s]) of SAEs as required by current applicable legislation for the 
concerned country. 
SAEs occurring after the completion of the clinical trial (i.e., after the safety follow-up visit 
[FU1/FU2]) should not be routinely sought or collected. However, such events should be 
reported to LEO (see contact details above) if the investigator becomes aware of them. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 86 of 169 
11.3.2 LEO reporting responsibilities 
Global Pharmacovigilance, LEO is responsible for assessing whether or not an SAE is 
expected. The relevant reference document for this clinical trial is:  
For the IMP, the Investigator’s Brochure, edition 16 and subsequent updates must be used. 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries.  
The IRB(s)/IEC(s) will be notified of SAEs according to the current applicable legislation for 
the concerned countries.  
For all countries except the US, all SAEs which are assessed as causally related to the IMP(s) 
by either the investigator or LEO (ICH E2A Guideline), and which are unexpected 
(Suspected, Unexpected Serious Adverse Reactions [SUSARs]), are subject to expedited 
reporting to regulatory authorities and IRB(s)/IEC(s) according to the current applicable 
legislation in the concerned countries. Investigators will be notified of such SUSARs and the 
evolving safety profile on an ongoing basis.  
For the US, as per Guidance for Industry and Investigators - Safety Reporting Requirements 
for INDs and BA/BE Studies, only those events for which the sponsor determines there is a 
reasonable possibility of a causal relationship are subject to IND Safety Reporting. 
Investigators will be notified of the evolving safety profile on an ongoing basis. 
11.4 Other events that require expedited reporting 
11.4.1 Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Follow Up Form (Part I). All such pregnancies 
must be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Follow Up Form (Part II) within 24 hours of first knowledge. 
The completed Pregnancy Follow Up Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO. Contact details are given in Section 11.3.1. 
Pregnant subjects must permanently discontinue IMP (see Section 9.8.1). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 87 of 169 
11.5 Reporting of other events 
11.5.1 Adverse events of special interest 
The events listed in Panel 14 are considered adverse events of special interest (AESIs) in this 
trial and will require that the investigator provides additional information to LEO. An AESI 
may be serious (requiring expedited reporting, Section 11.3) or non-serious. 
Panel 14  Adverse events of special interest 
Adverse event of special 
interest 
Additional information to be provided (if available1) 
Eczema herpeticum 
Skin findings: 

Lesion type.

Disseminated / localised.

Location.

Present in an area with visible eczema / no
visible eczema / present in areas with and
without eczema.

Monomorphic / polymorphic.
Confirmation of herpes simplex virus 
Malignancies diagnosed after 
randomisation, excluding basal 
cell carcinoma, localised 
squamous cell carcinoma of the 
skin, and carcinoma in situ of the 
cervix 
Histology report 
Oncology assessment  
Treatments (surgery, radiation, chemotherapy, other) 
Skin infections requiring 
systemic treatment 
Skin swab 

Outcome.
Conjunctivitis 
Aetiology (viral, bacterial, allergic, unknown) 
Bacterial culture outcome (for events with bacterial 
aetiology) 
Diagnosis confirmed by ophthalmologist  
Keratoconjunctivitis 
Aetiology (infectious, non-infectious, other, unknown) 
Bacterial culture outcome (for events with bacterial 
aetiology) 
Diagnosis confirmed by ophthalmologist 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 88 of 169 
Adverse event of special 
interest 
Additional information to be provided (if available1) 
Keratitis 
Aetiology (infectious, non-infectious, other, unknown) 
Bacterial culture outcome (for events with bacterial 
aetiology) 
Diagnosis of herpes simplex keratitis (for events with 
viral aetiology) 
Diagnosis confirmed by ophthalmologist 
1The additional data to be recorded in the eCRF are not a requirement, but are to be reported 
by the investigator, if available, for example as part of standard clinical practice.  
11.5.2 Overdose 
An overdose is defined as a subject receiving a dose of IMP in excess of that specified in this 
protocol.  
The term overdose must be documented on the AE form of the CRF. In addition, AEs 
originating from overdose must be documented on a separate line. 
LEO does not recommend specific treatment for an overdose. The investigator will use 
clinical judgment to treat any overdose if necessary. 
11.5.3 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP while in the control of the investigator or subject. Broadly, medication errors fall into 
four categories: wrong medication, wrong dose (including strength, form, concentration, 
amount), wrong route of administration, or wrong subject. 
The medication error must be documented on the AE form in the eCRF. In addition, AEs 
originating from a medication error must be documented on a separate line specifying the 
category of error (see definitions above). 
If the medication error is due to device malfunction, such malfunction must be reported as a 
device complaint as described in Section 9.11. 
11.5.4 Misuse 
Misuse refers to situations where the IMP is intentionally and inappropriately used not in 
accordance with the protocol. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 89 of 169 
The term misuse must be documented on the AE form in the eCRF. In addition AEs 
originating from misuse must be documented on a separate line. 
11.5.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IMP which is 
accompanied by harmful physical or psychological effects. 
The term abuse must be documented on the AE form in the eCRF. In addition, AEs 
originating from abuse must be documented on a separate line. 
11.5.6 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to screening, must be reported as an AE. 
11.6 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as of possible/probable relationship to the IMP for 
2 weeks or until the final outcome is determined, whichever comes first. SAEs must be 
followed up until a final outcome has been established, i.e. the follow-up may continue 
beyond the end of the clinical trial. For SAEs which have stabilised and cannot be expected to 
recover during study or safety follow-up periods, for example chronic illnesses, the final 
outcome should be considered recovered and a statement that the SAE has stabilised should 
be added to the narrative in the SAE form.  
11.7 Handling of an urgent safety measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined within the EU Directive as “…the occurrence of any new event 
relating to the conduct of the trial or the development of the investigational medicinal product 
where that new event is likely to affect the safety of the subjects, the sponsor and the 
investigator shall take appropriate urgent safety measures to protect the subjects against any 
immediate hazard.” (33). 
If the investigator becomes aware of information that necessitates an immediate change in the 
clinical trial procedure or a temporary halt to the clinical trial in order to protect clinical trial 
subjects from any immediate hazard to their health and safety, the investigator can do so 
without prior approval from LEO, regulatory authority(ies), or IRB(s)/IEC(s). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 90 of 169 
The investigator must immediately inform LEO - by contacting the clinical project manager 
or medical expert - of this change in the clinical trial procedure or of the temporary halt 
providing full details of the information and the decision making process leading to the 
implementation of the urgent safety measure. 
LEO must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 91 of 169 
12 Statistical methods 
12.1 Sample size 
A total of 780 subjects will be randomised 3:1 to initial treatment in this trial (585 subjects in 
the tralokinumab arm; 195 subjects in the placebo arm). The sample size is chosen to ensure 
that sufficient safety information is collected and to ensure a sufficient number of responders 
are re-randomised to maintenance treatment.  
The primary endpoints for initial treatment IGA 0/1 and EASI75 at Week 16 are to be 
evaluated hierarchically testing both hypotheses of no difference between active and placebo 
at the 5% significance level. The hypothesis for IGA 0/1 will be tested first; if significant, the 
EASI75 hypothesis will be tested. 
For the endpoint IGA 0/1 at Week 16, a sample size of 780 subjects randomised at 3:1 will 
provide >99% power to detect a difference between the 2 arms of 30% for tralokinumab and 
10% for placebo at a 5% 2-sided level of significance. For the endpoint EASI75 at Week 16 a 
sample size of 780 will likewise provide >99% power to detect a difference between 
tralokinumab and placebo at Week 16, assuming EASI75 response rates of 40% and 15%, 
respectively. 
With an IGA response rate of 30% at Week 16, 175 IGA responders initially treated with 
tralokinumab are expected to enter the maintenance treatment period (70 subjects on 
tralokinumab Q2W, 70 subjects on tralokinumab Q4W, 35 subjects on placebo). Assuming 
IGA response rates at Week 52 of 80%, 50% and 5%, respectively for Q2W, Q4W, and 
placebo, the power to show a difference at the 4% significance level will be >99% between 
Q2W and placebo and >99% between Q4W and placebo. 
With an EASI75 response rate of 40% at Week 16, 235 EASI75 responders initially treated 
with tralokinumab are expected to enter the maintenance treatment period (94 subjects on 
tralokinumab Q2W, 94 subjects on tralokinumab Q4W, 47 subjects on placebo). Assuming 
EASI75 response rates at Week 52 of 90%, 55% and 5%, respectively for Q2W, Q4W, and 
placebo, the power to show a difference at the 4% significance level will be >99% between 
Q2W and placebo and >99% between Q4W and placebo. 
12.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 92 of 169 
All subjects randomised to initial treatment are included in the full analysis set and will be 
analysed for efficacy up to Week 16 (visit 12). Exclusions from the full analysis set can be 
considered in special cases as described in ICH E9, Section 5.2.1, Full Analysis Set. If it is 
decided to exclude a randomised subject from the full analysis set, a justification addressing 
ICH E9 will be given. 
A per protocol analysis set will be used as an efficacy subset for the analysis of the primary 
endpoints up to Week 16 (visit 12), and analyses based on the per protocol analysis set will be 
performed to support the results obtained for the full analysis set. The per protocol analysis 
set will be defined by excluding subjects from the full analysis set for whom any of the 
following conditions apply:  

Receive no treatment with the IMP.

Provide no assessment of IGA or EASI following start of treatment.

Are known to have taken the wrong IMP throughout the initial treatment
period of the trial.

Do not fulfil all the inclusion criteria no. 3, 6, 7 and 8.
A maintenance analysis set will be defined as all subjects who receive tralokinumab in the 
initial treatment period and who are re-randomised to maintenance treatment. 
A safety analysis set will be defined by excluding subjects from the full analysis set who 
either received no treatment with IMP and/or for whom no post-baseline safety data are 
available.  
A maintenance safety analysis set will be defined as subjects in the full analysis set who are 
re-randomised to maintenance treatment at Week 16 (visit 12) and who have safety data 
available after Week 16. 
An open-label safety analysis set will be defined as subjects in the full analysis set who are 
still in the trial at Week 16 (visit 12), who have safety data available after Week 16 and who at 
any point in time enter the open-label treatment arm. 
Based on the above-mentioned rules, the inclusion/exclusion of subjects from the trial 
analysis sets will be documented in the statistical analysis plan update before breaking the 
randomisation code. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 93 of 169 
12.3 Statistical analysis 
12.3.1 Disposition of subjects 
Subject disposition will be presented separately for subjects in initial treatment, in 
maintenance treatment, and in open-label treatment. For all randomised subjects the reasons 
for permanent discontinuation of IMP and for leaving the trial in the initial treatment period 
will be presented by last visit attended and by treatment group. For the subjects in the 
maintenance safety analysis set, the reasons for permanent discontinuation of IMP and for 
leaving the trial or treatment arm will be presented by last visit attended and by the assigned 
treatment group at Week 16. For the subjects in the open-label safety analysis set, the reasons 
for permanent discontinuation of IMP and for leaving the trial will be presented by last visit 
attended. 
12.3.2 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented 
separately for all randomised subjects and for the maintenance analysis set. The presentations 
will be overall and by treatment group. Presentations of age, sex, ethnicity, race, baseline 
disease severity, and Worst Daily Pruritus NRS weekly average at baseline will also be given 
by region and by baseline disease severity (IGA 3 or 4). 
Demographics include age, sex, race, and ethnicity. Other baseline characteristics include vital 
signs (including height, weight, body mass index), duration of AD, concurrent diagnoses 
(from medical history and indications for concomitant medication), concomitant medication, 
and previous AD treatments.  
12.3.3 Exposure and treatment compliance 
12.3.3.1 Exposure 
Exposure to treatment will be presented for the safety analysis set (initial treatment), the 
maintenance safety analysis set (maintenance treatment), and open-label safety analysis set 
(open-label treatment) as days of exposure per treatment group. 
For the full trial period, the days of exposure on tralokinumab irrespective of treatment group 
will be summarised - subtracting potential periods on placebo - for the safety analysis set.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 94 of 169 
12.3.3.2 Treatment compliance 
Adherence to treatment regimen will be recorded in the eCRF. Where home-use is 
appropriate, the subject will be asked at each trial visit if IMP was administered as instructed. 
The log of drug administration may be used as source. If any complications or deviations in 
administration are observed, these will be described as protocol deviations. 
Adherence will be presented for the safety analysis set (initial treatment) and for the 
maintenance safety analysis set (maintenance treatment) for each treatment group. Adherence 
will also be presented for the open-label safety analysis set (open-label treatment). 
12.3.4 Multiple testing procedure 
To control the overall type 1 error rate, the primary analyses of the primary estimands for the 
primary and secondary endpoints for the initial and maintenance treatment will follow the 
testing procedure outlined in Panel 15. The hypothesis relating to a specific endpoint cannot 
be rejected unless all hypotheses relating to endpoints earlier in the hierarchy are also 
rejected.  
Panel 15  Testing procedure for primary, secondary, and maintenance endpoints 
Arrows indicate order of testing when superiority is shown for all endpoints within a box. 
DLQI, Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema Area and Severity Index 
score; IGA, Investigator’s Global Assessment; Q2W, every 2 weeks; Q4W, every 4 weeks. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 95 of 169 
The procedure will be as follows: 
IGA 0/1 at Week 16 between tralokinumab and placebo is evaluated at a 5% significance 
level. If the test is significant, EASI75 at Week 16 between tralokinumab and placebo is 
evaluated at a 5% significance level.  
If both these tests are significant, the significance level (alpha) will be split between the 
analyses of the 3 secondary endpoints at Week 16 and the analyses of the 2 maintenance 
endpoints at Week 52. These groups of tests are tested in parallel with alpha=1% for the 
endpoints at Week 16 and with alpha=4% for the maintenance endpoints at Week 52.  
The evaluations of the 3 secondary endpoints at Week 16 between tralokinumab and placebo 
will use the Holm method (26) for 3 ordered p-values at a 1% significance level to adjust for 
multiplicity. 
The hypotheses for the maintenance treatment endpoints will be tested sequentially in the 
specified order at the 4% significance level. The next hypothesis will only be tested if the 
former was significant.  
If all p-values for the 3 secondary endpoints at Week 16 are significant, then the hypotheses 
for the maintenance treatment endpoints can be evaluated at a 5% significance level. 
Conversely, if all p-values for the maintenance endpoints are significant, then the hypotheses 
for the 3 secondary endpoints at Week 16 can be evaluated at a 5% significance level.  
12.3.5 Analysis of initial treatment 
12.3.5.1 Analysis of primary endpoints 
Three estimands addressing different aspects of the trial objectives will be defined: 

Primary estimand: ‘composite’.

Secondary estimand: ‘hypothetical’.

Tertiary estimand: ‘treatment policy’.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 96 of 169 
The applied estimands incorporate two main types of events that influence how the treatment 
effects are estimated: 

Initiation of rescue medication: Some of the estimands use the initiation of rescue
medication as an event that modifies the applied value of an endpoint, e.g. by defining a
subject receiving rescue medication as a non-responder.

Permanent discontinuation of IMP: This event occurs when a subject is permanently
withdrawn from the treatment or the trial as described in Section 8.5. This can either
happen at his/her own initiative or at the investigator’s discretion. The event also includes
the possibility of a subject being lost to follow-up. The timing of the event is defined as
the date of the early termination visit for withdrawn subjects or – in the case of a subject
lost to follow-up – the date of the last known visit to the clinic. As for the rescue
medication, the event type is used to modify an applied endpoint value.
All analyses will be based on the full analysis set unless otherwise specified. 
12.3.5.1.1 Primary estimand: ‘composite’ 
The primary estimand for the primary endpoints will be: 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
achieved without rescue medication, regardless of treatment discontinuation.
The primary estimand assesses the expected difference in response rates (defined as response 
obtained without initiation of any rescue medication) after 16 weeks, resulting from initiation 
of a treatment regimen with tralokinumab compared to a treatment regimen with placebo.  
Primary analysis for the primary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Subjects who prior to the Week 16 visit have 
received rescue medication will be considered non-responders, reflecting an assumption that 
initiation of rescue medication indicates failure of the randomised treatment to achieve 
response, and that a (possible) observed positive response after initiation of rescue medication 
is not attributable to the randomised treatment. Missing data for subjects who did not attend 
the Week 16 visit and where rescue medication has not been used prior to Week 16, will be 
imputed as non-responders.  
The difference in response rates between treatment groups will be analysed using the 
Cochran-Mantel-Haenszel test stratified by region (North America, Japan, and Europe) and 
baseline disease severity (IGA 3 or 4). The treatment estimate and the corresponding 95% CI 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 97 of 169 
will be presented. The null hypothesis of no difference in response rates between 
tralokinumab and placebo will be tested against the 2-sided alternative that there is a 
difference.  
The primary endpoints will be tested sequentially at a 5% significance level. IGA 0/1 will be 
tested first, and, if significant, then EASI75 will be tested. If both primary null hypotheses are 
rejected, the secondary endpoints and the maintenance endpoints will be tested.  
Sensitivity analyses for the primary estimand 
Two sensitivity analyses are specified for the primary estimand. In both cases the same 
Cochran-Mantel-Haenszel test as used for the primary analysis will be applied including 
stratification by region and baseline disease severity. 
The purpose of the analyses is to assess the robustness of results of the primary analysis with 
respect to the retrieved data at Week 16 and assumptions regarding missing Week 16 data.  
Sensitivity analysis 1: All subjects who have permanently discontinued IMP prior to Week 16 
will be imputed as non-responders, even if no rescue medication has been used. This is to 
reflect a situation where retrieved efficacy data and concomitant medications could be 
registered less accurately for subjects who have discontinued treatment.  
Sensitivity analysis 2: Rather than imputing all subjects who do not attend the Week 16 visit 
and where rescue medication has not been used as non-responders, the following approach 
will be applied. If subjects have withdrawn due to an AE or due to lack of efficacy, they are 
still considered non-responders. Data missing for other reasons will be imputed using last 
observation carried forward (LOCF), hereby assuming that the last value is a more reliable 
estimate of the missing response (than a non-response). 
Supplementary analysis 
The primary analysis of the primary estimand is repeated based on the per protocol analysis 
set. 
12.3.5.1.2 Secondary estimand: ‘hypothetical’ 
The secondary estimand for the primary endpoints will be: 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 98 of 169 

Treatment difference in response rates of IGA 0/1 and EASI75 after 16 weeks
if all subjects adhered to the treatment regimen in the sense that they did not
discontinue IMP permanently and no rescue medication was made available
before Week 16.
The secondary estimand assesses the expected difference in response rates achieved when 
adhering to the treatment regimen tralokinumab with no rescue medication as compared to a 
treatment regimen with placebo with no rescue medication.  
Primary analysis of the secondary estimand 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be applied in the analysis.  
IGA 0/1 responder imputation  
Imputation of missing binary IGA 0/1 data at Week 16 will be done using multiple 
imputations of the underlying 5-point IGA values within the 2 groups defined according to 
randomised treatment arm assuming that data is missing at random within each arm. 
1. In each group, intermittent missing values will be imputed using LOCF to obtain a
monotone missing data pattern.
2. An ordinal logistic regression model assuming proportional odds will be fitted to the
IGA value at Week 2. The model will include effects of region, and baseline disease
severity (IGA 3 or 4) as factors. The estimated parameters, and their variances, will be
used to impute missing IGA values at Week 2. 100 copies of the dataset will be
generated (seed=11109925).
3. For each of the 100 copies of the dataset, missing values at Week 4 will be imputed in
the same way as for Week 2. The imputations will be based on a proportional odds
logistic regression model with effects of region and baseline disease severity (IGA 3 or
4) together with the IGA value at Week 2 as factors. The estimated parameters, and
their variances, will be used to impute missing values at Week 4. 
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the IGA values from the two preceding visits
will be included as factors in addition to region and baseline disease severity. The
missing binary IGA 0/1 response at Week 16 will be derived from the corresponding
underlying imputed IGA value.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 99 of 169 
EASI75 responder imputation 
Imputation of missing binary EASI75 data at Week 16 will be done using multiple 
imputations of the underlying 72-point EASI values within the two groups defined according 
to randomised treatment arm assuming that data is missing at random within each arm.  
1. Intermittent missing values will be imputed in each group using a Markov Chain
Monte Carlo method to obtain a monotone missing data pattern and 100 copies of the
dataset will be generated (seed=29099725).
2. An analysis of covariance (ANCOVA) model is fitted to the EASI value at Week 2.
The model will include effects of baseline EASI as a covariate, and region, and
baseline disease severity (IGA 3 or 4) as factors. The estimated parameters, and their
variances, will be used to impute missing EASI values at Week 2. 100 copies of the
dataset will be generated (seed=11109925).
3. For each of the 100 copies of the dataset, missing EASI values at Week 4 will be
imputed in the same way as for Week 2. The imputations will be based on the same
ANCOVA model with effects of baseline EASI as a covariate, and region, and baseline
disease severity (IGA 3 or 4) as factors together with the EASI value at Week 2 as
covariate. The estimated parameters, and their variances, will be used to impute
missing values at Week 4.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the modification that only the EASI values from the preceding two visits
will be included as covariates in addition to baseline EASI as a covariate, and region
and baseline disease severity as factors. The missing binary EASI75 response at
Week 16 will be derived from the corresponding underlying imputed EASI value.
Analysis of Week 16 response 
For each of the 100 complete data sets, the difference in response rates (either the IGA 0/1 or 
the EASI75) between treatment groups will be analysed using the Cochran-Mantel-Haenszel 
test stratified by region (North America, Japan, and Europe) and baseline disease severity 
(IGA 3 or 4). The estimates and standard errors from the 100 analyses will be pooled to one 
estimated treatment difference and associated standard error using Rubin’s rule to draw 
inference. From these pooled estimates, the 95% CI for the treatment difference will be 
calculated.  
Sensitivity analysis for the secondary estimand 
Rather than assuming that observations are missing at random within each treatment arm, it is 
assumed that missing data from subjects who discontinue IMP permanently/receive rescue 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 100 of 169 
medication in the tralokinumab arm will resemble missing data from subjects from the 
placebo arm who do not discontinue IMP permanently/receive rescue medication. The 
underlying assumption is that the effect of tralokinumab following rescue medication or 
permanent treatment discontinuation is similar to the effect of placebo. It should be noticed 
that this assumption is pronouncedly conservative in favour of placebo as it tends to minimise 
the differences between arms.  
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab arm as well as the placebo arm will be imputed from 
observed data in the placebo arm (using a so-called copy-reference approach). With this 
exemption, the stepwise multiple imputation procedure and subsequent analysis will be 
conducted in the same way as specified for the primary analysis of the secondary estimand. 
12.3.5.1.3 Tertiary estimand: ‘treatment policy’ 
The tertiary estimand for the primary endpoints will be: 

Treatment difference in response rate after 16 weeks between tralokinumab
and placebo regardless of rescue medication and treatment discontinuation.
The tertiary estimand assesses the average difference in response rates, resulting from 
initiation of a treatment regimen with tralokinumab and additional rescue medication as 
compared to a treatment regimen with placebo and additional rescue medication.  
Primary analysis for the tertiary estimand 
Data retrieved at Week 16 for subjects who have permanently discontinued treatment prior to 
Week 16 will be included in the analysis.  
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment arm and whether or not subjects have 
permanently discontinued IMP prior to Week 16. Within a given treatment arm, retrieved data 
from discontinued subjects will be used to impute missing data for other discontinued 
subjects. Similarly, the available data from not discontinued subjects will be used to impute 
data for such patients where the Week 16 value is missing.  
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way as specified for the primary analysis of the secondary estimand. 
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16 will be too small to facilitate the same imputation model as mentioned above. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 101 of 169 
Consequently, an imputation model with only region and baseline effects (IGA as a factor and 
EASI as a covariate [only for EASI75]) will be applied for discontinued subjects. Some 
factors may have to be omitted, depending on the observed data, e.g. if retrieved subjects only 
come from one region or if they all have the same baseline severity. 
The imputed datasets will be analysed in the same way as specified for the primary analysis of 
the secondary estimand. 
Sensitivity analyses for the tertiary estimand 
Rather than imputing Week 16 data as described in the primary analysis of the tertiary 
estimand, missing observations will be imputed as ‘non-responders’. The assumption reflects 
that discontinued subjects without retrieved data at Week 16 are more likely to be non-
responders than resembling discontinued subjects with retrieved data at Week 16. 
12.3.5.2 Analysis of secondary endpoints 
The 3 secondary endpoints evaluate the impact of 16 weeks of treatment on (i) severity and 
extent of AD, (ii) itch, and (iii) HRQoL. The corresponding endpoints are (i) the change from 
baseline to Week 16 in SCORAD, (ii) reduction (Y/N) of Worst Daily Pruritus NRS average 
score for the past week (hereinafter ‘Worst Daily Pruritus NRS weekly average’) of at least 4 
from baseline to Week 16, and (iii) change from baseline to Week 16 in DLQI score. 
Subject-reported worst daily itch over the last week prior to baseline will be used to calculate 
the baseline itch (see also inclusion criterion no. 9).  
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 is a binary endpoint, and 
it will be analysed as described for the primary endpoint EASI75 using all three estimands 
with the modification of the ANCOVA imputation model that reduction of Worst Daily 
Pruritus NRS weekly average replaces EASI where preceding values are used as covariates.  
The change from baseline to Week 16 in SCORAD and DLQI, respectively, are continuous 
endpoints and will be analysed as described below. 
All analyses will be based on the full analysis set unless otherwise specified. 
12.3.5.2.1 Primary estimand for the continuous secondary endpoints: 
‘hypothetical’ 
The primary estimand for the continuous secondary endpoints will be: 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 102 of 169 

Treatment difference in change from baseline to Week 16 in SCORAD and DLQI,
respectively, if all subjects adhered to the treatment regimen in the sense that they did
not discontinue IMP permanently and no rescue medication was made available before
Week 16.
The primary estimand assesses the expected benefit when adhering to the treatment regimen 
tralokinumab with no rescue medication as compared to a treatment regimen with placebo 
with no rescue medication.  
Primary analysis of the primary estimand (continuous secondary endpoints) 
Data collected after permanent discontinuation of IMP or after initiation of rescue medication 
will not be included in the analysis.  
The endpoints will be analysed using a repeated measurements model on the post baseline 
responses up to Week 16 with an unstructured covariance matrix, Kenward-Roger 
approximation to estimate denominator degrees of freedom, and the mean modelled as 
follows (shown for change from baseline in SCORAD): 
Change from baseline in SCORAD 
= treatment × visit + baseline SCORAD × visit + region + baseline IGA 
This model assumes that data is missing at random within each treatment arm. The estimates 
will be presented with nominal p-values and 95% CI at each visit. The primary comparison 
between tralokinumab and placebo will be at Week 16. 
Sensitivity analysis for the primary estimand (continuous secondary endpoints) 
Rather than assuming that observations are missing at random within each treatment arm it is 
assumed that missing data from subjects who discontinue treatment/receive rescue medication 
in the tralokinumab arm will resemble data from subjects from the placebo arm who do not 
discontinue treatment/receive rescue medication. Imputation of missing data at Week 16 will 
be done using a pattern mixture model where missing data in the tralokinumab arm as well as 
the placebo arm will be imputed from the placebo arm (using a so-called copy-reference 
approach). The procedure for the change from baseline in SCORAD at Week 16 is described 
below. The same procedure will be applied for the 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=29099725).
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 103 of 169 
2. For each of the 100 copies of the dataset, an ANCOVA model will be fitted to the
SCORAD value at Week 2 in the placebo group. The model will include effects of
baseline SCORAD as a covariate, and region and baseline disease severity (IGA 3 or
4) as factors. The estimated parameters, and their variances, will be used to impute
missing values at Week 2 for the placebo group as well as the tralokinumab group 
(seed=11109925).  
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 group.
The estimated parameters, and their variances, will be used to impute missing values
at Week 4 for both treatment groups.
4. This stepwise procedure will then be repeated sequentially for Week 6, 8, 10, 12, 14,
and 16 with the SCORAD values from the preceding two visits included as covariates
in addition to baseline SCORAD as a covariate, and region and baseline disease
severity as factors.
For each of the 100 imputed dataset, the change from baseline in SCORAD at Week 16 will 
be analysed using an ANCOVA model with effects of treatment, region, baseline disease 
severity (IGA 3 or 4), and baseline SCORAD value. The estimated difference at Week 16 will 
be derived together with the associated standard error. The estimates and standard errors from 
the 100 analyses are pooled to one estimate and associated standard error using Rubin’s rule 
to draw inference. From these pooled estimates, the 95% CI for the treatment difference will 
be calculated.  
12.3.5.2.2 Secondary estimand for the continuous secondary endpoints: 
‘treatment policy’ 
The secondary estimand for the continuous secondary endpoints will be: 

Treatment difference in change from baseline to Week 16 in SCORAD and
DLQI, respectively, between tralokinumab and placebo regardless of rescue
medication use and treatment discontinuation.
The secondary estimand assesses the average difference in change from baseline in SCORAD 
and DLQI after 16 weeks, resulting from initiation of a treatment regimen with tralokinumab 
and additional rescue medication as compared to a treatment regimen with placebo and 
additional rescue medication.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 104 of 169 
Primary analyses for the secondary estimand (continuous secondary endpoints) 
Data retrieved at Week 16 for subjects who have permanently discontinued IMP prior to 
Week 16 will be included in the analysis. Missing Week 16 data will be imputed using 
multiple imputations assuming that data is missing at random within the groups used for 
imputation. 
Imputation of missing data at Week 16 will be done using multiple imputations within 
4 groups defined according to randomised treatment arm and whether or not subjects have 
discontinued treatment prior to Week 16. Within a given treatment arm, retrieved data from 
discontinued subjects will be used to impute missing data for other discontinued subjects. 
Similarly, the available data from not discontinued subjects will be used to impute data for 
such subjects where the Week 16 value is missing.  
For not discontinued subjects, the stepwise multiple imputations procedure will be conducted 
in the same way as specified for the imputation of the underlying EASI values in the primary 
analysis of the secondary estimand for the binary endpoints. 
For discontinued subjects, it is expected that the number of subjects with retrieved data at 
Week 16 will be too small to facilitate the same imputation model as mentioned just above. 
Consequently, an imputation model with only region and baseline effects (IGA as a factor and 
baseline SCORAD / DLQI as a covariate) will be applied for discontinued subjects. Some 
factors may have to be omitted, depending on the observed data, e.g. if retrieved subjects only 
come from one region or if they all have the same baseline severity. 
Each of the 100 imputed datasets will be analysed and the resulting estimates and standard 
errors pooled as described in the sensitivity analyses for the primary estimand for the 
continuous secondary endpoints. 
Sensitivity analyses for the secondary estimand (continuous secondary endpoints) 
Rather than assuming that observations are missing at random, it is assumed that missing data 
from subjects in the tralokinumab arm who have/have not discontinued treatment prior to 
Week 16 will resemble data from subjects from the placebo arm who have/have not 
discontinued treatment prior to Week 16.  
Imputation of missing data at Week 16 will be done using a pattern mixture model where 
missing data in the tralokinumab arm as well as the placebo arm will be imputed from the 
placebo arm (copy-reference approach). With this exemption, the multiple imputation 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 105 of 169 
procedure and analysis will be conducted in the same way as described for the primary 
analysis of the secondary estimand for the continuous secondary endpoints. 
12.3.5.3 Analysis of additional secondary endpoints 
To support the primary endpoints, EASI50 at Week 16, EASI90 at Week 16 and the change 
from baseline to Week 16 in EASI score will be analysed and presented for the full analysis 
set. EASI50 and EASI90 will be analysed as described for the primary analysis of the primary 
estimand for the primary endpoints, and the change from baseline to Week 16 will be analysed 
as described for the primary analysis of the primary estimand for the continuous secondary 
endpoints. 
To support the secondary endpoints on severity and extent of AD, at least 75% reduction in 
SCORAD score (SCORAD75) at Week 16, and SCORAD50 at Week 16 will be analysed and 
presented for the full analysis set. Both endpoints will be analysed as described for the 
primary analysis of the primary estimand for the primary endpoints. 
To support the secondary endpoint on worst daily itch, the change from baseline to Week 16 
in Worst Daily Pruritus NRS weekly average and the reduction of Worst Daily Pruritus NRS 
weekly average of at least 3 (from baseline to Week 16) will be analysed and presented for the 
full analysis set. The change from baseline to Week 16 in Worst Daily Pruritus NRS weekly 
average will be analysed as described for the primary analysis of the primary estimand for the 
continuous secondary endpoints. The reduction of Worst Daily Pruritus NRS weekly average 
of at least 3 (from baseline to Week 16) is a binary endpoint and will be analysed as described 
for the primary analysis of the primary estimand for the primary endpoints. 
To support the secondary endpoint on HQoL, the binary endpoint reduction from baseline to 
Week 16 of DLQI of ≥4 points will be analysed and presented for the subjects in the full 
analysis set with a baseline DLQI ≥4 similarly to the analysis described for the primary 
analysis of the primary estimand for the primary endpoints.  
12.3.5.4 Analysis of other endpoints 
12.3.5.4.1 Efficacy over time 
To further pursue the objectives supported by the five Week 16 endpoints in the confirmatory 
test hierarchy, these endpoints (as well as the change in Worst Daily Pruritus NRS [weekly 
average]) will be evaluated at each scheduled assessment up to Week 14 or each week up to 
Week 15: 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 106 of 169 

IGA 0/1 at each scheduled assessment until Week 14.

EASI75 at each scheduled assessment until Week 14.

Change in SCORAD from baseline to each scheduled assessment until
Week 14.

Change from baseline to each week through Week 1 to 15 in Worst Daily
Pruritus NRS (weekly average).

Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4 from
baseline to each week through Week 1 to 15.

Change in DLQI score from baseline to each scheduled assessment until
Week 14.
Nominal p-values for test of a treatment difference and 95% CI for the difference will be 
presented at each scheduled visit (or each week for Worst Daily Pruritus NRS) using the same 
approach as applied for the primary analysis of the relevant endpoint in the primary estimand. 
For the binary endpoints, the same Cochran-Mantel-Haenszel test as for the Week 16 
assessment will be applied. For the continuous endpoints, the repeated measurements model 
already described previously for the Week 16 assessments facilitates that the p-values, 
treatment differences and 95% CIs can be derived for each visit up to Week 14 (or Week 15 
for the change in Worst Daily Pruritus NRS) in the same analysis that already will be made 
for the corresponding Week 16 assessments. 
12.3.5.4.2 Patient-reported outcomes 
The PROs POEM, DLQI, EQ-5D-5L, SF-36, WPAI-GH, HADS, and TSQM will be 
summarised by treatment group and visit using descriptive statistics. The summaries will be 
made separately for the initial treatment and the maintenance treatment. Data from the initial 
treatment period will be presented for the full analysis set and data from the maintenance 
treatment period will be presented for the maintenance analysis set.  
The PROs collected in the eDiaries on a daily basis (Worst Daily Pruritus NRS, Average Daily 
Pruritus NRS, Eczema-related Sleep NRS, PGI-B, and PGI-S) will all be summarised over 
time by treatment group using descriptive statistics. The summaries will be separate for the 
initial treatment and the maintenance treatment. Data from the initial treatment period will be 
presented for the full analysis set and data from the maintenance treatment period will be 
presented for the maintenance analysis set. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 107 of 169 
The Average Daily Pruritus NRS collected over the last week prior to baseline will be used to 
calculate the baseline average daily itch. A minimum of 4 Average Daily Pruritus NRS scores 
out of the 7 days is required to calculate the baseline average score.  
To investigate a possible early onset of itch relief, a reduction in Worst Daily Pruritus NRS 
weekly average of at least 3 from baseline to Week 2 will be summarised by treatment group 
and analysed as described for the primary analysis of the primary estimand for the primary 
endpoints.  
In the subgroup of subjects with either HADS anxiety subscale score ≥8 or HADS depression 
subscale score ≥8 at baseline, the proportion of subjects with both HADS anxiety subscale 
score <8 and HADS depression subscale score <8 at Week 16 will be summarised by 
treatment group and analysed as described for the primary analysis of the primary estimand 
for the primary endpoints.  
In the subgroup of subjects with a baseline POEM score of at least 4, the proportion of 
subjects with a reduction in POEM score of at least 4 at Week 16 will be summarised by 
treatment group and analysed as described for the primary analysis of the primary estimand 
for the primary endpoints. 
The change from baseline to Week 16 in Eczema-related Sleep NRS weekly average, HADS, 
POEM, SF-36, WPAI-GH, and the EQ-5D-5L index will be summarised by treatment group 
and domain, where applicable, and analysed as described above for the primary analysis of 
the primary estimand of the continuous secondary endpoints. For the Eczema-related Sleep 
NRS score, the mean over the last 7 days prior to randomisation will be used as the baseline 
value. 
The treatment satisfaction (TSQM) at Week 16 will be summarised by treatment group and 
domain and compared between treatments using an analysis of variance model including 
treatment, region and baseline IGA as factors. 
For the PGI-B, a day of ‘no or slight bother’ is defined as answering the question with ‘not at 
all’ or ‘slightly’. The subjects’ number of days of ‘no or slight bother’ will be tabulated per 
treatment group for the initial treatment period. The mean number of days will be presented 
with 95% CIs and compared between the 2 treatment groups using an analysis of variance 
model including treatment, region, and baseline IGA as factors. In this analysis, data collected 
after permanent discontinuation of IMP or after initiation of rescue medication will be 
disregarded. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 108 of 169 
12.3.5.4.3 Skin microbiology 
The incidence of skin colonisation with S. aureus will be presented by visit and treatment 
group for the subjects in the full analysis set. The incidence at Week 16 will be compared 
between the tralokinumab treatment group and the placebo group among subjects who are 
positive at baseline using a chi-squared test. 
12.3.6 Analysis of maintenance treatment  
12.3.6.1 Analysis of maintenance endpoints 
For the two dichotomous maintenance endpoints, IGA 0/1 and EASI75 at Week 52, an 
adapted version of the primary estimand for the primary endpoints will be considered: 

Treatment difference in response rates of IGA 0/1 and EASI75 after 52 weeks
achieved without rescue medication and without transfer to open-label treatment
The adapted estimand takes into account that throughout the maintenance period subjects will 
be actively discontinued from the treatment randomised at Week 16 and transferred to the 
open-label tralokinumab arm if they meet the prespecified treatment failure criteria described 
in Section 7.1.  
This estimand assesses the expected difference in response rates (defined as response obtained 
without initiation of any rescue medication and without transfer to open-label treatment) after 
52 weeks in patients responding to tralokinumab at Week 16 (as measured by a positive IGA 
0/1 or EASI75 response), resulting from a maintenance treatment regimen with tralokinumab 
Q2W or tralokinumab Q4W compared to a treatment regimen with placebo. 
Primary analysis for the maintenance estimand 
All subjects who prior to the Week 52 visit have received rescue medication, including TCS, 
and/or been transferred to the open-label tralokinumab arm will be considered 
non-responders.  
This reflects an assumption that initiation of rescue medication or transfer to open-label 
treatment indicates failure of the re-randomised treatment assigned at Week 16, and that a 
(possible) observed positive response thereafter is not attributable to the treatment received 
from Week 16. In addition, all subjects with missing endpoint data at Week 52 visit will be 
imputed as non-responders. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 109 of 169 
The 4 hypotheses of primary interest for maintenance treatment will be tested sequentially 
with the next hypothesis in the sequence only being tested if the previous one was significant. 
The multiple testing procedure planned to control the overall type 1 error rate for the trial is 
described in detail in Section 12.3.4. The maintenance endpoints will be evaluated in the 
following order: 

No difference between Q2W and placebo for IGA 0/1 at Week 52.

No difference between Q2W and placebo for EASI75 at Week 52.

No difference between Q4W and placebo for IGA 0/1 at Week 52.

No difference between Q4W and placebo for EASI75 at Week 52.
For the IGA 0/1 endpoint, the analysis will be based on the subjects in the maintenance 
analysis set who obtained an IGA of 0/1 at Week 16 without rescue medication. For the 
EASI75 endpoint, the analysis will be based on the subjects in the maintenance analysis set 
who obtained an EASI75 at Week 16 without rescue medication.  
For each endpoint (IGA 0/1 and EASI75 at Week 52) the estimated response rates and 
corresponding 95% CIs, and the pairwise treatment differences will be presented. The 
difference in response rates between treatment groups will be analysed using the 
Cochran-Mantel-Haenszel test stratified by region. The null hypotheses of no difference in 
response rates will be tested against the two-sided alternative that there is a difference.  
Sensitivity analysis for the maintenance estimand 
In a sensitivity analysis, data missing at Week 52 for subjects who did not receive rescue 
medication, did not transfer to open-label and did not withdraw from the trial due to AE or 
lack of efficacy will be imputed using LOCF. 
Pooled analyses across both LP0162-1325 and LP0162-1326 
In order to achieve more precise estimates of clinical response within treatment groups in the 
maintenance period, analyses of IGA 0/1 and EASI75 at Week 52 will be performed on 
pooled data from the 2 trials LP0162-1325 and LP0162-1326. For each endpoint (IGA 0/1 
and EASI75 at Week 52) the estimated response rates and corresponding 95% CIs and the 
pairwise treatment differences will be presented. The difference in response rates between 
treatment groups will be analysed using the Cochran-Mantel-Haenszel test stratified by region 
within trial. The pooled analyses will only be presented in marketing authorisation 
applications. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 110 of 169 
12.3.6.2 Analysis of other maintenance endpoints 
12.3.6.2.1 Time to relapse 
The following 2 types of relapse will be considered and analysed: 

Relapse according to IGA: first assessment of an IGA≥2 or initiation of rescue
medication after initiation of maintenance treatment among subjects in the
maintenance analysis set who obtained an IGA 0/1 at Week 16 without rescue
medication.

Relapse according to EASI75: first time of not achieving EASI75 or initiation of
rescue medication after initiation of maintenance treatment among subjects in the
maintenance analysis set who obtained EASI75 at Week 16 without rescue medication.
Kaplan-Meier curves of time to relapse will be estimated and presented by treatment for the 
maintenance analysis set. In a supplementary exploratory analysis, tralokinumab Q2W vs. 
placebo and tralokinumab Q4W vs. placebo will be compared using a log-rank test stratified 
by region.  
Subjects leaving the trial without meeting the relapse criteria will be censored at the date of 
the last assessment visit. 
12.3.6.2.2 Continued treatment for non IGA responders 
The number of responders according to IGA 0/1 at Week 52 will be tabulated for the subgroup 
of subjects in the maintenance analysis set who are re-randomised meeting the EASI75 
criterion but not the IGA 0/1 criterion at Week 16. 
12.3.6.2.3 Supportive maintenance 
To support the maintenance objective, the response IGA 0/1 or EASI75 at Week 52 will be 
presented and analysed as described above for the primary analysis of the maintenance 
estimand for subjects in the maintenance analysis set who did not receive rescue medication 
prior to Week 16. 
12.3.7 Analysis of safety 
The analyses of safety will be based on the safety analysis sets. The reporting of safety data 
will be presented separately for the initial treatment, the maintenance treatment, and the 
open-label treatment.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 111 of 169 
12.3.7.1 Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred terms and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised, however, all AEs recorded during the course of 
the trial will be included in the subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP or if started before the first use of IMP 
(applicable if subject had a wash-out) and worsened in severity thereafter. The tabulations 
described in the following will only include the treatment-emergent events. In each of the 
tabulations, AEs will be defined by MedDRA preferred terms within primary SOC. 
An overall summary of the number of treatment-emergent AEs, number (percentage) of 
subjects with any treatment-emergent AEs, SAEs, deaths, premature discontinuations from the 
trial due to AEs, treatment-related AEs and severe AEs will be presented. 
The number of AEs and the number of subjects experiencing each type of AE will be 
tabulated by treatment group. The percentage of subjects with AEs in the initial treatment 
period will be compared between treatment groups by a chi-square test or Fisher’s exact test 
(if expected cell count < 5). 
The severity for each type of AE will be tabulated by treatment group.  
The causal relationship to IMP for each type of AE will be tabulated by treatment group. 
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
experiencing each type of related AE will be tabulated. The percentage of subjects with 
related AEs in the initial treatment period will be compared between treatment groups by a 
chi-square test or Fisher’s exact test (if expected cell count <5). 
SAEs and AESIs will be evaluated separately. A narrative for each SAE will be given. AESIs 
and AEs leading to withdrawal from trial will be tabulated and listed.  
12.3.7.2 Vital signs 
The change in vital signs (blood pressure, heart rate, body temperature) from baseline to each 
visit will be summarised by visit and treatment group as mean, standard deviation, median, 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 112 of 169 
minimum and maximum values for the safety analysis set, the maintenance safety analysis 
set, and the open-label safety analysis set. 
12.3.7.3 Clinical laboratory evaluation 
The change in each of the laboratory parameters from baseline to each visit will be 
summarised by visit and treatment group as mean, standard deviation, median, minimum and 
maximum values for the safety analysis set, the maintenance safety analysis set, and the 
open-label safety analysis set. 
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at end of treatment. Subjects with 
laboratory parameters outside the reference range will be listed. 
12.3.7.4 Pharmacokinetics 
All the PK samples in the trial are trough samples apart from the Week 15 sample. Area under 
the curve (AUC) will be calculated for subjects where all the 3 samples planned at Week 14, 
15 and 16 have measurable concentrations. The Ctrough concentration and the calculated AUC 
will be listed by treatment group and descriptive statistics will be provided.  
Ctrough and AUC values from subjects with positive ADA/nAb will be compared to values 
from subject with negative ADA/nAb if data permits.  
The PK data will be merged with those from other clinical trials with tralokinumab for a 
population-based meta-analysis. Results of the meta-analysis will be presented in a separate 
pharmacometrics report outside of the CTR. 
12.3.7.5 Anti-drug antibodies 
ADA status (positive versus negative) at each visit will be summarised by treatment group for 
initial, maintenance and open-label treatment. If considered relevant, descriptive statistics 
including number of subjects, mean, standard deviation, median, and range of the actual ADA 
titres by treatment group and visit will be provided. The ADA status across the trial for each 
subject (positive versus negative) will also be classified and summarised by treatment group.  
The association of ADA status across the trial (positive vs. negative) with AEs/SAEs may be 
evaluated. In addition, the association of ADA titres (≥ median titre in positive subjects versus 
< median titre) with AE/SAEs may be evaluated for ADA-positive treated subjects only. The 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 113 of 169 
ADA-positive subjects across the trial may also be divided into persistent positive versus 
transient positive. A subject will be considered as persistent positive if he/she has positive 
ADA for at least 2 consecutive visits with ADA assessment. Otherwise, the subject will be 
considered as transient ADA positive. The associations between ADA and AE/SAEs may be 
summarised for both persistent positive subjects versus transient positives subjects.  
For subjects who develop ADA, the IGA score and change in EASI at end of treatment will be 
listed.  
Evaluations of nAB will be conducted on those serum samples that test positive for ADA. The 
test sample is deemed positive or negative for the presence of nAb to tralokinumab relative to 
a pre-determined (in assay validation), statistically derived cut point.  
For ADA, all subjects with titre information will be listed. 
12.3.8 Interim analysis 
No interim analysis is planned. 
12.3.9 Analysis of data per last subject’s Week 52 visit 
To support submission for regulatory approval, the trial will be unblinded once all randomised 
subjects have completed the Week 52 visit. All pre-specified analyses related to the initial and 
maintenance treatment period will be based on the data cut-off date of the last subject’s 
Week 52 visit. The CTR will include all data from all randomised subjects from the initial and 
maintenance treatment period and all available data from the open-label treatment period and 
safety follow-up period as per data cut-off date. 
Once all subjects have completed the open-label treatment period and safety follow-up period, 
an addendum to the original CTR will be written, summarising the final results from the 
open-label treatment period and safety follow-up period. 
12.3.10 
General principles 
Unless otherwise stated, all significance tests will be two-sided using the 5% significance 
level. All CIs will be presented with 95% degree of confidence. 
An observed-cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 114 of 169 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation, minimum and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan update will be finalised before breaking the 
randomisation code. 
Any changes from the statistical analysis planned in this clinical trial protocol will be 
described and justified in a protocol amendment, the statistical analysis plan update and/or in 
the CTR dependent on the type of deviation.  
12.3.11 
Handling of missing values 
Procedures for handling of missing values are included under the sections describing the 
individual analyses. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 115 of 169 
13 References 
1. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and
other health and demographic factors: a US population-based study. J Allergy Clin
Immunol. 2013;132(5):1132-1138.
2. Hanifin JM, Reed ML, Eczema Prevalence and Impact Working Group. A
population-based survey of eczema prevalence in the United States. Dermatitis.
2007;18(2):82-91.
3. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358(14):1483-1494.
4. Weidinger S, Novak N. Atopic dermatitis. Lancet. 2016;387(10023)1109-1122.
5. Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, et al. Atopic dermatitis
is associated with a decrement in health-related quality of life. Int J Dermatol.
2002;41(3):151-158.
6. Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et al. Guidelines for
treatment of atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol Venereol.
2012;26(9):1176-1193.
7. Eichenfield LF, Tom WL, Berger TG, Krol A, Paller AS, Schwarzenberger K, et al.
Guidelines of care for the management of atopic dermatitis: section 2. Management and
treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol.
2014;71(1):116-132.
8. Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, Bergman JN, et al.
Guidelines of care for the management of atopic dermatitis: section 3. Management and
treatment with phototherapy and systemic agents. J Am Acad Dermatol.
2014;71(2):327-349.
9. Tazawa T, Sugiura H, Sugiura Y, Uehara M. Relative importance of IL-4 and IL-13 in
lesional skin of atopic dermatitis. Arch Dermatol Res. 2004;295(11):459-464.
10. Omori-Miyake M, Yamashita M, Tsunemi Y, Kawashima M, Yagi J. In vitro assessment of
IL-4- or IL-13-mediated changes in the structural components of keratinocytes in mice
and humans. J Invest Dermatol. 2014;134(5):1342-1350.
11. Aleksza M, Lukács A, Antal-Szalmás P, Hunyadi J, Szegedi A. Increased frequency of
intracellular interleukin (IL)-13 and IL-10, but not IL-4, expressing CD4+ and CD8+
peripheral T cells of patients with atopic dermatitis. Br J Dermatol. 2002;147(6):1135-
1141.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 116 of 169 
12. Purwar R, Werfel T, Wittmann M. IL-13-stimulated human keratinocytes preferentially
attract CD4+CCR4+ T cells: possible role in atopic dermatitis. J Invest Dermatol.
2006;126(5):1043-1051.
13. Oh MH, Oh SY, Lu J, Lou H, Myers AC, Zhu Z, Zheng T. TRPAA1-dependent pruritus in
IL-13-induced chronic atopic dermatitis. J Immunol. 2013;191(11):5371-5382.
14. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of
interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest
Dermatol. 2009;129:742-751.
15. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two
phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016
Dec 15;375(24):2335-2348.
16. May RD, Monk PD, Cohen ES, Manuel D, Dempsey F, Davis NH, et al. Preclinical
development of CAT-354, an IL-13 neutralizing antibody, for the treatment of severe
uncontrolled asthma. Br J Pharmacol. 2012;166(1):177-193.
17. Thom G, Minter R. Optimization of CAT-354, a therapeutic antibody directed against
interleukin-13, using ribosome display. Methods Mol Biol. 2012;805:393-401.
18. Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME. Inhibition of
human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-
interleukin-13 antibody (CAT-354). Clin Exp Allergy. 2005;35(8):1096-1103.
19. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and
severity index (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol.
2001;10(1):11-18.
20. European Task Force on Atopic Dermatitis. Severity scoring of atopic dermatitis: the
SCORAD index. Consensus report of the European task force on atopic dermatitis.
Dermatology. 1993;186(1):23-31.
21. Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure: development
and initial validation of a new tool for measuring atopic eczema severity from the patients'
perspective. Arch Dermatol. 2004;140(12):1513-1519.
22. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – a simple practical
measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210-216.
23. Greiner W, Weijnen T, Nieuwenhuizen M, Oppe S, Badia X, Busschbach J, et al. A single
European currency for EQ-5D health states. Results from a six-country study. Eur J Health
Econ. 2003;4(3):222-231.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 117 of 169 
24. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand.
1983;67(6):361-370.
25. Mansouri Y, Guttman-Yassky E. Immune pathways in atopic dermatitis, and definition of
biomarkers through broad and targeted therapeutics. J Clin Med. 2015;4(5):858-873.
26. Holm S. A simple sequentially rejective multiple test procedure. Scan J Stat.
1979;6(2):65-70.
27. Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 statement:
updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.
28. Harmonising Outcome Measures for Eczema (HOME). EASI scoring table for aged 8 and
over [homepage on the Internet]. Available from:
http://www.nottingham.ac.uk/homeforeczema/index.aspx [cited 21-Nov-2016].
29. Bancroft AJ, Artis D, Donaldson DD, Sypek JP, Grencis RK. Gastrointestinal nematode
expulsion in IL-4 knockout mice is IL-13 dependent. Eur J Immunol. 2000;30(7):2083-
2091.
30. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, Rowland CR.
Validation of a general measure of treatment satisfaction, the Treatment Satisfaction
Questionnaire for Medication (TSQM), using a national panel study of chronic disease.
Health Qual Life Outcomes. 2004;2:12.
31. Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised
nomenclature for allergy for global use: report of the Nomenclature Review Committee of
the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-
836.
32. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I.
Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
33. European Parliament and Council of The European Union. Directive 2001/20/EC of 4
April 2001 on the approximation of the laws, regulations and administrative provisions of
the Member States relating to the implementation of good clinical practice in the conduct
of clinical trials on medicinal products for human use [2001], article 10.
34. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol.
1980;92(Suppl):44-47.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 118 of 169 
35. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et
al. Second symposium on the definition and management of anaphylaxis: Summary report
-- Second National Institute of Allergy and Infectious Diseases/Food Allergy and
Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397.
36. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;
164(7):1035-1043.
37. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. Bacterial
community variation in human body habitats across space and time. Science. 2009;
326(5960):1694-1697.
38. Cardona ID, Cho SH, Leung DY. Role of bacterial superantigens in atopic dermatitis:
implications for future therapeutic strategies. Am J Clin Dermatol. 2006;7(5):273-279.
39. Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, et al. Temporal shifts in
the skin microbiome associated with disease flares and treatment in children with atopic
dermatitis. Genome Res. 2012;22(5):850-859.
40. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work
productivity and activity impairment instrument. Pharmacoeconomics.
1993;4(5):353-365.
41. World Health Organization. WHO model prescribing information: drugs used in skin
diseases. Geneva. 1997.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 119 of 169 
Appendix 1: Protocol summary 
Name of  
investigational 
medicinal product 
Tralokinumab 
Name of active 
substance 
Human recombinant IL-13 monoclonal antibody. 
Title of trial/ 
trial ID/ 
EudraCT no./ 
ClinicalTrials.gov 
no. 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the 
efficacy and safety of tralokinumab monotherapy in subjects with 
moderate-to-severe atopic dermatitis (AD) who are candidates for systemic 
therapy – ECZTRA 1 (ECZema TRAlokinumab trial no. 1) / 
LP0162-1325 / 2016-004200-65 / NCT03131648 
International 
coordinating 
investigator 
Andreas Wollenberg, Prof. Dr. med. Dr. h.c. 
Sponsor’s name/ 
address 
LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark 
Estimated number 
of trial sites and 
distribution 
Approximately 130 sites in Europe, North America, and Japan. 
Main objectives 
Primary objective: 
To evaluate the efficacy of tralokinumab compared with placebo in treating 
moderate-to-severe AD. 
Secondary objectives: 
To evaluate the efficacy of tralokinumab on severity and extent of AD, itch, 
and health related quality of life compared with placebo. 
Maintenance objective: 
To evaluate maintenance of effect with continued tralokinumab dosing up to 
52 weeks compared to placebo for subjects achieving clinical response at 
Week 16. 
Methodology 
Overview 
The trial will consist of a screening period of 2 to 6 weeks (Weeks -6/-2 to 0), 
an initial treatment period of 16 weeks (Weeks 0 to 16) and a maintenance 
treatment period of 36 weeks (Weeks 16 to 52). A 14-week off-treatment 
follow-up period for the assessment of safety is also included (Weeks 52 to 66). 
All subjects will use an emollient at least twice daily for at least 14 days before 
randomisation and will continue this treatment throughout the trial. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 120 of 169 
Methodology 
(continued) 
Trial design 
Subjects found eligible following the screening period will be randomised 3:1 
to tralokinumab 300 mg Q2W or placebo. Randomisation will be stratified by 
region and disease severity. 
Subjects achieving a clinical response at Week 16 (defined as Investigator’s 
Global Assessment [IGA] of 0 or 1 on a 5-point scale ranging from 0 [clear] to 
4 [severe], or at least 75% reduction in Eczema Area and Severity Index 
[EASI] score from baseline [EASI75]) will continue into maintenance 
treatment that will continue until Week 52.  
Subjects randomised to tralokinumab in the initial treatment period will be 
re-randomised 2:2:1 to one of the following Q2W maintenance regimens 
stratified by region and IGA response at Week 16 (IGA 0/1 or IGA >1): 

Tralokinumab 300 mg Q2W.

Alternating dose administrations tralokinumab 300 mg and placebo
(‘tralokinumab Q4W’).

Placebo.
Subjects randomised to placebo in the initial treatment period who achieve a 
clinical response at Week 16 (defined by IGA of 0 or 1, or EASI75) will 
continue to receive placebo Q2W in the maintenance treatment period. 
Subjects not achieving a clinical response at Week 16 as well as those who 
meet the criteria listed below during maintenance treatment will be transferred 
to open-label tralokinumab 300 mg Q2W treatment with optional use of TCS 
up to Week 52. 
Transfer to open-label treatment 
Subjects with IGA=0 at Week 16: IGA of at least 2 and not achieving EASI75 
over at least a 4-week period (i.e., over 3 consecutive visits). 
Subjects with IGA=1 at Week 16: IGA of at least 3 and not achieving EASI75 
over at least a 4-week period (i.e., over 3 consecutive visits).   
Subjects with IGA >1 at Week 16: not achieving EASI75 over at least a 4-week 
period (i.e., over 3 consecutive visits). 
For selected countries 
Subjects transferring to open-label treatment will have the option to 
self-administer tralokinumab in their home after adequate training (at 3 dosing 
visits in the open-label period after additional consent has been obtained) by 
site staff at the investigator’s discretion. 
For selected countries 
Subjects who join the open-label tralokinumab arm at Week 16 will continue an 
additional 16 weeks of open-label treatment in order to secure at least 52 weeks 
of active therapy (Week 52 to Week 68). 
Number of subjects 
to be enrolled 
A total of 780 subjects will be randomised 3:1 to initial treatment (585 subjects 
to tralokinumab; 195 subjects to placebo). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 121 of 169 
Main criteria for 
inclusion 

Age 18 and above.

Diagnosis of AD as defined by the Hanifin and Rajka (1980) criteria
for AD.

Diagnosis of AD for ≥1 year.

Subjects who have a recent history of inadequate response to treatment
with topical medications or for whom topical treatments are otherwise
medically inadvisable.

AD involvement of ≥10% body surface area at screening and baseline.

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 numeric rating scale (NRS) average score of ≥4
during the week prior to baseline.

Stable dose of emollient twice daily (or more, as needed) for at least
14 days before randomisation.
Main criteria for 
exclusion 

Active dermatologic conditions that may confound the diagnosis of
AD.

Use of tanning beds or phototherapy within 6 weeks prior to
randomisation.

Treatment with systemic immunosuppressive/immunomodulating
drugs and/or systemic corticosteroid within 4 weeks prior to
randomisation.

Treatment with TCS and/or TCI within 2 weeks prior to randomisation.

Active skin infection within 1 week prior to randomisation.

Clinically significant infection within 4 weeks prior to randomisation.

A helminth parasitic infection within 6 months prior to the date
informed consent is obtained.

Tuberculosis requiring treatment within the 12 months prior to
screening.

Known primary immunodeficiency disorder.
Investigational 
medicinal products 
Tralokinumab 
150 mg/mL solution for subcutaneous (SC) injection in an accessorised 
pre-filled syringe, 1.0 mL fill volume. Each kit contains 1 syringe. 
Placebo 
Placebo solution for SC injection in an accessorised pre-filled syringe, 1.0 mL 
fill volume. Each kit contains 1 syringe. 
Duration of 
treatment 
Screening period (including wash-out, if applicable) up to 6 weeks, treatment 
period of 52 weeks (or 68 weeks in selected countries), follow-up period of 
14 weeks (subjects may enter the long-term extension trial [LP0162-1337, 
ECZTEND], at any time during the safety follow-up period). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 122 of 169 
Main assessments 
Investigator assessments 

Investigator’s Global Assessment (IGA).

Eczema Area and Severity Index (EASI).

Scoring Atopic Dermatitis (SCORAD).
Subject assessments 
A total of 12 patient-reported outcomes (PROs) will be collected. The 
following 5 PROs will be assessed on a daily basis using an electronic diary: 
Worst Daily Pruritus NRS, Average Daily Pruritus NRS, Eczema-related Sleep 
NRS, Patient Global Impression of Bother (PGI-B), and Patient Global 
Impression of Severity (PGI-S). 
The following 7 PROs will be completed at the trial site during visits: Patient 
Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), 
EQ 5D 5L, SF 36 (acute recall), Work Productivity and Activity Impairment – 
General Health (WPAI GH), Hospital Anxiety and Depression Scale (HADS), 
and Treatment Satisfaction Questionnaire for Medicine (TSQM). 
Safety assessments 
Vital signs, physical examination, ECG, laboratory testing, pharmacokinetics 
(PK), anti-drug antibodies, and adverse event reporting. 
Other assessments 
Assessment of skin colonisation with Staphylococcus aureus, skin microbiome 
characterisation, serum biomarkers, skin biopsies, photographs. 
Primary endpoints 

IGA score of 0 (clear) or 1 (almost clear) at Week 16.

EASI75 at Week 16.
Secondary 
endpoints 
Secondary endpoints 

Change in SCORAD from baseline to Week 16.

Reduction of Worst Daily Pruritus NRS (weekly average) of at least 4
from baseline to Week 16.

Change in DLQI score from baseline to Week 16.
Additional secondary endpoints 

AE/SAE frequency by preferred term.

Frequency of anti-drug antibodies.

EASI50 at Week 16.

EASI90 at Week 16.

Change from baseline to Week 16 in EASI score.

SCORAD75 at Week 16.

SCORAD50 at Week 16.

Change from baseline to Week 16 in Worst Daily Pruritus NRS
(weekly average).

Reduction of Worst Daily Pruritus NRS (weekly average) of at least 3
from baseline to Week 16.

Reduction from baseline to Week 16 of DLQI of ≥4 points among
subjects with baseline DLQI ≥4.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 123 of 169 
Secondary 
endpoints 
(continued) 
Maintenance endpoints 

IGA of 0/1 at Week 52 among subjects with IGA of 0/1 at Week 16
achieved without rescue medication after initial randomisation to
tralokinumab.

EASI75 at Week 52 among subjects with EASI75 at Week 16 achieved
without rescue medication after initial randomisation to tralokinumab.
Statistical methods 
Primary endpoints 
The difference in response rates between treatment groups will be analysed 
using the Cochran-Mantel-Haenszel test stratified by region and disease 
severity.  
The primary endpoints will be tested sequentially at a 5% significance level. 
First IGA 0/1 and, if significant, EASI75. If both primary null hypotheses are 
rejected, the secondary endpoints will be tested. 
Secondary endpoints 
The change from baseline to Week 16 in SCORAD will be analysed using a 
repeated measurements model on the post baseline responses up to Week 16. 
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 is a binary 
endpoint, and as such it will be analysed as described for the primary endpoint. 
Change from baseline to Week 16 in DLQI will be analysed the same way as 
change in SCORAD. 
Maintenance endpoints 
The 4 hypotheses of primary interest for maintenance treatment will be tested 
sequentially with the next hypothesis in the sequence only being tested if the 
previous one was significant. The maintenance endpoints will be evaluated in 
the following order: 

No difference between Q2W and placebo for IGA 0/1 at Week 52.

No difference between Q2W and placebo for EASI75 at Week 52.

No difference between Q4W and placebo for IGA 0/1 at Week 52.

No difference between Q4W and placebo for EASI75 at Week 52.
For each endpoint (IGA 0/1 and EASI75 at Week 52) the estimated response 
rates and corresponding 95% CIs, and the pairwise treatment differences will 
be presented. The difference in response rates between treatment groups will be 
analysed using the Cochran Mantel-Haenszel test stratified by region.  
A multiple testing procedure to control the overall type 1 error rate for the trial 
will be used. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 124 of 169 
Appendix 2: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. (ICH Harmonized Tripartite Guideline for Good Clinical Practice, 
E6 (R1)). 
This definition includes: 

accidental injuries, events related to trial procedures, reasons for any
unfavourable and unplanned change in medication (drug and/or dose),
clinically significant worsening of pre-existing conditions, or reasons for
admission to hospital or surgical procedures unless these were planned before
enrolment. It also includes AEs commonly observed and AEs anticipated based
on the pharmacological effect of the IMP. In addition, any laboratory
abnormality assessed as clinically significant by the investigator must be
recorded as an AE.
Serious adverse event definition 
An SAE is any untoward medical occurrence that 

results in death.

is life-threatening.

requires inpatient hospitalisation or prolongation of existing hospitalisation.
Planned hospitalisation or planned prolonged hospitalisation do not fulfill the
criteria for being an SAE but should be documented in the subject’s medical
record.

results in persistent or significant disability/incapacity.

is a congenital anomaly/birth defect.
or 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 125 of 169 

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 hospitalization, development of drug dependency or drug abuse.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 126 of 169 
Appendix 3: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to 
the subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probable, 
possible or not related according to the following: 
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
Disappears or decreases on cessation or reduction in dose of the IMP. 
Reappears or worsens upon re-challenge. 
Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Follows a known pattern of response to the IMP. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 127 of 169 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
Does not reappear or worsen upon re-challenge. 
Does not follow a known pattern of response to the IMP. 
Outcome 
The outcome of the event should be classified and handled as follows: 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing. 
Recovered/re
solved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 128 of 169 
Appendix 4: Trial governance considerations 
Appendix 4A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 

Consensus ethical principles derived from international guidelines including the
current version of the Declaration of Helsinki and Council for International
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines.

Current version of applicable ICH Good Clinical Practice (GCP) Guidelines.

Applicable laws and regulations.
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial as 
required.  
The protocol, protocol amendments, subject information leaflet including the informed 
consent form (ICF), Investigator’s Brochure, and other relevant documents (for example 
advertisements) must be submitted to an IRB/IEC by the investigator (in collaboration with 
LEO, if applicable) and reviewed and approved by the IRB/IEC prior to enrolment of 
subjects.  
Any amendments to the protocol must be approved by/receive favourable opinion from 
relevant regulatory authorities and IRBs/IECs as required prior to the implementation. 
The investigator will be responsible for the following: 

Providing written summaries of the status of the trial to the IRB/IEC annually or more
frequently in accordance with the requirements, policies, and procedures established
by the IRB/IEC.

Notifying the local IRB/IEC of SAEs or other significant safety findings as required
by IRB/IEC procedures.

Providing oversight of the conduct of the trial at the trial site and adherence to
applicable national and international legislation.
Appendix 4B: Informed consent process 
Subjects shall receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 129 of 169 
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 must be 
obtained prior to any clinical trial related procedure being carried out in accordance with ICH 
GCP (4.8) and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Subject card 
At screening, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address(es) and telephone number(s) of relevant trial 
site staff including the number for the investigator in case of emergency situations. The 
subject card also includes a local telephone number for the emergency unblinding CRO to be 
used if the investigator or delegated site staff cannot be reached or if unblinding in the IWRS 
cannot be performed. 
Appendix 4C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO and shall not be used by the 
investigator for purposes other than this clinical trial. 
The investigator agrees that LEO may use any and all information, data and results from this 
clinical trial in connection with the development of the IMPs and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners. 
Subjects will be assigned a unique identifier (subject ID) by LEO. Any subject’s records or 
datasets that are transferred to LEO will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred.  
Subjects must be informed that their personal trial-related data will be used by LEO in 
accordance with local data protection law.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 130 of 169 
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by LEO, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example age, gender, health 
condition, height, medical history, test results, etc.) which shall be collected as part of the 
clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO and third parties acting on behalf of LEO. 
Processing of personal data on behalf of LEO requires a written agreement between LEO and 
the relevant party which covers collection, processing and transfer of personal data in the 
clinical trial. In certain cases an agreement on transfer of personal data may also be required. 
Investigators and LEO must ensure that collection, processing and transfer of personal data 
are in compliance with applicable legislation on data protection and privacy. 
Subjects (or their legally acceptable representative) must be asked to consent to the collection, 
processing and transfer of their personal data to EU and non-EU countries for the purpose of 
conducting the clinical trial, research and development of new or existing products/services, 
improving existing products/services, applying for marketing authorisations for 
products/services, marketing of products/services and other related activities. 
LEO has obtained the necessary authorisations for the processing of personal data collected in 
the trial. 
Appendix 4D: Record keeping, quality control, and data handling 
Case report forms 
Data will be collected by means of electronic data capture unless transmitted to LEO or 
designee electronically (e.g., laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into electronic CRFs. Data recorded in the eCRFs will be 
accessible to the trial site and LEO personnel immediately after entry. The CRFs 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 CRFs 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 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 131 of 169 
CRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data, and the date, time and reason for the change will be identified in the audit trail. 
Principles for data entry 
Clinically significant abnormal findings at the (first) screening visit will be documented as 
medical history in the eCRF. 
If an abnormal finding (vital signs, physical examination, laboratory tests, ECG) at any other 
visit than the (first) screening visit is considered by the investigator to be clinically 
significant, it will be reported as an AE in accordance with Section 11.2. Further, any 
clinically significant deterioration of a pre-existing condition as well as any new clinically 
significant sign, symptom or illness observed after screening will be reported as an AE in 
accordance with Section 11.2. 
Source data 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be one source defined at any time for 
any data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed by medically qualified investigators.  
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 

Date(s) of conducting the informed consent process, including date of
provision of subject information.

A statement from the investigator to verify that each of the eligibility criteria
are met.

Subject ID.

The fact that the subject is participating in a clinical trial in AD including
treatment arms of tralokinumab or placebo for 52 weeks (68 weeks in selected
countries).

Other relevant medical information.
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 132 of 169 
Trial monitoring 
During the course of the trial ,CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to perform ongoing source data verification to confirm that data entered into the 
CRF 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 study agreements, ICH GCP, and all applicable regulatory requirements. 
The monitoring visit intervals will depend on the trial site’s recruitment rate, the compliance 
of the trial site with the protocol and GCP. 
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, e.g. medical records, laboratory reports, 
appointment books, etc. If the electronic medical record does not have a visible audit trail, the 
investigator must provide the CRA with signed and dated printouts. In addition, relevant site 
staff should be available for discussions at monitoring visits and between monitoring visits 
(e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. LEO will assess all 
protocol deviations and decide if any of these deviations must be reported to the regulatory 
authorities as a serious breach of GCP and the protocol, as required by local legislation. 
Protocol deviations will be included in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO or inspections from domestic or 
foreign regulatory authorities or from IRBs/IECs. Audits and inspections may take place 
during or after the trial. The investigator and the site staff as well as LEO staff have an 
obligation to cooperate and assist in audits and inspections. This includes giving auditors and 
inspectors direct access to all source documents and other documents at the trial site relevant 
to the clinical trial. This includes permission to examine, verify and reproduce any records 
and reports that are important to the evaluation of the trial. If the trial site is contacted for an 
inspection by competent authorities, LEO must be notified immediately. 
Data handling 
Subject data should be entered into the CRF as soon as possible after each visit in accordance 
with the requirements described in the Clinical Trial Agreement, if applicable. Queries for 
discrepant data will be generated automatically by the system upon entry or manually by the 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 133 of 169 
CRA, sponsor’s medical expert, or the data manager. All queries will be raised electronically 
within the electronic data capture system. This systematic validation will ensure that a clean 
and consistent database is provided for the statistical analysis. 
An electronic PRO (ePRO) solution will be used to capture patient-reported data (data from 
questionnaires completed at the trial site and eDiary data). By the use of an ePRO, data will 
be available immediately after data entry and available for monitors and site personnel, 
including the investigator, with read access only. The ePRO system is a separate application 
from the eCRF and data captured from the eCRF and the ePRO will be stored on different 
servers during data capture. Data from both systems will be included in the final trial 
database. 
External data transfers from vendors to LEO will be transmitted and handled via a secure file 
transfer protocol site.  
Transmissions of electronic data from external data providers and of ePRO data to the clinical 
database are illustrated in Panel 16. 
Panel 16  Transmission of electronic data 
CTR, clinical trial report; ECG, electrocardiogram; eCRF, electronic case report form; ePRO, 
electronic patient-reported outcome. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 134 of 169 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents including the Investigator Trial File (ICH E6, Guideline for Good Clinical 
Practice) until LEO informs the investigator that the documents are no longer to be retained or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No records may be destroyed during the retention period without the written approval of 
LEO. No records may be transferred to another location or party without written acceptance 
from LEO. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with a copy of the eCRFs and 
ePRO data for all subjects enrolled at the trial site. This is done after completion of the trial 
and before access to the eCRF/ePRO is revoked. Audit trail information will be included. 
eCRFs and ePRO data must be available for inspection by authorised representatives from 
LEO, from regulatory authorities and/or IEC/IRBs. 
Appendix 4E: Registration, reporting and publication policy 
Basic information of this clinical trial will be registered in the global data registry, 
www.clinicaltrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO in accordance with 
LEO’s Position on Public Access to Clinical Trial Information, latest 12 months after trial 
completion. Results may also become reported in www.ClinicalTrials.gov, 
www.clinicaltrialsregister.eu and national data registries in accordance with applicable law 
and regulations after clinical trial completion or premature termination.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 135 of 169 
In the case of a multi-centre trial the first publication will be a joint multi-centre publication. 
Multi-centre publications will be prepared in collaboration between LEO and the members of 
a writing group, which shall be appointed by LEO. 
Publication by an investigator of his/her trial results shall not be made public before the first 
multi-centre publication. 
If no multi-centre publication has been submitted for publication within 18 months after the 
clinical trial has been completed or terminated at all trial sites and all data have been received, 
defined as database lock of the clinical trial, the investigator shall have the right to publish the 
results from the clinical trial generated by the investigator, subject to the following notice 
requirements: 
Prior to submitting or presenting a manuscript relating to the clinical trial to a publisher, 
reviewer or other outside person, the investigator shall provide to LEO a copy of all such 
manuscripts, and LEO shall have rights to review and comment. Upon the request of LEO, the 
investigator shall remove any confidential information (other than results generated by the 
investigator) prior to submitting or presenting the manuscripts. The investigator shall, upon 
the request of LEO, delay the publication or presentation to allow LEO to protect its 
inventions and other intellectual property rights described in any such manuscripts. In case the 
first multi-centre publication is still ongoing and has not been made public at the time of 
notification, LEO and the writing group may also delay the publication or presentation if the 
manuscript is deemed to harm the ongoing multi-centre publication. 
In case of publications made by the investigator after the first multi-centre publication has 
been published, the above-mentioned requirements must still be followed. 
LEO complies with recommendations from the International Committee of Medical Journal 
Editors and with the positions of the International Federation of Pharmaceutical 
Manufacturers & Associations (IFPMA), European Federation of Pharmaceutical Industries 
and Associations (EFPIA), Japan Pharmaceutical Manufacturers Association (JPMA) and 
Pharmaceutical Research and Manufacturers of America (PhRMA) on disclosure of 
information about clinical trials, trial results and authorship. 
Appendix 4F: Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 136 of 169 
Appendix 4G: Financial disclosure 
Investigators will provide LEO with sufficient, accurate financial information as requested to 
allow LEO to submit complete and accurate financial certification or disclosure statements to 
the appropriate regulatory authorities. Investigators are responsible for providing information 
on financial interests during the course of the clinical trial and for 1 year after completion of 
the clinical trial, or for a longer period of time if required by local legislation. 
Appendix 4H: Committee structure 
Patient safety will be carefully assessed by an independent Data Monitoring Committee 
(DMC). All members will be independent of the trial (i.e. they will not be participating 
investigators or employees at participating sites) and of LEO (i.e. they will not be LEO 
employees). The DMC members are experienced with clinical trials and will be responsible 
for assessing the safety of the subjects through assessment of the safety of the treatment 
regimen during the trial and through monitoring the overall conduct of the trial. Refer to 
Appendix 8 for a list of trial committee members. 
The DMC will review data on a regular basis. Additional meetings may also be called on an 
ad hoc basis, as requested by the DMC or LEO. All data collected at the time of the data cut-
off/scheduled meetings will be included in the summaries for the DMC, including data from 
subjects still ongoing in the trial. The DMC will examine summaries and listings of AEs, 
specific laboratory parameters and subject disposition data as detailed in the DMC Charter. 
Full details of the analyses to be presented to the DMC will be specified in a separate DMC 
statistical analysis plan.  
The DMC will have an independent statistician and an independent administrator who will 
remain independent of the trial management team.  
The chairman of the DMC, in conjunction with the other members, will communicate their 
recommendations to LEO’s clinical project manager after each meeting. The chairman of the 
DMC will provide written reports to LEO after each formal review to indicate the 
committee’s recommendation regarding safety concerns and trial continuation. Further details 
on all aspects relating to the DMC are provided in the DMC charter. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 137 of 169 
Appendix 4I: Trial and site closure 
Premature termination of trial or trial site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the clinical 
trial, part of the trial or a trial site at any time, but agreement on procedures to be followed 
must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO must promptly inform IRB/IECs and 
provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO or investigator may include but are not 
limited to: 

Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, LEO’s procedures, or GCP guidelines.

Inadequate recruitment of subjects by the investigator.

Discontinuation of further IMP development.
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Trial enrolment will be 
stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO will undertake arrangements for the 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 138 of 169 
Appendix 4J: Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(consolidated) clinical trial protocol, including any amendment(s) and the CTR on behalf of 
all clinical trial investigators and as agreed to in an International Coordinating Investigator 
Agreement. 
The national coordinating investigators are responsible for national issues relating to the 
clinical trial as agreed to in a National Coordinating Investigator Agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a Clinical Trial Agreement. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 139 of 169 
Appendix 5: Hanifin and Rajka (1980) diagnostic criteria for AD 
From Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol. 1980;92 
(Suppl):44-47. 
Major Features: must have 3 or more of the following: 

Pruritus

Typical morphology and distribution:
o
Flexural lichenification or linearity in adults
o
Facial and extensor involvement in infants and children

Chronic or chronically-relapsing dermatitis

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Features: should have 3 or more of the following: 

Xerosis

Ichthyosis, palmar hyperlinearity, or keratosis pilaris

Immediate (type 1) skin-test reactivity

Raised serum IgE

Early age of onset

Tendency toward cutaneous infections (especially S. aureus and herpes simplex) or
impaired cell-mediated immunity

Tendency toward non-specific hand or foot dermatitis

Nipple eczema

Cheilitis

Recurrent conjunctivitis

Dennie-Morgan infraorbital fold

Keratoconus

Anterior subcapsular cataracts

Orbital darkening

Facial pallor or facial erythema

Pityriasis alba

Anterior neck folds

Itch when sweating

Intolerance to wool and lipid solvents

Perifollicular accentuation

Food intolerance

Course influenced by environmental or emotional factors

White dermographism or delayed blanch
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 140 of 169 
Appendix 6: Guidance for anaphylaxis diagnosis 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. Second 
symposium on the definition and management of anaphylaxis: Summary report -- Second National 
Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol. 2006;117(2):391-397. 
The National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and Anaphylaxis 
Network Guidance for Anaphylaxis Diagnosis (FAAN) define anaphylaxis as a serious allergic 
reaction that is rapid in onset and may cause death. They recognize 3 categories of anaphylaxis, with 
criteria designated to capture from 80% of cases (category 1) to >95% of all cases of anaphylaxis (for 
all 3 categories).  
Clinical criteria for diagnosing anaphylaxis 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING: 

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak
expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg,
hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen for that
patient (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen
lips-tongue-uvula)

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF,
hypoxemia)

Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope,
incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that patient (minutes to several hours):
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 141 of 169 

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
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 142 of 169 
Appendix 7: Country-specific requirements 
JAPAN 
Section 6 Objectives and endpoints 
In Japan, the maintenance endpoints of IGA 0/1 and EASI75 at Week 52 for subjects 
achieving clinical response at Week 16 are evaluated as primary maintenance endpoints. 
This regulatory requirement will have no impact on the analysis since an adjustment for 
multiplicity is implemented for these 2 endpoints. Please see Section 12.3.4 for details on 
the multiple testing procedure applied to control the overall type 1 error rate for the 
trial. 
Section 8.2 Inclusion criteria - Inclusion criterion no. 1 
Written informed consent and any locally required authorisation obtained from the subject 
prior to performing any protocol-related procedures, including screening evaluations.  
In Japan, the legal representative must sign the informed consent if the subject is below 
20 years of age. 
Section 8.2 Inclusion criteria - Inclusion criterion no. 2 
Age 18 and above. 
In Japan, inclusion criterion no. 2 will be as follows: Japanese subjects aged 18 and 
above. 
Section 9.9.3 Drug accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
In Japan, it is the Head of Institute who is responsible for the IMP at the trial site. 
Used syringes will be destroyed at the trial site provided the trial site has procedures in place 
for such IMP destruction. 
Trial sites which do not have such IMP destruction procedures in place will dispose used 
syringes in sharps bins which will be shipped to the contract manufacturing organisation 
(CMO). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 143 of 169 
In Japan, used syringes will be destroyed at the trial sites. 
Section 9.11 Reporting product complaints 
Any defects or issues with the IMP as well as any device deficiency (including malfunctions, 
use errors, and inadequate labelling) must be reported to Global Pharmacovigilance, LEO on 
the trial-specific (paper) Complaint Form within 3 days of first knowledge.  
Critical complaints (defined as any issue, defect, or device deficiency that has or potentially 
could have a serious impact for the subject [e.g., SAE or large particles in the syringe]) must 
be reported to Global Pharmacovigilance, LEO within 24 hours.  
In Japan, product complaints must be reported to Pharmacovigilance, LEO K.K. using 
the contact information below: 
Fax number: +81 3 4243 3311 
E-mail address: clinical_trial_jp@leo-pharma.com
Note: reports sent to the above fax number and email address will automatically be 
forwarded to Global Pharmacovigilance, LEO. 
Section 10.1 Overview 
Subjects participating in the trial will be under careful supervision of a dermatologist or 
allergist. Investigators must be experienced in treating AD and have documented experience 
and/or training in use of the assessments required by the protocol and must be either a 
physician, certified physician’s assistant, or advanced registered nurse practitioner. 
In Japan, investigators must be a dermatologist. 
Section 11.3.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO on the (paper) SAE Form within 24 hours of first 
knowledge. The completed SAE form must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO. 
In Japan, SAEs must be reported to Pharmacovigilance, LEO K.K. using the contact 
information below: 
Fax number: +81 3 4243 3311 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 144 of 169 
E-mail address: clinical_trial_jp@leo-pharma.com
Note: reports sent to the above fax number and email address will automatically be 
forwarded to Global Pharmacovigilance, LEO. 
Section 11.3.2 LEO reporting responsibilities 
Global Pharmacovigilance, LEO will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
countries. 
In Japan, Pharmacovigilance, LEO Pharma K.K. will be responsible for notifying the 
regulatory authorities and concerned investigators of SAEs. 
Section 11.4.1 Pregnancy 
Any pregnancy occurring during the clinical trial must be reported to LEO within 24 hours of 
first knowledge using the (paper) Pregnancy Follow Up Form (Part I). All such pregnancies 
must be followed up until delivery or termination and final outcome must be reported on the 
(paper) Pregnancy Follow Up Form (Part II) within 24 hours of first knowledge. 
The completed Pregnancy Follow Up Forms must be faxed or scanned and e-mailed to Global 
Pharmacovigilance, LEO. 
In Japan, any pregnancy must be reported to Pharmacovigilance, LEO K.K. using the 
contact information below: 
Fax number: +81 3 4243 3311 
E-mail address: clinical_trial_jp@leo-pharma.com
Note: reports sent to the above fax number and email address will automatically be 
forwarded to Global Pharmacovigilance, LEO. 
Appendix 4A: Regulatory and ethical considerations 
The protocol, protocol amendments, subject information leaflet including the informed 
consent form (ICF), Investigator’s Brochure, and other relevant documents (for example 
advertisements) must be submitted to an IRB/IEC by the investigator (…). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 145 of 169 
In Japan, the documents will be submitted to the IRB/IEC by the sponsor (LEO 
Pharma K.K.).  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 146 of 169 
Appendix 8: Contact list 
Contact list of LEO, protocol authors, vendors, and trial committees 
Contact details for the clinical project manager, national lead CRA (NLCRA), and sponsor’s 
medical expert are provided to the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO’ or ‘the sponsor’ in this clinical trial protocol) is the 
sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
LEO Pharma K.K. is the sponsor of the clinical trial in Japan on behalf of LEO Pharma A/S: 
LEO Pharma K.K. 
3-11-6 Iwamotocho
Chiyoda-ku 
Tokyo 101-0032 
Japan 
Protocol authors 
Andreas Wollenberg, Prof. Dr. med. Dr. h.c., International coordinating investigator, 
Department of Dermatology and Allergy, Ludwig-Maximilian University Munich, Germany 
, M.Sc. Stat, Principal Statistician, LEO Pharma A/S, Denmark 
,, MD, Senior Global Medical Science Lead, LEO Pharma A/S, Denmark 
, PhD, Senior Principal Scientific Advisor, LEO Pharma A/S, Denmark 
, MD, Senior PV Advisor, LEO Pharma A/S, Denmark 
, M.Sc. Pharm, Clinical Project Manager, LEO Pharma A/S, Denmark 
, PhD, Medical Communication Scientist, LEO Pharma A/S, Denmark 
eDoc-00631888 - Version
4. 0
PPD
PPD
PPD
PPD
PPD
PPD


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 147 of 169 
CROs/vendors 
Service 
Name and address 
Data management 
Quanticate Ltd. 
Bevan House, 9-11 Bancroft Court, Hitchin, Hertfordshire 
SG5 1LH 
United Kingdom 
ePRO 
CRF Health Management Ltd. 
3rd Floor, Brook House, 229-243 Shepherds Bush Road, 
Hammersmith, London W6 7AN 
United Kingdom 
ECG 
Cardiabase S.A.S. 
Villa Alsacienne, 78 Avenue du XXe Corps, 54000 Nancy 
France 
Central Lab 
ACM Global Central Laboratory 
23 Hospital Fields Road, York YO10 4DZ 
United Kingdom 
PK analysis and ADA 
Covance Laboratories Ltd. 
Otley Road, Harrogate, North Yorkshire, HG3 IPY 
United Kingdom 
Photography 
Canfield Scientific, Inc. 
253 Passaic Ave., Fairfield, NJ 07004 
United States of America 
IWRS 
Quanticate Ltd. 
Bevan House, 9-11 Bancroft Court, Hitchin, Hertfordshire 
SG5 1LH 
United Kingdom 
CMO  
Almac Clinical Services Ltd. 
Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 
5QD, United Kingdom 
CRO services in Japan 
intellim Corporation 
18F, Mainichi Intecio, 3-4-5 Umeda, Kita-ku, Osaka 530-0001 
Japan 
Emergency unblinding CRO 
C3i, Inc.  
25 Lindsley Drive, Morristown, NJ 07960  
United States of America 
Microbiology 
AROS Applied Biotechnology A/S 
Palle Juul-Jensens Boulevard 82, DK-8200 Aarhus N  
Denmark 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 148 of 169 
Service 
Name and address 
Biomarkers (IL-13, IL-17 and 
IL-22 serum analysis) 
Eurofins Pharma Bioanalytics Services US Inc. 
15 Research Park Drive, St. Charles, MO 63304 
United States of America  
Biomarkers (other serum 
biomarkers) 
Eurofins Pharma Bioanalysis Services UK Ltd. 
90 Park Drive, Milton Park, Abingdon, OX14 4RY 
United Kingdom 
Skin biopsies (gene expression 
analysis) 
AROS Applied Biotechnology A/S 
Palle Juul-Jensens Boulevard 82, DK-8200 Aarhus N 
Denmark 
Trial committees  
Data Monitoring Committee 
Role 
Name 
Chairman 
, Dr. med. Dr. phil. 
Technical University of Munich, Germany 
Member 
, MD 
University of Michigan, USA 
Member 
, BSc MSc CStat CSci 
S-cubed Biometrics Ltd, UK 
eDoc-00631888 - Version
4. 0
PPD
PPD
PPD


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 149 of 169 
Appendix 9: WHO model prescribing information for classification of 
topical corticosteroids  
Hydrocortisone and betamethasone are examples of low- and high-potency topical 
corticosteroids (TCS). TCS have been ranked in terms of potency into 4 groups consisting of 
7 classes. Class I TCS are the most potent and Class VII TCS are the least potent (Panel 17). 
Efficacy and side-effects are greatest with the Class I ultra-high-potency preparations which 
should only be used for limited time periods (2‒3 weeks).  
Representative preparations by group are listed in the table below according to the WHO 
model prescribing information for drugs used in skin diseases (41). These groups may vary 
depending on the formulation and concentration and should be considered approximate. In 
general, ointments are more potent than creams or lotions. Potency is also increased when 
TCS are used under occlusive dressings or in intertriginous areas. 
Panel 17  Classification of topical corticosteroids 
Potency 
Class Topical corticosteroid 
Formulation 
Ultra high 
I 
Clobetasol propionate 
Cream, 0.05% 
Diflorasone diacetate 
Ointment, 0.05% 
High 
II 
Amcinonide 
Ointment, 0.1% 
Betamethasone dipropionate 
Ointment, 0.05% 
Desoximetasone 
Cream or ointment, 0.025% 
Fluocinonide 
Cream, ointment, or gel, 0.05% 
Halcinonide 
Cream, 0.1% 
III 
Betamethasone dipropionate 
Cream, 0.05% 
Betamethasone valerate 
Ointment, 0.1% 
Diflorasone diacetate 
Cream, 0.05% 
Triamcinolone acetonide 
Ointment, 0.1% 
Moderate 
IV 
Desoximetasone 
Cream, 0.05% 
Fluocinolone acetonide 
Ointment, 0.025% 
Fludroxycortide 
Ointment, 0.05% 
Hydrocortisone valerate 
Ointment, 0.2% 
Triamcinolone acetonide 
Cream, 0.1% 
V 
Betamethasone dipropionate 
Lotion, 0.02% 
Betamethasone valerate 
Cream, 0.1% 
Fluocinolone acetonide 
Cream, 0.025% 
Fludroxycortide 
Cream, 0.05% 
Hydrocortisone butyrate 
Cream, 0.1% 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 150 of 169 
Panel 17  Classification of topical corticosteroids (continued) 
Potency 
Class Topical corticosteroid 
Formulation 
Moderate 
V 
Hydrocortisone valerate 
Cream, 0.2% 
Triamcinolone acetonide 
Lotion, 0.1% 
Low 
VI 
Betamethasone valerate 
Lotion, 0.05% 
Desonide 
Cream, 0.05% 
Fluocinolone acetonide 
Solution, 0.01% 
VII 
Dexamethasone sodium phosphate 
Cream, 0.1% 
Hydrocortisone acetate 
Cream, 1% 
Methylprednisolone acetate 
Cream, 0.25% 
Source: WHO model prescribing information: drugs used in skin diseases (41). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 151 of 169 
Appendix 10: Protocol amendment history 
The Protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.  
Amendment 2 (12-Dec-2017) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The reason for the amendment is due to a request for changes from the Health Authorities in 
the US after their review of the protocol.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 152 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 6.1 
Trial objectives and 
endpoints: Initial 
treatment period of 
Weeks 0 to 16 
EASI90 has been added as an additional 
secondary endpoint. 
Added to further 
substantiate the clinical 
relevance of the treatment 
effect on the change from 
baseline to Week 16 in 
EASI score.  
Section 6.1 
Trial objectives and 
endpoints: Initial 
treatment period of 
Weeks 0 to 16 
The following other objective has been added: 
To evaluate the efficacy over time of 
tralokinumab on severity and extent of AD, 
itch, and health-related quality of life 
compared with placebo. 
Added to allow for an 
evaluation of the efficacy 
of tralokinumab over time 
on severity and extent of 
AD, itch, and 
health-related quality of 
life compared with 
placebo. 
The following endpoints have been added as 
other endpoints: 

IGA 0/1 at each scheduled assessment
until Week 14.

EASI75 at each scheduled assessment
until Week 14.

Change in SCORAD from baseline to
each scheduled assessment until Week 14.

Change from baseline to each week
through Week 1 to 15 in Worst Daily
Pruritus NRS (weekly average).

Reduction of Worst Daily Pruritus NRS
(weekly average) of at least 4 from
baseline to each week through Week 1 to
15.

Change in DLQI score from baseline to
each scheduled assessment until Week 14.
Added to allow for an 
evaluation of the efficacy 
of tralokinumab over time 
on severity and extent of 
AD, itch, and 
health-related quality of 
life compared with 
placebo. 
The following other endpoints have been 
removed: 

Reduction of Worst Daily Pruritus NRS
(weekly average) of at least 4 from
baseline to Week 2

Change from baseline to Week 2 in Worst
Daily Pruritus NRS (weekly average).
Removed because these 
2 endpoints are covered by 
the new endpoints above 
(change from baseline to 
each week; reduction from 
baseline to each week). 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 153 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 6.1 
Trial objectives and 
endpoints: Initial 
treatment period of 
Weeks 0 to 16 
The following endpoints have been added as 
other endpoints: 

HADS anxiety and HADS depression
scores <8 at Week 16 in subjects with
baseline HADS anxiety or
HADS depression subscale scores of ≥8.

Reduction from baseline to Week 16 of
POEM of ≥4 points among subjects with
baseline POEM ≥4.
To evaluate the 
patient-reported outcomes 
and health care resource 
utilisation. 
Section 6.2 
Trial objectives and 
endpoints: 
Maintenance 
treatment period of 
Week 16 to 52 for 
responders at 
Week 16 

IGA of 0/1 at Week 52 among subjects
with IGA of 0/1 at Week 16 achieved
without rescue medication after initial
randomisation to tralokinumab.

EASI75 at Week 52 among subjects with
EASI75 at Week 16 achieved without
rescue medication after initial
randomisation to tralokinumab.

IGA 0/1 or EASI75 at Week 52 among
subjects with IGA 0/1 or EASI75 at
Week 16 achieved without rescue
medication.
The maintenance endpoints of IGA 0/1 and 
EASI75 at Week 52 for subjects achieving 
clinical response at Week 16 without rescue 
medication are considered secondary 
endpoints. 
In Japan, the maintenance endpoints of IGA 
0/1 and EASI75 at Week 52 for subjects 
achieving clinical response at Week 16 
without rescue medication are evaluated as 
primary maintenance endpoints. 
To evaluate the 
maintenance of effect 
achieved with 
tralokinumab.  
Section 7.1 
Overall trial design 
A 16 14-week off treatment follow-up period 
for the assessment of safety is also included 
(Weeks 52 to 66). 
All subjects will complete a 1614-week off 
treatment follow-up period for the assessment 
of safety and ADA at Week 66 (or Week 82). 
Clarification that the 
follow-up period has a 
duration of 14 weeks since 
the maintenance period 
and the open-label arm 
both include the Week 52 
visit. Since the last dose of 
IMP is administered at 
Week 50 (or Week 66), 
the follow-up visit will 
occur 16 weeks after last 
IMP administration. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 154 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 7.1 
Overall trial design 
Transfer to open-label may occur at any visit 
while the subject is in the maintenance 
treatment period but no earlier than 
Week 22.   
Clarification that transfer 
to open-label requires a 
persistent worsening of 
disease observed over 
3 consecutive visits in the 
maintenance period. 
Section 8.2 
Inclusion criteria 
(no. 9) 
Worst Daily Pruritus NRS at baseline will be 
calculated from daily assessments of worst itch 
severity (Worst Daily Pruritus NRS) during the 
7 days immediately preceding randomisation 
(Day -6 to 0). 
Clarification of how Worst 
Daily Pruritus NRS at 
baseline will be calculated. 
Inclusion criteria 
(no. 11) 
The subjects must have used the contraceptive 
method continuously for at least 1 month prior 
to the pregnancy test at baseline. 
Clarification that female 
subjects of childbearing 
potential must have used a 
highly effective form of 
birth control for at least 
1 month prior to baseline. 
Section 10.5.2.2 
Small biomarker 
panel (all subjects) 
All subjects will have blood samples taken for 
analysis of a small panel of biomarkers. The 
biomarkers to be analysed include, but are 
not limited to, the following: (periostin, 
DPP4, CCL17 (also known as thymus and 
activation regulated chemokine [TARC]), 
IL-13, IL-17, IL-22, and beta-defensin 4A 
[(DEFB4A]). 
Clarification that the small 
biomarker panel may 
include more than 
7 biomarkers. 
Section 10.5.3 
Skin biopsies 
(selected trial sites) 
Histology/immunohistochemistry/in-situ 
hybridisation 

T cells (e.g., CD3+ and CD8+), dendritic
cells (e.g., CD11c+, FcεR1),
monocytes/macrophages (e.g., CD68),
neutrophils (e.g., myeloperoxidase),
epidermal markers (e.g., epidermal 
thickness, keratin type I cytoskeletal 16, 
proliferation marker protein Ki 67, protein 
S100 A, filaggrin, loricrin). 
Neutrophils will not be 
analysed because 
neutrophil levels are not 
expected to change. 
Section 11.5.6 
Aggravation of 
condition 
Any clinically significant aggravation/ 
exacerbation/worsening of any medical 
condition(s), compared to baseline screening, 
must be reported as an AE. 
Clarification that AE 
reporting starts at 
screening, not baseline. 
This is in alignment with 
the information given in  
Section 11.1 and 
Appendix 4D. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 155 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.2 
Trial analysis sets 
A per protocol analysis set will be used as an 
efficacy subset for the analysis of the primary 
endpoints up to Week 16 (visit 12) 
The per protocol analysis set will be defined 
by excluding subjects from the full analysis set 
for whom any of the following conditions 
apply:  

receive no treatment with the IMP.

provide no efficacy data assessment of
IGA or EASI following start of
treatment.

are known to have taken the wrong IMP
throughout the initial treatment period of
the trial.

do not fulfil all the disease defining
inclusion criterion (i.e. inclusion criterion
no. 3) inclusion criteria no. 3, 6, 7 and 8. 
Further exclusion of subjects or subject data 
will be decided upon after a blinded review of 
the data, reviewing all the remaining in  and 
exclusion criteria, but focusing on concomitant 
medication that may affect AD and also 
considering compliance/adherence and 
violations of visit windows. 
Specification that the per 
protocol analysis set will 
be used for analysis of the 
primary endpoints only. 
To predefine the criteria 
leading to exclusion from 
the per protocol analysis 
set, rather than deferring 
until a blinded review of 
the data. 
Section 12.3.1 
Disposition of 
subjects 
For all randomised subjects the reasons for 
permanent discontinuation of IMP and for 
leaving the trial in the initial treatment period 
will be presented by last visit attended and by 
treatment group. For the subjects in the 
maintenance safety analysis set, the reasons for 
permanent discontinuation of IMP and for 
leaving the trial or treatment arm will be 
presented by last visit attended and by the 
assigned treatment group at Week 16. For the 
subjects in the open-label safety analysis set, 
the reasons for permanent discontinuation of 
IMP and for leaving the trial will be presented 
by last visit attended. 
Clarification that reasons 
for permanent 
discontinuation of IMP 
will be presented. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 156 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.3.2 
Demographics and 
other baseline 
characteristics 
The presentations will be overall and by 
treatment group. Presentations of age, sex, 
ethnicity, race, baseline disease severity, and 
Worst Daily Pruritus NRS weekly average at 
baseline will also be given by region and by 
baseline disease severity (IGA 3 or 4). 
Baseline disease severity 
added since this is also a 
stratification factor, in 
addition to region. 
Section 12.3.5.1 
Analysis of primary 
endpoints 
This section has been amended to implement 
the concept of estimands together with the 
pre-specification of sensitivity analyses. The 
primary analyses of the primary endpoints are 
unchanged compared to the statistical analysis 
plan provided in the original protocol dated 
03-Mar-2017. 
To pre-specify the method 
of handling missing data. 
Section 12.3.5.2 
Analysis of 
secondary endpoints 
This section has been amended to implement 
the concept of estimands together with the 
pre-specification of sensitivity analyses. The 
primary analyses of the secondary endpoints 
are unchanged compared to the statistical 
analysis plan provided in the original protocol 
dated 03-Mar-2017. 
To pre-specify the method 
of handling missing data. 
Section 12.3.5.3 
Analysis of 
additional secondary 
endpoints 
This section has been updated to describe the 
statistical analysis of the additional secondary 
endpoint EASI90. 
To describe the statistical 
analysis of new endpoint. 
Section 12.3.5.4.1 
Efficacy over time 
This is a new section describing the statistical 
analysis of the 6 new other endpoints which 
address efficacy over time. 
To describe the statistical 
analysis of new endpoints. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 157 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.3.5.4.2 
Patient-reported 
outcomes 
This section has been updated to include a 
description of the statistical analysis of the 
following 2 new other endpoints: 

HADS anxiety and HADS depression
scores <8 at Week 16 in subjects with
baseline HADS anxiety or HADS
depression subscale scores of ≥8

Reduction from baseline to Week 16 of
POEM of ≥4 points among subjects with
baseline POEM ≥4.
The description of the analysis of the following 
2 endpoints have been removed from this 
section: 

Reduction of at least 4 from baseline to
Week 2 in Worst Daily Pruritus NRS
weekly average

Change from baseline to Week 2 in Worst
Daily Pruritus NRS weekly average.
To describe the statistical 
analysis of new endpoints. 
The analysis of these 
endpoints is now covered 
by the new section 
12.3.5.4.1. 
For the PGI-B, a day of ‘no or slight bother’ is 
defined as answering the question with ‘not at 
all’ or ‘slightly’. The subjects’ number of days 
of ‘no or slight bother’ will be tabulated per 
treatment group for the initial treatment period. 
The mean number of days will be presented 
with 95% CIs and compared between the 
2 treatment groups using an analysis of 
variance model including treatment, region, 
and baseline IGA as factors. In this analysis, 
data collected after permanent 
discontinuation of IMP or after initiation of 
rescue medication will be disregarded. 
Clarification regarding 
data collected after 
permanent discontinuation 
of IMP or after initiation 
of rescue medication, to 
align with the primary 
estimand for the 
continuous secondary 
endpoints. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 158 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.3.6.1 
Analysis of 
maintenance 
endpoints 
The main changes are as follows: 

An estimand framework has been
introduced for the analysis of the
maintenance endpoints. The primary
analysis provided in the statistical analysis
plan in the original protocol dated
03-Mar-2017 is unchanged.

Clarification has been added on the
analysis set for the maintenance endpoints
IGA of 0/1 at Week 52 and EASI75 at
Week 52.

The sensitivity analysis allowing TCS
treatment under certain conditions has
been removed (mild to moderate strengths
[WHO classification] TCS, on ≤250 cm2
affected BSA, for ≤5 consecutive days,
not more often than every 4 weeks,
<3 courses from Week 16 to Week 50 and
last course is completed prior to the
Week 50 visit, allowing at least a 2-week
washout prior to the Week 52
assessment).

An LOCF sensitivity analysis has been
introduced.
To conduct a sensitivity 
analysis which is similar 
to the sensitivity analysis 
no. 2 for the primary 
estimand for the primary 
endpoints. The sensitivity 
analysis described in the 
original protocol – which 
allowed TCS under certain 
conditions – is 
inconsistent with the 
rescue medication 
algorithm applied in the 
initial treatment period. 
Section 12.3.6.2.1 
Time to relapse 
Initiation of rescue medication is now 
considered an event of relapse, rather than a 
censoring of the time to relapse. 
A clarification has been added that only 
subjects who achieve response at Week 16 
without rescue medication will be included in 
the analysis.  
Clarification that the log-rank test will be 
stratified by region and that this test is 
considered a supplementary exploratory 
analysis. 
Initiation of rescue 
medication is unlikely to 
be independent of the time 
to relapse, hence it is not 
considered appropriate to 
consider it a censoring 
event.  
The log-rank test will be 
stratified according to 
region, to align with the 
analysis of the binary 
maintenance endpoints. 
Clarification that the 
log-rank test is considered 
a supplementary 
exploratory analysis. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 159 of 169 
Section number 
and name 
Description of change 
Brief rationale 
Section 12.3.6.2.3 
Supportive 
maintenance 
To support the maintenance objective, the 
response IGA 0/1 or EASI75 at Week 52 will 
be presented and analysed as described above 
for the primary analysis of the maintenance 
estimand for all subjects in the maintenance 
analysis set who did not receive rescue 
medication prior to Week 16 The estimated 
response rates and corresponding 95% CIs, and 
the pairwise treatment differences will be 
presented. 
To clarify that only 
subjects who achieve 
response at Week 16 
without rescue medication 
will be included in the 
analysis.  
Section 12.3.9 
Analysis of data per 
last subject’s 
Week 52 visit 
This is a new section which specifies that the 
trial will be unblinded once all randomised 
subjects have completed the Week 52 visit. All 
pre-specified analyses related to the initial and 
maintenance treatment period will be based on 
the data cut-off date of the last subject’s 
Week 52 visit. 
To support submission for 
regulatory approval. 
Appendix 1 
Protocol summary 
Updated with the changes described above, as 
applicable. 
To reflect updated text in 
protocol. 
Appendix 4B 
Informed consent 
process 
Subjects must be re-consented to the most 
current version of the ICF(s) during their 
participation in the trial, if required. 
Clarification that subjects 
will only be re-consented 
to a new version of the 
ICF(s), if deemed 
necessary. 
Appendix 4H 
Committee structure 
Refer to Appendix 8 for contact details on all a 
list of trial committee members. 
As the DMC has been 
established, the list of 
committee members has 
been included; however, 
contact details are not 
provided in the protocol. 
Appendix 8 
Contact list 
Members of the DMC have been listed. 
DMC has now been 
contracted. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not 
been summarised. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 160 of 169 
Amendment 1 (28-Aug-2017) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The reason for the amendment is due to a request for changes from the Health Authorities in 
Europe after their review of the protocol.  
Note: In the table below, text added to the protocol is written in bold and deleted text has a 
line through it. 
Section number and 
name 
Description of change 
Brief rationale 
Section 2 
Trial identification 
ClinicalTrials.gov number: 
NCT03131648 
ClinicalTrials.gov identifier 
received and it has therefore been 
added. 
Section 3 
Schematic of trial 
design 
Section 4 
Schedule of 
procedures 
Section 7.1  
Overall trial design 
Section 7.3 
End of trial definition 
All subjects in the trial will have a 
safety follow-up visit (end of trial 
visit) 16 weeks after last injection of 
IMP, including those that are offered 
participation in the long-term 
extension trial conducted under a 
separate protocol (LP0162-1337).  
Details regarding enrolment of 
subjects into the long-term extension 
have been removed. 
To ensure that safety follow-up 
information is collected for all 
subjects enrolled in this trial, and 
to ensure that a safety evaluation 
can be made based on data 
collected after IMP has been 
discontinued. Furthermore, the 
evaluation of anti-drug antibodies 
is considered to be most reliable 
when samples are taken in the 
absence of IMP. 
Details regarding enrolment of 
subjects into trial LP0162-1337 
will be described in the protocol 
for LP0162-1337. 
Section 4 
Schedule of 
procedures 
2 blood samples (PK and anti-drug 
antibodies) have been added at 
Week 4 (visit 5). 
To better monitor potential 
development of immunogenicity. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 161 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 4 
Schedule of 
procedures 
Section 7.1  
Overall trial design 
Appendix 1  
Protocol summary 
The criteria for transfer to open-label 
treatment have been changed: 
(i) Persistent IGA of 2 and not
achieving EASI75 over at least a 4
week period (i.e., subjects must have 
IGA of 2 and not achieve EASI75 at 3 
consecutive visits). 
(ii) On a single occasion, an IGA of at
least 3 and not achieving EASI75. 
(iii) On a single occasion not
achieving EASI50 with an IGA of at 
least 2. 
Subjects with IGA=0 at Week 16:  
IGA of at least 2 and not achieving 
EASI75 over at least a 4-week 
period (i.e., over 3 consecutive 
visits). 
Subjects with IGA=1 at Week 16:  
IGA of at least 3 and not achieving 
EASI75 over at least a 4-week 
period (i.e., over 3 consecutive 
visits).   
Subjects with IGA >1 at Week 16:  
Not achieving EASI75 over at least 
a 4-week period (i.e., over 
3 consecutive visits). 
To keep subjects who entered 
maintenance treatment with 
IGA 0/1 in maintenance treatment 
until they have a sustained 2-step 
change in IGA (IGA of 0 
becoming ≥2; IGA of 1 becoming 
≥3). 
Section 4 
Schedule of 
procedures 
Section 7.1  
Overall trial design 
Section 8.2  
Inclusion criteria 
Section 9.4 
Background 
treatment 
(emollients) 
Appendix 1 
Protocol summary 
All subjects must use an emollient 
twice daily (or more, as needed) 
Clarification that the use of 
background treatment (emollients) 
is at least twice daily or more, as 
needed. This change has been 
implemented throughout the 
document.  
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 162 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 4 
Schedule of 
procedures 
Section 7.1  
Overall trial design 
The following text has been added to 
footnote no. 1 in Panel 2:  
Similarly, for subjects who only 
require a 2-week wash out, 
screening visits 1 and 2 will be 
combined (Week -2). 
In Section 7.1, the following text has 
been added under Screening period: 
Similarly, if only a 2-week wash-out 
is required, screening visits 1 and 2 
will be combined (Week -2; visit 2). 
Specification that the 2 screening 
visits (visits 1 and 2) will be 
combined for subjects who only 
require a 2-week wash-out. 
Section 5.1 
Atopic dermatitis 
Treatment recommendations for AD 
include topical therapies, the main 
being topical corticosteroids (TCS). 
Unfortunately, TCS and topical 
calcineurin inhibitors (TCIs) have 
limited efficacy in patients with 
moderate to severe disease. TCS and 
non-biologic other treatment options 
like topical calcineurin inhibitors 
(TCI) and systemic therapies are all 
associated with toxicities with long-
term use (6-8). 
Corrections as no toxicities have 
been reported with long-term 
treatment with TCIs. 
Section 5.5 
Benefit/risk 
assessment 
A number of theoretical potential 
risks have been identified that are 
described in the current Investigator’s 
Brochure, including hypersensitivity 
reactions, infusion reactions, immune 
complex disease, and severe 
infections, malignancies, and 
interference with reproductive 
function 
Infusion reactions have been 
deleted from the list since they are 
not relevant for this trial. 
Malignancies and interference 
with reproductive function added 
to align with the Investigator’s 
Brochure. 
Section 8.3  
Exclusion criteria 
10. Receipt of any marketed (i.e.
immunoglobulin, anti-IgE) or
investigational biologic agent,
including dupilumab
18. History of anaphylaxis following
any biologic therapy.
Dupilumab is now approved in 
USA, and has therefore been 
added to exclusion criterion no. 
10. 
Clarification on which kind of 
previous anaphylaxis will lead to 
exclusion. A large proportion of 
subjects with moderate to severe 
AD will have had food allergies 
and other allergies during 
childhood, manifested as 
anaphylaxis, with no relevance for 
later risk of anaphylactic reactions 
to tralokinumab. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 163 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 8.5 
Discontinuation 
Section 4 
Schedule of 
procedures 
Subjects who permanently 
discontinue treatment IMP for any 
reason will be asked to attend an 
early termination visit and return 
to the trial site for 1 or 2 additional 
visits as indicated below depending 
on the time of discontinuation of 
IMP should attend an early 
termination visit and a safety follow
up visit 16 weeks after last 
administration of IMP (see the SoP 
[Section 4] for data to be collected at 
these visits). The investigator will 
review any AEs which will be 
followed up according to 
Section 11.6, if the subject agrees. 
Subjects who permanently 
discontinue IMP prior to Week 16 
will be asked to attend: 

Early termination visit.

Nominal Week 16 visit
(16 weeks after
randomisation).

Safety follow-up visit (16 weeks
after last administration of
IMP).
Subjects who discontinue IMP at 
Week 16 or after Week 16 will be 
asked to attend:  

Early termination visit.

Safety follow-up visit (16 weeks
after last administration of
IMP).
If a subject withdraws from the trial, 
he/she may request destruction of any 
samples taken and not tested, and the 
investigator must document this in the 
site’s trial records.  
Reason(s) for discontinuation from 
IMP and withdrawal from the trial 
must be recorded in the medical 
records 
Clarification that subjects who 
permanently discontinue IMP 
prior to Week 16 should also be 
assessed at the nominal Week 16 
visit. This will allow sensitivity 
analyses of primary endpoints and 
secondary endpoints in the initial 
treatment period. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 164 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 9.3.2 
Emergency 
unblinding of 
individual subject 
treatment 
An emergency unblinding request can 
be made by the investigators, other 
HCPs who are not members of the 
trial staff, or authorised LEO 
personnel. 
Provisions are in place for 24-hour 
emergency unblinding of individual 
subject treatment. If emergency 
unblinding is required, the requester 
investigator can unblind a subject’s 
treatment in the IWRS. For a 
requester who is not a member of 
the trial staff and who does not 
without have access to the IWRS 
(e.g., an HCP not involved in the trial 
a physician at an emergency room), 
a local contact number for the 
emergency unblinding CRO is 
provided on the subject card (see 
Appendix 4B) to be used if the 
investigator or delegated site staff 
cannot be reached. 
Clarification regarding the 
procedure for emergency 
unblinding of the individual 
subject’s treatment. 
Emergency unblinding CRO 
Clarification throughout the 
section that the unblinding CRO is 
to be used for emergency 
unblinding only. 
Section 9.11 
Reporting product 
complaints 
Appendix 7 
Country-specific 
requirements (Japan) 
Any defects or issues with the IMP as 
well as any device deficiency 
(including malfunctions, use errors, 
and inadequate labelling) must be 
reported to Global 
Pharmacovigilance, LEO on the 
trial-specific (paper) Device 
Complaint Form within 3 days of first 
knowledge. Critical complaints 
(defined as any issue, defect, or 
device deficiency that has or 
potentially could have a serious 
impact for the subject [e.g., SAE or 
large particles in the syringe]) must 
be reported to Global 
Pharmacovigilance, LEO within 24 
hours.  
Clarification that product 
complaints related to the IMP 
itself must also be reported as 
product complaints.  
Clarification that any device 
deficiency must be reported as a 
product complaint. 
Clarification that critical 
complaints are subject to 
expedited reporting. 
Clarification that adverse events in 
connection with product 
complaints are to be reported as 
adverse events or serious adverse 
events as appropriate. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 165 of 169 
Section number and 
name 
Description of change 
Brief rationale 
This report Complaint forms should 
contain a detailed description of the 
defect, issue, or malfunction device 
deficiency, including whether it the 
malfunction led to an AE. (S)AEs 
which occur due to a defect or issue 
with the IMP or due to a device 
deficiency will be reported by the 
investigator as described in Sections 
11.2 and 11.3. 
Section 10.1 
Overview 
Investigator assessments (performed 
only by adequately trained 
investigators; the same investigator 
should perform all the evaluations for 
a given subject throughout the entire 
trial period) in the following order: 
1.
SCORAD component C,
then component A and B.
2.
IGA.
3.
EASI.
Clarification that SCORAD 
component C (completed by the 
subject) will be completed prior to 
any investigator assessments.  
Section 10.3.1.1 
Investigator’s Global 
Assessment 
Clinical signs and morphological 
descriptors have been added to the 
IGA scale in Panel 10. 
Added following a request from 
the FDA. 
Section 10.3.1.2 
Eczema Area and 
Severity Index 
Footnote added to Panel 12 on the 
EASI severity score scale:  
Half-points (0.5; 1.5; 2.5) may also 
be used. 
Clarification that the EASI 
severity score scale also includes 
half-points (in alignment with the 
eCRF and the trial manual).  
Sections 10.3.2.1 
Eczema related Sleep 
numeric rating scale 
to 10.3.2.12 
Treatment 
Satisfaction 
Questionnaire for 
Medicine 
All 12 questionnaires are provided in 
the investigator trial file and not in a 
trial manual. 
Clarification on where 
questionnaires are filed. 
Section 10.4.5  
Laboratory testing 
The central laboratory will provide 
results in conventional units to trial 
sites in the US and in SI units to 
trial sites in Europe and Asia; the 
trial sites in the units preferred by the 
trial sites while the results that are 
transferred to the trial database will 
always be in conventional and SI 
units. 
Clarification regarding the units of 
the results from the clinical 
laboratory assessments provided 
to the trial sites across regions. 
Clarification that results 
transferred to the trial database 
will be in both conventional and 
SI units. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 166 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 10.4.7 
Anti-drug antibodies 
measurements 
Samples will be retained for as long 
as the quality of the material 
permits evaluation but for no 
longer than 15 years after 
marketing authorisation. 
Clarification regarding storage of 
ADA samples. 
Section 10.5.1.2 
Staphylococcus 
aureus colonisation 
To minimise the variation between 
trial sites, a traditional culture based 
non quantitative method for 
determining S. aureus colonisation 
will be determined usedusing an 
RNA-based method (quantitative 
real-time polymerase chain 
reaction). 
The RNA-based method is more 
reliable than the culture-based 
method when swabs have been 
frozen. 
Section 10.6  
Estimate of total 
blood volume 
collected 
Total volume of blood to be 
withdrawn has been changed from 
420 mL to 435 mL 
2 blood samples (PK and anti-drug 
antibodies) have been added at 
Week 4 
Section 11.4.1 
Pregnancy 
Pregnant subjects must permanently 
discontinue from the trial IMP (see 
Section 9.8.1). 
Alignment between Sections 9.8.1 
and 11.4.1. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 167 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Section 11.5.1 
Adverse events of 
special interest 
Malignancies diagnosed after 
randomisation, excluding basal cell 
carcinoma, localised squamous cell 
carcinoma of the skin, and 
carcinoma in situ of the cervix 
Conjunctivitis, keratoconjunctivitis, 
and keratitis added as adverse events 
of special interest. The additional 
information about these events that 
the investigators will provide to LEO 
is also included in Panel 14. 
Basal cell carcinoma, localised 
squamous cell carcinoma of the 
skin, and carcinoma in situ of the 
cervix will be reported on standard 
AE forms as no additional 
information (e.g., histology report, 
oncology assessment, treatments) 
regarding these conditions need to 
be reported. 
These event types are common in 
the target population and should 
be monitored closely as per 
request from the authorities. 
Section 11.7 
Handling of an urgent 
safety measure 
LEO must act immediately upon 
receipt of the urgent safety measure 
notification in accordance with the 
internal procedures and local 
legislation. 
Clarification that the handling of 
urgent safety measures will be in 
accordance with local legislation. 
Section 12.3.6.1 
Analysis of 
maintenance 
endpoints 
The pooled analyses will only be 
presented in marketing 
authorisation applications 
Clarification that the pooled 
analyses of data from 
LP0162-1325 and LP0162-1326 
will be presented in marketing 
authorisation applications. 
Section 12.3.7.1 
Adverse events 
An overall summary of the number 
of treatment-emergent AEs, number 
(percentage) of subjects with any 
treatment-emergent AEs, SAEs, 
deaths, premature discontinuations 
from the trial due to AEs, treatment-
related AEs and severe AEs will be 
presented. 
Number of treatment-emergent 
AEs and deaths added to comply 
with ClinicalTrials.gov reporting 
requirements. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 168 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Appendix 4 B 
Informed consent 
process 
At screening, subjects will be 
provided with a card stating that they 
are participating in a clinical trial and 
which contains contact address(es) 
and telephone number(s) of relevant 
trial site staff including the number 
for the investigator in case of 
emergency situations. The subject 
card also includes a local telephone 
number for the emergency 
unblinding CRO to be used if the 
investigator or delegated site staff 
cannot be reached or if unblinding 
in the IWRS cannot be performed. 
Clarification that the subject card 
also includes emergency numbers 
for emergency unblinding by the 
investigator and the emergency 
unblinding CRO (as also clarified 
in Section 9.3.2). 
Appendix 4D 
Record keeping, 
quality control, and 
data handling 
Protocol deviations will be 
documented and notified to the 
investigator. LEO will assess all 
protocol deviations and decide if 
any of these deviations must be 
reported to the regulatory 
authorities as a serious breach of 
GCP and the protocol, as required 
by local legislation. Protocol 
deviations will be included in the 
CTR. Protocol deviations will be 
assessed by LEO and included in the 
CTR. 
Clarification that it will be 
evaluated whether protocol 
deviations (non-compliances) 
must be reported to the regulatory 
authorities as a serious breach of 
GCP and the protocol.  
Appendix 8 
Contact list 
Update of the protocol authors. 
Due to change in the 
responsibilities of the sponsor’s 
personnel. 
Emergency unblinding CRO 
Microbiology 
Biomarkers 
Skin biopsies 
The name and address for the 
emergency unblinding CRO has 
been added. 
The name and address for the 
laboratory responsible for 
analysing skin swab data has been 
added. 
The name and address for the 
2 laboratories responsible for 
serum biomarker analysis has 
been added. 
The name and address for the 
laboratory responsible for gene 
expression analysis has been 
added. 
eDoc-00631888 - Version
4. 0


Trial ID: LP0162-1325 
Date: 14-Aug-2018 
Version: 4.0 
Page 169 of 169 
Section number and 
name 
Description of change 
Brief rationale 
Appendix 9 
WHO model 
prescribing 
information for 
classification of 
topical 
corticosteroids 
New appendix 
Guidance for the investigators 
regarding the classification of 
topical corticosteroids as well as 
examples have been added to the 
protocol. In Section 9.7 (Rescue 
treatment), a cross reference to 
Appendix 9 has also been added. 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, have therefore not been 
summarised. 
eDoc-00631888 - Version
4. 0


Signature Page for eDoc-00631888 v4.0
Electronic signatures made within eTMF LEO are considered to be a
legally binding equivalent of traditional handwritten signatures.
Reason for signing: Approved
Manage
ver Verdict(s)
Name: 
Capacit
Date of signature: 16-Aug-2018 17:22:10
GMT+0000
Reason for signing: Approved
Manage
Verdict(s)
Name: 
Capacit
Date of signature: 17-Aug-2018 06:55:39
GMT+0000
Reason for signing: Approved
Manage
s)
Name: 
Capacit
Date of signature: 17-Aug-2018 10:01:46
GMT+0000
eDoc-00631888 - Version
4. 0
PPD
PPD
PPD

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
 
Official title: Tralokinumab monotherapy for moderate-to-severe atopic dermatitis ECZTRA 1 (ECZema TRAlokinumab trial no. 1) 
LEO Pharma number: LP0160-1325 
NCT number: NCT03131648 
Date: 20-May-2019 
 


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 1 of 31 
Statistical Analysis Plan 
Tralokinumab monotherapy for moderate-to-severe atopic dermatitis 
ECZTRA 1 (ECZema TRAlokinumab trial no. 1) 
Phase 3 – Efficacy and safety trial 
A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and 
safety of tralokinumab monotherapy in subjects with moderate-to-severe atopic dermatitis 
who are candidates for systemic therapy 
LEO Pharma A/S 
Trial ID: 
LP0162-1325 
Date: 
20-May-2019
Version: 
Final 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 2 of 31 
1 Statistical Analysis Plan Approval 
1.1 Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan. 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document. 
 
Biostatistics Lead, Global Clinical Operations 
 
Medical Lead, Medical Science and Safety 
 
QC Statistician, Biostatistics 
TMF-000040709 - Version
1. 0
PPD
PPD
PPD


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 3 of 31 
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). 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 4 of 31 
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 
3.1 List of Abbreviations ......................................................................................................... 6 
4 Introduction ........................................................................................................................... 8 
5 Trial Analysis Sets ................................................................................................................. 9 
6 Statistical Analysis ............................................................................................................... 11 
6.1 Baseline Characteristics .................................................................................................. 11 
6.2 Disposition ....................................................................................................................... 11 
6.3 Rescue medication ........................................................................................................... 11 
6.4 Compliance ...................................................................................................................... 12 
6.5 Exposure .......................................................................................................................... 12 
6.6 Analysis of Efficacy ........................................................................................................ 12 
6.6.1 
Multiple testing procedure ........................................................................................... 12 
6.6.2 
Primary and secondary binary endpoints .................................................................... 14 
6.6.3 
Continuous secondary endpoints ................................................................................. 15 
6.6.4 
Multiple imputation ..................................................................................................... 17 
6.6.5 
Secondary and other efficacy analysis ........................................................................ 18 
6.7 Analysis of Safety ........................................................................................................... 22 
6.7.1 
Adverse Events ............................................................................................................ 22 
6.7.2 
Vital signs .................................................................................................................... 23 
6.7.3 
ECG ............................................................................................................................. 23 
6.7.4 
Laboratory Data ........................................................................................................... 23 
6.7.5 
Urinalysis ..................................................................................................................... 24 
6.7.6 
Staphylococcus aureus ................................................................................................ 25 
6.7.7 
Pharmacokinetics and anti-drug antibodies ................................................................. 25 
6.7.8 
Biomarkers .................................................................................................................. 25 
6.7.9 
Biopsy biomarkers ....................................................................................................... 25 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 5 of 31 
6.8 General Principles ........................................................................................................... 26 
6.8.1 
Baseline value .............................................................................................................. 26 
6.8.2 
Definition of trial periods and date of permanent discontinuation of IMP ................. 26 
6.8.3 
Incomplete recordings ................................................................................................. 28 
6.8.4 
Conventions regarding time of day for efficacy assessments and concomitant 
medication ................................................................................................................... 29 
6.8.5 
Treatment Completers ................................................................................................. 30 
6.8.6 
Early termination and unscheduled visits .................................................................... 30 
6.8.7 
Handling of Drop-outs and Missing Values ................................................................ 30 
6.8.8 
Treatment Labels ......................................................................................................... 31 
7 References ........................................................................................................................... 31 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 6 of 31 
3 List of Abbreviations 
3.1 List of Abbreviations 
AD 
atopic dermatitis 
ADA 
anti-drug antibodies 
ADaM 
Analysis data model 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BMI 
body mass index 
BSA 
body surface area 
DK 
Denmark 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
EASI50 
At least 50% reduction in EASI score 
EASI75 
At least 75% reduction in EASI score 
EASI90 
At least 90% reduction in EASI score 
ECG 
electrocardiogram 
EQ-5D-5L 
EuroQoL 5-Dimension Health Questionnaire 5 Level 
HADS 
Hospital Anxiety and Depression Scale 
ICH 
International Conference on Harmonisation 
IGA 
Investigator’s Global Assessment 
IMP 
investigational medicinal product 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAB 
neutralising antibodies 
NRS 
numeric rating scale 
PGI-B 
Patient Global Impression of Bother 
PGI-S 
Patient Global Impression of Severity 
POEM 
Patient Oriented Eczema Measure 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 7 of 31 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SCORAD 
Scoring Atopic Dermatitis 
SCORAD50 
At least 50% reduction in SCORAD score 
SCORAD75 
At least 75% reduction in SCORAD score 
SF-36 
36-Item Short Form Health Survey
SOC 
System Organ Class 
TCS 
topical corticosteroid 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
WPAI-GH 
Work Productivity and Activity Impairment – General Health 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 8 of 31 
4 Introduction 
The statistical analysis will be performed as outlined in the Clinical Trial Protocol including 
amendments.  
This Statistical Analysis Plan is prepared before the unblinding of the trial and supplements 
the Clinical Trial Protocol, which otherwise describes the originally planned statistical 
analyses of all endpoints in an intended exhaustive manner. The Statistical Analysis Plan 
contains a more technical and detailed elaboration of some points related to the 
implementation of the statistical analyses already described in the Clinical Trial Protocol. 
In addition, the Statistical Analysis Plan includes supplementary statistical analyses and 
aspects that are introduced after the latest protocol amendment, of which all are initiated as 
responses to FDA advices. 
Supplementary analyses introduced according to LEO response to 
 letter dated 
; Ref ID: 
:
1. A tipping point analysis introduced as a sensitivity analysis number 3 for the primary
estimand (‘composite’) for the primary endpoints (IGA 0/1 and EASI75) and the
secondary endpoint (reduction of Pruritus NRS weekly average of at least 4 (yes/no)).
2. Analyses of a new tertiary estimand (‘composite’) for the continuous secondary
confirmatory endpoints (change in SCORAD and change in DLQI). Analyses apply
non-responder imputation for subjects who received rescue medication. A tipping
point sensitivity analysis is included.
Other supplementary analyses introduced for consistency: 
3. The same analysis and tipping point sensitivity analysis as above implemented as a
new tertiary (‘composite’) estimand for the two secondary additional endpoints
‘Change from baseline to Week 16 in EASI score’ and ‘Change from baseline to Week
16 in Worst Daily Pruritus NRS (weekly average)’.
Modification of the US testing hierarchy introduced by LEO in Meeting Background Material 
for 
 meeting dated 
; Ref ID: 
 to address 
 
letter dated 
; Ref ID: 
: 
4. A dedicated modified confirmatory testing hierarchy applied in the US submission.
The originally specified testing hierarchy is kept for non-US submissions (e.g. to EMA
and PMDA).
TMF-000040709 - Version
1. 0
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 9 of 31 
The first aspect is addressed in section 6.6.2, the 2nd and 3rd are addressed in section 6.6.3 
while the 4th aspect is presented in section 6.6.1. 
5 Trial Analysis Sets 
The trial analysis sets are defined in the protocol and the following modifications to the 
analysis sets for the initial- and maintenance periods are introduced. 
All subjects randomised to initial treatment who were exposed to IMP are included in the full 
analysis set (FAS) and will be analysed for efficacy up to Week 16 (visit 12). For subjects not 
exposed to IMP, the decision to withdraw can’t be biased by knowledge of the assigned 
treatment due to the blinding. This definition of the FAS implements the consideration 
mentioned in the protocol regarding special excluded cases with reference to ICH E9, Section 
5.2.1. 
The safety analysis set comprises all subjects randomised to initial treatment who were 
exposed to IMP. The protocol further specifies to exclude subjects from the safety analysis set 
for whom no post-baseline safety data are available. However, since all subjects receive the 
first dose of IMP in connection with the Week 0 visit and are subsequently monitored for 
immediate drug reactions, all exposed subjects are considered to have post-baseline safety 
data available and no such further exclusions will be made. 
The maintenance analysis set is defined in the protocol as all subjects who receive 
tralokinumab in the initial treatment period and who are re-randomised to maintenance 
treatment. In addition to this, subjects who are not exposed to maintenance treatment will be 
excluded from the maintenance analysis set. This follows the same principle that leads to 
exclusion of unexposed subjects from the full analysis set and is in alignment with ICH E9. 
The maintenance safety analysis set comprises all subjects who are re-randomised and receive 
at least one dose of maintenance treatment. 
The open-label safety analysis set comprises all subjects who at any point in time enter the 
open-label treatment arm and receive at least one dose of open-label treatment. 
For the follow-up period the safety follow-up analysis set will be used as the basis for 
evaluation of adverse events during the follow-up period. It comprises all subjects for whom 
date of last contact is after the date of exposure end, where exposure end is defined as the 
Week 52 visit (Week 68 visit for subjects enrolled in short-term extension) for subjects 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 10 of 31 
completing the treatment period, and otherwise the date of permanent discontinuation of IMP 
for subjects not completing the treatment period. See also section 6.8.2 for further details. 
For analysis of efficacy subjects will be included ‘as randomised’. 
For analysis of safety, if a subject is mistakenly given an experimental therapy other than that 
to which they were randomized, they should be analyzed ‘as-treated’, thus included in the 
group according to the therapy actually received by the subject. The below rules will be 
applied. 
Subjects who received at least one dose of tralokinumab during the initial treatment period 
will be analysed in the tralokinumab treatment group. Although this may dilute the AE rate in 
the tralokinumab treatment group slightly by including in the denominator subjects who only 
received one dose of active treatment, it will ensure that no significant drug reactions to 
tralokinumab will erroneously be assigned to placebo. 
Subjects in the maintenance safety analysis set will be analysed as follows: 
Week 16 Tralokinumab responders will be displayed in tables for the maintenance period 
according to actual treatment defined as:  

Tralokinumab Q2W if
o
subject was randomised to Tralokinumab Q2W and at least one dose of active
treatment was administered, or
o
subject was randomised to placebo, but more than half of the administered
doses contained active treatment.

Tralokinumab Q4W if
o
subject was randomised to Tralokinumab Q4W and at least one dose of active
treatment was administered, or
o
subject was randomised to placebo but at least one and at most half of the
administered doses contained active treatment.

Placebo if only placebo doses were administered
By assigning subjects randomised to placebo who got at least one active treatment to the Q4W 
arm a potential safety signal in the Q2W group is not deflated. 
Week 16 placebo responders will be displayed in the “Week 16 placebo responders / Placebo” 
column in summary tables, regardless of actual treatment received. Any deviations from the 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 11 of 31 
planned treatment regimen (i.e. if any active doses are given) will be described as protocol 
deviations. 
6 Statistical Analysis 
6.1 Baseline Characteristics 
Baseline characteristics will be summarised and listed. 
Baseline characteristics for subjects transferred to open-label treatment at Week 16 will be 
presented by previous treatment and overall.  
Duration of AD in years will be calculated as (age at Week 0) minus (age at onset of AD). 
The table of concomitant medication at baseline will include medication starting before the 
first dose of IMP which does not end before the first dose of IMP. For further details, see 
Section 6.8.3 and Section 6.8.4. 
6.2 Disposition 
Subject disposition will be summarised and listed. 
6.3 Rescue medication 
Rescue medication is defined by the following algorithm: Concomitant medications with 
Dermatitis atopic or Dermatitis infected as the preferred term for the indication and either 
ATC2 code H02 or D07, or ATC4 code D11AH or Preferred name Methotrexate, Ciclosporin, 
Azathioprine, Mycophenolate-mofetil, Mycophenolate-sodium, Mycophenolate-acid or 
Dupilumab. 
According to the protocol investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue treatment. Therefore, if 
rescue medication has start date the same day as an efficacy assessment, then the assumption 
will be that the assessment is not influenced by the rescue medication, see also Section 6.8.4. 
Rescue medication will be summarised separately for the initial and maintenance period. In 
addition, a summary table of rescue medication by type (topical and systemic) and by overall 
group (corticosteroids, immunosuppressants and other) will be made.  
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 12 of 31 
For subjects continuing with maintenance or open-label treatment at Week 16, the table of 
rescue medication during initial treatment period will include rescue medication taken (but 
not necessarily initiated) between the first dose of initial treatment and the first dose of either 
maintenance or open-label treatment. For subjects who do not continue with maintenance or 
open-label treatment, the table of rescue medication during initial treatment period will 
include medications taken after the first dose and before the (nominal) Week 16 visit (or 
before day 7*16=112 after first dose, in case the (nominal) Week 16 visit did not take place).  
The table of rescue medication during the maintenance treatment period will include rescue 
medication taken (but not necessarily initiated) after the first maintenance dose and exclude 
rescue medication initiated during the follow-up period.  
6.4 Compliance 
Compliance will be summarised and listed. 
6.5 Exposure 
The exposure time during the initial, maintenance and open-label periods, respectively, will be 
defined as detailed in Section 6.8.2. Exposure time will be summarised and listed. 
Patient years of exposure (PYE) for a period will be calculated as the difference between the 
start date and time and the end date and time for the period divided by 60x60x24x365.25. 
6.6 Analysis of Efficacy 
Efficacy will be analysed as described in the Clinical Trial Protocol. 
6.6.1 Multiple testing procedure 
To control the overall type 1 error rate, the primary analyses of the primary estimands for the 
primary and secondary endpoints for the initial and maintenance treatment will for the US 
submission follow a dedicated modified confirmatory testing hierarchy as outlined in Panel 1 
below. 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 13 of 31 
Panel 1 Testing procedure for US submission 
Arrows indicate order of testing when superiority is shown for all endpoints within a box. 
DLQI, Dermatology Life Quality Index; EASI75, at least 75% reduction in Eczema Area and Severity Index 
score; IGA, Investigator’s Global Assessment; Q2W, every 2 weeks; Q4W, every 4 weeks. 
IGA 0/1 at Week 16 between tralokinumab and placebo is evaluated at a 5% significance 
level. If the test is significant, EASI75 at Week 16 between tralokinumab and placebo is 
evaluated at a 5% significance level. If the second test is also significant, Pruritus at Week 16 
between tralokinumab and placebo is evaluated at a 5% significance level. 
If all three tests are significant, the significance level (alpha) will be split between the 
analyses of the 2 secondary endpoints at Week 16 and the analyses of the 2 maintenance 
endpoints at Week 52. These groups of tests are tested in parallel with alpha=1% for the 
endpoints at Week 16 and with alpha=4% for the maintenance endpoints at Week 52.  
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 14 of 31 
The evaluations of the 2 secondary endpoints at Week 16 between tralokinumab and placebo 
will use the Holm method (3) for 2 ordered p-values at a 1% significance level to adjust for 
multiplicity. 
The hypotheses for the maintenance treatment endpoints will be tested sequentially in the 
specified order at the 4% significance level. The next hypothesis will only be tested if the 
former was significant.  
If all p-values for the 2 secondary endpoints at Week 16 are significant, then the hypotheses 
for the maintenance treatment endpoints can be evaluated at a 5% significance level. 
Conversely, if all p-values for the maintenance endpoints are significant, then the hypotheses 
for the 2 secondary endpoints at Week 16 can be evaluated at a 5% significance level. 
For non-US submissions, the testing hierarchy defined in the protocol will be applied. 
6.6.2 Primary and secondary binary endpoints 
Sensitivity analysis 2 for the primary estimand (binary endpoints) 
In the sensitivity Analysis 2 for the primary estimand, the protocol specifies that "If subjects 
have withdrawn due to an AE or due to lack of efficacy, they are still considered non-
responders". Such subjects will be identified based on their reason for permanent 
discontinuation of IMP. 
Sensitivity analysis 3 for the primary estimand (binary endpoints) 
A tipping point analysis using multiple imputation (MI) as an additional sensitivity analysis 
(not described in the protocol) for the primary estimand for the primary endpoints (IGA 0/1 
and EASI75) and the secondary binary endpoint (reduction of Pruritus NRS weekly average 
of at least 4 (yes/no); Pruritus NRS ≥ 4) will be done.  
The purpose of the sensitivity analysis is to assess the robustness of results of the primary 
analysis for the primary estimand with respect to the assumption regarding missing Week 16 
data among subjects who did not use any rescue medication. The procedure will be as 
follows: subjects in the tralokinumab arm with missing Week 16 data will per default be 
considered non-responders while missing Week 16 data (i.e. response yes (=1)/ no (=0)) for 
subjects in the placebo arm who did not use rescue medication will be imputed from a 
Bernoulli distribution with parameter p (ranging from 0 to 1). By varying the parameter p, 
different percentages of placebo subjects will be assumed to be responders (deviating from the 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 15 of 31 
default zero (0) percent of the primary estimand). The tipping-point is then found as the value 
of p (in the range from 0 to 1) which changes the conclusion (of the primary analysis) from 
significant to non-significant. 
Based on published data from other placebo-controlled clinical trials conducted in subjects 
with moderate-severe atopic dermatitis2, the response rate for IGA 0/1,  EASI75 and Pruritus 
NRS ≥ 4 at Week 16 among all placebo subjects is low (in the order of 10% for IGA 0/1 and 
Pruritus NRS ≥ 4, and 15% for EASI75, respectively). Thus, a tipping-point value (p) above 
0.1 for IGA 0/1 and Pruritus NRS ≥ 4 and above 0.15 for EASI75, respectively, is not 
considered to be clinically plausible. As indicated above, p=0 corresponds to the primary 
analysis for the primary estimand. The MI procedure will include the following steps for each 
value of p: 

100 copies of the dataset will be generated (seed=11109925) and missing Week 16
data will be imputed for subjects in the placebo arm from a Bernoulli distribution with
parameter p.
For each of the 100 complete data sets, the difference in response rates will be analysed as 
specified for the primary analysis for the primary estimand and the estimates and standard 
errors from the 100 analyses will be combined using Rubin’s rule to form a unique point 
estimate and standard error. 
6.6.3 Continuous secondary endpoints 
Primary analysis of primary estimand (continuous secondary endpoints) 
It is specified in the protocol that the continuous secondary endpoints will be analysed using a 
repeated measurements model on the post baseline responses up to Week 16. Data collected 
after permanent discontinuation of IMP or after initiation of rescue medication will not be 
included in the analysis.  
However, some subjects may not have any post-baseline data collected before initiation of 
rescue medication. To ensure that all subjects are included in the analysis, the baseline value 
will for these subjects be carried forward as the first post-baseline assessment, corresponding 
to imputing a change of 0 at the first post-baseline assessment. 
Tetriary (composite) estimand (continuous secondary endpoints) 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 16 of 31 
For the continuous secondary endpoints (i.e. change in SCORAD and DLQI), an analysis is 
introduced where subjects who received rescue medication are considered non-responders. 
This new analysis aim to estimate the treatment effect for a ‘Composite‘ estimand which is 
currently not pre-specified in the protocol for the continuous secondary endpoints. Thus, a 
new tertiary ‘Composite’ estimand for the continuous secondary endpoints is introduced.  
Primary analysis for the tertiary (composite) estimand (continuous secondary endpoints): Data 
retrieved at Week 16 for subjects who have permanently discontinued IMP prior to Week 16 
will be included in the analysis. Subjects who prior to the Week 16 visit have received rescue 
medication will be considered non-responders by using worst observation carried forward 
(including the baseline value).   
Missing Week 16 data among subjects who did not use rescue medication will be imputed 
using MI (100 copies of the dataset, seed=11109925) assuming missing at random (MAR) 
within arms (based on sequential use of an ANCOVA model for Week 2, 4, 6, .. and 16). For 
subjects who dropout without any use of rescue medication, missing data at subsequent visits 
will be imputed under the assumption that the subject adheres to the randomised treatment 
regimen, i.e. the stepwise imputation model will be estimated based on available data from all 
subjects but excluding individual subject data captured after initiation of rescue medication or 
permanent discontinuation of IMP. For each of the 100 imputed datasets, the continuous 
secondary endpoint will be analysed using an ANCOVA model with effects of treatment, 
region, baseline disease severity (IGA 3 or 4), and baseline value. The estimates and standard 
errors from the 100 analyses will be combined using Rubin’s rule to form a unique point 
estimate and standard error. 
As a sensitivity analysis for the tertiary estimand, a tipping point analysis using MI will be 
performed with the purpose to assess the robustness of results of the primary analysis for the 
tertiary estimand with respect to the MAR assumption regarding missing Week 16 data among 
subjects who did not use any rescue medication.  The tipping analysis will assess how severe 
the departure from the MAR assumption in the tralokinumab arm has to be in order to impact 
the results (i.e. changes the conclusion of primary analysis of the tertiary estimand) from 
significant to non-significant).  
The tipping point analysis will be performed using the MAR imputed Week 16 data from 
primary analysis of the tertiary estimand. For each of the 100 imputed datasets, Δ will be 
added to the imputed values for subjects in the tralokinumab arm (Δ = 0 implies MAR) and 
thereby the imputed values will be ‘shifted’ by Δ. Each of the 100 modified imputed datasets 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 17 of 31 
will then be analysed in the same way as for the primary analysis for the tertiary estimand. 
The tipping-point is then found as the value of Δ which changes the conclusion (of the 
primary analysis) from significant to non-significant and will be judged from a clinical point 
of view.  
The implications of the missing not at random assumptions will be compared to the 
implication of the missing at random assumptions by visual inspection. 
Tetriary (composite) estimand (continuous additional secondary endpoints) 
The two continuous secondary additional endpoints ‘Change from baseline to Week 16 in 
EASI score’ and ‘Change from baseline to Week 16 in Worst Daily Pruritus NRS (weekly 
average)’ will be analysed as described for the two continuous secondary endpoints above, 
including the tipping point sensitivity analysis. 
6.6.4 Multiple imputation 
For the analysis of the primary and secondary endpoints, multiple imputation will be carried 
out as specified in the protocol, using SAS PROC MI. For multiple imputations related to the 
treatment policy estimand and the hypothetical estimand sensitivity analyses, the seed 
11109925 will be used. The remaining seeds are specified in the protocol. 
When performing mulitiple 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 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 18 of 31 
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) 
6.6.5 Secondary and other efficacy analysis 
Reduction of Worst Daily Pruritus NRS weekly average of at least 4 
The analyses will be based on subjects in the FAS with a baseline Pruritus NRS weekly 
average of at least 4. 
The binary endpoint was to be analysed as described for the primary endpoint EASI75 using 
all three estimands. It is however expected that subjects will not fill in the eDiary when they 
have discontinued treatment, and it is considered likely, there will be no nominal Week 16 
data available for discontinued subjects. If this is the case, the primary analysis of the tertiary 
estimand will not be estimated for this endpoint. The corresponding sensitivity analysis for 
the tertiary estimand, analysing subjects with missing Week 16 data as non-responders, while 
otherwise using observed data for the remaining subjects, will still be conducted. 
Calculation of Weekly average of pruritus NRS 
The weekly average will only be calculated if at least 4 assessment are available. When 
calculating the baseline value for the weekly average of Worst Daily Pruritus, the daily 
assessments in the 7 days preceding the randomisation will be used, including the day of 
randomisation. 
For the initial treatment period, the NRS weekly average for Week 1 will be calculated based 
on scores recorded on day 1 to day 7 (where day 0 is the day of the first dose). Similarly, for 
Weeks 2 to Week 15, the weekly average for Week x will be calculated based on scores 
recorded on day 7*x-6 to day 7*x (where day 0 is the day of first dose). To account for the 
actual day maintenance or open-label treatment is initiated, the Week 16 weekly average will 
instead be based on the last 7 days before (and including) the day of the Week 16 visit, thus 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 19 of 31 
ensuring that the Week 16 weekly average is based on data from the initial treatment phase 
only, and also ensuring alignment in timing with other Week 16 efficacy endpoints. Also, for 
the calculation of Week 1 to Week 15 weekly averages, any scores recorded after the Week 16 
visit date will be disregarded (only relevant if Week 16 visit is out of window). 
For Week 17 of the maintenance treatment period, the weekly average will be based on the 
first 7 days after (not including) the Week 16 visit. For Week 18 to Week 52 of the 
maintenance treatment period, the weekly average for Week x will be calculated based on 
scores recorded on day 7*x-6 to day 7*x (where day 0 is the day of the first dose). Any scores 
recorded after initiation of open-label treatment will be disregarded.  
PGI-B and PGI-S 
For the PGI-B and PGI-S, which are not numerical, the worst score recorded during the week 
will be presented instead of weekly averages. The worst score will be derived if at least one 
measurement is available for the week in question. The same rules regarding visit windowing 
apply as for weekly average pruritus NRS described above. The daily scores will be presented 
graphically.  
Percentage change in EASI score, initial treatment period 
In addition to the repeated measurements analysis of absolute reduction in EASI score during 
the initial treatment period which was planned in the protocol, the same analysis will be 
conducted for the percentage change from baseline in EASI scores during the initial treatment 
period. 
Subgroup analyses 
To access the consistency in response rate across subgroup the following subgroup analyses 
will be performed for the primary estimand: 

IGA 0/1 by baseline IGA

IGA 0/1 by region

EASI75 by baseline IGA

EASI75 by region
Efficacy analyses open-label period 
For the open-label treatment period IGA, EASI75, EASI and SCORAD will be summarised 
by visit and initial treatment for subjects who transferred to open-label treatment at Week 16, 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 20 of 31 
and by week since transfer to open-label and at Week 52, by previous maintenance treatment 
for subjects who transferred to open-label treatment after Week 16. IGA, EASI and SCORAD 
for subject who transferred to open-label treatment at Week 16 and IGA for subject who 
transferred to open-label treatment after Week 16 will be presented in figures. 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 21 of 31 
Scoring of PROs 
POEM 
Scored according to: 
https://www.nottingham.ac.uk/research/groups/cebd/documents/methodological-
resources/poem-for-self-completion.pdf 
DLQI 
Scored according to: 
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-
index-dlqi/dlqi-instructions-for-use-and-scoring/ 
EQ-5D-
5L 
Index values calculated according to: 
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-
sets/crosswalk-index-value-calculator/ 
The UK value sets will be used. 
HADS 
The HADS consists of 14 items, 7 of which are related to anxiety and 7 related 
to depression. The maximum score is 21 for each subscale (anxiety and 
depression).  
If one question is missing within a subscale, the response to that question will 
be imputed as the mean of the remaining questions in that subscale. If more than 
one question is missing within a subscale, the subscale is considered missing.  
SF-36 
Scored by QualityMetric Health Outcomes(tm) Scoring Software 5.0 Q provided 
with license.  
WPAI-
GH 
Scored according to: 
http://www.reillyassociates.net/WPAI_Scoring.html 
TSQM 
v.II
Scored according to User Manual for the Treatment Satisfaction Questionnaire 
for Medication (TSQM) 1.0 provided with license.  
PROs in the open-label period 
By mistake PROs are reported in some instances for subjects in the open-label period. These 
data will be presented in listings only. 
Missing baseline assessments 
When the baseline value is missing, endpoints concerning a change from baseline will not 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.  
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 22 of 31 
6.7 Analysis of Safety 
6.7.1 Adverse Events 
Adverse events will be summarised and listed. 
Assignment of AEs to periods 
An adverse event will be assigned to a given period (initial, maintenance, open-label or 
follow-up) if the start date is after the start date and before the end date of that period (see 
Section 6.8.2, Table 4). 
For AEs with start day on the same day as the first dose was given, only AEs starting after the 
first dose was given will be considered treatment emergent and assigned to the initial 
treatment period.  
AEs with start date on the same day as the first dose of maintenance treatment will be 
assigned to the initial or maintenance period depending on whether the AE started before or 
after the dose was given. 
AEs with start date on the same day as the first dose of open-label treatment will be assigned 
to the previous treatment period (can be initial or maintenance) or assigned to the open-label 
period depending on whether the AE started before or after the dose was given.  
AEs starting on the day of exposure end (as defined in Section 6.8.2) will be assigned to the 
last treatment period. 
For handling of incomplete start dates of adverse events, see Section 6.8.3. 
Sort order of AE tables 
Generally, AE tables by system organ class and/or preferred term will be sorted by decreasing 
number of affected subjects: 

For the initial treatment period, AE tables will be sorted by decreasing number of affected
subjects in the Tralokinumab Q2W group.

For the maintenance treatment period, AE tables will be sorted by decreasing total number
of affected subjects in the Tralokinumab treatment groups (sum of Q2W and Q4W).

For the entire treatment period, AE tables will be sorted by decreasing number of affected
subjects in the “Tralokinumab total” group.
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 23 of 31 

For the follow-up period, AE tables will be sorted by decreasing total number of affected
subjects in the Tralokinumab treatment groups (sum of Q2W, Q4W and Q2W+optional
TCS).
6.7.2 Vital signs 
Vital signs will be summarised and listed. 
For the summary tables of vital signs by visit, the last pre-dose vital sign assessment will be 
presented. If no dosing occurs at a visit, the last assessment recorded at the visit will be 
presented. For the first 3 IMP dosing visits in both the initial and open-label treatment period, 
subjects will be monitored after IMP administration for immediate drug reactions for a 
minimum of 2 hours with vital signs taken every 30 minutes or until stable, these 
measurements will only be listed. 
6.7.3 ECG 
ECG data will be summarised and listed. The overall central evaluation of ECG will be 
presented using shift tables. 
6.7.4 Laboratory Data 
Laboratory data will be summarised and listed. 
For the laboratory values, if the value is below the lower limit of quantification, half of the 
lower limit will be used for quantitative summaries. If the value if above the upper limit of 
quantification, the upper limit value will be used. 
If more than one laboratory value is reported for the same visit, the latest value will be used in 
summary statistics and analyses. 
Potentially clinically significant values will be defined as displayed in Table 2. 
Table 2: Potentially clinically significant biochemistry and haematology values 
Protocol Lab parameter SI Unit 
PCS low 
PCS High 
Biochemistry 
Sodium 
mmol/L < 129 mmol/L, 
< 125 mmol/L 
> 160 mmol/L
Potassium 
mmol/L < 3 mmol/L, 
< 2.5 mmol/L 
> 6.5 mmol/L,
> 7.5 mmol/L
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 24 of 31 
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 x 109/L, 
< 0.5 x 109/L 
> 5.0 x 109/L
Monocytes, absolute count 109/L 
< 0.1 x 109/L 
> 0.8 x 109/L
Eosinophils, absolute 
count 
109/L 
N/A 
> 1.5, > 5.0
Basophils, absolute count 
109/L 
N/A 
> 0.2
Thrombocytes 
109/L 
< 100 x 109/L, 
< 30 x 109/L,  
< 10 x 109/L 
> 450 x 109/L
PCS: potentially clinically significant; ULN: Upper limit of normal, i.e. upper limit of normal 
reference range. 
6.7.5 Urinalysis 
Urinalysis data will be summarised and listed. 
Potentially clinically significant values will be defined as displayed in Table 3. 
Table 3 Potentially clinically significant urinalysis values 
Protocol lab parameter 
(ACM lab parameter) 
SI Unit 
PCS low 
PCS High 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 25 of 31 
Erythrocytes 
/HPF 
N/A 
> 3, >10, >25, >30
Leucocytes 
/HPF 
N/A 
> 10
Casts (Hyaline casts) 
/LPF 
N/A 
> 2
Casts (WBC casts) 
/LPF 
N/A 
Few, Moderate, Many 
Casts (RBC casts) 
/LPF 
N/A 
Few, Moderate, Many 
Casts (Waxy casts) 
/LPF 
N/A 
Few, Moderate, Many 
Casts (Granular casts) 
/LPF 
N/A 
Few, Moderate, Many 
PCS: potentially clinically significant; HPF: high power field; LPF: low power field; ULN: 
Upper limit of normal, i.e. upper limit of normal reference range. 
6.7.6 Staphylococcus aureus 
Staphylococcus aureus colonization based on skin swab samples will be summarised and 
listed. 
6.7.7 Pharmacokinetics and anti-drug antibodies 
Pharmacokinetics and anti-drug antibodies data will be summarised and listed. 
6.7.8 Biomarkers 
The small panel biomarkers; periostin, DPP4, hBD2, TARC, IL-13, IL-17, IL-22, and IgE will 
be summarized and listed. Other potential biomarkers from the small panel will be presented 
in a separate report.  
As described in the protocol the large panel biomarkers will be presented in a separate report. 
6.7.9 Biopsy biomarkers 
Skin biopsies will be taken at selected trial sites. 
The Histology/immunohistochemistry markers; epidermal thickness, FLG, CD3, CD1a, and 
CD11c and gene expression analysis; IFN, IL-13, CCL17, CCL22, IL-17A, IL-22, S100A12, 
and LOR will be summarised and listed. All other skin biopsy markers will be presented in a 
separate report. 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 26 of 31 
6.8 General Principles 
6.8.1 Baseline value 
Unless otherwise specified, the baseline value is defined as the latest pre-dose assessment. 
6.8.2 Definition of trial periods and date of permanent discontinuation of 
IMP 
Date of permanent discontination of IMP 
Defined for subjects who have a reason for permanent discontinuation of IMP recorded. 
Defined as date of early termination visit (if existing), otherwise date of the last visit, 
excluding safety follow-up and nominal Week 16 visit.  
Exposure start  
Date and time of first dose. 
Exposure end (subjects not enrolled in short term extension) 
Date of Week 52 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. 
Exposure end (subjects enrolled in short term extension) 
Date of Week 68 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. 
At DBL 1 all data up to and including LSLV, April 11, 2019 is included. For subjects ongoing 
at DBL 1 (i.e. subjects ongoing in short term extension), exposure end will be set to date of 
data cut-off April 11, 2019. 
Trial periods 
The time from exposure start to exposure end will be divided into initial period, maintenance 
period and open-label period, and remaining time after exposure end will be assigned to the 
follow-up period as shown in Table 4 (ADaM variable APHASE). The ADaM variable 
APERIODC will indicate the latest treatment (initial, maintenance or open-label) at any given 
time point, thus not including a follow-up period (Table 5).  
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 27 of 31 
Table 4: Start and end time of trial periods (ADaM variable APHASE). 
APHASE 
Start of period 
End of period (only if start date exists) 
Initial 
period 
Exposure start 
Date and time (minus 1 second) of first maintenance 
dose (if existing) 
else 
Date and time (minus 1 second) of first open-label dose 
(if existing)  
else 
Exposure end  
Maintenance 
period 
Date and time of 
first maintenance 
dose (if existing) 
Date and time (minus 1 second) of first open-label dose 
(if existing)  
else  
Exposure end  
Open-label 
period 
Date and time of 
first open-label 
dose (if existing) 
Exposure end 
Follow-up 
period1
Exposure end 
(plus 1 second) 
Date of safety follow-up visit (if existing) at time 
23:59:00 
else 
Date of last contact at time 23:59:00 
1) Only applicable if date of last contact is not equal to date of exposure end.
Table 5: Start and end time of trial periods (ADaM variable APERIODC). 
APERIODC Start of period 
End of period (only if start date exists) 
Initial period 
Exposure start 
Date and time (minus 1 second) of first maintenance 
dose (if existing) 
else 
Date and time (minus 1 second) of first open-label dose 
(if existing)  
else 
Date of last contact at time 23:59:00  
Maintenance 
period 
Date and time of 
first maintenance 
dose (if existing) 
Date and time (minus 1 second) of first open-label dose 
(if existing)  
else  
Date of last contact at time 23:59:00  
Open-label 
period 
Date and time of 
first open-label 
dose (if existing) 
Date of last contact at time 23:59:00 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 28 of 31 
6.8.3 Incomplete recordings 
Adverse events 
If the AE start day is missing, but AE start month and year are not missing, the following rules 
apply: 

If the year and month of the AE start is before the year and month of the exposure
start, or if the AE end date is complete and before the exposure start, the AE will not
be considered treatment emergent.

If the year and month of the AE start is the same as the year and month of the
exposure start, the AE will be considered treatment emergent and assigned to the
initial treatment period, unless the AE has a complete end date which is before
exposure start.

If the year and month of the AE start is after the year and month of exposure start, it
will be assumed that the AE started on the first day of the month and the AE will be
assigned to the initial, maintenance, open-label or follow-up period accordingly.
If the AE start month is missing, but AE start year is not missing, the following rules apply: 

If the year of the AE start is before the year of the exposure start, or if the AE end
month is not missing and before the month of the exposure start, or if the AE has a
complete end date which is before the exposure start date, the AE will not be
considered treatment emergent.

If the year of the AE start is the same as the year of the exposure start, the AE will be
considered treatment emergent and assigned to the initial treatment period, unless the
AE end month is not missing and before the month of the exposure start or the AE has
a complete end date which is before the exposure start date.

If the year of the AE start is after the year of exposure start, it will be assumed that the
AE started on the 01 January and the AE will be assigned to the initial, maintenance,
open-label or follow-up period accordingly.
Concomitant medication 
For incomplete start dates of concomitant medication, the following rules apply: 

If a medication start day is missing, but start month and year is not missing, it will be
assumed that the start day is the first day of the month. If the medication start day and
month is missing, but start year is not missing, it will be assumed that the start day is
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 29 of 31 
01 January. If the medication start day, month and year is missing, it will be assumed 
that the medication was started before study 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 is not missing, it will be
assumed that the end day is the last day of the month. If the medication end day and
month is missing, but end year is not missing, it will be assumed that the end day was
31 December. If the medication end day, month and year is missing, it will be assumed
that the medication was ongoing at the end of the study, and the date will appear as
missing in the data.
6.8.4 Conventions regarding time of day for efficacy assessments and 
concomitant medication 
Efficacy assessments 
For the purpose of assigning trial periods to efficacy assessments, the convention will be that 
efficacy assessments are performed at time 00:00:00 in the morning. As a consequence, 
efficacy assessments performed on the day of transfer between two periods will be assigned to 
the first of the two periods.  
Concomitant medication 
For the purpose of associating concomitant medication with trial periods, the convention will 
be that the start time of day of concomitant medications is 23:59:59, and end time is 00:00:00, 
unless the start day is equal to the end day in which case both start and end time will be 
assumed to be 23:59:59. As a consequence, rescue medication starting on the day of transfer 
between two periods will be associated with the latter period only, and rescue medication 
ending on the day of transfer between two periods will be associated with the first period only 
(unless the start day is equal to the end day).  
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. 
TMF-000040709 - Version
1. 0


Trial ID: LP0162-1325 
Date: 20-May-2019 
Version: 1.0 
Page 30 of 31 
6.8.5 Treatment Completers 
A subject who has not permanently discontinued IMP before Week 52 will be defined as a 
treatment completer. 
6.8.6 Early termination and unscheduled visits 
When no data is available from a certain scheduled post-baseline visit for a particular subject, 
data from early termination visits and unscheduled visits have the potential to replace data 
from that particular scheduled visit in data summaries, provided the data is collected between 
6 days before and 7 days after the planned time point for the scheduled visit, as displayed 
below.  
Visit (Target day) 
Visit window (Day is date of assessment 
minus date of first dose) 
Week 2 (Day 14) 
Day 8 to 21 
Week x (Day 7*x) (where x= 4, 6, ..., 52) 
Day 7*x-6 to 7*x+7 
Week x (Day 7*x) (where x=54, 56, ..., 68) 
(only applicable for subjects enrolled in 
short-term extension) 
Day 7*x-6 to 7*x+7 
Safety follow-up 
106-119 days after last dose
When both unscheduled and early termination visits exist within the given visit window, the 
early termination visit will be selected for analysis. When no early termination visits and 
several unscheduled visits exist, the unscheduled visit closest to the target day will be selected 
for analysis. If the difference is a tie, the latest unscheduled visit will be selected. 
6.8.7 Handling of Drop-outs and Missing Values 
Missing values will be handled as described in the Clinical Trial Protocol. 
Week 16 LOCF 
As specified in the protocol, a sensitivity analysis of the primary endpoint will impute Week 
16 missing values using LOCF. The LOCF value will be defined as the last assessment 
obtained up to and including day 7*16+7=119 after the first dose, i.e. the last assessment 
before or within the window for mapping an early termination visit to Week 16.  
TMF-000040709 - Version
1. 0




Signature Page for TMF-000040709 v1.0
Electronic signatures made within eTMF LEO are considered to be a
legally binding equivalent of traditional handwritten signatures.
Reason for signing: Approved
QC App
Name: 
Capacit
Date of signature: 20-May-2019 09:58:31
GMT+0000
Reason for signing: Approved
Manage
ver Verdict(s)
Name: 
Capacit
Date of signature: 20-May-2019 11:09:02
GMT+0000
Reason for signing: Approved
Manage
Verdict(s)
Name: 
Capacit
Date of signature: 20-May-2019 11:25:21
GMT+0000
TMF-000040709 - Version
1. 0
PPD
PPD
PPD