LEO 90100 Twice Weekly Maintenance Regimen for Psoriasis Vulgaris
Phase: PHASE3
Conditions: Psoriasis Vulgaris
Sponsor: LEO Pharma

Cover Page 
Official title: A phase 3 trial comparing the efficacy and safety of LEO 90100 aerosol foam with the aerosol foam vehicle used 
twice weekly as long-term maintenance therapy in subjects with psoriasis vulgaris. 
LEO Pharma number: LP0053-1004 
NCT number: NCT02899962 
Date: 12-Apr-2018 

Clinical Trial Protocol 
LEO 90100 twice weekly maintenance regimen for psoriasis vulgaris 
A phase 3 trial comparing the efficacy and safety of LEO 90100 aerosol foam with the 
aerosol foam vehicle used twice weekly as long-term maintenance therapy in subjects with 
psoriasis vulgaris. 
A 12-month, international, multi-centre, randomised, vehicle controlled, double-blind, 2-arm, 
parallel group trial. 
ICH GCP statement:  The clinical trial will be conducted in compliance with the clinical 
trial protocol, GCP and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
LP0053-1004 
EudraCT no 
2016-000556-95 
Date: 
12-Apr-2018
Version: 
7.0 
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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 
Medical Lead, Medical Sciences and Safety 
, MSc Pharm 
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: 
Mark Lebwohl, MD 
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.  
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Protocol amendment summary of changes table 
Document history 
Document 
Protocol version 
Protocol date 
Date of errata 
sheet 
Amendment 6 (non-substantial) 
7.0 
12-Apr-2018 
NA1 
Amendment 5 (non-substantial) 
6.0 
22-Aug-2017 
25-Aug-2017 
Amendment 4 (non-substantial) 
5.0 
05-Jul-2017 
05-Jul-2017 
Amendment 3 (substantial) 
4.0 
14-Dec-2016 
22-Dec-2016 
Amendment 2 (non-substantial) 
3.0 
07-Sep-2016 
07-Sep-2016 
Amendment 1 (substantial) 
2.0 
19-Aug-2016 
22-Sep-2016 
Original protocol 
1.0 
14-Apr-2016 
NA 
1)
According to new company procedures, separate protocol errata sheets are no longer produced. When a
protocol is updated, changes since previous version are listed in a protocol summary of changes table
located directly before the table of contents.
NA, not applicable. 
Protocol amendment summary of changes tables for previous amendments (that is, no. 1 to 5) 
are provided in Appendix 12. 
Amendment 6 (12-Apr-2018) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (38) because it neither significantly impacts the safety or physical/mental 
integrity of subjects nor the scientific value of the trial.  
Overall rationale for the amendment 
The protocol was updated to clarify how to handle subjects who experience a worsening of 
psoriasis during the follow-up phase.  
Note: The table below describes the changes in each section. Changes have either been 
summarised (written with plain text only) or marked as tracked changes (text added to the 
protocol is written in bold and deleted text has a line through it). 
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Section number 
and name 
Description of change 
Brief rationale 
Section 3.3.3 
Rationale for trial 
design 
Section 6.1.1 
Overview 
Section 6.1.3 
Initial open-label 
treatment phase 
Appendix 1 
Protocol summary 
The trial will include a screening phase of 
up to 4 weeks, an open-label treatment 
phase of 4 weeks, a randomised double-
blind maintenance phase of up to 52 
weeks, and a follow-up phase of up to 8 
weeks. 
This trial is a multi-centre, prospective 
trial, consisting of an initial open-label 
treatment phase of 4 weeks followed by a 
randomised, double-blind, vehicle-
controlled, maintenance phase of up to 52 
weeks in subjects with psoriasis vulgaris. 
Subjects who achieve treatment success 
(PGA score of ‘clear’ or ‘almost clear’ 
with at least a 2-grade improvement from 
baseline) at Visit 2 will be randomised in a 
ratio of 1:1 in a double-blind fashion to 
either LEO 90100 or vehicle (maintenance 
IP) twice weekly for up to 52 weeks.   
Methodology: (…) maintenance phase of 
up to 52 weeks in subjects with psoriasis 
vulgaris, and an 8-week follow-up period. 
Duration of treatment: (…) A maintenance 
phase: randomised treatment (LEO 90100 
or vehicle) twice weekly for up to 52 
weeks 
Clarification that the maintenance 
phase has a duration of 52 weeks 
and that the follow-up phase has a 
duration of 8 weeks. 
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Section number 
and name 
Description of change 
Brief rationale 
Section 3.3.3 
Rationale for trial 
design 
Section 12.1 
Adjudication 
Committee 
The investigators will record all adverse 
events (AEs), and an independent 
adjudication panel of dermatologists 2 
dermatologists and one endocrinologist 
will review all treatment-emergent AEs 
(blinded data) to identify adverse drug 
reactions of concern associated with long-
term topical corticosteroid use. 
A panel of three 2 dermatologists and one 
endocrinologist (“Adjudication Panel”) 
will review all reported treatment-
emergent AEs to identify AEs of concern 
associated with long-term use of topical 
corticosteroids where a causal relationship 
between the trial medication and the event 
is at least a reasonable possibility. 
The Adjudication Panel will not review 
AEs which occurred prior to 
application of the first dose of IP; this 
includes AEs reported by screening 
failures (who per definition did not start 
open-label treatment). 
Since side effects from steroids 
may also be endocrine-related, it 
was decided to include an 
endocrinologist in the adjudication 
committee. 
It has been specified that the 
Adjudication Panel will only 
review treatment-emergent AEs. 
Section 3.3.3 
Rationale for trial 
design 
Section 8.12.1 
Safety laboratory 
blood analysis  
Therefore, adrenal function testing will be 
undertaken in a subset of approximately 
30 randomised subjects with at least 
moderate psoriasis affecting at least 10% 
between 10 and 30% of the BSA. The 
aim is to achieve approximately 25 
subjects undergoing HPA axis testing 
after 52 weeks of exposure.  
Adrenal function testing will be 
undertaken in a subset of approximately 
30 randomised subjects with psoriasis 
affecting more than 10% between 10 and 
30% of the BSA. The aim is to include 
25 subjects undergoing HPA axis 
testing after 52 weeks of exposure. This 
means that up to 60 subjects fullfilling the 
inclusion/exclusion criteria for this part of 
the trial may need to be enrolled and 
ACTH-tested at Visit 1 and Visit 2. 
The number of randomised subjects 
may need to be adjusted to achieve 
the required exposure data. This 
will depend on the actual drop-out 
rate in the trial. 
It has been specified that subjects 
undergoing HPA axis testing 
should have psoriasis affecting 
between 10 and 30% of the BSA in 
agreement with inclusion criterion 
no. 12. 
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Section number 
and name 
Description of change 
Brief rationale 
Section 5.3 
Safety assessments 
Section 11.3.8 
General principles 
Effect on HPA axis (in a subset of subjects 
with disease involvement >10% BSA of 
between 10 and 30% of BSA), based on 
serum cortisol ≤18 mcg/dL 30 minutes 
after cosyntropin injection at Week 4, 
Week 28, and end of trial (Week 56) or 
early withdrawal. 
Furthermore, the inclusion criteria for 
participating in the HPA axis test are 
either “Moderate” or “Severe” in the 
baseline PGA assessment or and a 
baseline BSA of at least 10% between 10 
and 30%.  
It has been specified that subjects 
undergoing HPA axis testing 
should have psoriasis affecting 
between 10 and 30% of the BSA in 
agreement with inclusion criterion 
no. 12. 
Section 6.1.5 
Follow-up phase 
(FU2) 
For subjects undergoing the 
adrenocorticotropic hormone (ACTH) 
challenge test, a follow-up visit (Visit 
FU2) will take place 28 days after the 
ACTH challenge test performed at the end 
of treatment (Visit 15/Early Withdrawal) 
if this the end of treatment test showsed 
a serum cortisol concentration ≤18 mcg/dl 
at both 30 minutes and 60 minutes after 
ACTH challenge (39, 40).  
If the results of the ACTH challenge test 
at Visit FU2 continue to show a serum 
cortisol concentration ≤18mcg/dl at both 
30 minutes and 60 minutes after ACTH 
challenge, further ACTH challenge tests 
should be performed, but not more often 
than at 4-weekly intervals, until the 
adrenal suppression resolves (i.e. serum 
cortisol concentration >18mcg/dl at 
30 minutes or at 60 minutes after the 
ACTH-challenge, or at both time 
points).  
Refer to Section 8.12.1 for further 
details on the ACTH challenge test. 
To avoid overdiagnosing adrenal 
insufficiency, only subjects with 
abnormal results at both timepoints 
after ACTH challenge (30 minutes 
and 60 minutes) will need to come 
back to the trial site for additional 
ACTH challenge tests. 
Section 6.1.5 
Follow-up phase 
(FU3) 
It has been clarified when the 8-week 
follow-up phase will start.  
It has been specified how subjects who 
experience a worsening of their psoriasis 
during the follow-up phase should be 
handled. 
Clarification that subjects who 
leave the trial after the initial 
treatment period will also need to 
be followed-up for 8 weeks (in 
agreement with the definition of 
rebound [section 11.3.6.2]). 
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Section number 
and name 
Description of change 
Brief rationale 
Section 6.2 
Sample size 
Section 16.1 
Trial Completion 
Procedures 
A total of 380 subjects should be 
randomised in the trial in order to have 
power for the primary maintenance 
treatment objective. In order to achieve 
380 randomised subjects it is estimated 
that 832 subjects should be included in the 
trial.  
The total number of subjects treated in 
the trial should also be sufficient to 
comply with ICH E1 regarding long 
term safety. The aim is to achieve at 
least 300 subjects with 26 weeks of 
exposure and at least 100 subjects with 
52 weeks of exposure. 
For the HPA axis test, up to 60 subjects 
(with BSA over 10%) may need to be 
enrolled to achieve approximately 30 
randomised subjects at Visit 2 the aim is 
to achieve approximately 25 subjects 
undergoing HPA axis testing after 
52 weeks of exposure. 
If among the 380 randomised subjects 
there are less than 30 subjects undergoing 
HPA axis testing then the recruitment of 
subjects for the HPA axis testing will 
continue until approximately 30 subjects 
have been randomised for the HPA axis 
testing. The total number of randomised 
subjects can exceed 380 in order to 
achieve a sufficient number of subjects 
for long-term evaluation of safety and 
HPA testing. 
This will also include information on 
when the threshold of 20% of subjects 
with a ‘mild’ PGA is reached, and when a 
sufficient number of subjects (30 
randomised approximately 25 subjects 
with 52 weeks of exposure) have been 
included in the HPA axis part of the trial. 
The number of randomised subjects 
may need to be adjusted to achieve 
the required exposure data. This 
will depend on the actual drop-out 
rate in the trial. 
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Section number 
and name 
Description of change 
Brief rationale 
Section 6.3 
Randomisation 
The maximum number of subjects to be 
enrolled with ‘mild’ disease according to 
the PGA is capped at 20% to ensure 
similar distribution of disease severity at 
baseline as in previous LEO 90100 short-
term trials and hence similar trial 
population. 
This paragraph has been re-worded 
and moved to section 10.6; the cap 
of 20% of mild subjects refers to 
the population who will be treated 
with open-label IP, not the 
randomised subject population 
(who have already been exposed to 
4 weeks open-label treatment). 
Section 7.8.3 
Restrictions during 
the trial – 
follow-up period 
Note that treatment with Enstilar® or 
IP is not allowed during the follow-up 
period (Section 6.1.5).  
Otherwise, there are no restrictions on the 
use of concomitant treatment during the 
follow-up period. 
Specification that use of Enstilar® 
or IP is not allowed during the 
follow-up period. 
This sentence was deleted since 
restrictions may apply to subjects 
who are in follow-up due to 
abnormal ACTH test results. 
Section 8.1 
Schedule of trial 
procedures 
Clarification that the FU3 visit will occur 
8 weeks after end of treatment or early 
withdrawal. 
A visit window (±4 days) for the FU3 visit 
has been included. 
In the previous version of the 
protocol, the FU3 visit and any 
unscheduled visits during the 
follow-up phase were all described 
as FU3. A clear distinction has 
been made between FU3 and 
unscheduled follow-up visit. 
It has been specified that concomitant 
medications and concomitant procedures 
should be recorded at the FU3 visit. 
To monitor use of any medication 
up to the FU3 visit. 
An unscheduled follow-up visit has been 
included. 
To clarify how to handle subjects 
who experience a worsening of 
psoriasis during the follow-up 
phase.  
Footnote no. 19 updated to specify that 
FU2 visit is only required if 
end-of-treatment serum cortisol 
concentration is ≤18 mcg/dl at both 
30 minutes and 60 minutes after ACTH 
challenge test. 
To avoid overdiagnosing adrenal 
insufficiency, only subjects with 
abnormal results at both timepoints 
after ACTH challenge (30 minutes 
and 60 minutes) will need to come 
back to the trial site for additional 
ACTH challenge tests. 
Footnotes no. 21 and 22 have been 
updated to reflect the difference between 
an unscheduled follow-up visit and the 
FU3 visit. 
To clarify how to handle subjects 
who experience a worsening of 
psoriasis during the follow-up 
phase. 
23) After end of treatment visit (Visit 15
or Early Withdrawal) only events of
rebound are routinely collected.
Footnote deleted since all AEs, 
including rebound events, will be 
collected during the whole trial up 
to the FU3 visit. 
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Section number 
and name 
Description of change 
Brief rationale 
23) Subjects with a serum cortisol
concentration ≤18mcg/dl at both 30
minutes and 60 minutes after ACTH
challenge at FU2 will be followed up
until the adrenal suppression resolves.
Further ACTH challenge tests must be
captured in the UNS FU page in the
eCRF.
Footnote added to remind 
investigators about the criteria for 
further follow-up of ACTH 
subjects. The footnote also 
describes where such follow-up 
information should be recorded in 
the eCRF. 
24) If the subject withdraws prior to
completing the initial open-label 
treatment phase, the ACTH-challenge 
should not be performed.  
Footnote added for clarification in 
agreement with Section 8.12.1.  
25) Only required if last FU3 is
performed at the trial site 
Footnote added to clarify that 
certain investigator assessments at 
FU3 are only required if the visit is 
performed at the trial site. 
Section 8.12.1 
Safety laboratory 
blood analysis 
If the result of the ACTH challenge test at 
Visit 15 (end of maintenance phase), or at 
early withdrawal) shows a serum cortisol 
concentration ≤18 mcg/dl at both 
30 minutes and 60 minutes after the 
ACTH challenge, a further ACTH 
challenge test is required 4 weeks later 
(FU2 visit). 
If the results of the ACTH-challenge test 
at this visit the FU2 visit continue to show 
a serum cortisol concentration ≤18mcg/dl 
at both 30 minutes and 60 minutes after 
ACTH challenge, further ACTH challenge 
tests should be performed, but not more 
often than at 4-weekly intervals, until the 
adrenal suppression resolves (i.e. serum 
cortisol concentration >18mcg/dl at 
30 minutes or at 60 minutes after the 
ACTH challenge, or at both time points). 
The data from such further ACTH 
challenge tests must be captured in the 
unscheduled follow-up visit page in the 
eCRF. 
To avoid overdiagnosing adrenal 
insufficiency, only subjects with 
abnormal results at both timepoints 
after ACTH challenge (30 minutes 
and 60 minutes) will need to come 
back to the trial site for additional 
ACTH challenge tests. 
It has been specified where to 
capture data from further ACTH 
challenge tests. 
Section 8.12.1 
Safety laboratory 
blood analysis 
After this Within 10 minutes after blood 
sampling, CORTROSYN® / Synacthen®  
is will be injected, as described in section 
10.9.  
A time window for the injection of 
CORTROSYN® / Synacthen® has 
been specified to clarify the 
procedure.  
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Section number 
and name 
Description of change 
Brief rationale 
Section 9.1 
Collection of 
adverse events 
AEs, including events of rebound,  must 
be collected from time of first trial-related 
activity after the subject has signed the 
informed consent form until the end of 
treatment FU3 visit. Events of rebound 
will be collected during the follow up 
period to end of trial. Refer to section 
11.3.6. 2  for a definition of rebound. 
To clarify that rebound events will 
be collected during the whole trial 
up to the FU3 visit. 
Section 9.5 
Follow-up for 
Final Outcome of 
Adverse Events 
Once a subject has completed the 
treatment phases of the trial FU3 visit, 
AEs classified as possibly or probably 
related to the IPs should be followed for 
14 days or until the final outcome is 
determined, whichever comes first.  
To clarify that related AEs will be 
followed up from the FU3 visit 
rather than from end of treatment. 
Section 10.6 
Treatment 
assignment 
A cap on the number of subjects with 
‘mild’ disease according to the PGA is set 
at 20%. The maximum number of 
subjects to be included in the open-label 
phase with ‘mild’ disease according to 
the PGA at baseline (visit 1) is capped 
at 20% to ensure similar distribution of 
disease severity at baseline as in 
previous LEO 90100 short-term trials 
and hence similar trial population. 
Clarification that the cap of 20% of 
mild subjects refers to the baseline 
population who will be treated with 
open-label IP, not the randomised 
subject population (who have 
already been exposed to 4 weeks 
open-label treatment). 
10.9.1 
CORTROSYN® 
and Synacthen® 
Table 15: 
Ampoules: 10 times 1 ml 1 ml ampoules 
Pack size corrected. 
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Section number 
and name 
Description of change 
Brief rationale 
Section 11.1 
Determination of 
sample size 
Recruitment will be stopped when 380 
subjects are randomised. However, if 
among the 380 randomised subjects there 
are less than 30 subjects undergoing HPA 
axis testing then the recruitment of 
subjects for the HPA axis testing will 
continue until approximately 30 subjects 
have been randomised for the HPA axis 
testing. The total number of randomised 
subjects can exceed 380. 
For the HPA axis testing, the aim is to 
achieve approximately 25 subjects 
undergoing HPA axis testing after 
52 weeks of exposure. 
The total number of subjects treated in 
the trial should also be sufficient to 
comply with ICH E1 regarding long 
term safety. The aim is to achieve at 
least 300 subjects with 26 weeks of 
exposure and at least 100 subjects with 
52 weeks of exposure. 
All randomised subjects have been 
exposed for 4 weeks during the open-label 
treatment phase. During the maintenance 
phase with 380 randomised subjects, 
assuming an exponential decline and a 
drop-out rate of 30% over 52 weeks, we 
can expect to have 326 subjects exposed 
for 22 weeks and 273 subjects exposed for 
48 weeks. This means that we will have 
326 subjects exposed for a total of 
26 weeks, and 273 subjects exposed for a 
total of 52 weeks. 
If the actual drop out rate is higher 
than the assumed drop out rate of 30%, 
more subjects will be recruited and 
randomised to achieve at least 
380 randomised subjects, including at 
least 300 subjects with 26 weeks of 
exposure and at least 100 subjects 
(including approximately 25 subjects 
undergoing HPA axis testing) with 
52 weeks of exposure. 
Recruitment will be stopped when a 
sufficient number of subjects are 
randomised in order to obtain the 
above, considering the observed 
randomisation and drop-out rates. 
The number of randomised subjects 
may need to be adjusted to achieve 
the required exposure data. This 
will depend on the actual drop-out 
rate in the trial. 
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Section number 
and name 
Description of change 
Brief rationale 
Section 12.1 
Adjudication 
Committee 
The (sub)investigator assessment of causal 
relationship of the use of trial medication 
to the event, location of cutaneous events, 
severity, and seriousness. 
It has been specified that the 
Adjudication Panel will also review 
the severity of the treatment-
emergent AEs. 
Appendix 6 
Contact list 
List of protocol authors have been 
removed. 
A protocol may have multiple 
authors during its life-cycle. A log 
of all protocol authors is kept at 
LEO. 
The 3 members of the Adjudication Panel 
have been listed. 
2 dermatologists and one 
endocrinologist have now been 
contracted to the Adjudication 
Panel. 
Appendix 12 
Protocol 
amendment 
history 
New appendix. 
To provide overview of the 
changes to the protocol. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not been 
summarised. 
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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 ..................................................................................................................... 13 
List of Tables ............................................................................................................................ 20 
List of Figures .......................................................................................................................... 20 
2 Trial Identification ............................................................................................................... 21 
3 Introduction and Rationale .................................................................................................. 21 
3.1 Psoriasis vulgaris ............................................................................................................. 21 
3.2 Experience with Investigational Product ......................................................................... 21 
3.3 Trial Rationale ................................................................................................................. 22 
3.3.1 
Background ................................................................................................................. 22 
3.3.2 
Research hypothesis .................................................................................................... 23 
3.3.3 
Rationale for trial design ............................................................................................. 24 
3.4 Ethical Considerations ..................................................................................................... 29 
4 Trial Objectives ................................................................................................................... 31 
4.1 Primary Objective ............................................................................................................ 31 
4.2 Secondary Objectives ...................................................................................................... 31 
4.3 Exploratory Objective ..................................................................................................... 32 
5 Trial Endpoints .................................................................................................................... 32 
5.1 Primary Endpoint(s) ........................................................................................................ 32 
5.2 Secondary Endpoints ....................................................................................................... 32 
5.3 Safety assessments .......................................................................................................... 32 
6 Trial Design ......................................................................................................................... 32 
6.1 Overall Trial Design ........................................................................................................ 32 
6.1.1 
Overview ..................................................................................................................... 33 
6.1.2 
Screening/Washout Phase ............................................................................................ 34 
6.1.3 
Initial open-label treatment phase ............................................................................... 35 
6.1.4 
Maintenance phase ...................................................................................................... 35 
6.1.4.1 
Relapse at a regular 4-week (scheduled) visit ......................................................... 36 
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6.1.4.2 
Relapse between regular 4-week (scheduled) visits – more than one week prior to 
the next regular visit ................................................................................................ 37 
6.1.4.3 
Relapse between regular 4 week (scheduled) visits – less than one week to the next 
regular visit .............................................................................................................. 38 
6.1.5 
Follow-up Phase .......................................................................................................... 40 
6.2 Sample Size ..................................................................................................................... 42 
6.3 Randomisation ................................................................................................................. 43 
6.4 Blinding ........................................................................................................................... 43 
7 Trial Population and Withdrawal ......................................................................................... 43 
7.1 Subject Eligibility ............................................................................................................ 43 
7.2 Inclusion Criteria ............................................................................................................. 44 
7.3 Exclusion Criteria ............................................................................................................ 45 
7.4 Screening failures ............................................................................................................ 47 
7.5 Subject Enrolment Log .................................................................................................... 47 
7.6 Subject Identification List ............................................................................................... 48 
7.7 Subject card ..................................................................................................................... 48 
7.8 Restrictions during Trial .................................................................................................. 48 
7.8.1 
Restrictions prior to the start of treatment (Visit 1) ..................................................... 48 
7.8.2 
During the Trial Treatment Phase (open-label treatment phase and maintenance phase)
 ..................................................................................................................................... 49 
7.8.3 
Follow-up period ......................................................................................................... 52 
7.9 Discontinuation ............................................................................................................... 52 
8 Trial Schedule and Assessments .......................................................................................... 53 
8.1 Schedule of Trial Procedures ........................................................................................... 53 
8.2 Demographics .................................................................................................................. 59 
8.3 Fitzpatrick Skin Type ...................................................................................................... 59 
8.4 Height and Weight ........................................................................................................... 59 
8.5 Vital Signs ....................................................................................................................... 59 
8.6 Physical Examination ...................................................................................................... 59 
8.7 Medical History ............................................................................................................... 60 
8.8 Concomitant Medication and Procedures ........................................................................ 60 
8.9 Pregnancy Test ................................................................................................................. 61 
8.10 Adverse Events ................................................................................................................ 61 
8.11 Other Safety Assessments ............................................................................................... 61 
8.12 Laboratory Assessments .................................................................................................. 62 
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8.12.1 Safety Laboratory Blood Analysis .............................................................................. 63 
8.12.2 Safety Urinalysis ......................................................................................................... 65 
8.12.3 Pharmacodynamic (PD) Assessments ......................................................................... 66 
8.12.3.1 Blood sampling for serum biomarkers (for consenting subjects) ............................ 66 
8.12.4 Total Blood Volume ..................................................................................................... 66 
8.13 Patient Reported Outcomes ............................................................................................. 67 
8.13.1 DLQI ........................................................................................................................... 68 
8.13.2 EQ-5D-5L-PSO ........................................................................................................... 68 
8.13.3 WPAI:PSO ................................................................................................................... 68 
8.13.4 Psoriasis symptom inventory (PSI) ............................................................................. 69 
8.13.5 Subject’s Global Assessment of Disease Severity ...................................................... 70 
8.14 Subject assessment of local safety and tolerability ......................................................... 70 
8.15 Photography ..................................................................................................................... 70 
8.16 Investigator Assessments ................................................................................................. 71 
8.16.1 Definition of the body areas to be assessed (treatment areas) ..................................... 71 
8.16.2 Physician’s Global Assessment of Disease Severity (PGA) ....................................... 72 
8.16.3 Physician’s Assessment of the Extent and Severity of Clinical Signs (Redness, 
Thickness, Scaliness) (m-PASI) .................................................................................. 73 
8.16.4 Investigator’s Assessment of the Body Surface Area (BSA) Involvement of Psoriasis 
Vulgaris on Trunk and Limbs ...................................................................................... 74 
8.16.5 Investigator’s Assessment of the Severity of the Target Lesion/Target Location 
(Redness, Thickness, Scaliness) .................................................................................. 75 
8.17 Dispensing of IP .............................................................................................................. 75 
8.18 Return of IP and Compliance .......................................................................................... 75 
8.19 End of Trial Form ............................................................................................................ 75 
9 Adverse Events .................................................................................................................... 75 
9.1 Collection of Adverse Events .......................................................................................... 76 
9.1.1 
Application site reactions: Assessment of local safety and tolerability ...................... 76 
9.2 Reporting of Adverse Events in the eCRF ...................................................................... 76 
9.2.1 
Additional requirements for reporting of adverse events of concern associated with 
long-term topical corticosteroid use ............................................................................ 77 
9.2.2 
Actions Taken as a Consequence of an AE ................................................................. 77 
9.3 Other Events to be Reported ........................................................................................... 78 
9.3.1 
Pregnancy .................................................................................................................... 78 
9.3.2 
Overdose ...................................................................................................................... 78 
9.3.3 
Medication Error ......................................................................................................... 78 
9.3.4 
Misuse ......................................................................................................................... 78 
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9.3.5 
Abuse ........................................................................................................................... 79 
9.3.6 
Aggravation of Condition ............................................................................................ 79 
9.3.7 
Lack of Efficacy .......................................................................................................... 79 
9.3.8 
Adverse Events of Special Interest .............................................................................. 79 
9.4 Additional Reporting Requirements for Serious Adverse Events ................................... 79 
9.4.1 
Investigator Reporting Responsibilities ...................................................................... 79 
9.4.2 
LEO Reporting Responsibilities .................................................................................. 80 
9.5 Follow-up for Final Outcome of Adverse Events ........................................................... 81 
10 Investigational Product(s) .................................................................................................... 81 
10.1 Investigational Product Description ................................................................................ 81 
10.2 Administration of Investigational Products ..................................................................... 83 
10.3 Precautions/Overdosage .................................................................................................. 85 
10.4 Packaging of Investigational Products ............................................................................ 86 
10.5 Storage of Investigational Products ................................................................................. 87 
10.6 Treatment Assignment ..................................................................................................... 88 
10.6.1 Randomisation Code List ............................................................................................ 88 
10.7 Drug Accountability and Compliance Checks ................................................................ 89 
10.7.1 Drug Accountability .................................................................................................... 89 
10.7.2 Trial Product Destruction ............................................................................................ 89 
10.7.3 Treatment Compliance ................................................................................................ 89 
10.8 Emergency Unblinding of Individual Subject Treatment ................................................ 90 
10.9 CORTROSYN®  (cosyntropin) / Synacthen® (tetracosactid) for Injection ..................... 90 
10.9.1 CORTROSYN® and Synacthen® ................................................................................. 90 
10.9.1.1 Packaging and Labelling .......................................................................................... 92 
10.9.1.2 Storage ..................................................................................................................... 92 
10.9.1.3 Reconstitution and Administration of CORTROSYN® (in the US) ........................ 92 
10.9.1.4 Precautions ............................................................................................................... 92 
10.9.1.5 Drug Accountability ................................................................................................. 93 
10.9.2 0.9% Sodium Chloride Injection, USP, for Reconstitution of CORTROSYN® (in the 
US) ............................................................................................................................... 93 
10.9.2.1 Packaging and Labelling .......................................................................................... 93 
10.9.2.2 Storage ..................................................................................................................... 93 
10.9.2.3 Precautions ............................................................................................................... 94 
10.9.2.4 Drug Accountability ................................................................................................. 94 
11 Statistical Methods .............................................................................................................. 94 
11.1 Determination of Sample Size ......................................................................................... 95 
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11.2 Definition of Trial Analysis Sets ..................................................................................... 96 
11.3 Statistical Analysis .......................................................................................................... 97 
11.3.1 Disposition of Subjects ................................................................................................ 97 
11.3.2 Demographics and other Baseline Characteristics ...................................................... 97 
11.3.3 Exposure and Treatment Compliance .......................................................................... 98 
11.3.3.1 Exposure .................................................................................................................. 98 
11.3.3.2 Treatment compliance .............................................................................................. 99 
11.3.3.3 Analysis of Primary Efficacy Endpoint ................................................................... 99 
11.3.3.4 Analysis of Secondary Efficacy Endpoints ........................................................... 100 
11.3.3.5 Number of days in remission ................................................................................. 100 
11.3.3.6 Number of relapses during maintenance phase ..................................................... 101 
11.3.4 Exploratory Analysis of Efficacy .............................................................................. 101 
11.3.4.1 m-PASI ................................................................................................................... 101
11.3.4.2 Subjects in remission at each visit ......................................................................... 101 
11.3.4.3 Time to when PASI75 is no longer fulfilled .......................................................... 101 
11.3.4.4 Time to first relapse according to m-PASI ............................................................ 102 
11.3.4.5 Efficacy after treatment of relapse ......................................................................... 103 
11.3.4.6 Target lesion/location scores .................................................................................. 103 
11.3.4.7 Body Surface Area (BSA) ..................................................................................... 103 
11.3.4.8 Number of active treatment days during maintenance phase ................................ 103 
11.3.5 Analysis of Patient-Reported Outcomes ................................................................... 103 
11.3.5.1 Dermatology Life Quality Index (DLQI) .............................................................. 104 
11.3.5.2 EQ-5D-5L-PSO ..................................................................................................... 104 
11.3.5.3 WPAI:PSO ............................................................................................................. 104 
11.3.5.4 Psoriasis Symptom Inventory ................................................................................ 104 
11.3.5.5 Subject’s Global Assessment of Disease Severity ................................................. 105 
11.3.6 Analysis of Safety ..................................................................................................... 105 
11.3.6.1 Adverse Events ...................................................................................................... 105 
11.3.6.2 Rebound ................................................................................................................. 106 
11.3.6.3 Local safety and tolerability .................................................................................. 106 
11.3.6.4 ACTH-Challenge test ............................................................................................ 107 
11.3.6.5 Vital Signs and Physical Findings ......................................................................... 107 
11.3.6.6 Clinical Laboratory Evaluation .............................................................................. 107 
11.3.7 Interim Analysis ........................................................................................................ 108 
11.3.8 General Principles ..................................................................................................... 108 
11.3.9 Handling of Missing Values ...................................................................................... 109 
12 Trial Committees ............................................................................................................... 109 
12.1 Adjudication Committee ............................................................................................... 109 
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13 Case Report Forms and Data Handling ............................................................................. 110 
13.1 Case Report Forms (CRFs) ........................................................................................... 110 
13.2 Data Handling ................................................................................................................ 111 
13.3 Source Data ................................................................................................................... 112 
13.4 Trial Monitoring ............................................................................................................ 113 
14 Handling of an Urgent Safety Measure ............................................................................. 113 
15 Quality Assurance/Audit.................................................................................................... 114 
16 Completion of Trial ........................................................................................................... 114 
16.1 Trial Completion Procedures ......................................................................................... 114 
16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site ............................. 115 
16.2 Provision for Subject Care Following Trial Completion ............................................... 115 
16.3 Archiving of Trial Documents ....................................................................................... 115 
17 Ethics and Regulatory Authorities ..................................................................................... 116 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and 
Regulatory Authorities .................................................................................................. 116 
17.2 Ethical Conduct of the Trial .......................................................................................... 116 
17.3 Subject Information and Informed Consent .................................................................. 116 
17.4 Processing of Personal Data .......................................................................................... 116 
18 Insurance ............................................................................................................................ 117 
19 Use of Information............................................................................................................. 117 
20 Publication ......................................................................................................................... 117 
21 Responsibilities .................................................................................................................. 118 
22 List of Abbreviations ......................................................................................................... 120 
23 Definition of terms............................................................................................................. 122 
24 References ......................................................................................................................... 123 
Appendix 1: Protocol Summary ............................................................................................. 128 
Appendix 2: U.S. Prescribing information for CORTROSYN® (cosyntronin) for injection 134 
Appendix 3: Summary of Product Characteristics for Synacthen® (Tetracosactide) Ampoules 
250mcg .............................................................................................................................. 141 
Appendix 4: Definitions of Adverse Events and Serious Adverse Events ............................. 149 
Appendix 5: Classification of Adverse Events ....................................................................... 151 
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Appendix 6: Contact list of LEO, vendors, trial committees and coordinating investigators 153 
Appendix 7: EQ-5D-5L-PSO ................................................................................................. 155 
Appendix 8: DLQI ................................................................................................................. 160 
Appendix 9: WPAI:PSO ......................................................................................................... 162 
Appendix 10: Psoriasis Symptom Inventory (PSI) – 24 hours recall .................................... 164 
Appendix 11: Psoriasis Symptom Inventory (PSI) – 7 days recall ........................................ 165 
Appendix 12: Protocol amendment history ............................................................................ 166 
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List of Tables 
Table 1: Prohibited Medication including Non-Drug Therapies and Procedures (for all 
subjects) ............................................................................................................ 49 
Table 2: Prohibited Medication including Non-Drug Therapies and Procedures (for subjects 
performing HPA axis test) ................................................................................ 50 
Table 3: Permitted concomitant anti-psoriatic treatment ......................................................... 52 
Table 4: Schedule of Trial Procedures ...................................................................................... 54 
Table 5: Fitzpatrick Skin Classification ................................................................................... 59 
Table 6: Skin Reaction Scores – Physician’s Assessment ........................................................ 62 
Table 7: Skin Reaction Scores – Subject’s Assessment ........................................................... 62 
Table 8: Blood volume drawn from each subject during the trial ............................................ 67 
Table 9: Disease Severity Grading – Subject’s Assessment..................................................... 70 
Table 10: Disease Severity Grading – Physician’s Assessment ............................................... 72 
Table 11: Description of Enstilar®/LEO 90100 Aerosol Foam ................................................ 82 
Table 12: Description of Enstilar® vehicle/LEO 90100 Aerosol Foam Vehicle ....................... 83 
Table 13: Administration of Investigational Products .............................................................. 84 
Table 14: Description of CORTROSYN® (used in the US) ..................................................... 91 
Table 15: Description of Synacthen® (used in Europe) ............................................................ 91 
Table 16: Mean and median waiting times and hazards according to number of relapses per 
year ................................................................................................................... 95 
List of Figures 
Figure 1 Trial Design ................................................................................................................ 33 
Figure 2 Relapse at a regular 4-week (scheduled) visit ........................................................... 37 
Figure 3 Relapse between regular 4-week (scheduled) visits – more than one week prior to the 
next regular visit ............................................................................................... 38 
Figure 4 Relapse between regular 4 week (scheduled) visits – less than one week to the next 
regular visit ....................................................................................................... 39 
Figure 5 Flow of Electronic Data ........................................................................................... 112 
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2 Trial Identification 
EudraCT number: 2016-000556-95 
IND number: 114063 
3 Introduction and Rationale 
3.1 Psoriasis vulgaris 
Psoriasis is an inflammatory skin disease that occurs in approximately 2% of the worldwide 
population (1, 2). In addition to skin manifestations, psoriasis is associated with multiple co-
morbidities e.g. arthritis and cardiovascular disease (3, 4). The hallmark of psoriasis is 
inflammation of the skin as a result of excessive response to danger signals. In the majority of 
subjects, psoriasis manifests as plaque type psoriasis, clinically seen as sharply demarcated, 
elevated, scaling, erythematous plaques located predominantly on the scalp, extensor sides of 
elbows and knees, and the sacral region (3, 5, 6). Skin lesions can be painful, pruritic and may 
cause significant emotional and physical discomfort (7, 8). 
The majority of affected subjects has mild to moderate disease and can be treated with topical 
therapies (9). In the group of subjects with moderate to severe psoriasis, topical therapies are 
also appropriate as adjunct to either phototherapy, systemic or biologic agents (9, 10). One of 
the advantages of topical therapies is a reduced risk of systemic toxicity compared to other 
treatment modalities.  
Psoriasis is a life-long disease for most patients and there is a need for a safe long-term 
treatment strategy. When psoriasis treatment is discontinued, lesions will likely recur.  
Optimal management of psoriasis must therefore include a strategy for initial rapid relief of 
symptoms as well as a long-term strategy to maintain remission.  
3.2 Experience with Investigational Product 
LEO 90100 aerosol foam (referred to as LEO 90100) is a combination product developed for 
the topical treatment of psoriasis vulgaris. It contains calcipotriol 50 mcg/g and 
betamethasone 0.5 mg/g (as dipropionate). LEO 90100 is packed in an aluminium can with 
dimethyl ether (DME) and butane propellants. The propellants evaporate quickly after 
application leaving a foam on the skin surface.  
LEO 90100 is available on the market in United Stated (US) and the European Union (EU) 
(under the trade name Enstilar® foam) for treatment of psoriasis vulgaris for up to 4 weeks. 
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The clinical efficacy and safety of LEO 90100 has been documented in vehicle- and active 
comparative trials of 4 weeks duration. Three controlled safety and efficacy trials involving 
more than 900 subjects, which formed the basis for marketing approval, demonstrated that 
LEO 90100 is highly efficacious for the treatment of adult patients with psoriasis vulgaris 
over a 4-week period. The data showed that LEO 90100 is a more efficacious treatment option 
than calcipotriol plus betamethasone dipropionate (calcipotriol/BDP) ointment and the 
individual active ingredients, based on investigator-assessed treatment success and the 
proportion of subjects achieving at least 75% improvement in Psoriasis Area and Severity 
Index (PASI; PASI75). LEO 90100 was well tolerated, with a safety and tolerability profile 
comparable to calcipotriol/BDP ointment and the individual active ingredients. Furthermore, a 
maximum use systemic exposure trial in subjects with moderate to severe extensive psoriasis 
found no clinically relevant impact on the Hypothalamic-Pituitary-Adrenal (HPA) axis or 
calcium homeostasis after 4 weeks of treatment with LEO 90100 (mean amount administered 
62 g/week versus approximately 30 g/week in the other 4 week trials). 
Data supporting the safety and efficacy of LEO 90100 for up to 12 weeks are derived from a 
12-week safety and efficacy trial in 460 subjects with psoriasis vulgaris (Trial LP0053-1003),
which compared LEO 90100 to calcipotriol/BDP gel. This trial showed that prolonged
treatment for up to 12 weeks led to continued improvement in disease severity in both the
LEO 90100 and calcipotriol/BDP gel arms, with improvement being more pronounced in the
LEO 90100 arm. The treatment with LEO 90100 for up to 12 weeks was not associated with
any new safety findings compared to 4 weeks treatment; the safety profile of LEO 90100 over
12 weeks was similar to that of calcipotriol/BDP gel over 12 weeks. These data, together with
the data from the 4-week controlled safety and efficacy trials, highlighted that the superior
efficacy of the foam is achieved without compromising tolerability.
Further information regarding LEO 90100 relevant to clinical trials can be found in the 
Investigator’s Brochure (IB) (11). 
3.3 Trial Rationale 
3.3.1 Background 
While data is available from trials of 4-week and 12-week duration supporting the efficacy of 
LEO 90100 in clearing psoriasis, long-term safety and treatment strategies utilizing 
LEO 90100 for long-term disease management have not been investigated. The aim of this 
trial is to evaluate the use of LEO 90100 for maintenance therapy and to document long-term 
safety and efficacy. The goal of a maintenance treatment would be to prolong remission as 
long as possible while minimising adverse effects.   
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Various regimens using corticosteroids as monotherapy or in combination with a non-steroidal 
agent such as vitamin D analogue or ammonium lactate have been evaluated for maintenance 
of response (12, 13, 14, 15, 16). The results show that approaches utilising alternating 
weekend and weekday treatment are effective and safe. However, they involve the use of 
multiple products on different days which may be challenging for a patient in terms of 
adherence to treatment. Therefore, a maintenance regimen which uses a single fixed-
combination product could simplify treatment. There is evidence to suggest that twice weekly 
intermittent use of calcipotriol/BDP combination gel is effective in maintaining efficacy and 
reducing relapse rate compared to as needed use on the scalp (16). Based on these 
observations, twice-weekly use of LEO 90100 for maintenance of response would provide a 
simple and convenient regimen, which could contribute to patient adherence. The use of only 
one product for both clearance and maintenance treatment, and just adjusting the frequency of 
application, would be expected to contribute to patient acceptance, compliance and thereby 
successful outcomes. 
3.3.2 Research hypothesis 
The present trial will evaluate the efficacy and safety of LEO 90100 used as a long-term 
twice-weekly maintenance therapy compared with vehicle. Following an initial 4-week period 
where all subjects will be treated with LEO 90100 in accordance with the currently approved 
labeling, they will be randomised to receive either LEO 90100 or vehicle per the twice weekly 
maintenance regimen for 52 weeks. In cases of relapse, affected subjects in either treatment 
group will again receive LEO 90100 to apply once daily for 4 weeks on active areas on trunk 
and limbs. Thus, the vehicle arm will also utilise re-treatment as needed, similar to the use in 
clinical practice for the licensed calcipotriol/BDP products. Thus, the trial will compare two 
ways of using LEO 90100: a proactive approach with fixed twice-weekly maintenance 
regimen with a conventional, reactive approach. The research hypothesis is that the proactive 
twice-weekly maintenance use of LEO 90100 will prolong the time to relapse and reduce the 
frequency of relapses in subjects with psoriasis vulgaris, as compared with vehicle while still 
maintaining a favorable safety profile. It is further hypothesized with regard to long-term 
efficacy that subjects who receive LEO 90100 twice weekly will demonstrate superior 
response to those randomised to receive vehicle, as measured by the number of days in 
remission.  
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3.3.3 Rationale for trial design 
Overall design and treatment duration 
The trial will include a screening phase of up to 4 weeks, an open-label treatment phase of 
4 weeks, a randomised double-blind maintenance phase of 52 weeks, and a follow-up phase 
of 8 weeks. 
In the initial open-label phase, all subjects will receive treatment with LEO 90100 once daily 
for 4 weeks. The purpose of this initial period of daily treatment is to allow clearance 
(“treatment success”) of the psoriatic lesions so that subjects will enter the maintenance phase 
in a symptom-free state. Treatment success is defined as a Physician’s Global Assessment of 
disease severity (PGA) score of ‘clear’ or ‘almost clear’ with at least 2-grade improvement 
from baseline. 
In the maintenance phase, subjects will be randomised to receive twice weekly treatment with 
either LEO 90100 or vehicle (maintenance investigational product [maintenance IP]). At 
relapse (defined as a PGA score of at least ‘mild’), both treatment groups will receive 
LEO 90100 (rescue investigational product [rescue IP]) to apply once daily on affected areas 
on trunk and limbs, with the purpose of regaining the disease control. Subjects will be treated 
for 4 weeks with rescue IP on areas with active psoriasis, and will be instructed to also treat 
any additional areas that may become active during this 4-week period with rescue IP. During 
relapse subjects will continue twice weekly treatment with maintenance IP on areas that are 
not active. Subjects who do not achieve ‘clear’ or ‘almost clear’ according to the PGA after 
4 weeks will exit the trial. A duration of 12 months for the maintenance phase was chosen as 
it allows an assessment of prevention of relapse over a period of time during which relapse 
would be expected to occur on a regular basis. A 12-month duration will allow assessment of 
the frequency of relapses and the number of days in remission, which are important 
parameters in the assessment of utility of long-term maintenance therapy.  
Importantly, the maintenance treatment duration of 12 months following 4 weeks of initial, 
once daily treatment is considered appropriate to obtain adequate data on the long-term safety 
and efficacy of LEO 90100.  
Frequency of applications during the maintenance phase and drug amount 
Data from several small trials with intermittent use of topical corticosteroids indicate that 
twice-weekly application on weekends is an effective and safe regimen. The twice-weekly 
regimen used in this trial with 3 or 4 days between applications has been selected based on a 
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discussion with a panel of dermatologists. This regimen is justified by published data and 
in-house studies as outlined below. There is broad consensus in the literature that the stratum 
corneum can act as a reservoir for topically applied drugs and that this can reduce the 
frequency of applications (17). The effect of clobetasol propionate applied topically on rabbit 
skin was studied by Abidi et al. (18) who concluded that a single dose maintained full 
anti-inflammatory effect for 4 days. Proprietary data on calcipotriol/BDP combination 
products  suggest that the half-life in the skin is approximately 3 days (19, 20). These data 
support the effectiveness of a twice-weekly regimen with 3 or 4 days between applications. 
The maximum allowance of maintenance IP during maintenance phase is set at 3 cans (3 x 
60 g) for 4 weeks. This ensures that subjects will have sufficient maintenance IP to use up to 
15 g/day (maximum daily dose according to the product labeling) twice weekly during each  
4-week period. Note that due to the visit window of +/- 4 days, subjects may need up to
9 applications during a 4-week period. This amount is considered adequate as 15 g is
sufficient to cover more than 30% of body surface area (BSA), and it is supported by previous
experience from LEO 90100 clinical trials where subjects with extensive psoriasis (15-30% of
BSA) used on average 9 g per day, and subjects in short–term efficacy and safety trials used
on average less than 5 g.
Subjects 
In order to qualify for the trial, subjects must meet the inclusion/exclusion criteria, which are 
designed to select a population that is representative for the target population and are 
consistent with the criteria used in the short-term pivotal trials in psoriasis vulgaris; i.e., 
subjects of all disease severities amenable to topical therapy, with psoriasis lesions on the 
trunk and/or limbs involving between 2-30% of BSA. The eligibility criteria are selected to 
prevent any confounding issues with diagnosis and minimize any possible effect of concurrent 
diseases or concomitant medications on clinical assessment.  
Assessments and endpoints 
Clinical assessments including PGA, assessment of severity of a target lesion/location, signs 
and extent of psoriasis (to calculate PASI) will be obtained by trial investigators at each trial 
visit. Subjects will be required to complete a self-assessment of disease severity as well as 
quality of life questionnaires, and to capture psoriasis symptoms using the Psoriasis Symptom 
Inventory (21, 22) on a regular basis during the trial.  
The primary endpoint will be the time to first relapse. Relapse is defined as a PGA score of at 
least ‘mild’, i.e., worsening of psoriasis from ‘clear’ or ‘almost clear’ (a score required for 
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entering the maintenance phase) to the same level of disease severity as required at study 
entry, thus necessitating the re-initiation of once daily treatment on the active area(s). The 
secondary endpoints, the number of relapses and the number of days in remission (‘clear’ or 
‘almost clear’), are considered to be clinically meaningful.  
One of the safety endpoints is the rebound phenomenon. Rebound may signify a severe 
deterioration of psoriasis that is significantly worse than before the treatment was initiated or 
a change in the character of the psoriasis (e.g., from plaque to pustular form), or both. Per the 
Committee for Human Medicinal Products (CHMP) guideline on clinical investigation of 
medicinal products indicated for treatment of psoriasis (23), rebound is defined as “worsening 
of psoriasis over baseline value (e.g. PASI>125%) or new pustular, erythrodermic or more 
inflammatory psoriasis occurring within 2 months of stopping therapy. A simple worsening of 
psoriasis beyond 2 months of therapy may represent the natural course of the disease (relapse) 
rather than a rebound associated with drug”. The National Psoriasis Foundation Medical 
Advisory Board (US) has also proposed a standard definition of rebound (24). Rebound is 
said to occur if the PASI is 125% or greater than baseline, or if new generalized pustular, 
erythrodermic or more inflammatory psoriasis occurs within 3 months of stopping therapy. 
However,  these definitions may not be optimal in patients with mild disease, with low PASI, 
where even a minor worsening in disease severity may fulfill the criteria for PASI >125%, 
without in fact being a severe and sudden worsening which is characteristic of rebound. 
Therefore, for the purpose of this trial, rebound will be defined as (i) an m-PASI ≥12 AND an 
increase in m-PASI of ≥125% of the baseline value, or (ii) new pustular, erythrodermic or 
more inflammatory psoriasis either a) within 2 months after discontinuation of once-daily 
treatment in the initial open-label phase, b) within 2 months after discontinuation of once- 
daily relapse treatment, or c) within 2 months after end of maintenance treatment (up to Visit 
FU3). Hence, only psoriasis that becomes considerably worse than it has previously been will 
be considered as rebound.  
Assessment of target lesion/location is included as a complement to the PGA to capture 
information on severity of individual signs, i.e. redness, thickness and scaliness of target 
plaques. To document the development of response over time, target lesion/location 
photographs will be taken in a subset of patients recruited at one or a few selected sites 
equipped with adequate  photographic equipment. Subjects will need to give a separate 
written consent for the collection of photographs. Even if they do not accept the collection of 
photographs, they may still participate in the main part of the trial.  
One of the main objectives of this trial is to investigate the long-term safety of LEO 90100 
over 56 (4 + 52) weeks, especially to evaluate the risk of corticosteroid-related cutaneous 
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adverse reactions and possible systemic effect during prolonged or repeated use of the 
product. The investigators will record all adverse events (AEs), and an independent 
adjudication panel of 2 dermatologists and one endocrinologist will review all treatment-
emergent AEs (blinded data) to identify adverse drug reactions of concern associated with 
long-term topical corticosteroid use. 
Because of the potential effect of vitamin D analogue containing products on calcium 
metabolism, there will be safety analyses of the parameters of calcium metabolism from blood 
and urine samples. As in previous LEO 90100 safety and efficacy trials, albumin-corrected 
serum calcium and spot urine calcium-creatinine ratio will be analysed in samples collected at 
baseline, Week 4 and at the end of trial.  
Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment 
has been reported, however, physiologic adrenal suppression is a common occurrence of little 
clinical significance (25). Pathologic adrenal suppression from topical corticosteroid use is a 
very rare occurrence; after nearly half a century of world-wide topical steroid use, there is 
only a few clinical cases describing prolonged corticosteroid-induced pathological adrenal 
suppression (25). Furthermore, these cases occurred in adults using at least two times the 
maximum recommended dose of super-potent corticosteroids for as long as 18 months or, in 
the single case that did not exceed this dosage, involved continuous use for 5 years. It is not 
considered to be ethically justified to perform adrenal function testing on all patients in the 
present trial, as the risk of clinical adrenal insufficiency with the use of topical corticosteroids 
is low and such testing involves an invasive technique. Therefore, adrenal function testing 
will be undertaken in a subset of randomised subjects with at least moderate psoriasis 
affecting between 10 and 30% of the BSA. The aim is to achieve approximately 25 subjects 
undergoing HPA axis testing after 52 weeks of exposure. The testing will be done at selected 
trial sites using the ACTH stimulation test. The proposed sample size is in line with the 
typical sample size for trials evaluating effect of topical corticosteroids on the HPA axis 
function (26) and also a previous recommendation by the US Food and Drug Agency (FDA) 
for a maximum use systemic exposure trial (LEO 90100-30). Testing will be done at baseline, 
at the end of the initial open-label phase (Week 4), at Week 28, and at the end of trial (Week 
56 or at early withdrawal). 
Subjects will need to give a separate written consent for having ACTH challenge tests 
performed. If they do not agree to the having ACTH challenge tests performed, they may still 
participate in the main part of the trial. 
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Local safety and tolerability will be evaluated by the scoring of application site skin reactions 
using the same assessment as used in the short-term trials with LEO 90100. Clinical signs and 
symptoms will be assessed on a 4-point scale (from absent to severe). Perilesional erythema, 
oedema, dryness, and erosion will be assessed by investigator and application site burning or 
pain will be assessed by subject. 
To support clinical decision-making when treating psoriasis patients, it is important to 
consider quality of life. Therefore, evaluation of quality of life is included in this trial by 
means of the generic EQ-5D-5L-PSO questionnaire, the Dermatology Life Quality Index 
(DLQI) and the Work Productivity and Activity Impairment: Psoriasis questionnaire 
(WPAI:PSO). The EQ-5D-5L-PSO is a standardised instrument for use as a measure of health 
outcome. DLQI is a validated dermatology specific questionnaire, which measures specific 
factors influencing the quality of life for patients with skin disease. WPAI:PSO is a 
questionnaire which assesses the impact of psoriasis on patients’ ability to work and perform 
regular activities. These questionnaires will complement the physicians’ assessments to obtain 
a more complete understanding of the subject’s disease status and potential changes during 
this trial.  
A Psoriasis Symptom Inventory (PSI) is included to assess the severity of psoriasis symptoms 
throughout the induction (open-label) and the maintenance phase. It is anticipated that the 
symptom diary data recorded on a weekly basis will provide a more sensitive measure of the 
effect of maintenance treatment than the monthly assessments of the PGA by investigators. 
Concomitant treatments 
During the course of the trial, subjects must not use any concomitant treatments that have a 
possible effect on psoriasis vulgaris on the treatment areas (trunk and/or limbs). This includes 
various systemic treatments (e.g. systemic corticosteroids, retinoids, methotrexate, ciclosporin 
and other immunosuppressants and biological therapies) as well as topical treatments. Use of 
any drug except the IP for the treatment of psoriasis vulgaris is prohibited on the treatment 
areas, only emollients are allowed (but only on days when IP is not being applied).  
As LEO 90100 contains a potent steroid, it is not allowed to be used on the face, axillae, and 
groin. Only mild steroids or non-steroidal products will be allowed on these areas.  
As the purpose of this trial is to evaluate the efficacy of maintenance treatment on the body, 
subjects with severe or extensive scalp psoriasis requiring treatment with potent or 
superpotent steroids will be excluded.  
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A stable concomitant treatment regimen (no start or change of dosage during the trial) with 
drugs that have a potential effect on psoriasis (e.g., beta blockers, anti-malarials, angiotensin-
converting enzyme (ACE) inhibitors and lithium) is allowed during the trial. Although these 
drugs have a potential effect on psoriasis, they are not known to cause fluctuations in disease 
severity and therefore should not affect the subject’s response to trial medication.  
Prior to randomisation, a washout period should be completed if the subject is treated, or has 
recently been treated with anti-psoriatic treatments or other relevant medication that could 
influence the outcome of the trial. Additional restriction apply for subjects participating in the 
HPA axis test. 
Biomarkers 
Psoriasis is an immune mediated inflammatory skin disease and is associated with serious 
morbidities, such as cardiovascular disease, diabetes, depression and psoriatic arthritis. 
Potential biomarkers related to inflammation, cardiovascular disease and metabolic syndrome 
have been identified. In patients with severe psoriasis responding to systemic therapy, 
biomarkers of cardiovascular disease have been demonstrated to improve (27). In this trial, a 
panel of serum biomarkers is being investigated in order to assess inflammation and 
cardiovascular risk. Blood samples will be taken at baseline, at Week 28, and at the end of 
treatment (for patients who have completed at least 40 weeks of the trial from baseline) in a 
patient population with ‘mild’ to ‘severe’ disease treated with topical therapy.  
Subjects will need to give a separate written consent for the collection of these blood samples. 
If they do not agree to the collection of samples for this purpose, they may still participate in 
the main part of the trial.  
3.4 Ethical Considerations 
Psoriasis vulgaris is a chronic disease requiring long-term therapy for most patients. Various 
formulations of topical corticosteroids, topical vitamin D analogues and their combination 
have been shown to provide safe and effective initial therapy to achieve clearance of the 
lesions. However, disease signs usually recur within a few months after discontinuation of 
treatment in the majority of patients (28) .  
LEO 90100 is a combination product of calcipotriol 50 mcg/g and betamethasone 0.5 mg/g 
(as dipropionate). Long-term safety of both active components of LEO 90100, used 
individually or in combination, has been well documented. Long-term studies of calcipotriol 
have shown that it is well tolerated with few adverse effects (29, 30). The local adverse effects 
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of calcipotriol are related to skin irritation, including burning, itching, and erythema. With the 
exception of skin irritation, side effects of topical calcipotriol are usually minimal; the risk of 
hypercalcemia/hypercalciuria is low when the drug is used appropriately. 
The long-term use of products containing potent or super-potent topical corticosteroids can 
have a multitude of adverse cutaneous side effects, such as skin atrophy, telangiectasia, striae 
and tachyphylaxis. Systemic reactions due to topical use of corticosteroids are rare in adults, 
however, they can be severe. Adrenocortical suppression, cataract, infection, impaired 
glycaemic control of diabetes mellitus, and increase of intra-ocular pressure can occur, 
especially after long-term treatment of large areas and/or with doses exceeding recommended 
doses. Therefore, intermittent maintenance treatment is a commonly recommended approach 
for corticosteroids to control the signs of psoriasis while reducing drug exposure and thereby 
the risk for adverse effects (31). 
LEO 90100 (calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g [as dipropionate]) has proved 
to be a highly effective and well tolerated treatment for psoriasis vulgaris with a favourable 
benefit/risk profile when used for 4 and up to 12 weeks (11), but no long-term trials or 
investigations of the risk of skin atrophy or duration of remission and risk of rebound have 
been conducted.  
The long-term use of repeated courses of the calcipotriol/BPD combination has been 
investigated with the ointment and gel formulation (Daivobet® ointment and Daivobet® gel), 
and demonstrated to provide safe, efficacious management of psoriasis of the body and scalp 
over the course of one year (32, 33). The treatment did not appear to be associated with a 
higher incidence of corticosteroid-related AEs during the long-term therapy than calcipotriol-
based regimens. 
The purpose of the present trial is to investigate if LEO 90100 can be used by patients to 
provide safe and efficacious long-term management of psoriasis. In particular, the trial will 
investigate whether twice weekly applications of LEO 90100 is able to maintain the initial 
clinical efficacy for a longer period of time as compared to twice weekly application of 
vehicle. Since both treatment groups will receive LEO 90100 once daily for 4 weeks in case 
of relapse, the vehicle arm will utilise re-treatment as needed and thus  reflect normal clinical 
use of the product  (i.e., 4 weeks courses of once daily treatment upon re-occurrence of active 
lesions). This means that also subjects in the vehicle arm will be provided with medication 
effective in the treatment of psoriasis. 
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Comparisons of safety data between LEO 90100 and the two other marketed formulations 
show that the systemic safety profile and short-term AE profile of LEO 90100 are similar to 
those of calcipotriol/BDP ointment and calcipotriol/BDP gel, and no new safety concerns 
have emerged for LEO 90100 beyond those already described for the calcipotriol/BDP 
combination product in the ointment and gel formulations. Based on the fact that the potency 
of LEO 90100 is only moderately increased when compared to Daivobet® ointment, with no 
enhanced systemic effects, and the short-term safety profiles of the two formulations are 
similar, no specific safety or tolerability concerns are anticipated with the proposed long-term 
treatment. 
Subjects participating in the trial will be under careful supervision of a dermatologist or 
general practitioner experienced in Good Clinical Practice (GCP) clinical trials and in the 
handling of psoriasis vulgaris during the entire course of the trial and will be required to 
attend planned trial visits every 4 weeks as well as unscheduled visits in case of relapse. At 
either their own, or the physician’s discretion, subjects may be withdrawn from the trial at any 
time. 
Overall, the expected benefits related to long-term therapy outweighs the anticipated risks and 
inconvenience for the participating subjects. 
4 Trial Objectives 
4.1 Primary Objective 
The primary objective is to evaluate the efficacy of a twice weekly maintenance regimen with 
LEO 90100 compared to vehicle in the prevention of relapse in subjects with psoriasis 
vulgaris. 
4.2 Secondary Objectives 

To evaluate the long-term efficacy (up to 52 weeks) of LEO 90100 used twice
weekly as maintenance therapy compared to vehicle in subjects with psoriasis
vulgaris

To evaluate the long-term safety of LEO 90100 (up to 52 weeks) in subjects with
psoriasis vulgaris
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4.3 Exploratory Objective 

To evaluate the effect of long-term treatment on biomarkers of inflammation and
cardiovascular disease (this part of the trial is optional and will be reported
separately from the clinical trial report).
5 Trial Endpoints 
5.1 Primary Endpoint(s) 

Time to first relapse (at least ‘mild’ according to the PGA).
5.2 Secondary Endpoints 

Number of days in remission (‘clear’ or ‘almost clear’ according to the PGA)
during the maintenance phase

Number of relapses during the maintenance phase.
Other endpoints planned to be analysed in this trial can be found  in section 11.3.4. 
5.3 Safety assessments 

Adverse events of concern associated with long-term corticosteroid use

Incidence of rebound (as defined in section 11.3.6.2)

Local safety and tolerability assessment scores

Effect on calcium metabolism, based on change from baseline in serum calcium
and spot urinary calcium at Week 4 and the end of trial

Effect on HPA axis (in a subset of subjects with disease involvement of between 10
and 30% of BSA), based on serum cortisol ≤18 mcg/dL 30 minutes after
cosyntropin injection at Week 4, Week 28, and end of trial (Week 56) or early
withdrawal.
Exposure and standard safety data will be reported as described in sections 11.3.3 and 11.3.6. 
6 Trial Design  
6.1 Overall Trial Design 
The overall trial design is illustrated in Figure 1 below. 
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Figure 1 Trial Design 
6.1.1 Overview 
This trial is a multi-centre, prospective trial, consisting of an initial open-label treatment 
phase of 4 weeks followed by a randomised, double-blind, vehicle-controlled, maintenance 
phase of 52 weeks in subjects with psoriasis vulgaris.  
After the screening phase, subjects deemed eligible for the trial (adults with psoriasis vulgaris 
on the trunk and/or limbs rated as at least ‘mild’ according to the PGA, BSA 2-30% and 
m-PASI of at least 2) will be enrolled to the initial open-label phase, where they will apply
LEO 90100 once daily on the psoriatic lesions on trunk and/or limbs for 4 weeks.

Subjects who achieve treatment success (PGA score of ‘clear’ or ‘almost clear’ with
at least a 2-grade improvement from baseline) at Week 4 will be randomised in a
1:1 ratio to a maintenance phase of 52 weeks with LEO 90100 or vehicle
(maintenance IP) twice weekly.

Subjects who do not achieve treatment success after 4 weeks of once daily
treatment (i.e., non-responders) will be discontinued from the trial.
During the randomised maintenance phase, subjects will apply maintenance IP twice weekly 3 
or 4 days apart (fixed days) on all areas on the trunk and limbs where lesions have cleared or 
almost cleared after the initial open-label phase or after relapse treatment. Subjects will be 
assessed regularly at clinical visits (every 4 weeks). In addition, if in the opinion of the 
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subject, a relapse (exacerbation of psoriasis) has occurred between two regular monthly visits, 
the subject will be assessed by the investigator at an unscheduled visit.   
Following confirmation of a relapse the subject will be provided with rescue IP and will be 
asked to apply it to the active area(s) on trunk and/or limbs, irrespective of whether those 
areas were active at baseline or they are new lesions. The rescue IP is to be applied once daily 
on the active areas for 4 weeks. (Note: This treatment is referred to as ‘relapse’ or ‘rescue’ 
treatment). If additional areas become active during rescue treatment, these should also be 
treated once daily with rescue IP. During a relapse, areas that are not active will continue 
twice weekly maintenance treatment. 

If a score of ‘clear’/’almost clear’ according to the PGA is regained after 4 weeks,
the twice weekly maintenance regimen will be re-started on the now ‘clear’/’almost
clear’ area(s) according to the original randomisation scheme (for details see
section 6.1.4).

If a score of ‘clear’/almost clear’ according to the PGA is not regained after the 4
weeks of once daily rescue treatment, the subject will exit the trial.
A detailed description of each phase is provided in the section below. 
Planned date of enrolment of first subject: Q1-2017 
Planned date of completion of last subject: Q3-2019 
Estimated number of trial sites and country allocation: Approximately 58 sites in Canada, 
France, Germany, Poland, United Kingdom and United States.  
6.1.2 Screening/Washout Phase 
Prior to performance of any trial related procedure (including washout), signed informed 
consent must be obtained from the subject.  
A washout period will have to be completed for subjects who are or have recently been treated 
with anti-psoriatic treatments or other relevant medication not permitted as defined by the 
exclusion criteria (see Section 7.3). The washout is to ensure that no other treatment could 
interfere with the response obtained with the IPs in the trial. The duration of the washout 
period is limited for logistical reasons to a maximum of 4 weeks. Because the maximum 
washout is 4 weeks, subjects who have recently been treated with biologics that require more 
than a 4 week washout period (e.g. ustekinumab should not be used for 16 weeks prior to 
commencing the trial), will not be eligible for the trial unless they have been off- treatment for 
several weeks (e.g. at least 12 weeks for ustekinumab) prior to the eligibility evaluation. 
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Assessment of subject eligibility should be made at a Screening Visit, prior to commencing a 
washout period. Screening assessments and trial procedures to be performed at Screening 
Visit are outlined in Section 8. On completion of the washout period, confirmation of the 
subject’s ongoing eligibility for the trial will be made at Visit 1. 
However, if no washout is needed the subject can enter Visit 1 directly. 
6.1.3 Initial open-label treatment phase 
Eligible subjects will first enter an initial open-label treatment phase, where they will be 
instructed to apply LEO 90100 once daily on the psoriatic lesions on trunk and limbs for 
4 weeks. All trial medication needed for 4 weeks (7 cans of LEO 90100) will be dispensed at 
Visit 1.    
The first application of the trial medication should be made at Visit 1 under the supervision 
and instruction of the trial staff or at home on the same day the subject attended Visit 1. For 
detailed treatment instructions, see section 10.2. 
After 4 weeks, subjects will be asked to return to the trial site for clinical evaluation and 
medication accountability (Visit 2). All trial medication dispensed at Visit 1 will be collected. 
Subjects who achieve treatment success (PGA score of ‘clear’ or ‘almost clear’ with at least a 
2-grade improvement from baseline) at Visit 2 will be randomised in a ratio of 1:1 in a
double-blind fashion to either LEO 90100 or vehicle (maintenance IP) twice weekly for 52
weeks.
The randomisation of subjects will be stratified by trial site, HPA axis testing, and by baseline 
disease severity, as determined by the PGA at Visit 1.  
Randomised subjects will receive the supply of maintenance IP for 4 weeks and will be 
instructed on how to apply it during the maintenance phase and what to do in case of relapse. 
Subjects who do not achieve treatment success after this initial open-label treatment phase 
will exit the trial.  
6.1.4 Maintenance phase 
During the maintenance phase, subjects will apply the randomised maintenance IP twice 
weekly on trunk and limbs to the areas where lesions have cleared or almost cleared after 
treatment was initiated at baseline. Any additional non-active psoriatic lesions (i.e. lesions not 
present at baseline that have been cleared or almost cleared by rescue treatment during a 
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relapse) should be treated with maintenance IP as well. Maintenance IP should be applied 3 or 
4 days apart. The choice of the application days will be left to subjects’ preference, and  these 
days will be fixed throughout the trial (e.g., Thursday and Sunday); this needs to be settled at 
Visit 2. Subjects will be assessed by the investigator at the trial site every 4 weeks from 
Visit 2 to Visit 15. Furthermore, depending on when relapse occurs in relation to the regular 
4-week visits (also referred to as ‘scheduled’ visits), additional (unscheduled) visits may be
needed (outlined below).
All regular 4-week (scheduled) visits between or after an unscheduled visit or relapse 
follow-up visit should be performed. 
Based on these rules, there are the following options: 
6.1.4.1 Relapse at a regular 4-week (scheduled) visit 
In case a relapse of psoriasis (defined as PGA of at least ‘mild’) is observed by the 
investigator at a regular monthly visit, the subject will be provided with rescue IP and 
instructed to apply it on the affected areas on trunk and limbs once daily for 4 weeks (all 
active psoriatic lesions including any new areas that become active during this 4-week 
treatment period).  
Twice weekly maintenance treatment will continue unchanged on areas that are not active. 
The subject will return to the trial site 4 weeks later to attend the regular monthly visit, where, 
if the subject is ‘clear’ or ‘almost clear’ according to PGA, maintenance treatment will be 
resumed on those areas. If the PGA of ‘clear’ or ‘almost clear’ is not achieved after 4 weeks of 
rescue treatment, the subject will exit the trial. For illustration, see Figure 2 below.  
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Figure 2 Relapse at a regular 4-week (scheduled) visit 
6.1.4.2 Relapse between regular 4-week (scheduled) visits – more than one 
week prior to the next regular visit 
If, in the opinion of the subject, a relapse of psoriasis occurs between regular visits when there 
is more than one week (7 days) to the next planned visit, the subject will contact the trial 
site to be assessed by the investigator at an unscheduled visit.  
If relapse is confirmed by the investigator, the subject will be provided with rescue IP and 
instructed to apply it once daily for 4 weeks on any active psoriatic lesions on trunk and limbs 
during this time.  
Twice weekly maintenance treatment will continue unchanged on areas that have not relapsed. 
The subject will be examined at the next regular 4-week visit, but even if ‘clear’/’almost 
clear’ at the regular visit, rescue treatment will continue. A relapse follow-up visit will take 
place at a relapse follow-up visit 4 weeks after the unscheduled visit where relapse treatment 
was initiated. If the subject is ‘clear’ or ‘almost clear’ according to PGA at this relapse follow-
up visit, maintenance treatment on those areas will be resumed and the subject will follow the 
planned visit schedule.  
If the subject is not ‘clear’or ‘almost clear’ according to PGA after 4 weeks of relapse 
treatment, they will exit the trial. For illustration, see Figure 3 below. 
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Figure 3 Relapse between regular 4-week (scheduled) visits – more than one week prior 
to the next regular visit  
6.1.4.3 Relapse between regular 4 week (scheduled) visits – less than one 
week to the next regular visit 
If a relapse/exacerbation of psoriasis occurs within one week (7 days) prior to the next 
scheduled visit, the subject should attend the next scheduled visit and the procedure 
described in section 6.1.4.1 should be followed. For illustration, see Figure 4 below. 
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Figure 4 Relapse between regular 4 week (scheduled) visits – less than one week to the 
next regular visit  
Trial visits (initial open-label treatment phase and maintenance phase) 
The total trial duration will be up to 64 weeks (including 8 weeks follow-up) and will include 
at least 15 regular visits. 
All post-randomisation visits (Visits 3 to 15) should be performed within ± 4 days of the 
scheduled time relative to Visit 2; if the visit is performed outside of the visit window, the 
investigator should record the reason in the subject’s medical record. The same visit window 
(± 4 days) is applicable for the follow-up of any unscheduled visits due to relapse. 
The maintenance IP will be dispensed at each regular visit (from Visit 1 to Visit 14) and used 
maintenance IP will be collected at the next regular visit (from Visit 2 to Visit 15). Rescue IP 
will either be dispensed at a regular visit and collected at the next regular visit, or be 
dispensed at an unscheduled visit and collected at a relapse follow-up visit 4 weeks later, as 
applicable. The number of cans to be dispensed depending on the different trial phases is 
specified in section 10.4. Subjects should not discontinue treatment themselves between the 
trial visits. This applies to both maintenance treatment and rescue treatment following relapse. 
The DLQI and EQ-5D-5L-PSO questionnaires will be completed at each visit to the site. 
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In addition, the subjects will be asked to complete the WPAI:PSO at baseline (Visit 1), at 
randomisation (Visit 2/Week 4), after approximately 6 months (Visit 8/Week 28) and at the 
end of treatment (Visit 15/Week 56).   
At baseline (Visit 1), subjects will be instructed on how to capture psoriasis symptoms in the 
eDiary (e.g. erythema, scaliness, itching, etc…) using the PSI.  
At home, subjects will complete the PSI daily during the open-label treatment phase (starting 
at Visit 1), then weekly during the first 28 weeks of the maintenance phase (Weeks 4 to 28) 
and the 2 last weeks of the maintenance phase (Week 54 to 56 - only applicable for 
completers).  
The eDiary will also be used to record adherence to the once daily treatment regimen during 
the initial open-label treatment phase as well as the twice weekly and once-daily treatment 
regimens during the maintenance phase and relapse.  
6.1.5 Follow-up Phase 
There are three types of follow-up visits, here listed in chronological order: 
Follow-up Visit 1 (FU1):  
A follow up visit 1 is only relevant for subjects with an ongoing AE at end of treatment. A 
follow-up visit/contact (FU1) should be conducted 14 (± 2) days after the last on-treatment 
visit (Visit 15/Early Withdrawal), unless the final outcome of the event, as defined below, has 
been determined before then. 
This follow-up visit/contact (FU1) will take place only if: 
1. there is an on-going SAE at the last on-treatment visit.
2. there is an on-going non-serious AE at the last on-treatment visit which is classified as
possibly or probably related to the IPs
3. the albumin-corrected serum calcium is above the reference range at the last
on-treatment visit
4. the calcium:creatinine ratio  is above the reference range and clinically significant at
the last on-treatment visit
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Where the (sub)investigator considers it appropriate, the Follow-up Visit may be performed as 
a telephone contact. If a subject also is elegible for a follow up visit 2 (FU2), the follow-up on 
the ongoing AE can wait until FU2 (see below). 
Follow-up Visit 2 (FU2): 
For subjects undergoing the adrenocorticotropic hormone (ACTH) challenge test, a follow-up 
visit (Visit FU2) will take place 28 days after the ACTH challenge test performed at the end of 
treatment (Visit 15/Early Withdrawal) if the end of treatment test shows a serum cortisol 
concentration ≤18 mcg/dl at both 30 minutes and 60 minutes after ACTH challenge (39, 40).  
If the results of the ACTH challenge test at Visit FU2 continue to show a serum cortisol 
concentration ≤18mcg/dl at both 30 minutes and 60 minutes after ACTH challenge, further 
ACTH challenge tests should be performed, but not more often than at 4-weekly intervals, 
until the adrenal suppression resolves (i.e. serum cortisol concentration >18mcg/dl at 
30 minutes or at 60 minutes after the ACTH-challenge, or at both time-points). 
Refer to Section 8.12.1 for further details on the ACTH challenge test. 
Follow-up visits should be performed within ±4 days of the scheduled time; if they are 
outside this window, the (sub)investigator should record the reason in the subject’s medical 
record but LEO do not need to be notified. 
Follow-up Visit 3 (FU3): 
All subjects should be followed up for events of rebound for 8 weeks after last application of 
IP. The different scenarios are outlined below: 

Subjects who do not use rescue medication at Visit 15 will have a final contact
(FU3) 8 weeks after Visit 15. Relapses confirmed at Visit 15 will be treated at the
investigator’s discretion; treatment with Enstilar® or IP is not allowed.

Subjects who have completed 4 weeks of rescue treatment at Visit 15 (that is,
Visit 15 is a relapse follow-up visit, see section 6.1.4.1) will have a final contact
(FU3) 8 weeks after Visit 15.

For subjects who use rescue medication at Visit 15 (that is, rescue medication was
dispensed at an unscheduled visit after Visit 14 [see section 6.1.4.2]), the 8-week
follow-up period will start after completion of the 4-week rescue treatment regimen
(that is, at the relapse follow-up visit).
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
Subjects who withdraw early from the trial, including subjects who leave the trial
after the initial 4 weeks open-label treatment, will also have a follow-up visit (FU3)
8 weeks after their last IP application.
Subjects who experience rebound during the follow-up period prior to the FU3 visit will 
contact the site as soon as possible for an unscheduled follow-up visit (see below). 
If the subject has not experienced a worsening of their psoriasis during the 8-week follow-up 
period, the FU3 contact may be conducted as a telephone contact, at the discretion of the 
investigator. If rebound is confirmed at the FU3 visit, the subject will be followed up for 
14 days or until resolution (whichever occurs first). If the rebound is considered an SAE, the 
event 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 (see section 9.5). 
Rebound events in the follow-up period will be reported as (S)AEs in accordance with 
sections 9.2 and 9.4.1. See section 9.5 for the follow-up of related AEs during and after the 
trial.  
Unscheduled follow-up visit 
At the last treatment visit (Visit 15/Early Withdrawal), subjects should be instructed to contact 
the site if they experience a worsening of their psoriasis within the following 8 weeks to 
schedule a follow-up visit (’unscheduled follow-up’). The unscheduled follow-up visit should 
take place no more than 7 days after the initial contact. 
If a relapse or rebound is confirmed at an unscheduled follow-up visit, the subject will be 
treated at investigator’s discretion according to clinical practice. Note that relapse or rebound 
should not be treated with trial medication or Enstilar® during the follow-up period. The 
subject may come back to the trial site for another unscheduled follow-up visit, at the 
investigator’s discretion. The subject will continue in the follow-up phase until the FU3 visit. 
If the subject experiences another worsening of their psoriasis within the 8-weeks follow-up 
period, they will contact the site again for a new unscheduled follow-up visit. 
6.2 Sample Size 
A total of 380 subjects should be randomised in the trial in order to have power for the 
primary maintenance treatment objective. In order to achieve 380 randomised subjects it is 
estimated that 832 subjects should be included in the trial.  
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The total number of subjects treated in the trial should also be sufficient to comply with ICH 
E1 regarding long-term safety. The aim is to achieve at least 300 subjects with 26 weeks of 
exposure and at least 100 subjects with 52 weeks of exposure. 
For the HPA axis test, the aim is to achieve approximately 25 subjects undergoing HPA axis 
testing after 52 weeks of exposure. 
The total number of randomised subjects can exceed 380 in order to achieve a sufficient 
number of subjects for long-term evaluation of safety and HPA testing. 
The statistical power considerations for this sample size are described in section 11.1. 
6.3 Randomisation 
Subjects will be randomised in a 1:1 ratio to receive LEO 90100 or vehicle twice weekly 
during the maintenance phase. Randomisation will be stratified by trial site, HPA axis testing, 
and by baseline disease severity (mild, moderate, severe). 
6.4 Blinding 
During the open-label treatment phases (initial and relapse treatment), all subjects will receive 
LEO 90100.  
During the maintenance phase, this trial is double-blind. Therefore, the packaging and 
labelling of the IPs must contain no evidence of their identity. It is not considered possible to 
differentiate between the IPs solely by sensory evaluation. No effects of the IPs which would 
reveal the identity of the individual treatment allocations are expected. Consequently, it is 
expected that the subjects and the site staff remain unaware of the individual treatment 
assignment during the conduct of the clinical trial. 
7 Trial Population and Withdrawal 
7.1 Subject Eligibility  
The (sub)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 “Schedule of Trial Procedures” [cf. 8.1].  
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Any implementation of national requirements/law for the subject’s participation in the clinical 
trial must be ensured and described in the submission documentation to authorities/ethics 
committees, as applicable. 
7.2 Inclusion Criteria 
1. Signed and dated informed consent obtained prior to any trial related activities
(including washout period)
2. Age 18 years or above
3. A clinical diagnosis of psoriasis vulgaris for at least 6 months involving the trunk
and/or limbs, amenable to treatment with  maximum of 100 g of trial medication per
week
4. Psoriasis vulgaris on the trunk and/or limbs (excluding psoriasis on the genitals and
skin folds) involving 2-30% of the body surface area (BSA)
5. A Physician's Global Assessment of disease severity (PGA) of at least ‘mild’ on trunk
and limbs at Visit 1
6. A m-PASI score of at least 2 at Visit 1
7. A target lesion/target location of at least 3 cm at its longest axis located on the body
(i.e., not on the scalp, face or intertriginous areas), scoring at least 1 (‘mild’) for each
of redness, thickness and scaliness, and at least 4 in total by the Investigator’s
Assessment of Severity of the Target Lesion/Location
8. Females of child-bearing potential must have a negative urine pregnancy test at Visit 1
9. Females of child-bearing potential must agree to use a highly effective method of birth
control during the trial*
10. Able to communicate with the investigator and understand and comply with the
requirements of the trial
*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 implants, injectables, combined oral contraceptives, some intra-
uterine devices, sexual abstinence or vasectomised partner. The subjects must have used the
contraceptive method continuously for at least 1 month prior to the pregnancy test, and must
continue using the contraceptive method for at least 1 week after the last application of trial
medication. A female is defined as not of child-bearing potential if she is postmenopausal (12
months with no menses without an alternative medical cause), or surgically sterile (hysterectomy or
bilateral overiectomy).
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Additional inclusion criteria for subjects undergoing HPA axis test (assigned sites 
only): 
11. Signed and dated informed consent obtained for having ACTH challenge tests
performed
12. An extent of psoriasis vulgaris on trunk and/or limbs of disease severity (PGA) of at
least ‘moderate’ affecting between 10 and 30% of the body surface area (BSA)
excluding psoriatic lesions of genitals and skin folds at Visit 1
13. At Visit 1, a normal HPA axis function including a serum cortisol concentration above
5 mcg/dl before ACTH-challenge and above 18 mcg/dl 30 minutes after ACTH-
challenge.
7.3 Exclusion Criteria 
1. Systemic treatment with biological therapies, whether marketed or not, with a possible
effect on psoriasis vulgaris within the following time periods prior to Visit 1:

etanercept – within 4 weeks prior to Visit 1

adalimumab, infliximab – within 8 weeks prior to Visit 1

ustekinumab – within 16 weeks prior to Visit 1

secukinumab – within 12 weeks prior to Visit 1

other products – within 4 weeks/5 half-lives prior to Visit 1 (whichever is
longer)
2. Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris
(e.g. corticosteroids, retinoids, methotrexate, ciclosporin and other
immunosuppressants) within 4 weeks prior to Visit 1
3. Systemic treatment with apremilast within 4 weeks prior to Visit 1
4. Subjects who have received treatment with any non-marketed drug substance (i.e. a
drug which has not yet been made available for clinical use following registration)
within 4 weeks/5 half-lives (whichever is longer) prior to Visit 1
5. Psoralen combined with Ultraviolet A (PUVA) therapy within 4 weeks prior to Visit 1
6. Ultraviolet B (UVB) therapy within 2 weeks prior to Visit 1
7. Topical anti-psoriatic treatment on the trunk and/or limbs (except for emollients) within
2 weeks prior to Visit 1
8. Topical treatment on the face, scalp and skin folds with corticosteroids, or vitamin D
analogues within 2 weeks prior to Visit 1
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9. Severe and/or extensive scalp psoriasis which, in the opinion of the investigator,
requires treatment with potent or super-potent corticosteroids which will be prohibited
during the trial
10. Pre-existing overt atrophy or teleangiectasia in treatment areas
11. Planned initiation of, or changes to, concomitant medication that could affect psoriasis
vulgaris (e.g. beta blockers, antimalarial drugs, lithium, ACE inhibitors) during the trial
12. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis
13. Subjects with any of the following conditions present on the treatment area: viral (e.g.
herpes or varicella) lesions of the skin, fungal and bacterial skin infections, parasitic
infections, skin manifestations in relation to syphilis or tuberculosis, acne vulgaris,
atrophic skin, striae atrophicae, fragility of skin veins, ichtyosis, ulcers and  wounds
14. Other inflammatory skin disorders (e.g. seborrhoeic dermatitis or contact dermatitis) on
the treatment area that may confound the evaluation of psoriasis
15. Planned excessive exposure of area(s) to be treated with trial medication to either
natural or artificial sunlight (including tanning booths, sun lamps etc.) during the trial
16. Known or suspected disorders of calcium metabolism associated with hypercalcaemia
17. Known or suspected hypersensitivity to component(s) of investigational products
18. Current participation in any other interventional clinical trial
19. Previously screened in this trial
20. In the opinion of the (sub)investigator, the subject is unlikely to comply with the
clinical trial protocol (e.g. due to alcoholism, drug addiction or psychotic state)
21. Females who are pregnant, wishing to become pregnant during the trial or are
breastfeeding
22. Subjects in close affiliation with the trial personnel (e.g. immediate family member or
subordinate), subjects being a member of the clinical trial personnel, or being an
employee of the sponsor or a contract research organization (CRO) involved in the trial
23. Subjects who are institutionalized by court order or by local authority.
Additional exclusion criteria for subjects undergoing HPA axis test (assigned sites 
only): 
24. A history of allergic asthma, serious allergy or serious allergic skin rash
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25. Known or suspected hypersensitivity to component(s) of CORTROSYN® (including
cosyntropin/tetracosactide) (in the US) / Synacthen® (including tetracosactide) (in
Europe)
26. The use of inhaled corticosteroids in the 4 weeks prior to Visit 1 or during the trial
27. Systemic corticosteroid treatment in the 12 weeks prior to Visit 1 or during the trial
28. Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks prior to
Visit 1 or during the trial
29. Systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole, itraconazole,
metronidazole) within 4 weeks prior to Visit 1 or during the trial. Topical ketoconazole
within 2 weeks prior to Visit 1
30. Hypoglycemic sulfonamides within 4 weeks prior to Visit 1 or during the trial
31. Antidepressive medications within 4 weeks prior to Visit 1 or during the trial.
Oestrogen therapy (including contraceptives), antidepressant medications and any other
medication known to affect cortisol levels or HPA axis integrity within 4 weeks prior to
baseline
32. Not following nocturnal sleep patterns
33. Any of the following conditions, whether known or suspected:

depression and endocrine disorders (e.g. Cushing’s disease, Addison’s disease,
diabetes mellitus) known to affect cortisol levels or HPA axis integrity

cardiac disorders associated with abnormal QT intervals or rhythm disturbances
including clinically significant bradycardia or tachycardia

severe renal insufficiency

severe hepatic disorders.
7.4 Screening failures 
For screening failures the following must be collected: reason for not continuing in the trial, 
SAEs and AEs. Follow-up of SAEs must be carried out according to section 9.5. 
7.5 Subject Enrolment Log 
All subjects screened for this trial will be recorded on an enrolment log. The log will record 
whether subjects were enrolled or not. If a subject is not enrolled, the main reason for non-
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enrolment will be listed. The log will be prepared according to local regulations regarding 
personal data protection. 
Additionally, all subjects that fail screening will be accounted for in the electronic case report 
form (eCRF). These subjects will be identified by a subject ID and date or year of birth.  
7.6 Subject Identification List 
The (sub)investigator must maintain a list of all subjects entering the open-label phase 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 is kept by the 
investigator and must not be copied or retained by LEO. 
At screening visit, each subject must be assigned a unique subject ID to protect the subject's 
identity and which will be used in lieu of the subject's name when the (sub)investigator 
reports trial-related data. 
The subject ID is distinct from the randomisation code number. 
7.7 Subject card 
At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact address(es) and telephone number(s) of relevant trial site staff. 
7.8 Restrictions during Trial 
Use of concomitant treatment must be recorded in the subject’s medical record and the eCRF 
(treatment/drug name, dose, indication and dates of start and stop). 
7.8.1 Restrictions prior to the start of treatment (Visit 1) 
The washout phase is up to 4 weeks (28 days). Subjects who are being treated with 
medications requiring more than 4 weeks washout will not be eligible for the trial.  
However, subjects might be eligible if they had a treatment-free period prior to entering the 
trial (i.e. having signed the Informed Consent). 
Note: the treatment-free period prior to entering the trial is not a trial related procedure and 
accordingly not part of the trial defined wash-out phase. The earliest possible wash-out start  
date to record in the eCRF is the day the subject entered the trial (i.e. having signed the 
Informed Consent). 
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To account for an adequate treatment-free period, the date of last use of the excluded 
medication will be recorded in the eCRF. 
Treatments requiring washout 
Treatments requiring washout before Visit 1 are listed in Table 1 (all subjects) and Table 2 
(subjects performing HPA axis test) below, together with the required individual washout 
periods.  
7.8.2 During the Trial Treatment Phase (open-label treatment phase and 
maintenance phase) 
Treatments which cannot be used during the treatment period (Visit 1 to Visit 15) are listed in 
Table 1 (applicable to all subjects).  
Table 1: Prohibited Medication including Non-Drug Therapies and Procedures (for all 
subjects) 
Prohibited Medication including Non-
Drug Therapies and Procedures 
Location 
Exclusion Period 
Restrictions 
Systemic treatment with biological therapies 
(marketed and not marketed), with a possible 
effect on psoriasis vulgaris 
Not 
applicable 

Etanercept: within 4 weeks prior to Visit
1

Adalimumab, infliximab: within 8
weeks prior to Visit 1

Ustekinumab: within 16 weeks prior to
Visit 1

Secukinumab:  within 12 weeks prior to
Visit 1

Other products:  within 4 weeks/5 half-
lives prior to Visit 1 (whichever is
longer) and any time during the trial
treatment phase
Systemic treatment with therapies other than 
biologicals, with a possible effect on 
psoriasis vulgaris (e.g., corticosteroids, 
retinoids, methotrexate, ciclosporin and 
other immunosuppressants)  
Not 
applicable 
Within 4 weeks prior to Visit 1 and any time 
during the trial treatment phase 
Systemic treatment with apremilast 
Not 
applicable 
Within 4 weeks prior to Visit 1 and any time 
during the trial treatment phase 
Use of non-marketed/other IPs 
Body and 
scalp 
Within 4 weeks or 5 half-lives (whichever is 
longer) prior to visit 1 and any time during the 
trial treatment phase 
Psoralen combined with UVA therapy 
(PUVA) 
Body and 
scalp 
Within 4 weeks prior to Visit 1 and any time 
during the trial treatment phase 
UVB therapy 
Body and 
Scalp 
Within 2 weeks prior to Visit 1 and any time 
during the trial treatment phase 
Any topical treatment on the body or scalp 
Body and 
Within 2 weeks prior to visit 1 and any time 
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Prohibited Medication including Non-
Drug Therapies and Procedures 
Location 
Exclusion Period 
Restrictions 
including corticosteroids (except for 
emollients, non-steroid medicated shampoos 
and low potency corticosteroids on sensitive 
areas), see Table 3 
Scalp 
during the trial treatment phase. On areas treated 
with IP, emollients should not be used on days 
where IP is being applied. 
Initiation of, or changes to, concomitant 
medication that could affect psoriasis 
vulgaris (e.g. beta-blockers, lithium, anti-
malaria drugs, ACE inhibitors) 
Not 
applicable 
Any time during the trial treatment phase 
Vitamin D supplements > 400 IU/day,  
(note: stable dose of vitamin D supplements 
≤ 400 IU/day is permitted ) 
Not 
applicable 
Any time during the trial treatment phase 
Excessive exposure of treated areas to either 
natural or artificial sunlight that may affect 
psoriasis vulgaris. (i.e., normal lifestyle 
outdoor activities are permitted but 
deliberate exposure to sunlight or artificial 
ultraviolet light like tanning booths should 
be avoided) 
Body and 
Scalp 
Any time during the trial treatment phase 
For subjects performing HPA axis test, additional treatments requiring washout before Visit 1 
and prohibited during the trial are listed in Table 2 below, with the required individual 
washout periods: 
Table 2: Prohibited Medication including Non-Drug Therapies and Procedures 
(for subjects performing HPA axis test) 
Prohibited Medication including Non-Drug 
Therapies and Procedures 
Location 
Exclusion Period 
Restrictions 
Systemic treatment with corticosteroids 
Not 
applicable 
Within 12 weeks prior to V1 and any time 
during the trial treatment phase 
Inhaled corticosteroids 
Not 
applicable 
Within 4 weeks prior to V1 and any time during 
the trial treatment phase 
Oestrogen therapy (including contraceptives) 
or any other medication known to affect 
cortisol levels or HPA axis integrity   
Not 
applicable 
Within 4 weeks prior to V1 and any time during 
the trial treatment phase 
Enzymatic inductors (e.g., barbiturates, 
phenytoin, rifampicin), systemic or topical 
cytochrome P450 inhibitors (e.g., 
ketoconazole, itraconazole, metronidazole), 
hypoglycaemic sulfonamides, antidepressive 
medications  
Body and 
Scalp 
Within 4 weeks prior to V1 and any time during 
the trial treatment phase 
Topical ketoconazole 
Body and 
Scalp 
Within 2 weeks prior to V1 and any time during 
the trial treatment phase 
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For all subjects, a stable concomitant treatment regimen with other drugs that have a potential 
effect on psoriasis (e.g. beta-blockers, anti-malarials and ACE inhibitors) is allowed during 
the trial. 
Inhaled steroids are allowed during the trial (except during the last 4 weeks prior to ACTH-
challenge for subjects participating in the HPA axis part). 
Bath oils and moisturising soaps are allowed during the trial. 
Sunscreens are allowed but should not be applied at the same time as the trial medication (an 
interval of at least 1 hour is recommended between applications). 
Any skin conditions other than psoriasis may be treated with topical therapy as appropriate 
provided the treatment does not affect the assessment, treatment or severity of psoriasis. The 
topical therapy should be applied only on the target area(s) of the skin condition and not on 
the area(s) of psoriasis. 
Concomitant anti-psoriatic treatments allowed during the trial is listed in Table 3: 
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Table 3: Permitted concomitant anti-psoriatic treatment 
Location 
Permitted concomitant anti-psoriatic treatment 
Scalp 
Non-medicated and medicated shampoos/products except those 
that contain corticosteroids or vitamin D analogues (e.g., tar, 
salicylic acid, tazaroten, anthraline) are allowed. 
Topical use of mild corticosteroids (class 6-7) is allowed, but 
should be for short term use and be minimized to the largest 
possible extent. 
Trunk/limbs 
Bath oils and moisturizing soaps are allowed. 
Unlimited use of emollients (except within 6 hours of clinic 
visits) is allowed. 
Emollients used should not contain alpha-hydroxy acids, beta-
hydroxy acids or acetylic acid; Emollients containing urea acid 
(≤ 5%) are allowed. 
Face and sensitive areas 
Any topical treatments other than  class 1-5 corticosteroids or 
Vitamin D analogues (calcipotriol, calcitriol or tacalcitol) are 
allowed (e.g. topical calciuneurin inhibitors). 
Topical use of mild corticosteroids (class 6-7) is allowed, but 
should be for short term use and be minimized to the largest 
possible extent. 
Unlimited use of emollients is allowed. 
Bath oils and moisturizing soaps are allowed. 
Note: 
sensitive areas refers to armpits, groin, under the breasts and in other skin folds around the genitals 
and buttocks 
7.8.3 Follow-up period 
During the follow-up period, subjects who require a repeat ACTH-challenge test at FU2 
(Section 6.1.5) should not receive corticosteroid therapy (topical or systemic), enzymatic 
inductors, cytochrome P450 inhibitors, hypoglycemic sulfonamides, anti-depressive 
medications, estrogen therapy, or any other medication known to affect cortisol levels/HPA 
axis integrity. Such subjects should also continue to use contraception if they are of child-
bearing potential.  
Note that treatment with Enstilar® or IP is not allowed during the follow-up period 
(Section 6.1.5). 
7.9 Discontinuation 
Subjects may withdraw from the trial for any of the following reasons: 
1. Screening failure
2. Lack of efficacy: The (sub)investigator is free to withdraw the subject at any time based
on a medical judgement.
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3. Adverse event (please specify): Any adverse event (AE) that the (sub)investigator
considers unacceptable.
4. Withdrawal by subject: Subjects are free to withdraw from the clinical trial at any time
and for any reason.
5. Lost to follow-up
6. Death
7. Other (please specify): Other reasons than stated above which require the subject to
(be) withdraw(n) should be specified.
Subjects must be withdrawn from the trial for any of the following reasons: 
8. Subjects who do not achieve treatment success (PGA score of ‘clear’ or ‘almost clear’ 
with at least a 2-grade improvement from baseline) after initial 4-week treatment
9. Subjects who are not scored as ‘clear’ or ‘almost clear’ after 4-week treatment of
relapse
If adverse event or other is selected, a specification must be supplied. 
Subjects who are discovered, after enrolment/randomisation, not to have fulfilled all in-
/exclusion criteria at the time of enrolment should discontinue treatment unless the 
(sub)investigator, based on clinical and ethical evaluation, finds discontinuation inappropriate. 
The final efficacy assessment (at the correct scheduled time) should be attempted to be 
completed for all subjects. Such deviation(s) from the (Consolidated) Clinical Trial Protocol 
must be reported to LEO Pharma A/S (and Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), as appropriate) and recorded in the Clinical Study Report. 
Reason(s) for discontinuation from trial will be recorded in the eCRF. Subjects withdrawn 
will not be substituted.  
8 Trial Schedule and Assessments 
8.1 Schedule of Trial Procedures 
The schedule of trial procedures is shown in Table 4. 
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P-001 - Clinical Trial Protocol (template); version 18-Aug-2015 
Table 4: Schedule of Trial Procedures 
Screening 
Open-label 
phase 4 wks 
Maintenance phase 
Follow-up phase 
SV1) 
Visit 12) 
Baseline 
Visit 2 
Randomi- 
sation 
V3 to 
V14 
V15 
UNS/ 
Relapse FU 
visit17) 
Early 
Withdrawal FU118,20) FU219,20) 
FU321) 
UNS FU22) 
Frequency 
Every 4 weeks (from V1 to V15) relative to V2 
8 weeks 
after 
V15/EW 
As needed 
Visit window 
±4 days (from V1 to V15) 
No more than 
7 days after 
subject calls 
±2 days ±4 days 
±4 days ≤ 7 days after 
call 
Informed consent3) 
X 
Informed consent for 
biomarkers3) 
X 
Informed consent for 
ACTH challenge 
tests3) 
X 
Informed consent for 
photographs3) 
X 
Inclusion/Exclusion 
criteria 
X 
X 
Demographics 
X 
Fitzpatrick Skin type 
X 
Height and weight 
X 
Vital signs (BP, 
pulse) 
X 
X 
X 
X 
Physical 
examination 
X 
X4)
X 
X 
X25)
Medical history/ 
locations of psoriasis 
X 
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P-001 - Clinical Trial Protocol (template); version 18-Aug-2015 
Screening 
Open-label 
phase 4 wks 
Maintenance phase 
Follow-up phase 
SV1) 
Visit 12) 
Baseline 
Visit 2 
Randomi- 
sation 
V3 to 
V14 
V15 
UNS/ 
Relapse FU 
visit17) 
Early 
Withdrawal FU118,20) FU219,20) 
FU321) 
UNS FU22) 
Frequency 
Every 4 weeks (from V1 to V15) relative to V2 
8 weeks 
after 
V15/EW 
As needed 
Visit window 
±4 days (from V1 to V15) 
No more than 
7 days after 
subject calls 
±2 days ±4 days 
±4 days ≤ 7 days after 
call 
Previous anti-
psoriatic therapy 
X 
Concomitant 
medication and 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test5) 
X 
X 
X 
X 
X 
Randomisation 
X 
Adverse Event6) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory: 
Biochemistry 
X 
X7) 
X8) 
X8) 
X 
Laboratory: 25-OH 
Vitamin D 
X 
Urinalysis 
X 
X7) 
X8) 
X8) 
X 
Laboratory: ACTH 
challenge test 
(assigned sites 
only)9)   
X 
X 
X10) 
X 
X24) 
X23)
Sampling for 
biomarkers11) 
X 
X10) 
X12) 
X12) 
Subject’s Global 
Assessment of 
disease severity  
X 
X 
X 
X 
X 
X 
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P-001 - Clinical Trial Protocol (template); version 18-Aug-2015 
Screening 
Open-label 
phase 4 wks 
Maintenance phase 
Follow-up phase 
SV1) 
Visit 12) 
Baseline 
Visit 2 
Randomi- 
sation 
V3 to 
V14 
V15 
UNS/ 
Relapse FU 
visit17) 
Early 
Withdrawal FU118,20) FU219,20) 
FU321) 
UNS FU22) 
Frequency 
Every 4 weeks (from V1 to V15) relative to V2 
8 weeks 
after 
V15/EW 
As needed 
Visit window 
±4 days (from V1 to V15) 
No more than 
7 days after 
subject calls 
±2 days ±4 days 
±4 days ≤ 7 days after 
call 
Subject - Local 
safety and 
Tolerability  
X 
X 
X 
X 
X 
X 
Physician’s Global 
Assessment of 
disease severity  
X 
X 
X 
X 
X 
X 
X 
X25)
X 
Selection of the 
target lesion/location 
X 
Investigator’s 
Assessment of the 
Severity of the target 
lesion/location 
X 
X 
X 
X 
X 
X 
X25)
X 
Photographs of the 
target lesion/loc 11,13) 
X 
X 
X 
X 
X 
X 
Local safety and 
Tolerability – 
Physician 
X 
X 
X 
X 
X 
X 
X25)
X 
m-PASI
X 
X 
X 
X 
X 
X 
X25)
X 
BSA 
X 
X 
X 
X 
X 
X 
X25)
X 
DLQI 
X 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
WPAI:PSO 
X 
X 
X10) 
X 
X 
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P-001 - Clinical Trial Protocol (template); version 18-Aug-2015 
Screening 
Open-label 
phase 4 wks 
Maintenance phase 
Follow-up phase 
SV1) 
Visit 12) 
Baseline 
Visit 2 
Randomi- 
sation 
V3 to 
V14 
V15 
UNS/ 
Relapse FU 
visit17) 
Early 
Withdrawal FU118,20) FU219,20) 
FU321) 
UNS FU22) 
Frequency 
Every 4 weeks (from V1 to V15) relative to V2 
8 weeks 
after 
V15/EW 
As needed 
Visit window 
±4 days (from V1 to V15) 
No more than 
7 days after 
subject calls 
±2 days ±4 days 
±4 days ≤ 7 days after 
call 
Psoriasis symptom 
inventory 
Daily during the open-label phase 
Weekly during the first 28 weeks of the maintenance phase 
and the 2 last weeks of the maintenance phase (for completers only) 
Compliance 
check14)-eDiary 
Daily during the open-label phase  
Weekly during the maintenance phase (including relapse treatment) 
Subject treatment 
instructions 
X 
X 
X 
Dispensing of IP 
X 
X 
X 
X15) 
Return of IP 
X 
X 
X 
X16) 
X 
Drug compliance 
Form 
X 
X 
X 
X 
X 
End of Trial Form 
X 
X 
1) A washout period of up to 4 weeks must be completed if the subject is treated or has recently been treated with anti-psoriatic treatments or other relevant medication, as defined by
the exclusion criteria.
2) SV and Visit 1 can be performed at the same time for subjects who do not need a washout period.
3) Informed consent should be signed both by subject and (sub)investigator (medically qualified) before any trial related procedures are carried out. For subjects requiring a washout
period, informed consent should be completed prior to washout.
4) Physical Examination at Visit 2 is required if the subject will not be randomised
5) Only applicable for women of child-bearing potential.
6) AEs will be collected from the date of signing the informed consent form i.e. during the washout period.
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P-001 - Clinical Trial Protocol (template); version 18-Aug-2015 
7) If albumin-corrected serum calcium is above the normal range, or if calcium:creatinine ratio is above the normal range and judged as clinically significant at this visit, sampling
should be repeated at the following visit (Visit 3 or FU1)
8) If albumin-corrected serum calcium is above the normal range, or if calcium:creatinine ratio is above the normal range and judged as clinically significant at this visit, sampling
should be repeated at a follow-up visit
9) Applicable only to subjects performing HPA axis assessments. ACTH challenge test should be performed at 8.00 a.m. ±30 min after checking vital signs and collecting blood and
urine samples.
10) At Visit 8 (Week 28) only.
11) Only for subjects who consented for this procedure.
12) Or earlier in case of early withdrawal fors subjects who have completed at least 40 weeks of the trial from baseline.
13) At designated sites.
14) Treatment compliance will be recorded by the subject in an eDiary.
15) In case of relapse, LEO 90100 will be dispensed at any unscheduled visit during the maintenance phase.
16) Subjects will have to return LEO 90100 dispensed during any unscheduled visit (UNS) at the following relapse follow-up visit (Relapse FU) or at the next regular 4-week visit.
17) Unscheduled visit (UNS) or relapse follow-up visit (Relapse FU) to be performed in case a relapse of psoriasis occurs (see figures section 6.1.4).
18) FU1 visit should only be performed if required, e.g. in case a non-serious AE is classified as possibly or probably related to the trial treatment or an SAE is on-going at the last
on-treatment visit. Where the (sub)investigator considers it appropriate, the FU1 visit may be performed as a telephone contact. To be performed 2 weeks after the last on-treatment
visit.
19) FU2 visit only applicable for subjects for whom the ACTH challenge test at end of treatment shows a serum cortisol concentration ≤18 mcg/dl at both 30 minutes and 60 minutes
after ACTH-challenge. The FU2 visit will be performed 4 weeks after the last-on treatment visit.
20) If both FU1 and FU2 are applicable (only applicable for subjects performing HPA axis assessments), only FU2 (4 weeks after the last on-treatment visit) will be performed. All
assessments applicable at FU1 will be done at FU2.
21) Subjects will be followed up for 8 weeks after V15/EW for relapse/rebound evaluation. If the subject has not experienced a worsening of their psoriasis during the 8 week
follow-up period, the FU3 contact may be conducted as a telephone contact, at the discretion of the investigator.
22) Subjects who experience a worsening of their psoriasis during the follow-up phase prior to the FU3 visit will contact the site as soon as possible for an unscheduled follow-up
visit (section 6.1.5).
23) Subjects with a serum cortisol concentration ≤18mcg/dl at both 30 minutes and 60 minutes after ACTH challenge at FU2 will be followed up until the adrenal suppression
resolves. Further ACTH challenge tests must be captured in the UNS FU page in the eCRF.
24) If the subject withdraws prior to completing the initial open-label treatment phase, the ACTH-challenge test should not be performed.
25) Only required if last FU3 is performed at the trial site.
EW, early withdrawal; FU, follow-up; IP, investigational product; SV, screening visit; UNS, unscheduled visit; UNS FU, unscheduled follow-up visit; V, visit.
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8.2 Demographics 
Subject’s demographic details (date of birth or month/year only and self-reported age 
(depending on participating countries), sex, race, ethnic origin (ethnicity)) must be recorded. 
Subjects will self-report their ethnicity (Hispanic or Latino, not Hispanic or Latino) and race 
(American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other). 
8.3 Fitzpatrick Skin Type 
The skin type of the subjects will be recorded using the classification specified in Table 5. 
Table 5: Fitzpatrick Skin Classification 
Fitzpatrick 
Skin Type 
Skin Colour 
(unexposed skin) 
History (to first 30 to 45 minutes of sun exposure 
after a winter season of no sun exposure) 
I 
White 
Always burns easily; never tans 
II 
White 
Always burns easily; tans minimally 
III 
White 
Burns moderately; tans gradually (light brown) 
IV 
White 
Burns minimally; always tans well (moderate 
brown) 
V 
Brown 
Rarely burns; tans profusely (dark brown) 
VI 
Black 
Never burns; deeply pigmented 
8.4 Height and Weight 
The subject’s weight (with indoor clothing and without shoes) and the height (without shoes) 
will be recorded.  
8.5 Vital Signs 
Vital signs will include blood pressure (systolic and diastolic recorded in mmHg) and heart 
rate (beats per minute). Heart rate and blood pressure will be measured after approximately 5 
minutes resting.  
8.6 Physical Examination 
An abbreviated physical examination including general appearance, regional lymph nodes and 
dermatologic examination of the skin must be performed at visits indicated in section 8.1.  
Abnormal, clinical significant findings at the screening visit should be recorded as diagnoses 
in the Concomitant Medication page if medication is currently being taken for the condition. 
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If not, it will be documented as medical history in the eCRF. From Visit 1, any clinically 
significant deterioration of a pre-existing condition as well as any new illness, symptom or 
clinically significant sign will be reported as an AE in accordance with section 9.2. 
8.7 Medical History 
Relevant medical history and concurrent diagnoses will be recorded based on subject 
interview. The duration of psoriasis will be recorded (to the nearest whole year). 
Locations of Psoriasis 
The presence of psoriasis lesions on the trunk and limbs that constitute the treatment areas 
(upper leg, knee, lower leg including foot, upper arm, elbow, forearm including hand, chest, 
abdomen, neck, upper back, lower back) will be recorded. 
The presence of psoriasis affecting regions of the body not considered to be part of the 
treatment area (i.e. face, scalp, skin folds, genitals, palms, soles, and nails) will also be 
recorded. 
Previous anti-psoriatic therapy 
All previous anti-psoriatic treatment (systemic and topical medications and light therapy) 
used by the subject to treat their psoriasis vulgaris over the past 2 years will be recorded by 
pre-defined categories. Latest treatment (within 4 months) prior to screening will also be 
recorded. 
8.8 Concomitant Medication and Procedures 
Concomitant medication is defined as any medication used by a subject during the clinical 
trial apart from the IPs. Use of concomitant treatment must be recorded in the subject’s 
medical record and the eCRF (e.g. treatment/drug name, route of administration, total daily 
dose, indication and dates of start and stop). 
For topical treatment, it must be recorded if the concomitant treatment is within 2 cm (appr. 
1 inch) of the areas treated with the IP. 
Any concomitant medication and procedure must be recorded at visits indicated in 
Section 8.1. Details should include body location, diagnosis, start/stop date and if the 
procedure is inside the treatment areas. 
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8.9 Pregnancy Test 
A urine pregnancy test will be performed at the trial site at Visit 1, prior to randomisation 
(Visit 2), and at all the subsequent visits including the last on-treatment visit (or earlier in case 
of premature withdrawal). The test will only be performed in female subjects of child-bearing 
potential. The test kits will be provided by the Central Laboratory. 
8.10 Adverse Events 
AEs must be assessed and recorded as specified in section 9. 
8.11 Other Safety Assessments 
All physician’s dermatologic assessments of the treatment area must be performed by a 
dermatologist, certified physician’s assistant, advanced registered nurse practitioner or general 
practitioner experienced in treating psoriasis vulgaris. The same person should attempt to 
perform all dermatologic examinations of each individual subject. 
The following assessment must be performed:  
Assessment of Local Safety and Tolerability – physician and subject 
The assessment of local safety and tolerability will comprise signs assessed by the 
(sub)investigator and symptoms reported by the subject. The signs and symptoms are not 
required to be reported as AEs. 
At all treatment phase visits (as indicated in section 8.1), the (sub)investigator will assess 
application site reactions for the following signs: perilesional erythema, perilesional oedema, 
perilesional dryness, and perilesional erosion. The subject will assess the symptom 
‘application site burning or pain’. 
For perilesional erythema, oedema, dryness and erosion, the area for the (sub)investigator to 
assess is the perilesional area, defined as the band of skin within two (2) cm from the border 
of the psoriatic lesion, i.e. not the lesion itself, at any given time. The assessed signs must be 
present in this area, but may extend beyond it in a continuous manner.  
The area for the subject to assess application site burning or pain is the treatment area, 
including the band of skin within two (2) cm from the border of the area. The reported 
symptoms must be present in this area, but may extend beyond it in a continuous manner. 
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For each sign and symptom the highest (worst) skin reaction score across all treatment areas 
will be recorded by use of the following 4-point scale as specified in Table 6 (Physician’s 
assessment) and Table 7 (Subject’s assessment) respectively: 
Table 6: Skin Reaction Scores – Physician’s Assessment 
0 = absent 
1 = mild 
2 = moderate 
3 = severe 
Perilesional 
erythema: 
No perilesional 
erythema 
Slight, barely 
perceptible 
perilesional 
erythema 
Distinct 
perilesional 
erythema 
Marked, intense 
perilesional 
erythema 
Perilesional 
oedema: 
No perilesional 
oedema 
Slight, barely 
perceptible 
perilesional 
oedema 
Distinct 
perilesional 
oedema 
Marked, intense 
perilesional 
oedema 
Perilesional 
dryness: 
No perilesional 
dryness 
Slight, barely 
perceptible 
perilesional 
dryness 
Distinct 
perilesional 
dryness 
Marked, intense 
perilesional 
dryness 
Perilesional 
erosion: 
No perilesional 
erosion 
Slight, barely 
perceptible 
perilesional 
erosion 
Distinct 
perilesional 
erosion 
Marked, intense 
perilesional 
erosion 
Table 7: Skin Reaction Scores – Subject’s Assessment 
0 = absent 
1 = mild 
2 = moderate 
3 = severe 
Application site 
burning or pain: 
No burning or 
pain after 
application 
Slight, barely 
perceptible 
burning or pain 
after application 
Distinct burning 
or pain after 
application 
Marked, intense 
burning or pain 
after application 
For the subject assessment of application site burning or pain, the (sub)investigator will 
explain the categories of the scale to the subject and the subject will tell the (sub)investigator 
which category to mark. 
8.12 Laboratory Assessments 
For both blood analysis and urinalysis, the Central Laboratory will provide the materials and 
instructions necessary for the collection and transportation of the samples. 
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8.12.1 Safety Laboratory Blood Analysis 
Blood samples (27.5 ml) for biochemistry must be collected at the time points specified in the 
schedule of trial procedures (section 8.1).  
Because there will be no repeated blood sampling, venepuncture will be used rather than 
indwelling catheters to minimise subject discomfort and to reduce the extent of invasive 
procedures. 
Collection, handling and shipment instructions for blood samples for biochemistry are 
provided in a separate laboratory manual. 
Biochemistry 
The following analysis will be performed on the serum blood samples: 

Calcium – in samples collected at baseline (Visit 1), after 4 weeks (Visit 2) and
at the end of trial (Visit 15, or at withdrawal from trial), plus at FU1 Visit if
applicable

Albumin - in samples collected at baseline (Visit 1), after 4 weeks (Visit 2) and
at the end of trialt (Visit 15, or at withdrawal from trial), plus at FU1 Visit if
applicable

25-OH vitamin D  - at baseline (Visit 1) only
Albumin-corrected serum calcium will be calculated in mmol/L using the formula: 
Serum calcium (total) in mmol/L + (0.02 x [40-serum albumin in g/L]). 
The (sub)investigator must evaluate all results outside the reference range (‘clinically 
significant’ or ‘not clinically significant’) and sign and date. If any of the laboratory results 
are abnormal and judged as clinically significant, it should be recorded as an adverse event 
and the (sub)investigator should follow up with the subject as clinically appropriate.  
If the albumin-corrected serum calcium result is above the normal reference range at Visit 2, 
sampling should be repeated at the next visit. If the albumin-corrected serum calcium result is 
above the reference range at the last on-treatment visit, a follow-up visit should be performed 
for repeat sampling. 
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For subjects undergoing ACTH challenge test (Assigned sites only) 
Adrenal function testing will be undertaken in a subset of randomised  subjects with psoriasis 
affecting between 10 and 30% of the BSA. The aim is to include 25 subjects undergoing HPA 
axis testing after 52 weeks of exposure.  
The samples listed above will be taken before the ACTH-challenge test that is also scheduled 
for these visits.  
The t=0 (baseline) measurement of serum cortisol concentration for the ACTH-challenge test 
will be made from the biochemistry sample. 
The ACTH-challenge test will be performed at baseline (Visit 1), after 4 weeks (Visit 2), after 
28 weeks (Visit 8)  and at the end of trial (Visit 15 or at early withdrawal). If the subject 
withdraws prior to completing the initial open-label treatment phase, the ACTH-challenge test 
scheduled for Visit 2 should not be performed. If the subject discontinues the trial prior to 
week 56 (this also includes discontinuation due to not achieving ‘clear’ or ‘almost clear’ 
disease status following 4 weeks of once daily treatment following a relapse in psoriasis 
status), a follow-up visit must be scheduled within 7 days of the last treatment period visit for 
the purpose of performing the ACTH-challenge test, if the test was not perfomed on the same 
day (rescheduling required due to the time dependancy of the ACTH-challenge test).  
Subjects will not be included in this procedure of the trial if one of the following applies to 
the serum cortisol concentration at Visit 1: 
•
≤5 mcg/dl pre-stimulation (before CORTROSYN® / Synacthen® injection)
•
≤18 mcg/dl at 30 minutes after CORTROSYN® / Synacthen® injection
If the ACTH challenge test at Visit 15 (end of maintenance phase) or at early withdrawal 
shows a serum cortisol concentration ≤18 mcg/dl at both 30 minutes and 60 minutes after the 
ACTH challenge, a further ACTH-challenge test is required 4 weeks later (FU2 visit). 
If the results of the ACTH-challenge test at the FU2 visit continue to show a serum cortisol 
concentration ≤18mcg/dl at both 30 minutes and 60 minutes after ACTH challenge, further 
ACTH challenge tests should be performed, but not more often than at 4-weekly intervals, 
until the adrenal suppression resolves (i.e. serum cortisol concentration >18mcg/dl at 30 
minutes or at 60 minutes after the ACTH challenge, or at both time-points). The data from 
such further ACTH challenge tests must be captured in the unscheduled follow-up visit page 
in the eCRF. 
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The following procedures should be performed prior to the ACTH challenge tests: Heart rate 
and blood pressure, blood/urine sampling for central laboratory analysis 
(biochemistry/urinalysis), blood sampling for biomarkers and urine pregnancy test (in female 
subjects of child-bearing potential).   
To perform the ACTH challenge test, a 2.5 ml sample of venous blood will be drawn at 08.00 
a.m. ±30 minutes. This sample is also the one on which the biochemistry analyses are
performed, as detailed above. Within 10 minutes after blood sampling, CORTROSYN® /
Synacthen®  will be injected, as described in section 10.9. Two further 2.5ml samples of
venous blood will be drawn exactly 30 and 60 minutes after the injection (counting from the
end of the period over which the injection is given). Serum cortisol concentrations will be
determined for each blood sample by the Central Laboratory.
The stop time of CORTROSYN® / Synacthen® injection will be recorded in the eCRF. 
ACTH challenge tests will require the subject's specific consent.  
8.12.2 Safety Urinalysis 
A 10 - 15 ml spot urine sample will be collected at baseline (Visit 1), week 4 (Visit 2) and at 
the end of trial (Visit 15, or at withdrawal from trial), plus at FU1 Visit if applicable. 
The laboratory will report: 

Calcium

Creatinine

Calcium:creatinine ratio will be calculated.
The (sub)investigator must evaluate all calcium:creatinine ratio results outside the reference 
range (‘clinically significant’ or ‘not clinically significant’) and sign and date. If any of the 
calcium:creatinine ratio  results are abnormal and judged as clinically significant, it should be 
recorded as an AE.  
If the calcium:creatinine ratio result is above the normal reference range and judged as 
clinically significant at Visit 2, sampling should be repeated at the next visit. If the result is 
above the reference range at the last on-treatment visit and judged as clinically significant by 
the investigator, a follow-up visit should be performed for repeated sampling. 
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8.12.3 Pharmacodynamic (PD) Assessments 
8.12.3.1 Blood sampling for serum biomarkers (for consenting subjects) 
Blood samples will be drawn at Visit 1 (baseline), Visit 8 (Week 28) and Visit 15 (end of trial 
or earlier in case of early withdrawal in subjects who have completed at least 40 weeks of the 
trial from baseline) for analysis of biomarkers related to systemic inflammation, 
cardiovascular disease, and metabolic syndrome. Initially, baseline and end of trial samples 
from the 50 subjects with highest baseline disease score will be analysed. Depending on the 
results from this analysis, the remaining samples may be analysed using a more focused 
biomarker panel. The analysis will be performed at the Biomarker Laboratory after unblinding 
of the trial, and the results will be described in a separate report. The Central Laboratory will 
provide the materials for the collection and the Biomarker Laboratory will provide 
instructions necessary for the handling and transportation of the samples. 
The blood volume will not exceed 24 ml (8 ml at baseline, 8 ml at Week 28 and 8 ml at end of 
trial or earlier in case of early withdrawal in subjects who have completed at least 40 weeks of 
the trial from baseline).  
LEO will collect and store half of this blood volume for future use (i.e., for analyses not 
described above). The sample will be stored in the bio bank established by LEO. The samples 
will be used for future research performed by LEO. Collection, storage and future use of the 
samples will require the subject's consent and donation. Donation of the samples for future 
research is voluntary and subjects must give their separate written consent to confirm the 
donation and the terms associated herewith. 
8.12.4 Total Blood Volume 
The blood volumes drawn per subject for the different analyses are shown in Table 8. 
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Table 8: Blood volume drawn from each subject during the trial 
Baseline 
Week 4 
Week 28 
End of 
Trial 
Total 
Vitamin D 
5 ml 
27,5 ml 
Calcium and 
albumin 
7,5 ml 
7,5 ml 
7,5 ml 
Biomarker1 
8 ml 
8 ml 
8 ml 
24 ml 
ACTH 
challenge 
test1,2 
5 ml
5 ml 
7,5 ml 
5 ml 
22,5 ml 
1) Optional; requires separate consent by the subject
2) Selected sites only. Note that T=0 measurement of serum cortisol at Baseline,
Week 4, and End of Trial will be made from the biochemistry sample. 
The total blood volume collected during the trial will for most subjects not exceed 50 ml. 
Only if subjects participate in both the biomarker and the HPA axis part of the trial, will the 
volume exceed 50 ml, but will not exceed 100 ml. 
8.13 Patient Reported Outcomes 
The subject must make self-assessments of quality of life and health status/symptoms at visits 
specified in the schedule of trial procedures (section 8.1). To ensure unbiased answers, the 
PROs should be completed prior to other assessments on the day of completion of the 
questionnaires (when questionnaires are completed during the trial visits) and the site staff 
should not challenge the subject’s answers. However, the subjects should be encouraged to 
answer all questions in the questionnaires. 
The DLQI, EQ-5D-5L-PSO and WPAI:PSO will be completed at the trial site on an electronic 
slate/tablet. The PSI will be completed on an eDiary device, which will be provided for the 
subjects for use at home.  
Symptoms reported on the DLQI, EQ-5D-5L-PSO, WPAI:PSO and PSI will not be captured 
as AEs, unless they are specifically mentioned as an AE by the subject when they are asked 
the non-leading question: “How have you felt since I saw you last?”.  
However, the site should review the PRO responses and follow up with the subject if the 
subject e.g. indicates a different level of anxiety/depression than what the subject answers to 
the above-mentioned non-leading question, in order to ensure that the subject gets the proper 
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help at the trial site or is referred to / encouraged to seek help from e.g. his/her primary care 
physician. 
DLQI, EQ-5D-5L-PSO, WPAI:PSO and PSI data will be reported in the clinical trial report. 
The questionnaires should preferably be completed in the below sequence. 
8.13.1 DLQI 
The DLQI is a validated, patient-reported, 10-item questionnaire that captures the effects of 
dermatologic conditions on a patient’s health-related quality of life (HRQoL). The questions 
evaluate daily activities, symptoms and feelings, leisure, work or school, personal 
relationships, and treatment.  
The DLQI will be completed by the subject at the trial site at baseline (Visit 1), at all monthly 
visits during the maintenance phase, and at all unscheduled visits (see Appendix 8: DLQI). 
8.13.2 EQ-5D-5L-PSO 
The EuroQoL-5D-5L is a standardized, preference-based, non–disease-specific instrument for 
describing and valuing HRQoL (see Appendix 7: EQ-5D-5L-PSO). Its components include a 
questionnaire on five general health dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and two psoriasis-related health dimensions (skin 
irritation and self-confidence) each with five response levels, and a VAS represented on a 
thermometer that allows patients to assess their health status with a score ranging from 0 
(worst health) to 100 (best health). Responses to the questions on the five dimensions result in 
a health state that can be converted into an index score based on the valuation of EuroQoL-5D 
health states from general population samples. The index score ranges from 0.00 to 1.00, 
where a score of 1.00 indicates full health and a 0.05 change is considered clinically 
meaningful. 
EQ-5D-5L-PSO will be administered at baseline (Visit 1) and at all monthly visits during the 
maintenance phase, as well as at all unscheduled visits. This questionnaire will be filled out 
by the subject at the trial site. 
8.13.3 WPAI:PSO 
The impact of the psoriasis on subject’s ability to work and perform regular activities will be 
assessed by means of  the Work Productivity and Activity Impairment: Psoriasis (WPAI:PSO) 
questionnaire (see Appendix 9: WPAI:PSO).The Work Productivity and Activity Impairment 
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Questionnaire Specific Health Problem (WPAI-SHP) is a validated instrument that has been 
used to study the impact of various diseases, including psoriasis, on patients’ ability to work 
and perform daily activities. It can be used to assess the work productivity and activity 
impairment related to a variety of diseases, including psoriasis. It consist of 6 questions that 
measure work productivity and activity impairment related to skin psoriasis. Following the 
standard methodology, the following measures can be constructed from the questions: (1) 
current employment status; (2) absenteeism, defined as the percentage of time missed from 
work as a result of the disease; (3) presenteeism, defined as the percentage reduced 
productivity while working; (4) total activity impairment (TAI), defined as the percentage 
impairment in regular daily activities other than work; and (5) total work productivity 
impairment (TWPI), representing the total percentage of work impairment associated with 
psoriasis from both absenteeism and presenteeism. The percentage of impairment associated 
with psoriasis will be assessed by each patient.  
This questionnaire will be administered at baseline (Visit 1), at randomisation (Visit 2/Week 
4), after approximately 6 months (Visit 8/Week 28) and at the end of trial (Visit 15/Week 56). 
This questionnaire will be filled out by the subject at the trial site. 
8.13.4 Psoriasis symptom inventory (PSI) 
The PSI, an eight-item measure to assess the severity of psoriasis symptoms will be 
completed by subjects daily during the initial open-label treatment phase (starting at Visit 1) 
and then weekly during the first 28 weeks of the maintenance phase (Weeks 4 to 32 (Visits 2 
to 9)) and the 2 last weeks of the maintenance phase (Week 54 to 56 (Visits 14 to 15) - only 
applicable for completers).  
The eight symptoms include itch, redness, scaling, burning, cracking, stinging, flaking and 
pain. ‘Scaling’ refers to the skin forming plates or scales that represent compacted 
desquamated layers of stratum corneum, which may then peel off; ‘flaking’ refers simply to 
loss of dry skin cells. Subjects rate the severity of each symptom on a 5-point Likert-type 
rating scale ranging from 0 (not at all) to 4 (very severe). Individual item scores are summed 
for a total score, which ranges from 0 to 32. The PSI will be administered as a 24-h recall 
version during the initial open-label treatment phase and as a 7-day recall version during the 
maintenance phase (the 7-day version was previously shown to provide results equivalent to 
24-h recall version (22) (see  Appendix 10: Psoriasis Symptom Inventory (PSI) – 24 hours
recall and Appendix 11: Psoriasis Symptom Inventory (PSI) – 7 days recall respectively).
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At baseline (Visit 1) the subject will complete this questionnaire in the eDiary while at the 
trial site. The subject will then subsequently fill this out while at home for all other 
timepoints/periods.   
8.13.5 Subject’s Global Assessment of Disease Severity 
This assessment will be made from baseline (Visit 1) and at all monthly visits during the 
maintenance phase, as well as all unscheduled visits, based on the condition of the disease at 
the time of the evaluation and not in relation to the condition at a previous visit, by use of the 
5-point scale specified below in Table 9. This assessment has to be done before investigator’s
assessments. The (sub)investigator will explain the categories of the scale to the subject and
the subject will tell the (sub)investigator which category to mark.
Table 9: Disease Severity Grading – Subject’s Assessment 
Clear 
No psoriasis symptoms at all 
Very mild 
Very slight psoriasis symptoms, does not interfere with daily life 
Mild 
Slight psoriasis symptoms, interferes with daily life only occasionally 
Moderate 
Definite psoriasis symptoms, interferes with daily life frequently 
Severe 
Intense psoriasis symptoms, interferes with or restricts daily life very 
frequently 
8.14  Subject assessment of local safety and tolerability 
As stated in section 8.11, the assessment of local safety and tolerability will also include 
symptoms reported by the subject. The symptoms are not required to be reported as AEs. 
See section 8.11 for more details. 
8.15 Photography 
At a limited number of pre-selected trial sites, the target lesion/location selected for the 
Investigator’s Assessment of the Severity of the Target Lesion/Location (Redness, Thickness, 
Scaliness) may be photographed. 
Photographs will only be taken for subjects where additional photograph-specific informed 
consent has been obtained. Participating in the imaging assessments is entirely voluntary, and 
subjects who do not wish to have images collected will still be invited to participate in the 
trial without being part of the trial sub-population from which images are collected. 
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The designated sites will use their own equipment to take colour photographs and these 
imaging assessments will be performed according to local regulations. 
Photographs will only be taken of the psoriasis target lesion/location affecting the trunk and 
limbs and the images will only be used as supportive data to the clinical assessments (i.e. 
there will be no adjudication of images or statistical analysis). 
Subjects' name or other identifying information will not be used in the trial photographs or in 
any later use of the photographs.  
Images will be collected at each trial visit. The recommendation of images to be collected 
includes: 

Anatomical Image, used to confirm the location of the target lesion/location

Macro Image
The location of the target lesion/location will be recorded by means of a visual representation 
in the source records and 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 health care professionals. The 
photographs can also be part of training material used for training and educational purposes. 
8.16  Investigator Assessments 
All dermatologic assessments of the treatment area must be performed by a dermatologist, 
certified physician’s assistant, advanced registered nurse practitioner or general practitioner 
experienced in treating psoriasis vulgaris. The same person should attempt to perform all 
dermatologic examinations of each individual subject. 
8.16.1 Definition of the body areas to be assessed (treatment areas) 
The body areas which are to be assessed are the trunk and limbs.  
The trunk and limbs includes the arms* and trunk** and the legs***. 
*) arms include the back of the hands  
**) trunk includes the neck 
***) legs include the buttocks and the top of the feet 
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The face, scalp, genitals and skin folds (i.e. the axillae, the inguinal folds, the inter-gluteal 
folds and the infra-mammary folds) are not to be treated with the IPs or assessed as part of the 
efficacy analysis. Also palms and soles are excluded. 
The (sub)investigator must make the assessments described below. Ideally, all assessments for 
a subject should be made by the same (sub)investigator. 
8.16.2 Physician’s Global Assessment of Disease Severity (PGA) 
From screening , and at all monthly visits during the maintenance phase, as well as all 
unscheduled visits, the (sub)investigator will make a global assessment of the disease severity 
of psoriasis of the trunk and limbs using the 5-point scale specified in Table 10. This 
assessment will represent the average lesion severity on the trunk and limbs. 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. 
Table 10: Disease Severity Grading – Physician’s Assessment 
Clear (=0) 
Plaque thickening = no elevation or thickening over normal skin 
Scaling = no evidence of scaling 
Erythema = none (no residual red colouration but post-inflammatory 
hyperpigmentation may be present) 
Almost clear 
(=1) 
Plaque thickening = none or possible thickening but difficult to ascertain 
whether there is a slight elevation above normal skin level  
Scaling =  none or residual surface dryness and scaling 
Erythema = light pink colouration 
Mild (=2) 
Plaque thickening = slight but definite elevation  
Scaling = fine scales partially or mostly covering lesions 
Erythema = light red colouration 
Moderate (=3) 
Plaque thickening = moderate elevation with rounded or sloped edges 
Scaling = most lesions at least partially covered  
Erythema = definite red colouration 
Severe (=4) 
Plaque thickening = marked elevation typically with hard or sharp edges 
Scaling = non-tenacious scale predominates, covering most or all of the 
lesions  
Erythema = very bright red colouration 
Note: At Day 0 (Visit 1) disease severity must be graded as at least ‘Mild’ in order to meet 
inclusion criterion No. 6. 
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8.16.3 Physician’s Assessment of the Extent and Severity of Clinical Signs 
(Redness, Thickness, Scaliness) (m-PASI) 
From baseline (Visit 1), and at all monthly visits during the maintenance phase, as well as all 
unscheduled visits, the (sub)investigator will make assessments of the extent and severity of 
clinical signs of the subject’s psoriasis.  Assessment is not made for the head (i.e. the face and 
scalp). Hence, this PASI assessment is modified to exclude the head. 
The extent of psoriatic involvement will be recorded for each of the three areas (arms, trunk 
and legs) using the following scale: 
0  =  no involvement 
1  =  < 10% 
2  =  10 - 29% 
3  =  30 - 49% 
4  =  50 - 69% 
5  =  70 - 89% 
6  =  90 - 100% 
This assessment of extent is the percentage of that body area that is affected, and not the 
percentage global BSA affected (see section 8.16.4). For example, if one arm was totally 
affected, and the other arm was totally unaffected, the extent assessment for the arms would 
be 50% (half of the arms affected). 
The severity of the psoriatic lesions in each of the three areas will be recorded for each of the 
clinical signs of redness, thickness and scaliness. For each clinical sign, a single score, 
reflecting the average severity of all psoriatic lesions on given body region, will be 
determined according to the following scale: 
Redness 
0 
= 
none (no erythema) 
1 
= 
mild (faint erythema, pink to very light red) 
2 
= 
moderate (definite light red erythema) 
3 
= 
severe (dark red erythema) 
4 
= 
very severe (very dark red erythema) 
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Thickness 
0 
= 
none (no plaque elevation) 
1 
= 
mild (slight, barely perceptible elevation) 
2 
= 
moderate (definite elevation but not thick) 
3 
= 
severe (definite elevation, thick plaque with sharp edge) 
4 
= 
very severe (very thick plaque with sharp edge) 
Scaliness 
0 
= 
none (no scaling) 
1 
= 
mild (sparse, fine scale, lesions only partially covered) 
2 
= 
moderate (coarser scales, most of lesions covered) 
3 
= 
severe (entire lesion covered with coarse scales) 
4 
= 
very severe (very thick coarse scales, possibly fissured) 
PASI: 
The following formula will be used to calculate the m-PASI: 
Arms 0.2 (R + T + S)E = X  
Trunk 0.3 (R + T + S)E = Y 
Legs 0.4 (R + T + S)E = Z 
Where: R = score for redness; T = score for thickness; S = score for scaliness; E = score for 
extent. 
The sum of X + Y + Z gives the m-PASI which can range from 0 to 64.8. 
8.16.4 Investigator’s Assessment of the Body Surface Area (BSA) 
Involvement of Psoriasis Vulgaris on Trunk and Limbs 
From baseline (Visit 1), and at all monthly visits during the maintenance phase, as well as all 
unscheduled visits, the (sub)investigator will assess the extent of the subject’s psoriatic 
involvement on the trunk and limbs. The total psoriatic involvement on the trunk and limbs 
(excluding skin folds and genitals) will be recorded as a percentage of the total BSA, 
estimating that the surface of the subject’s full, flat palm (including the five digits) correlates 
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to approximately 1% of the total BSA. The purpose of this is to obtain an estimate of the area 
on the trunk and limbs to be treated with trial medication. 
8.16.5 Investigator’s Assessment of the Severity of the Target Lesion/Target 
Location (Redness, Thickness, Scaliness) 
At Visit 1 (baseline), the (sub)investigator will select a target lesion/target location. The target 
lesion/location should be at least 3 cm at its longest axis located on the body (i.e., not on the 
scalp, face or intertrigious areas). The location will be recorded in the eCRF as trunk, limb 
excluding elbow/knee, elbow or knee, and in more detail in the subject medical records to 
allow identification of the target lesion/location at subsequent visits.  
From baseline (Visit 1), and at all monthly visits during the maintenance phase, as well as all 
unscheduled visits, the (sub)investigator will assess the severity of the target lesion/location 
for each clinical sign (redness, thickness, scaliness) according to the same scale as for the 
Investigator’s Assessment of the Severity of Clinical Signs (redness, thickness, scaliness). At 
Visit 1, the scoring of the target lesion/location should be at least 1 for each of redness, 
thickness and scaliness, and at least 4 in total (see section 8.16.3 for scores).  
8.17 Dispensing of IP 
Refer to section 10.7.1 
8.18  Return of IP and Compliance 
Refer to sections 10.7.1 and 10.7.3 
8.19 End of Trial Form 
The End of Trial Form must be completed for all subjects who have signed informed consent. 
This includes e.g. date of last dose, last attended scheduled visit number, primary reason for 
withdrawal, etc. 
9 Adverse Events 

Adverse events and serious adverse events are defined in Appendix 4: Definitions
of Adverse Events and Serious Adverse Events

Classification of AEs in terms of severity, causality and outcome are defined in
Appendix 5: Classification of Adverse Events.
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9.1 Collection of Adverse Events 
AEs, including events of rebound,  must be collected from time of first trial-related activity 
after the subject has signed the informed consent form until the FU3 visit. Refer to 
section 11.3.6.2 for a definition of rebound. 
Abnormal findings observed at the screening visit should be recorded as diagnoses in the 
Concomitant Medication page if medication is currently being taken for the condition. If not, 
it will be documented as medical history in the eCRF. 
AEs must be assessed by medically qualified personnel. 
At all visits during the treatment phases, the subject will be asked a non-leading question by 
the (sub)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 (sub)investigator also observes 
the subject for any changes not reported by the subject and records these changes. 
9.1.1 Application site reactions: Assessment of local safety and tolerability 
Application site reactions (perilesional erythema, oedema, dryness, erosion and burning and 
pain) which match the criteria in the Local Safety and Tolerability Scale (see Section 8.11) are 
not to be reported as AEs in the eCRF even if they require treatment. Application site 
reactions other than those identified in the Local Safety and Tolerability scale must be 
recorded appropriately as AEs. Any application site reaction classified as SAEs must be added 
to the AE form in the eCRF and in addition reported to LEO on the SAE Form (according to 
“Investigator Reporting Responsibilities”, Section 9.4.1). Any treatment for an application site 
reaction must be recorded on the concomitant medication page of the eCRF. 
9.2 Reporting of Adverse Events in the eCRF 
AEs reported by the subject or observed by the (sub)investigator must be recorded on the AE 
form of the eCRF and should be described in the following manner: 
The AE term will 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 (e.g. 
allergic contact dermatitis).  
For cutaneous AEs the location must be part of the AE description and may be described as 
e.g. the face, scalp, back, chest, arm, leg, trunk or limb.
Additionally, the location should be described using the following terminology: 
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
Lesional/perilesional (≤ 2 cm from the area(s) treated with IPs) or

distant (>2 cm from the area(s) treated)
The duration of the AE must be reported as the start date and stop date of the event. In 
addition, it must be recorded whether the AE started prior to start of trial medication. 
AEs must be classified in terms of severity, causality and outcome according to the definitions 
in Appendix 5: Classification of Adverse Events. 
9.2.1 Additional requirements for reporting of adverse events of concern 
associated with long-term topical corticosteroid use 
If the (sub)investigator considers an AE to be one of concern associated with long-term 
topical corticosteroid use, this should be indicated in the AE section of the eCRF, and will 
require a detailed narrative of the AE to be entered, including a description of the clinical 
course, the area(s) affected if a cutaneous event (body location and approximate size), and 
predisposing concomitant conditions, medications, or history.  
If LEO suspects that an AE may be one of concern associated with long-term topical 
corticosteroid use, LEO may ask the (sub)investigator to provide additional information. 
The purpose of collecting these additional data is to provide as much information as possible 
on suspected events in order to aid the adjudication of events by the Adjudication Panel. 
9.2.2 Actions Taken as a Consequence of an AE 
Action taken with trial treatment: Any action taken with trial medication as a consequence of 
the AE must be recorded (dose not changed, drug interrupted, drug withdrawn, not applicable, 
unknown). 
Note regarding AEs of concern associated with long-term corticosteroid use: A 
(sub)investigator may consider an AE to be one of concern associated with long-term topical 
corticosteroid use and may wish to manage such an event by temporarily or permanently 
stopping trial medication usage.  Such a change in trial medication usage may apply to just 
the area(s) affected by the event, or its total use.  Such a change in trial medication usage must 
be documented in the eCRF. 
Other action taken: Any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
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Withdrawn due to AE: It must be recorded whether the AE leads to withdrawal from the trial. 
9.3 Other Events to be Reported 
9.3.1 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 (GPV), LEO (see section 9.4.1 for contact details).  
Please also confer with section 7.9, Discontinuation. 
9.3.2 Overdose 
Overdose refers to the administration of a quantity of a medicinal product given per 
administration or per day which is above the protocol defined dosage.  
In this clinical trial, the use of more than one 60g can in 4 days is considered an overdose. 
The term overdose must be documented on the AE form in the eCRF. In addition, AEs 
originating from overdose must be documented on a separate line.     
9.3.3 Medication Error 
Medication error refers to any unintentional error in the dispensing or administration of a 
medicinal product while in the control of the (sub)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).     
9.3.4 Misuse 
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
used not in accordance with the protocol. 
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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.     
9.3.5 Abuse 
Abuse relates to the sporadic or persistent, intentional excessive use of an IP 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. 
9.3.6 Aggravation of Condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s), 
compared to baseline, must be reported as an AE. 
Relapse of psoriasis during the maintenance phase of the trial or during the follow-up phase 
should not be reported as an AE. Rebound effect (defined as (i) an m-PASI ≥12 AND an 
increase in m-PASI of ≥125% of the baseline value, or (ii) new pustular, erythrodermic or 
more inflammatory psoriasis either a) within 2 months after discontinuation of once-daily 
treatment in the initial open-label phase, b) within 2 months after discontinuation of once-
daily relapse treatment, or c) within 2 months after end of maintenance treatment (up to Visit 
FU3)) must be reported as an AE. 
9.3.7 Lack of Efficacy 
Not applicable. 
9.3.8 Adverse Events of Special Interest 
None. For AEs of concern associated with long-term corticosteroid use, see sections 9.2.1 and 
9.2.2.  
9.4 Additional Reporting Requirements for Serious Adverse Events 
9.4.1 Investigator Reporting Responsibilities 
Any Serious Adverse Event (SAE) must be reported to LEO on the (paper) SAE Form – 
Clinical Trials within 24 hours of first knowledge. This report should contain an assessment of 
available information on seriousness, severity, causal relationship to the IPs, comparator or 
trial procedure, the action taken, the outcome to date, and a narrative description of the course 
of the event.  
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The completed SAE form must be faxed or scanned and e-mailed to GPV, LEO using the 
following fax number or e-mail address: 
Fax number: +45 7226 3287 
E-mail address: drug.safety@leo-pharma.com
It may be relevant for the (sub)investigator to enclose other information with the SAE form, 
such as anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc.  
Additionally, GPV, LEO may request further information in order to fully assess the SAE. The 
(sub)investigator must forward such information to GPV, LEO upon request by fax or e-mail 
(see contact details above).  
The investigator must notify the local IRB(s)/IEC(s) of SAEs as required by current 
applicable legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial (including any protocol required post-
treatment follow-up period) should not be routinely sought or collected. However, such events 
should be reported to GPV, LEO (drug.safety@leo-pharma.com) if the (sub)investigator 
becomes aware of them.  
9.4.2 LEO Reporting Responsibilities 
GPV, LEO is responsible for assessing whether or not a SAE is expected. The relevant 
reference document for this clinical trial is:  
LEO 90100 aerosol foam: the LEO 90100 Investigator's Brochure, edition 7 (11) and 
subsequent updates.  
GPV, 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. 
All SAEs which are assessed as causally related to the IP(s) by either the investigator or LEO, 
and which are not expected (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 
these on an ongoing basis. 
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9.5 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 has completed the FU3 visit, AEs classified as possibly or probably 
related to the IPs should be followed for 14 days 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.
If a rebound is confirmed at a FU3, the subject will be followed up for 14 days or until 
resolution, whichever occurs first, unless the event is considered an SAE. 
10 Investigational Product(s) 
10.1 Investigational Product Description 
The IPs are described in Table 11 and Table 12 respectively. 
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Table 11: Description of Enstilar®/LEO 90100 Aerosol Foam 
Finished product (brand) name/name 
investigational product 
Enstilar®/LEO 90100 aerosol foam 
Formulation 
Aerosol foam 
Active ingredient name/concentration 
Calcipotriol 50 mcg/g (as hydrate) and 
betamethasone 0.5 mg/g (as dipropionate) 
Excipients 
Paraffin, white soft; Paraffin, liquid; 
Polyoxypropylene stearyl ether; all-rac-alpha-
tocopherol; Dimethyl ether; Butane; 
Butylhydroxytoluene (E321)
Pack size(s) 
60 g 
Manufacturer of bulk medication (IP) 
LEO Laboratories Ltd, 285 Cashel Road, 
Dublin 12, Ireland 
Manufacturer of IP in primary packaging 
Colep Laupheim GmbH & Co. KG 
Fockestrasse 12 
88471 Laupheim, Germany  
and 
LEO Laboratories Ltd, 285 Cashel Road, 
Dublin 12, Ireland 
Certifier of 
IP in primary packaging 
LEO Pharma A/S, Industriparken 55, 
2750 Ballerup, Denmark 
Manufacturer of secondary packaging and 
labeling 
Klifo 
Smedeland 36, 2600 Glostrup, Denmark 
Certifier name of 
Secondary packaging and labeling 
LEO Pharma A/S, Industriparken 55, 2750 
Ballerup,  
Denmark 
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Table 12: Description of Enstilar® vehicle/LEO 90100 Aerosol Foam Vehicle 
Finished product (brand) name/name 
investigational product 
Enstilar® vehicle/LEO 90100 aerosol foam 
vehicle 
Formulation 
Aerosol foam 
Active ingredient name/concentration 
Not applicable 
Excipients 
Paraffin, white soft; Paraffin, liquid; 
Polyoxypropylene  stearyl ether; all-rac-alpha-
tocopherol; Dimethyl ether; Butane; 
Butylhydroxytoluene (E321)
Pack size(s) 
60 g 
Manufacturer of bulk medication (IP) 
LEO Laboratories Ltd, 285 Cashel Road, 
Dublin 12, Ireland 
Manufacturer of IP in primary packaging 
Colep Laupheim GmbH & Co. KG 
Fockestrasse 12 
88471 Laupheim, Germany 
and 
LEO Laboratories Ltd, 285 Cashel Road, 
Dublin 12, Ireland 
Certifier of 
IP in primary packaging 
LEO Pharma A/S, Industriparken 55, 
2750 Ballerup, Denmark 
Manufacturer of secondary packaging and 
labeling 
Klifo 
Smedeland 36, 2600 Glostrup, 
Denmark 
Certifier name of 
Secondary packaging and labeling 
LEO Pharma A/S, Industriparken 55, 2750 
Ballerup, 
Denmark 
10.2 Administration of Investigational Products 
The administration of IP is described in Table 13. 
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Table 13: Administration of Investigational Products 
Route of administration 
Topical 
Dosing range 
Not applicable 
Dosing frequency 
Initial open-label treatment phase: LEO 
90100 once daily for 4 weeks  
Maintenance phase: randomised 
maintenance IP twice weekly 3 or 4 days 
apart.  
In case of relapse: Rescue IP once daily for 4 
weeks on active lesions. 
Weekly maximum 
Initial open label phase: 100 g per week  
Treatment of relapse: 100 g per week for 
daily treatment  
Maintenance phase: 30 g per week (15 g per 
day)  
Time of day for dosing 
No specific requirements 
Relation of time of dosing of rescue IP and 
maintenance IP during relapse (on days 
requiring application of both IPs) 
Maintenance IP before rescue IP 
Relation of time of dosing to clinical 
assessments 
Preferably no dosing within 2 hours prior to 
the site  visit 
At Visit 1, the subject will be given a treatment instruction sheet describing the scenarios to be 
considered depending on the different treatment phases and they will receive verbal 
instruction about how to apply the trial medication.  

During the initial open-label treatment phase, subjects will be asked to apply
LEO 90100 once daily on the affected areas on trunk and limbs for 4 weeks. At
Visit 2 (after 4 weeks), subjects will have to return all containers with trial
medication and, if they have achieved treatment success (PGA score of ‘clear’ or
‘almost clear’ with at least a 2-grade improvement from baseline), they will be
dispensed new (blinded) medication according to the randomisation scheme.
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
During the maintenance phase, subjects will apply maintenance IP twice weekly on
trunk and limbs to areas where lesions have cleared or almost cleared after
treatment was initiated at baseline. Any new psoriatic lesions that have been cleared
by rescue treatment during relapse phase should be treated with maintenance IP as
well. The treatment should be applied 3 or 4 days apart. The choice of the
application days (two days) should be left to subjects’ preference (e.g., Thursday
and Sunday); these days will be fixed at Visit 2, recorded in the eCRF and subjects
will be asked to keep the selected days throughout the trial. To improve medication
adherence, electronic reminders will be sent to the subject every week on the
selected application days.

Following confirmation of a relapse during the maintenance phase, subjects will be
asked to apply rescue IP once daily on the active psoriatic lesions on trunk and
limbs for 4 weeks, while continuing twice-weekly maintenance treatment on non-
active lesions. Rescue IP will be dispensed at the visit when relapse is confirmed.
The rescue IP will be stopped after 4 weeks at a scheduled visit or at a relapse
follow-up visit, as applicable.
The first application of the IP should be made under supervision and instruction of a member 
of the trial staff or at home the same day the subject attended Visit 1. The IPs will be 
dispensed by a designated person. As described above, there will be different types of  
instructions for initial open-label, maintenance and relapse treatment phases. Subjects will 
always be reminded which instruction(s) to follow during the next 4-week period. 
When an application is to be administered on the same day as a trial visit, it should not be 
administered within 2 hours of the site visit. 
Missed application during the maintenance phase: 
LEO 90100 should be applied twice weekly 3 or 4 days apart on specific days. If an 
application is missed, the medication should be applied as soon as subject remembers. The 
next application should be made at the next scheduled dosing date.      
10.3 Precautions/Overdosage 
Overdose with calcipotriol may be associated with hypercalcaemia. Clinically important 
hypercalcaemia will be managed at the investigator’s discretion with rehydration, 
bisphosphonate administration or according to local standard of care. Hypercalcaemia should 
rapidly subside when treatment is discontinued. 
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Overdose with corticosteroid containing products may result in suppression of adrenal 
function which is usually reversible. In such cases, symptomatic treatment is indicated. In 
case of chronic toxicity, corticosteroid treatment must be discontinued gradually. 
10.4 Packaging of Investigational Products 
IPs will be supplied in bulk kits. 
During the initial open-label treatment phase, each subject will receive the necessary supplies 
for 4 weeks (7 cans of LEO 90100). These cans will be dispensed at Visit 1.  
Then, every 4 weeks during the maintenance phase subjects will receive the necessary 
supplies (3 cans of maintenance IP), which is sufficient for the visit interval when used twice 
per week. These kits will be dispensed at each scheduled visit until the end of the trial.  
In total, at least 14 dispensations will be made per subject over the duration of the trial (7 cans 
will be dispensed at Visit 1, and 3 cans will be dispensed at each visit from Visit 2 to Visit 14). 
In addition, in case of relapse during the maintenance phase, the subject will receive the 
necessary supplies (7 cans of rescue IP) to be treated once daily on the active lesions for 4 
weeks. 
During relapse treatment subjects may also be in maintenance treatment on areas where 
psoriasis is not active. To distinguish the rescue IP from the maintenance IP, the products are 
colour coded as follows: 

Open-label (initial or rescue) IP: yellow labels

Double-blind (maintenance) IP: white labels
The labelling of trial products must be in accordance with Annex 13, local regulations and 
trial requirements. 
Immediate Treatment Packaging - Individual Unit 
The primary packaging for the IPs consists of an aluminium can into which the formulation is 
pre-filled and subsequently administered through a continuous valve. Each individual can 
contains 60 g of IP.  Primary and secondary packaging materials will be individually labelled 
in accordance with local regulations. 
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10.5  Storage of Investigational Products 
All LEO supplied drugs must be stored in a secure and restricted area under the conditions 
specified on the label and remain in the original container until dispensed.  
Furthermore, the following storage conditions and handling precautions should be observed: 
For United States:  

Store at 20-25 °C. Excursions between 15-30°C permitted.

Contents under pressure. Do not puncture or incinerate.

Do not expose to heat or store at temperatures above 120°F (49°C). Do not freeze.

Flammable – avoid heat, flame or smoking when using this product.

Keep out of the reach of children.

Shake before use.

Wash hands after use.
For other countries: 

Store below 30°C.

Extremely flammable aerosol.

Pressurised container: May burst if heated.

Protect from sunlight.

Do not expose to temperatures exceeding 50°C.

Do not pierce or burn, even after use.

Do not spray on an open flame or other ignition source.

Keep away from sparks, open flames and other ignition sources.

No smoking.

Keep out of the reach of children.

Shake before use.

Wash hands after use.
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10.6  Treatment Assignment 
Subjects who have been found to comply with all the inclusion criteria and not to violate any 
of the exclusion criteria, and who achieve treatment success (PGA score of ‘clear’ or ‘almost 
clear’ with at least a 2-grade improvement from baseline) after the initial 4 week of once daily 
treatment with LEO 90100  will be randomised to receive treatment with either : 

LEO 90100 aerosol foam (also referred to as ‘LEO 90100’)

Aerosol foam vehicle (also referred to as ‘foam vehicle’)
Treatment assignment will be pre-planned according to a computer generated randomisation 
schedule in a 1:1 ratio. 
Subjects will be randomised centrally to treatment with LEO 90100 aerosol foam or LEO 
90100 aerosol foam vehicle using a stratified randomisation through an Interactive Web 
Response System (IWRS). 
Each investigator site will be supplied with sufficient trial products for the trial on an ongoing 
basis controlled by the IWRS. Randomisation will be stratified by trial site, HPA axis testing, 
and by baseline disease severity (mild, moderate, severe).  
The maximum number of subjects to be included in the open-label phase with ‘mild’ disease 
according to the PGA at baseline (visit 1) is capped at 20% to ensure similar distribution of 
disease severity at baseline as in previous LEO 90100 short-term trials and hence similar trial 
population. 
10.6.1 Randomisation Code List 
The randomisation code lists will be generated by LEO. 
During the clinical trial, the randomisation files must be kept inaccessible to staff involved 
with the conduct and administration of the clinical trial until the clinical trial is unblinded. 
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10.7  Drug Accountability and Compliance Checks 
10.7.1 Drug Accountability 
The investigator is fully responsible for the IP at the trial site and for maintaining adequate 
control of the IP and for documenting all transactions with them.  
Dispensing of IP may be delegated, e.g. to a hospital pharmacy, as locally applicable. 
At each visit, the IP, including (empty) containers dispensed at the previous visit, must be 
returned by the subject. An inventory (Individual Drug Accountability Form) must be kept of 
the IP given to and returned by each subject participating in the trial. This inventory must be 
available for inspection during monitoring visits and will be checked by the monitor to ensure 
correct dispensing of the IP. 
All IP supplied by the Contract Manufacturing Organisation (CMO) on behalf of LEO must 
be returned to the CMO. Prior to their return, they must be fully accounted for by the monitor 
with the help of the person responsible for dispensing the IP. Accountability must be 
documented by using drug accountability forms. 
The IP returned to the CMO will be reconciled with the Individual Drug Accountability 
Forms. All returned cans will subsequently be weighed by the CMO to determine the amount 
of the IP used between visits. 
10.7.2 Trial Product Destruction 
Used and unused trial products will be destroyed by the CMO according to LEO procedures. 
10.7.3 Treatment Compliance 
Treatment compliance will be recorded in an eDiary.  
During the open-label treatment phase, subjects will be asked to provide this information 
daily whereas treatment compliance will be recorded weekly during the entire maintenance 
phase (i.e., from Visit 2/Week 4 to the end of trial, irrespective of whether subject is on 
maintenance or once daily treatment). 
In case of non-compliance, the reason for it should be recorded in the eDiary. 
However, the (sub)investigator should remind the subject of the importance of following the 
instructions given including taking the trial medication as prescribed for respective phase of 
the trial.  
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The investigator (or designee)  should review the compliance data entered in the eDiary 
before each visit, and, in case of non-compliance, remind/re-train the subject to improve 
compliance. 
10.8 Emergency Unblinding of Individual Subject Treatment 
While the safety of a subject always comes first, it is still important to seriously consider if 
unblinding is necessary to ensure a subject’s safety. This section describes the procedures for 
unblinding a subject. An emergency unblinding request can be made by the investigator, 
(sub)investigators, other health care professionals or authorised LEO personnel. 
Emergency unblinding of individual subject treatment can be achieved by contacting the 
IWRS CRO to obtain information regarding an individual subject's treatment assignment. 
10.9 CORTROSYN®  (cosyntropin) / Synacthen® (tetracosactid) for 
Injection  
CORTROSYN® (used in the US) is a commercial solution for injection containing 
cosyntropin that will be used for the ACTH-challenge test. One ampoule contains cosyntropin 
PhEur 250 micrograms (equivalent to 25 IU ACTH). 
Synacthen® (used in Europe) is a commercial solution for injection containing 
tetracosactidhexaacetate that will be used for the ACTH challenge test. One ampoule contains  
1 ml of 0.28 mg tetracosactid-hexaacetate (0.25 mg tetracosactid which equals 25 IU ACTH). 
CORTROSYN® / Synacthen® is a non-Investigational Medicinal Product. The applicable 
product will be sourced by the trial sites, except in Poland. In Poland Synacthen® will be 
supplied by the sponsor. 
CORTROSYN® will be used in accordance with the U.S. Prescribing Information for the 
marketed product (see Appendix 2: U.S. Prescribing information for CORTROSYN® 
(cosyntronin) for injection). Synacthen® will be used in accordance with the SmPC (see 
Appendix 3: Summary of Product Characteristics for Synacthen® (Tetracosactide) Ampoules 
250mcg) 
10.9.1 CORTROSYN® and Synacthen® 
Cortrosyn® is described in Table 14 and Synacthen® is described in Table 15.    
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Table 14: Description of CORTROSYN® (used in the US) 
Finished product (brand) name (if 
available)/name investigational product 
CORTROSYN®  (cosyntropin) for Injection 
Formulation 
Sterile lyophilized powder to be reconstituted 
with 0.9% Sodium Chloride Injection, USP 
Active ingredient name/concentration 
Cosyntropin (α 1-24 corticotropin); 0.25mg 
per vial 
Excipients 
Mannitol, glacial acetic acid and sodium 
chloride. It contains no antimicrobial 
preservative. 
Pack size(s) 
Box of 10 vials of CORTROSYN® 
(cosyntropin) for Injection 
Manufacturer’s name 
11570 6th Street Rancho Cucamonga, CA 
91730, U.S.A. 
Supplier’s name 
Not Applicable. 
Certifier’s name 
11570 6th Street Rancho Cucamonga, CA 
91730, U.S.A. 
Table 15: Description of Synacthen® (used in Europe) 
Finished product (brand) name (if 
available)/name investigational product 
Synacthen® 
Formulation 
Solution for injection 
Active ingredient name/concentration 
Tetracosactid 0.25 mg/mL (i.e., 25 IU ACTH) 
Excipients 
Acetic acid, sodium acetate, sodium chloride, 
aqua ad inject. 
Pack size(s) 
1 ml ampoules 
Manufacturer’s name 
Products available on the local market will be 
used (according to the local marketing 
authorisation) 
To be sourced individually by sites (excluding 
Poland, where it will be supplied by the 
sponsor). 
Supplier’s name 
See above 
Certifier’s name 
See above 
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10.9.1.1 Packaging and Labelling 
The marketed product, as available in the US or in Europe will be used for this trial without 
any re-labelling or re-packaging of the product. 
In Poland trial sites will be provided the Synacthen® through the depot at Klifo in Glostrup, 
Denmark. 
10.9.1.2 Storage 
The product should be stored in a safe and secure place inaccessible for children and in 
accordance with the manufacturer’s instructions (e.g. product monograph or labels) specific to 
the chosen product.  
10.9.1.3 Reconstitution and Administration of CORTROSYN® (in the US) 
The contents of one vial (0.25mg of CORTROSYN®) should be reconstituted in 2 to 5ml of 
0.9% Sodium Chloride Injection, USP, and injected intravenously over a 2-minute period. The 
reconstituted drug product should be inspected visually for particulate matter and 
discoloration prior to injection. Reconstituted CORTROSYN® should be used promptly and 
should not be retained. Any unused portion should be discarded. 
10.9.1.4 Precautions 
Product specific precautions and handling instructions will be provided in the product 
monograph specific to the chosen product. 
General precautions for use with 0.9% Sodium Chloride Injection, USP (in connection to 
reconstitution of CORTROSYN® (in the US)) include: 
Do not use unless the solution is clear and seal intact.
Do not re-use containers.
Discard unused portion.
See the Prescribing Information for CORTROSYN® in Appendix 2: U.S. Prescribing 
information for CORTROSYN® (cosyntronin) for injection and for Synacthen® in Appendix 
3: Summary of Product Characteristics for Synacthen® (Tetracosactide) Ampoules 250mcg for 
further details. 
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Athletes should be aware that CORTROSYN® and Synacthen® contain active ingredients that 
may cause a positive result on doping tests. 
10.9.1.5 Drug Accountability 
The investigator is fully responsible for the CORTROSYN® / Synacthen® at the trial site. 
Dispensing of CORTROSYN® / Synacthen® may be delegated, e.g. to a hospital pharmacy, as 
locally applicable. The person responsible for dispensing the CORTROSYN® / Synacthen® 
will be responsible for maintaining adequate control and for documenting all transactions. All 
CORTROSYN® / Synacthen® sourced locally by the investigator (or designee) or from the 
depot at Klifo will be fully documented by use of (internal) drug accountability forms. An 
inventory will be kept of all CORTROSYN® / Synacthen® dispensed for each subject in the 
trial. The batch number/lot number and expiry date of the CORTROSYN® / Synacthen® 
dispensed will be recorded. This inventory must be available for inspection at monitoring 
visits and will be checked to ensure correct dispensing of CORTROSYN® / Synacthen®.  
10.9.2 0.9% Sodium Chloride Injection, USP, for Reconstitution of 
CORTROSYN® (in the US) 
0.9% Sodium Chloride Injection, USP will be sourced by the trial sites. There is no 
requirement for a specific brand or manufacturer to be used, however 0.9% Sodium Chloride 
Injection, USP is recommended for use based on the availability of an appropriate vial size for 
the reconstitution of CORTROSYN® as described in section 10.9.1.3. 
0.9% Sodium Chloride Injection, USP will be used in accordance with the product monograph 
specific to the chosen product. 
10.9.2.1 Packaging and Labelling 
The marketed product, as available in the United States, will be used for this trial without any 
relabeling or re-packaging of the product. 
10.9.2.2 Storage 
The product should be stored in a safe and secure place inaccessible for children and in 
accordance with the manufacturer’s instructions (e.g. product monograph or labels) specific to 
the chosen product. 
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10.9.2.3 Precautions 
Product specific precautions and handling instructions will be provided in the product 
monograph specific to the chosen product. 
General precautions for use with 0.9% Sodium Chloride Injection, USP include: 

Do not use unless the solution is clear and seal intact

Do not re-use containers

Discard unused portion
10.9.2.4 Drug Accountability 
The investigator is fully responsible for the 0.9% Sodium Chloride Injection, USP at the trial 
site. Dispensing of the 0.9% Sodium Chloride Injection, USP may be delegated, e.g. to a 
hospital pharmacy, as locally applicable. The person responsible for dispensing the 0.9% 
Sodium Chloride Injection, USP will be responsible for maintaining adequate control and for 
documenting all transactions. All 0.9% Sodium Chloride Injection, USP sourced locally by 
the investigator (or designee) will be fully documented by use of (internal) drug 
accountability forms. An inventory will be kept of all 0.9% Sodium Chloride Injection, USP 
dispensed for each subject in the trial. The batch number/lot number and expiry date of the 
0.9% Sodium Chloride Injection, USP dispensed will be recorded. This inventory must be 
available for inspection at monitoring visits and will be checked to ensure correct dispensing 
of the 0.9% Sodium Chloride Injection, USP. 
11 Statistical Methods 
The trial consists of two different periods of treatment. The subjects are enrolled in the trial at 
baseline. The first 4 weeks of treatment after a subject is included in the trial will be denoted 
the open-label treatment phase. If the subject obtains treatment success (i.e., PGA score of 
‘clear’ or ‘almost clear’ with at least 2-grade improvement from baseline) at the end of the 
open-label treatment phase, the subject is randomised. Otherwise the subject is discontinued 
from the trial. The second treatment period is denoted the maintenance phase. It starts at 
randomisation and ends at end of trial. The randomised maintenance treatment is twice 
weekly treatment with either LEO 90100 aerosol foam or LEO 90100 aerosol foam vehicle. 
Moreover, the subjecs treated twice weekly with LEO 90100 aerosol foam is referred to as the 
active treatment group and those treated twice weekly with vehicle is referred to as the vehicle 
group.  
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Note that the maintenance phase consists of maintenance treatment as well as periods of 4 
weeks treatment with rescue medication in case of relapse.  
In the following when referring to visit it means scheduled visit although not explicity stated. 
11.1 Determination of Sample Size 
For subjects with psoriasis vulgaris, the number of relapses per year is assumed to be between 
4 and 8. We assume that the time to event (first relapse) is a Poisson process, i.e. that events 
occur continuously and independently at a constant rate. Then the time between events is 
given by the exponential distribution. Time to event is analysed by means of the hazard 
function,  which can be thought of as the probability of experiencing an event now if you have 
not experienced one already. Table 16 shows the mean and median waiting times as well as 
hazards according to number of relapses per year. 
Table 16: Mean and median waiting times and hazards according to number of relapses 
per year 
Number of relapses per year 
4 
6 
8 
Mean waiting time (weeks) 
13.00 
8.67 
6.50 
Median waiting time (weeks) 
9.01 
6.01 
4.51 
Hazard 
0.077 
0.115 
0.154 
The drop-out rate observed in a long-term trial with calcipotriol/BDP ointment 
(MCB 0102 INT) was about 30 % over 52 weeks. Assuming an exponential decline this 
corresponds to a median waiting time for drop out at about 101 weeks. We assume that the 
same will be the case in this trial and that between 4 to 8 relapses will occur per year in the 
vehicle group. 
A 30 percent reduction in hazard, i.e. a hazard ratio of 0.7 for active treatment group relative 
to vehicle group is considered to be of clinical interest. 
With the above assumptions it follows using a two sample survival test that for detecting a 
hazard ratio of 0.7 for active treatment group relative to vehicle group, between 178 and 190 
subjects per group are needed in order to obtain a power of  90% for a 5% significance level. 
Thus, 380 subjects should be randomised. 
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In previous trials in similar populations, approximately 48% subjects treated with LEO 90100 
aerosol foam achieved treatment success after 4 weeks of treatment.  Assuming a binomial 
distribution with 48 % probability of success it is estimated that 832 subjects should be 
included in the trial in order to have 90 % probability of achieving at least 380 subjects to be 
randomised.  
For the HPA axis testing, the aim is to achieve approximately 25 subjects undergoing HPA 
axis testing after 52 weeks of exposure. 
The total number of subjects treated in the trial should also be sufficient to comply with 
ICH E1 regarding long-term safety. The aim is to achieve at least 300 subjects with 26 weeks 
of exposure and at least 100 subjects with 52 weeks of exposure. 
All randomised subjects have been exposed for 4 weeks during the open-label treatment 
phase. During the maintenance phase with 380 randomised subjects, assuming an exponential 
decline and a drop-out rate of 30 % over 52 weeks, we can expect to have 326 subjects 
exposed for 22 weeks and 273 subjects exposed for 48 weeks. This means that we will have 
326 subjects exposed for a total of 26 weeks, and 273 subjects exposed for a total of 
52 weeks.  
If the actual drop-out rate is higher than the assumed drop-out rate of 30%, more subjects will 
be recruited and randomised to achieve at least 380 randomised subjects, including at least 
300 subjects with 26 weeks of exposure and at least 100 subjects (including approximately 
25 subjects undergoing HPA axis testing) with 52 weeks of exposure. 
Recruitment will be stopped when a sufficient number of subjects are randomised in order to 
obtain the above, considering the observed randomisation and drop-out rates. 
11.2 Definition of Trial Analysis Sets 
All subjects enrolled in the trial (i.e. subjects for whom informed consent has been obtained 
and who have been registered in the clinical trial) will be accounted for in the clinical trial 
report. 
An open-label treatment phase safety analysis set will be defined by including all subjects 
exposed to treatment with IP whether randomised or not.   
All subjects randomised are included in the full analysis set and will be analysed for efficacy. 
Exclusions from the full analysis set can be considered in special cases as described in 
International Conference on Harmonisation (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. 
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A per protocol analysis set will be defined by excluding subjects from the full analysis set 
who:  

receive no treatment with the IPs after randomisation,

provide no efficacy data following start of maintenance treatment,

are known to have taken the wrong IPs throughout the maintenance phase of the
trial,

and/or do not fulfil the disease defining inclusion criteria (i.e. inclusion criteria 4, 5,
6, 7).
Further exclusion of subjects or subject data will be decided upon after a blind review of the 
data, reviewing all the remaining in- and exclusion criteria, but focusing on concomitant 
medication that may affect psoriasis vulgaris and also considering compliance/adherence and 
violations of visit windows. 
A maintenance phase safety analysis set will be defined by excluding subjects from the full 
analysis set who either received no treatment with IPs following randomisation and/or for 
whom no post-randomisation safety evaluations are available. 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the statistical analysis plan update before breaking the 
randomisation code. 
11.3 Statistical Analysis 
11.3.1 Disposition of Subjects 
The reasons for leaving the trial during the open-label treatment phase will be presented for 
all included subjects by last visit attended. 
The reasons for leaving the trial during the maintenance phase will be presented for all 
randomised subjects by last visit attended and by treatment group. 
11.3.2 Demographics and other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics measured at baseline 
will be presented both for all subjects included in the trial, and for all randomised subjects by 
treatment group. Presentations of age, sex, ethnicity, race and baseline m-PASI and PGA will 
also be given by centre. 
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Demographics include age, sex, race and ethnicity. Other baseline characteristics include skin 
type, height, weight, body mass index and vital signs, duration of psoriasis vulgaris, 
concurrent diagnoses (from medical history and indications for concomitant medication), 
concomitant medication, previous anti-psoriatic therapy, m-PASI, physician’s assessment of 
BSA involved, location of psoriasis, location of other psoriasis, and PGA.  
11.3.3 Exposure and Treatment Compliance 
11.3.3.1 Exposure 
The duration of exposure to treatment in a specific visit interval will be calculated as the 
number of days from date of first application of IP in that period to the date of last application 
of IP in that period, both days included.  
Duration of exposure during the open-label treatment phase will be summarized for the open-
label treatment phase safety analysis set. 
Duration of exposure during the maintenance phase will be summarized by treatment group 
for the maintenance phase safety analysis set.  
For each subject, the weight of IP used for each visit interval will be determined by 
calculating the difference between the weight of a set of full cans dispensed and the weight of 
the returned cans.  
The amount of IP used will be summarised for the total open-label treatment phase for the 
open-label treatment phase safety analysis set.   
The amount of IP used will be summarised by treatment group for each visit interval and for 
the total maintenance phase for the maintenance phase safety analysis set. 
The amount of rescue medication used will be summarised by treatment group for each visit 
interval and for the total maintenance phase for the maintenance phase safety analysis set.  
The total amount of IP and rescue medication used will be summarised by treatment group for 
each visit interval and for the total maintenance phase for the maintenance phase safety 
analysis set. 
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11.3.3.2 Treatment compliance 
For the open-label treatment phase, compliance with treatment instructions in terms of 
percentage missed applications will be summarised for the open-label treatment phase safety 
analysis set.   
For the maintenance phase, excluding periods of treatment with rescue medication, 
compliance with treatment instructions in terms of percentage missed applications will be 
summarised by treatment group both for each visit interval and for the total maintenance 
phase for the maintenance phase safety analysis set.  
For the periods of treatment with rescue medication during the maintenance phase, 
compliance with treatment instructions in terms of percentage missed applications will be 
summarised by treatment group for the maintenance phase safety analysis set. 
11.3.3.3 Analysis of Primary Efficacy Endpoint 
The primary endpoint is time to first relapse during the maintenance phase, where relapse is 
an exacerbation of psoriasis defined as a PGA of at least ‘mild’. This will be calculated as the 
number of days from randomisation to the day where the subject has the first relapse 
confirmed. For subjects who either do not encounter a relapse or are withdrawn from the trial, 
the number of days will be treated as a censored observation at the day of end of trial visit. 
The number of censored and uncensored observations, i.e. number of subjects without relapse 
or who are withdrawn from the trial, and number of subjects with relapse, will be summarised 
by treatment group. The time to first relapse will be summarised by treatment group for 
uncensored observations, i.e. subjects with relapse.  
The primary endpoint will be compared between treatments with the null hypothesis that they 
are equal against the alternative that they are different. The analysis will be performed both 
for the full analysis set (primary) and for the per protocol analysis set (supportive). The 
comparison will be done using a proportional hazards model with treatment group, trial site, 
and disease severity at baseline (as determined by the PGA) as factors. The estimate of the 
hazard ratio of active treatment group relative to vehicle group together with the 95% 
confidence interval and p-value will be presented.  
The estimated survival curves with confidence intervals will be presented graphically for each 
of the treatment groups.  Moreover the percentiles of the survivial distribution will be 
tabulated by treatment group. 
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The proportion of subjects who are still at risk for a first relapse will be compared between 
the two treatment groups at 26 and 52 weeks after randomisation.  
11.3.3.4 Analysis of Secondary Efficacy Endpoints 
The secondary endpoints will be analysed for the full analysis set, with the analysis for the per 
protocol analysis set being supportive. Adjustment for multiplicity will be done using the 
Holm-Bonferroni method (34).   
11.3.3.5 Number of days in remission 
The number of days in remission will be calculated for each subject as the total number of 
days in trial during the maintenance period minus the number of days in treatment of relapses, 
if any. If a subject is withdrawn from the trial for any reason, then the subject is considered 
not to be in remission from when the subject leaves the trial.  
The number of days in remission will be summarised by treatment group. 
The number of days in remission will be analysed by means of an analysis of variance 
(ANOVA) model with treatment group, trial site, and disease severity at baseline as factors. 
Estimated difference between active treatment group and vehicle group, 95% confidence 
interval, and p-value will be presented. 
In addition, two sensitivity analyses will be performed with different handling of missing 
data. If a subject is withdrawn from the trial for a drug related reason (lack of efficacy, AE, 
did not reach remission after treatment of relapse) then in both sensitivity analyses the subject 
is considered not to be in remission from when the subject leaves the trial. If a subject is 
withdrawn from the trial for a non-drug related reason (lost to follow-up, death, other) then 
the data is imputed differently in the two sensitivity analyses. During the blind review of the 
data the withdrawal reasons specified in the ‘Other’ category should be considered and if the 
specified reason is judged to be drug-related it should be documented in the statistical analysis 
plan before breaking the randomisation code. 
In the first sensitivity analysis, the subject’s observed part of the maintenance phase is 
assumed to be representative for the unobserved part of the maintenance phase when the 
subject is withdrawn due to a non-drug related reason. I.e. if the subject is in remission in 2 
months out of 3 in the observed part of the maintenance phase, then it is assumed that the 
subject would have been in remission in 8 out of 12 months in the maintenance phase, i.e. 
number of days in remission is imputed to be 8 months.  
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In the second sensitivity analysis, the subject’s last observation is carried forward (LOCF) 
when the subject is withdrawn due to a non-drug-related reason. I.e. if the subject is in 
remission the subject is considered to be in remission for the rest of the maintenance phase, 
and if the subject is not in remission, then subject is considered not to be in remission for the 
rest of the maintenance phase.  
11.3.3.6 Number of relapses during maintenance phase 
The number of relapses will be calculated as the sum of confirmed relapses for each subject. 
Subjects contribute with observed time only. The rate of relapses during the maintenance 
phase is assumed to be constant over time.  
The number of relapses will be analysed in a Poisson regression model with treatment group, 
trial site, and disease severity at baseline as factors, subject as a random effect,  and risk time 
as an offset. The risk time is the observed time at risk for each subject, i.e. the total time in 
trial during the maintenance phase time minus the periods of treatment of relapses, if any. The 
estimated incidence rate ratio for active treatment group relative to vehicle group with 95% 
confidence interval and p-value will be presented.  
A sensitivity analysis will be performed where subjects  who at some point do not achieve 
‘clear’ or ‘almost clear’ after treatment of a relapse are excluded.  
11.3.4 Exploratory Analysis of Efficacy 
All exploratory analyses of efficacy will be analyzed for the full analysis set. 
11.3.4.1 m-PASI 
m-PASI will be summarised by visit and treatment group.
11.3.4.2 Subjects in remission at each visit 
The number of subjects in remission at each visit will be summarised by treatment group. 
11.3.4.3 Time to when PASI75 is no longer fulfilled 
PASI75 will be based on the m-PASI which is calculated based on the Physician’s assessment 
of the extent and severity of the disease locally (trunk, arms and legs) as described in section 
8.16.3. 
PASI75 is defined as at least 75% reduction in the modified PASI from baseline. 
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Only subjects who have obtained PASI75 at the time of randomisation will be considered. 
The time to first time when PASI75 is no longer fulfilled will be calculated as the number of 
days from randomisation to the first day when the subject no longer fulfills PASI75. For 
subjects who either always fulfill PASI75 or are withdrawn from the trial the number of days 
will be treated as a censored observation at the day of the last observation.  
The number of censored and uncensored observations, i.e. number of subjects who either 
always fulfil PASI75 or are withdrawn from the trial, and number of subjects who at some 
point in time no longer fulfil PASI75, will be summarised by treatment group. The time to 
first time when PASI75 is no longer fulfilled will be summarised by treatment group for 
uncensored observations.   
The comparison between treatments of time to first time when PASI75 is no longer fulfilled 
will be done using a proportional hazards model with treatment group, trial site, and disease 
severity at baseline as factors. The estimate of the hazard ratio of active treatment group 
relative to vehicle group together with the 95% confidence interval and p-value will be 
presented. 
The estimated survival curves with confidence intervals will be presented graphically for each 
of the treatment groups.   
The proportion of subjects who are still at risk of not fulfilling PASI75 will be compared 
between the two treatment groups at 26 and 52 weeks after randomisation. 
11.3.4.4 Time to first relapse according to m-PASI 
Relapse according to m-PASI is included in this study in order to be able to compare with 
other studies where this definition is used. Relapse according to m-PASI occurs when the m-
PASI level exceeds the relapse according to m-PASI level. The relapse according to m-PASI 
level is defined as the baseline m-PASI value minus 50% of the reduction in m-PASI obtained 
from the baseline visit to the randomisation visit 4 weeks later.  
The time to first relapse according to m-PASI will be calculated as the number of days from 
randomisation to the  day when the subject has the first relapse according to m-PASI. For 
subjects who either  do not encounter a relapse according to m-PASI or are withdrawn from 
the trial, the number of days will be treated as a censored observation at the day of the last 
observation.  
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The number of censored and uncensored observations, i.e. number of subjects without relapse 
according to m-PASI or who are withdrawn from the trial, and number of subjects with 
relapse according to m-PASI will be summarised by treatment group. The time to first relapse 
according to m-PASI will be summarised by treatment group for uncensored observations.   
The comparison between treatments of time to first relapse according to m-PASI will be done 
using a proportional hazards model with treatment group, trial site, and disease severity at 
baseline as factors. The estimated survival curves with confidence intervals will be presented 
graphically for each of the treatment groups.   
11.3.4.5 Efficacy after treatment of relapse 
The proportion of subjects who obtain clear or almost clear after treatment of relapse will be 
summarised by number of relapse (1st, 2nd, 3rd etc) for each treatment group. 
11.3.4.6 Target lesion/location scores 
The target lesion/location scores will be summarised over time by treatment group. 
11.3.4.7 Body Surface Area (BSA) 
The affected BSA will be summarised over time by treatment group. 
11.3.4.8 Number of active treatment days during maintenance phase 
The number of active treatment days during the maintenance phase will be presented for each 
treatment group.  
For the active treatment group, it is the sum of days where treated with maintenance treatment 
(twice weekly) and days where treated with rescue medication (once daily during relapse).   
For the vehicle group, it is the sum of days where treated with rescue medication (once daily 
during relapse). 
11.3.5 Analysis of Patient-Reported Outcomes 
All patient-reported outcomes will be analysed for the full analysis set for the maintenance 
phase and for the open-label treatment phase safety analysis set for the open-label treatment 
phase.  
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11.3.5.1 Dermatology Life Quality Index (DLQI) 
A DLQI total score is the sum of the 10 equal-weighted questions and ranges from 0 (no 
quality of life impairment) to 30 (maximal quality of life impairment).  
During the open-label treatment phase, the total DLQI score will be summarised over time. 
During the maintenance phase, the total DLQI score will be summarised over time by 
treatment group. The total DLQI score will also be summarised over time by treatment group 
and relapse status, i.e. according to whether or not the subject has a confirmed relapse at that 
visit. 
At 12 and 52 weeks after randomization the mean DLQI will be compared between treatment 
groups for the full analysis set using a t-test. The comparison will be done both using 
observed data only and using last observation carried forward. Treatment differences, p-values 
and confidence intervals will be presented.  
11.3.5.2 EQ-5D-5L-PSO 
Each of the 5 dimensions ‘mobility’, ‘self-care’, ‘usual activities’, ‘pain/discomfort’, and 
‘anxiety/depression’, the index score, and each of the psoriasis bolt on dimensions (‘skin 
irritation’ and ‘self-confidence’) will be summarised over time by treatment group. 
Health on VAS score will be summarised over time by treatment group. 
11.3.5.3 WPAI:PSO 
Current employment status as well as the derived measures of absenteeism, presenteeism, 
activity impairment and work impairment will be summarised over time both for the open-
label treatment phase, and for the maintenance phase by treatment group.   
11.3.5.4 Psoriasis Symptom Inventory 
The total psoriasis symptom inventory score as well as each of the 8 individual scores will be 
summarised over time both for the open-label treatment phase, and for the maintenance phase 
by treatment group. 
At 12 and 52 weeks  after randomisation the mean total psoriasis symptom inventory score 
will be compared between treatment groups for the full analysis set using a t-test. The 
comparison will be done both using observed data only and using last observation carried 
forward. Treatment differences, p-values and confidence intervals will be presented.  
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11.3.5.5 Subject’s Global Assessment of Disease Severity 
The subject’s global assessment of disease severity will be summarised over time by 
treatment group. 
11.3.6 Analysis of Safety 
11.3.6.1 Adverse Events 
The below analyses will be performed both for the open-label treatment phase safety analysis 
set for the open-label treatment phase and for the maintenance phase safety analysis set for the 
maintenance phase. For the maintenance phase safety analysis set for the maintenance phase, 
AEs will be presented by treatment group.  
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 emergent 
with the trial treatment if started after the first application of IP or (applicable if there is a 
wash-out) if started before the first use of IP and worsened in severity thereafter.  The 
tabulations described in the following will only include the events that are emergent with trial 
treatment. In each of the tabulations, AEs are defined by MedDRA preferred terms within 
primary SOC. 
An overall summary of the number (percentage) of subjects with any treatment emergent AEs, 
SAEs, 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 AEs will be 
tabulated by treatment group. The percentage of subjects with AEs will be compared between 
treatment groups by a chi-square test or Fisher’s exact test (if expected cell count < 5). 
The severity for each type of AE will be tabulated by treatment group.. 
The causal relationship to trial medication for each type of AEs will be tabulated by treatment 
group.  
Related AEs are defined as AEs for which the (sub)investigator has not described the causal 
relationship to IPs as ‘not related’. The number of related AEs and the number of subjects 
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experiencing each type of related AE will be tabulated. The percentage of subjects with 
related AEs will be compared between treatment groups by a chi-square test or Fisher’s exact 
test (if expected cell count < 5). 
The above tabulations will be done for the total maintenance phase, for the first 28 weeks of 
the maintenance phase, and for the remaining 24 weeks of the maintenance phase separately. 
An AE will be included in the tabulations by its start date. If an AE is ongoing at Visit 2 or 
Visit 9 and worsened in severity after, the AE will be included in the tabulations of both 
affected periods. 
SAEs will be evaluated separately and a narrative for each will be given. 
AEs leading to withdrawal from trial or discontinuation of IPs will be listed. 
11.3.6.1.1 Adverse events associated with long term corticosteroid use 
The AEs which have been judged by the adjudication committee to be associated with long 
term corticosteroid use will be listed along with information about demography and baseline 
characteristics.  
11.3.6.2 Rebound 
Rebound will be defined as (i) an m-PASI ≥12 AND an increase in m-PASI of ≥125% of the 
baseline value, or (ii) new pustular, erythrodermic or more inflammatory psoriasis either a) 
within 2 months after discontinuation of once-daily treatment in the initial open-label phase, 
b) within 2 months after discontinuation of once-daily relapse treatment, or c) within
2 months after end of maintenance treatment (up to Visit FU3)
Number of rebounds within two months after entering the maintenance phase will be 
summarised by treatment group in a table.  
Number of rebounds occurring after the first two months of maintenance treatment (i.e. 
including the follow-up period) will be summarised by treatment group in another table. 
Subjects with m-PASI≥125% of baseline (Visit1) score and cases of rebound will be listed. 
11.3.6.3 Local safety and tolerability 
The local safety and tolerability signs perilesional erythema, perilesional oedema, perilesional 
dryness, and perilesional erosion, as well as the symptom ‘application site burning or pain’ 
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will be summarised over time both for the open-label treatment phase, and for the 
maintenance phase by treatment group. 
11.3.6.4 ACTH-Challenge test 
For the group of subjects undergoing the ACTH-challenge test, the number of subjects with 
serum cortisol concentration values ≤18 mcg/dl 30 minutes after the ACTH-challenge test will 
be summarised over time by treatment group.    
11.3.6.5 Vital Signs and Physical Findings 
The change in vital signs (blood pressure, heart rate, body temperature) from baseline to end 
of treatment phase will be summarised. 
The change in vital signs (blood pressure, heart rate, body temperature) from randomisation to 
end of trial will be summarised. 
11.3.6.6 Clinical Laboratory Evaluation 
The change in each of the laboratory parameters from baseline to end of open-label treatment 
phase will be summarised as mean, SD, median, minimum and maximum values. 
The change in each of the laboratory parameters from randomisation to end of trial will be 
summarised as mean, SD, median, minimum and maximum values for each treatment group. 
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within or above the reference range, respectively. 
A shift table will be produced showing the categories at baseline against those at end of 
treatment period. 
A shift table will be produced showing the categories at randomisation against those at end of 
trial. 
To identify subjects with clinically important laboratory changes in albumin-corrected serum 
calcium levels, LEO has defined threshold levels for concern for a clinically significant 
change based on the CTCAE v4.0 for grading of specific clinical laboratory results. These 
LEO-defined threshold levels correspond to a grade of at least ‘moderate’ (i.e. at least 2 on a 
5-point scale) according to the CTCAE v4.0. The low threshold level for the albumin-
corrected serum calcium is ‘<2.0 mmol/l’ and the high threshold level is ‘>2.9 mmol/l’.
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Additional  shift tables as described above will be produced for clinically significant values of 
albumin corrected serum calcium as defined by LEO, i.e., <2.0 mmol/l (lowthreshold) or >2.9 
mmol/l (high threshold), i.e. the shift tales will be for subjects with at least one clinically 
significant value of albumin corrected serum calcium. . 
Subjects with laboratory parameters outside the reference range will be listed. 
11.3.7 Interim Analysis 
No formal interim analyses are planned. However, analysis of the data from the open-label 
treatment phase might be performed prior to finalising the trial. This will have no impact on 
the continued conduct of the study nor the interpretation of the results as the open-label 
treatment phase is not blinded. 
11.3.8 General Principles 
All significance tests will be two-sided using the 5% significance level. All confidence 
intervals will be presented with 95% degree of confidence.  
An observed cases approach will be used for tabulations of data by visit (i.e. involving only 
those subjects who attended each specific visit). 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment group. Continuous data will be summarised using the mean, median, 
standard deviation (SD), minimum and maximum values. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan update will be finalised before breaking the 
randomisation code. 
The randomisation is stratified by treatment group, trial site, HPA axis testing and disease 
severity at baseline as factors. Usually, the statistical analysis of efficacy parameters takes all 
the stratification factors into account. However, the HPA axis test is a safety parameter, which 
is only determined at a small subset of sites and subjects. Hence stratification by HPA axis test 
is not applicable for all sites. Also, it is expected that two subjects per site will be randomised. 
This means that a statistical model having HPA axis testing as a factor may not converge, 
depending on whether subjects participating in the HPA axis test drop out. Furthermore, the 
inclusion criteria for participating in the HPA axis test are “Moderate” or “Severe” in the 
baseline PGA assessment and a baseline BSA between 10 and 30%. Including the 
stratification factor HPA axis testing would therefore introduce a confounding with the 
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stratification according to baseline PGA as well as sites. Therefore  the stratification 
according to HPA axis testing is not included in the statistical analyses. 
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 clinical trial report dependent on the type of deviation.  
11.3.9 Handling of Missing Values 
In the analysis of the primary endpoint, time to first relapse, missing data are treated as 
censored observations.   
For number of days in remission in the primary analysis a subject is considered not to be in 
remission from when the subject leaves the trial. Two sensitivity analyses with different 
imputation as detailed in section 11.3.3.5 are performed.  
For the secondary endpoint “number of relapses”, subjects only contribute with information 
until they leave the trial.     
There is no imputation of missing data for the exploratory analyses of efficacy and the 
analyses of patient-reported outcomes.  
12 Trial Committees   
12.1 Adjudication Committee 
A panel of 2 dermatologists and one endocrinologist (“Adjudication Panel”) will review all 
treatment-emergent AEs to identify AEs of concern associated with long-term use of topical 
corticosteroids where a causal relationship between the trial medication and the event is at 
least a reasonable possibility. 
The Adjudication Panel will not review AEs which occurred prior to application of the first 
dose of IP; this includes AEs reported by screening failures (who per definition did not start 
open-label treatment).  
The Adjudication Panel Members (APM) will be independent of the trial (i.e. they will not be 
participating (sub)investigators) and of LEO (i.e. they will not be LEO employees). They will 
also be blinded to treatment allocation at the time of the review. 
A listing of AEs will be provided to the APM consisting of the following data: 
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
AE reported Term (as reported in eCRF).

The MedDRA Preferred Term as coded by LEO.

The (sub)investigator assessment of causal relationship of the use of trial medication
to the event, location of cutaneous events, severity, and seriousness.

The (sub)investigator assessment of causal relationship of long-term use of
corticosteroids to the event. For such AEs of concern, the narrative recorded in the
eCRF will also be provided.

The date of onset, the outcome, and date of outcome.

The action taken with trial medication.
The listing will be generated for patients with complete data (i.e. source data verification 
(SDV) and SAE reconciliation have been performed). Several listings will be generated 
during the trial and adjudications performed on batches of ‘complete’ patients, until all 
patients are included in this process. 
The APM will be able to request eCRF pages and SAE reports on a per subject basis, should 
this be required for adjudication purposes.  
Each APM will perform the adjudication independently of the other APMs and of LEO.  If 
there is any discrepancies in the events identified by each APM, the APMs will discuss these, 
either by telephone or in a meeting.  If a consensus opinion of all three APMs on identified 
events is not reached, a conservative approach will be used by including events adjudicated to 
be related to trial medication by any APM, even if identified by just one of the APMs. 
The Clinical Project Manager (CPM)/National Lead Clinical Research Associate (NLCRA) is 
present at the time of adjudication to provide administrative support only; The CPM/NLCRA 
will not make any comments in relation to the adjudication of the AEs. 
13 Case Report Forms and Data Handling 
13.1 Case Report Forms (CRFs)  
Data will be collected by means of Electronic Data Capture (EDC). The investigator or staff 
authorised by the investigator will enter subject data into eCRFs. Data recorded in the eCRFs 
will be accessible to the trial site and LEO personnel  immediately after entry. The eCRFs 
must be maintained in an up-to-date state at the trial site at all times.  
The investigator must verify the correctness of the data entered by the site by electronically 
date and sign all eCRFs used. This signature information will be kept in the audit trail and 
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cannot be altered. Any correction(s) made by the (sub)investigator or authorised site staff to 
the eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require the re-signature by the investigator. The person making the change to 
the data,  and the date, time and reason for the change will be identified in the audit trail.  
For archiving purposes, each investigator will be supplied with a copy of the eCRFs for all 
subjects enrolled at the trial site. This is done after completion of the trial and before access to 
the eCRF is revoked. Audit trail information will be included. eCRFs must be available for 
inspection by authorised representatives from LEO, from regulatory authorities and/or 
IEC/IRBs. 
13.2 Data Handling 
Subject data should be entered into the eCRF as soon as possible after the visit in accordance 
with the time requirements described in the Clinical Trial Agreement with the sites. Queries 
for discrepant data may be generated automatically by the system upon entry or generated 
manually by the monitor or the trial data manager. All queries, whether generated by the 
system or by a user, will be in an electronic format. This systematic validation will ensure that 
a clean and consistent database is provided prior to the statistical analysis being performed.  
Some PRO data will be captured electronically on a tablet/slate (ePRO) at the site. Other PRO 
data as well as some compliance questions will be captured on a small tablet (eDiary) by the 
subjects at home. By the use of ePRO and eDiary data will be available immediately after 
data entry and available for monitors and the site personnel, including the clinical 
investigator, with read access only. The investigator (or designee) is expected to review ePRO 
and eDiary data, and remind and re-train the subject if appropriate to ensure data 
completeness. The ePRO and eDiary system is a separate application from the eCRF. Data 
captured from the eCRF will be stored on a different servers than data captured via ePRO and 
eDiary during data capture. Data from both systems will be included in the final study 
database. 
External data transfers from vendors to LEO will be transmitted and handled via a secure ftp 
site. 
Transmissions of electronic data from external data providers and of ePRO data (including 
eDiary data in the below illustration) to the clinical data base is illustrated in Figure 5. 
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Figure 5 Flow of Electronic Data 
13.3 Source Data 
For all data recorded, the source document must be defined in a source document agreement 
at each trial site. There must only be one source defined at any time for any data elements. 
The trial monitor will check the eCRFs for accuracy and completeness by verifying data 
recorded in the eCRF against source data to ensure such records are consistent.   
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 (sub)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 (date of enrolment) including
date of provision of subject information

Subject ID
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
Randomisation code number (if applicable)

The fact that the subject is participating in a clinical trial in psoriasis vulgaris
including treatment arms of LEO 90100 or vehicle for up to 56 weeks

Other relevant medical information

Allocated treatment once the randomisation code has been broken (if applicable)
13.4  Trial Monitoring 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol 
and GCP are adhered to, that all issues have been recorded to perform source data verification 
and to monitor drug accountability. 
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, monitors 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 monitor 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).  
14 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.” (Article 10(b) of Directive 2001/20/EC). 
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). 
The investigator must immediately inform LEO - by contacting the ICTM or medical expert - 
of this change in the clinical trial procedure or of the temporary halt providing full details of 
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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 the internal procedures. 
15 Quality Assurance/Audit 
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. 
16 Completion of Trial 
16.1 Trial Completion Procedures 
End of trial is defined as the date of the last subject’s last visit. 
Investigators will be informed when subject recruitment is to cease. This will also include 
information on when the threshold of 20% of subjects with a ‘mild’ PGA is reached, and 
when a sufficient number of subjects (approximately 25 subjects with 52 weeks of exposure) 
have been included in the HPA axis part of the trial. 
Trial enrolment will be stopped at a trial site when the total requested number of subjects 
randomised for the clinical trial has been obtained, irrespective of the specific site’s planned 
inclusion number. 
Upon completion of the clinical trial, LEO must undertake arrangements for the collection 
and disposal of any unused trial material that the investigator is not required to keep in his/her 
files. 
When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record. 
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16.1.1 Criteria for Premature Termination of the Trial and/or Trial Site 
LEO, the investigator, the IRB/IECs or competent authorities may decide to stop the trial, part 
of the trial or a trial site at any time, but agreement on procedures to be followed must be 
obtained. 
If a 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. 
Due to the design of this trial, there are no statistical criteria for trial termination. 
16.2 Provision for Subject Care Following Trial Completion 
After the completion of the trial, the subjects will be treated at the investigator’s discretion or 
referred to other physician(s) according to standard practice (subjects should not be treated 
with Enstilar® until after the final follow-up visit (FU3)). 
16.3 Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store the essential trial docu-
ments 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 (e.g. 
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 clinic/practice or retires before the end of the required storage period. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
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17 Ethics and Regulatory Authorities 
17.1 Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) and Regulatory Authorities 
Written approval or favourable opinion must be obtained from relevant IRB/IECs prior to the 
enrolment of subjects. 
Any amendments to the approved clinical trial must be approved by/receive favourable 
opinion from relevant IRBs/IECs and regulatory authorities as required prior to the 
implementation. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial, as 
required. 
17.2 Ethical Conduct of the Trial 
This clinical trial must be conducted in accordance with the principles of the revision current 
at the start of the trial of the World Medical Association (WMA), Declaration of Helsinki, 
Ethical Principles for Medical Research Involving Human Subjects. 
17.3 Subject Information and Informed Consent 
All 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 
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.  
17.4  Processing of Personal Data 
This protocol specifies the personal data on trial subjects (e.g. age, gender, health condition, 
height, medical history, test results, etc.) which shall be collected as part of the 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 and LEO. 
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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 national legislation on data protection and privacy. 
The investigator/institution may be considered as data controller when they wish to use 
personal data collected in the clinical trial for their own purpose such as publication of 
clinical trial results.  
Subjects must be asked to consent to the collection, processing and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
If required, LEO has obtained the necessary authorisations for the processing by LEO of 
personal data collected in the trial.  
18 Insurance 
LEO has taken out relevant insurances covering the subjects in the present clinical trial in 
accordance with applicable laws and regulations. 
19 Use of Information 
This clinical trial protocol as well as all other information, data and results relating to this 
clinical trial and/or to the IP(s) 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 IP(s) and, therefore, may disclose 
and/or transfer information, data and/or results to other investigators, regulatory authorities 
and/or commercial partners. 
20 Publication 
Basic information of this clinical trial will be posted on the website: www.clinicaltrials.gov 
before the first subject enters into the clinical trial (35, 36) 
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Results will be made available on LEO’s web site according to LEO’s position on access to 
clinical trial information. 
This clinical trial is multi-centre, and publication by an investigator of his/her trial results 
shall not be made before the first multi-centre publication is made public. Such multi-centre 
publication will be prepared in collaboration between LEO and the members of a writing 
committee, which shall be appointed by LEO. 
If there is no multi-centre publication within eighteen (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 Committee 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 be followed. 
LEO also subscribes to the joint position of the innovative pharmaceutical industry (37) for 
public disclosure of clinical trial results in a free, publicly accessible database, regardless of 
outcome. 
21 Responsibilities 
The international coordinating investigator (ICI) is responsible for the approval of the 
(Consolidated) Clinical Trial Protocol, Clinical Trial Protocol Amendment(s) and the Clinical 
Trial Report on behalf of all clinical trial investigators and as agreed to in an international 
coordinating investigator agreement. 
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The national coordinating investigator(s) are responsible for national issues relating to the 
clinical trial as agreed to in a national coordinating investigator agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement. 
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22 List of Abbreviations 
ACE 
Angiotensin-Converting Enzyme 
ACTH 
Adrenocorticotropic Hormone 
AE 
Adverse Event 
APM 
Adjudication Panel Member 
BSA 
Body Surface Area 
CHMP 
Committee for Human Medicinal Products 
CMO 
Contract Manufacturing Organisation 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
DLQI 
Dermatology Life Quality Index 
DME 
Dimethyl Ether 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic Diary 
EU 
European Union 
FDA 
Food and Drug Agency 
GCP 
Good Clinical Practice 
GPV 
Global Pharmacovigilance 
HPA 
Hypothalamic-Pituitary-Adrenal 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
ICTM 
International Clinical Trial Manager 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
m-PASI
Modified Psoriasis Area Severity Index 
NLCRA
National Lead Clinical Research Associate 
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PASI 
Psoriasis Area Severity Index 
PASI 75 
A 75% reduction in the modified Psoriasis Area and Severity Index 
PGA 
Physician’s Global Assessment of disease severity 
PRO 
Patient Reported Outcome 
PSI 
Psoriasis Symptom Inventory  
PUVA 
Psoralen combined with Ultraviolet A 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
UVB 
Ultraviolet B 
WMA 
World Medical Association  
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23 Definition of terms 
Throughout this document, the following terminology is used when referring to the treatment 
groups in the clinical trials. Please note that calcipotriol is identical to calcipotriene. 
Calcipotriol is the international non-proprietary name (INN) and calcipotriene is the US 
adopted name (USAN). 
Names used in text and tables 
LEO 90100 
Cutaneous foam, one gram contains 50 mcg of calcipotriol (as 
monohydrate) and 0.5 mg of betamethasone (as dipropionate). With the 
propellants, this corresponds to
mcg of calcipotriol (as monohydrate) 
and
mg of betamethasone (as dipropionate) per gram of pressurised 
formulation in the can. Also referred to as LEO 90100 aerosol foam (US 
defined dosage form). 
Foam vehicle or 
vehicle 
LEO 90100 vehicle 
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24 References 
1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in
the United States. J Am Acad Dermatol. 2014 Mar;70(3):512-6.
2. Augustin M, Reich K, Glaeske G, Schaefer I, Radtke M. Co-morbidity and age-related
prevalence of psoriasis: Analysis of health insurance data in Germany. Acta Derm
Venereol. 2010 Mar;90(2):147-51.
3. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis.Lancet. 2007
Jul 21;370(9583):263-71
4. Gisondi P, Tessari G, Conti A, Piaserico S, Schianchi S, Peserico A, Giannetti A,
Girolomoni G. Prevalence of metabolic syndrome in patients with psoriasis: a
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38. European Parliament and Council of The European Union. Directive 2001/20/EC of
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insufficiency. Swiss Med Wkly. 2014;144:w13987.
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Appendix 1: Protocol Summary 
Name of finished/ 
investigational 
product 
LEO 90100 aerosol foam 
Name of active 
substance 

Calcipotriol

Betamethasone dipropionate
Title of trial/trial 
ID/EudraCT no. 
LEO 90100 twice weekly maintenance regimen for psoriasis 
vulgaris/LP0053-1004/2016-000556-95 
Coordinating 
investigator(s) 
Name of international coordinating investigator: Dr Mark Lebwohl 
Sponsor’s name/ 
address 
LEO Pharma A/S (referred to as ‘LEO’ in the clinical trial protocol) 
Estimated 
number of trial 
sites and 
distribution 
Approximately 58 sites in Canada, France, Germany, Poland, United 
Kingdom, United States  
Trial period 
Planned date of enrolment of first subject: Q1-2017 
Planned date of completion of last subject: Q3-2019 
Main objective(s) 

To evaluate the efficacy of a twice weekly maintenance regimen with
LEO 90100 compared to vehicle in the prevention of relapse in
subjects with psoriasis vulgaris.

to evaluate the long-term safety of LEO 90100 (up to 52 weeks) in
subjects with psoriasis vulgaris.
Methodology 
This trial is a 12-month, international, multi-centre, randomised, vehicle 
controlled, double-blind, 2-arm, parallel group trial consisting of an 
initial open-label treatment phase of 4 weeks followed by a randomised, 
double-blind, vehicle-controlled, maintenance phase of 52 weeks in 
subjects with psoriasis vulgaris, and an 8-week follow-up period. After 
completing the open-label phase, subjects should have a disease severity 
(PGA) of ‘clear’ or ‘almost clear’ with at least a 2-grade improvement 
from baseline to continue into the maintenance phase. 
Number of 
subjects to be 
enrolled 
A total of 832 subjects should be included in the trial in order to have 
90% probability of achieving at least 380 subjects to be randomised.  
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Main criteria for 
inclusion 

Signed and dated informed consent obtained prior to any trial related
activities (including washout period)

Age 18 years or above

A clinical diagnosis of psoriasis vulgaris for at least 6 months
involving the trunk and/or limbs, amenable to treatment with a
maximum of 100 g of trial medication per week

Psoriasis vulgaris on the trunk and/or limbs (excluding psoriasis on
the genitals and skin folds) involving 2-30% of the body surface area
(BSA)

A Physician's Global Assessment of disease severity (PGA) of at
least ‘mild’ on trunk and limbs at Visit 1

A m-PASI score of at least 2 at Visit 1

Females of child-bearing potential must have a negative urine
pregnancy test at Visit 1

Females of child-bearing potential must agree to use a highly
effective method of birth control during the trial
Additional criteria for subjects undergoing HPA axis test

Signed and dated informed consent for ACTH challenge tests

Psoriasis vulgaris on trunk and/or limbs of disease severity (PGA) of
at least ‘moderate’ affecting between 10 and 30% of the body surface
area (BSA) excluding psoriatic lesions of genitals and skin folds at
Visit 1

At Visit 1, a normal HPA axis function including a serum cortisol
concentration above 5 mcg/dl before ACTH-challenge and above 18
mcg/dl 30 minutes after ACTH-challenge
Main criteria for 
exclusion 

Systemic treatment with biological therapies, whether marketed or
not, with a possible effect on psoriasis vulgaris within the following
time periods prior to Visit 1:
o etanercept – within 4 weeks prior to Visit 1
o adalimumab, infliximab – within 8 weeks prior to Visit 1
o ustekinumab – within 16 weeks prior to Visit 1
o secukinumab – within 12 weeks prior to Visit 1
o other products – within 4 weeks/5 half-lives prior to Visit 1
(whichever is longer) 
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
Systemic treatment with all other therapies with a possible effect on
psoriasis vulgaris (e.g. corticosteroids, retinoids, methotrexate,
ciclosporin and other immunosuppressants) within 4 weeks prior to
Visit 1

Systemic treatment with apremilast within 4 weeks prior to Visit 1

Subjects who have received treatment with any non-marketed drug
substance (i.e. a drug which has not yet been made available for
clinical use following registration) within 4 weeks/5 half-lives
(whichever is longer) prior to Visit 1

Psoralen combined with Ultraviolet A (PUVA) therapy within 4
weeks prior to Visit 1

Ultraviolet B (UVB) therapy within 2 weeks prior to Visit 1

Topical anti-psoriatic treatment on the trunk and/or limbs (except for
emollients) within 2 weeks prior to Visit 1

Topical treatment on the face, scalp and skin folds with
corticosteroids, or vitamin D analogues within 2 weeks prior to Visit
1

Severe and/or extensive scalp psoriasis which, in the opinion of the
investigator, requires treatment with potent or super-potent
corticosteroids which will be prohibited during the trial

Pre-existing overt atrophy or teleangiectasia in treatment areas

Planned initiation of, or changes to, concomitant medication that
could affect psoriasis vulgaris (e.g. beta blockers, antimalarial drugs,
lithium, ACE inhibitors) during the trial

Current diagnosis of guttate, erythrodermic, exfoliative or pustular
psoriasis

Subjects with any of the following conditions present on the
treatment area: viral (e.g. herpes or varicella) lesions of the skin,
fungal and bacterial skin infections, parasitic infections, skin
manifestations in relation to syphilis or tuberculosis, acne vulgaris,
atrophic skin, striae atrophicae, fragility of skin veins, ichtyosis,
ulcers and  wounds

Other inflammatory skin disorders (e.g. seborrhoeic dermatitis or
contact dermatitis) on the treatment area that may confound the
evaluation of psoriasis
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
Known or suspected disorders of calcium metabolism associated
with hypercalcaemia
Note: Additional exclusion criteria for subjects undergoing HPA 
axis test (assigned sites only) apply 
Investigational 
product(s) 
LEO 90100 aerosol foam, calcipotriol (as monohydrate) 50 mcg/g and 
betamethasone (as dipropionate) 0.5 mg/g and LEO 90100 aerosol foam 
vehicle (no active ingredient), for topical use 

Initial open-label treatment phase: LEO 90100 once daily for 4
weeks

Maintenance phase: randomised treatment (LEO 90100 or vehicle)
twice weekly, 3 or 4 days apart

Treatment of relapse: LEO 90100 once daily for 4 weeks on relapse
areas, while psoriasis areas without relapse continue on maintenance
Investigational 
reference 
product(s) 
Aerosol foam vehicle 
Duration of 
treatment 

A Washout period up to 4 weeks

An initial open-label treatment phase: LEO 90100 once daily for
4 weeks

A maintenance phase: randomised treatment (LEO 90100 or vehicle)
twice weekly for 52 weeks

A follow-up period of 8 weeks.
Main assessments 
Physician’s Global Assessment of Disease Severity (PGA)

Physician’s Assessment of the Extent and Severity of Clinical Signs
(Redness, Thickness, Scaliness) (m-PASI)

Safety laboratory bood samples

Safety urinalysis

Adverse events
Primary endpoint 
Time to first relapse (at least ‘mild’ according to the PGA) 
Secondary 
endpoint(s) 

Number of days in remission (‘clear’/‘almost clear’ according to the
PGA) during the maintenance phase

Number of relapses during the maintenance phase
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Statistical 
methods 
Primary endpoint 
The primary endpoint is time to first relapse during the maintenance 
period where relapse is an exacerbation of psoriasis defined as a PGA of 
at least ‘mild’. This will be calculated as the number of days from 
randomisation to the day where the subject has the first relapse 
confirmed. For subjects who either do not encounter a relapse or are 
withdrawn from the trial, the number of days will be treated as a 
censored observation at the day of end of trial visit. 
The number of censored and uncensored observations, i.e. number of 
subjects without relapse and number of subjects with relapse, will be 
summarised by treatment group. The time to first relapse will be 
summarised by treatment group for uncensored observations, i.e. 
subjects with relapse.  
The primary endpoint will be compared between treatments with the null 
hypothesis that they are equal against the alternative that they are 
different. The analysis will be performed both for the full analysis set 
(primary) and for the per protocol analysis set (supportive). The 
comparison will be done using a proportional hazards model with 
treatment group, trial site, HPA axis testing, and severity at baseline (as 
determined by the PGA) as factors. The estimate of the hazard ratio of 
active treatment group relative to vehicle group together with the 95% 
confidence interval and p-value will be presented.  
The estimated survival curves with confidence intervals will be 
presented graphically for each of the treatment groups.  Moreover the 
percentiles of the survivial distribution will be tabulated by treatment 
group.The proportion of subjects who are still at risk for a first relapse 
will be compared between the two treatment groups 24 and 52 weeks 
after randomisation.   
Secondary endpoints 
The secondary endpoints will be analysed for the full analysis set, with 
the analysis for the per protocol analysis set being supportive. 
Adjustment for multiplicity will be done using the Holm-Bonferroni 
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method. 

Number of days in remission
The number of days in remission will be calculated for each subject as 
the total number of days in trial during the maintenance period minus the 
number of days in treatment of relapses, if any. If a subject is withdrawn 
from the trial for any reason, then the subject is considered not to be in 
remission from when the subject leaves the trial.  
The number of days in remission will be summarised by treatment 
group.  
The number of days in remission will be analysed by means of an 
analysis of variance (ANOVA) model with treatment group, trial site, 
HPA axis testing, and severity at baseline as factors. Estimated difference 
between active treatment group and vehicle group, 95% confidence 
interval, and p-value will be presented. 

Number of relapses during maintenance phase
The number of relapses will be calculated as the sum of confirmed 
relapses for each subject. Subjects contribute with observed time only. 
The rate of relapses during the maintenance phase is assumed to be 
constant over time.  
The number of relapses will be analysed in a Poisson regression model 
with treatment group, trial site, HPA axis testing, and severity at baseline 
as factors, subject as a random effect,  and risk time as an offset. The risk 
time is the observed time at risk for each subject, i.e. the total time in 
trial during the maintenance period time minus the periods of treatment 
of relapses, if any. The estimated incidence rate ratio for active treatment 
group relative to vehicle group with 95% confidence interval and p-value 
will be presented.  
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Appendix 2: U.S. Prescribing information for CORTROSYN® 
(cosyntronin) for injection 
CORTROSYN®™ 
FOR DIAGNOSTIC USE ONLY 
(cosyntropin) for Injection 
DESCRIPTION 
CORTROSYN™ (cosyntropin) for Injection is a sterile lyophilized powder in vials containing 
0.25 mg of CORTROSYN™ and 10 mg of mannitol to be reconstituted with 1 mL of 0.9% 
Sodium Chloride Injection, USP. Administration is by intravenous or intramuscular injection. 
Cosyntropin is α 1 - 24 corticotropin, a synthetic subunit of ACTH. It is an open chain 
polypeptide containing, from the N terminus, the first 24 of the 39 amino acids of natural 
ACTH. The sequence of amino acids in the 1 - 24 compound is as follows: 
Ser - Tyr - Ser - Met - Glu - His - Phe - Arg - Trp - Gly - Lys - Pro - Val - Gly - Lys - Lys - Arg - Arg - Pro - Val - Lys - Val - Tyr - Pro 
1 
  2    3    4    5  
 6    7  
  8  
  9 
  10    11   12    13   14    15   16    17   18    19    20    21    22   23   24 
CLINICAL PHARMACOLOGY 
CORTROSYN™ (cosyntropin) for Injection exhibits the full cortico-steroidogenic activity of 
natural ACTH. Various studies have shown that the biologic activity of ACTH resides in the 
N-terminal portion of the molecule and that the 1 - 20 amino acid residue is the minimal
sequence retaining full activity. Partial or complete loss of activity is noted with progressive
shortening of the chain beyond 20 amino acid residues. For example, the decrement from 20
to 19 results in a 70% loss of potency. 
The pharmacologic profile of CORTROSYN™ is similar to that of purified natural ACTH. It 
has been established that 0.25 mg of CORTROSYN™ will stimulate the adrenal cortex 
maximally and to the same extent as 25 units of natural ACTH. This dose of CORTROSYN™ 
will produce maximal secretion of 17-OH corticosteroids, 17- ketosteroids and / or 17 - 
ketogenic steroids. 
The extra-adrenal effects which natural ACTH and CORTROSYN™ have in common include 
increased melanotropic activity, increased growth hormone secretion and an adipokinetic 
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effect. These are considered to be without physiological or clinical significance. 
Animal, human and synthetic ACTH (1-39) which all contain 39 amino acids exhibit similar 
immunologic activity. This activity resides in the C-terminal portion of the molecule and the 
22-39 amino acid residues exhibit the greatest degree of antigenicity. In contrast, synthetic
poly-peptides containing 1-19 or fewer amino acids have no detectable immunologic activity.
Those containing 1-26, 1-24 or 1-23 amino acids have very little immunologic although full
biologic activity. This property of CORTROSYN™ assumes added importance in view of the
known antigenicity of natural ACTH.
INDICATIONS AND USAGE 
CORTROSYN™ (cosyntropin) for Injection is intended for use as a diagnostic agent in the 
screening of patients presumed to have adrenocortical insufficiency. Because of its rapid 
effect on the adrenal cortex it may be utilized to perform a 30-minute test of adrenal function 
(plasma cortisol response) as an office or outpatient procedure, using only 2 venipunctures 
(see DOSAGE AND ADMINISTRATION section). 
Severe hypofunction of the pituitary - adrenal axis is usually associated with subnormal 
plasma cortisol values but a low basal level is not per se evidence of adrenal insufficiency and 
does not suffice to make the diagnosis. Many patients with proven insufficiency will have 
normal basal levels and will develop signs of insufficiency only when stressed. For this reason 
a criterion which should be used in establishing the diagnosis is the failure to respond to 
adequate corticotropin stimulation. When presumptive adrenal insufficiency is diagnosed by a 
subnormal CORTROSYN™ test, further studies are indicated to determine if it is primary or 
secondary. 
Primary adrenal insufficiency (Addison’s disease) is the result of an intrinsic disease process, 
such as tuberculosis within the gland. The production of adrenocortical hormones is deficient 
despite high ACTH levels (feedback mechanism). Secondary or relative insufficiency arises 
as the result of defective production of ACTH leading in turn to disuse atrophy of the adrenal 
cortex. It is commonly seen, for example, as result of corticosteroid therapy, Sheehan’s 
syndrome and pituitary tumors or ablation. 
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The differentiation of both types is based on the premise that a primarily defective gland 
cannot be stimulated by ACTH whereas a secondarily defective gland is potentially functional 
and will respond to adequate stimulation with ACTH. Patients selected for further study as the 
result of a subnormal CORTROSYN™ test should be given a 3 or 4 day course of treatment 
with Repository Corticotropin Injection USP and then retested. Suggested doses are 40 USP 
units twice daily for 4 days or 60 USP units twice daily for 3 days. Under these conditions 
little or no increase in plasma cortisol levels will be seen in Addison’s disease whereas higher 
or even normal levels will be seen in cases with secondary adrenal insufficiency. 
CONTRAINDICATION 
The only contraindication to CORTROSYN™ (cosyntropin) for Injec-tion is a history of a 
previous adverse reaction to it. 
PRECAUTIONS 
General 
CORTROSYN™ (cosyntropin) for Injection exhibits slight immunologic activity, does not 
contain animal protein and is therefore less risky to use than natural ACTH. Patients known to 
be sensitized to natural ACTH with markedly positive skin tests will, with few exceptions, 
react negatively when tested intradermally with CORTROSYN™. Most patients with a 
history of a previous hypersensitivity reaction to natural ACTH or a pre-existing allergic 
disease will tolerate CORTROSYN™. Despite this however, CORTROSYN™ is not 
completely devoid of immunologic activity and hypersensitivity reactions including rare 
anaphylaxis are possible. Therefore, the physician should be pre-pared, prior to injection, to 
treat any possible acute hypersensitivity reaction. 
Drug Interactions 
Corticotropin may accentuate the electrolyte loss associated with diuretic therapy. 
Carcinogenesis, Mutagenesis, Impairment of Fertility.  
Long term studies in animals have not been performed to evaluate carcinogenic or mutagenic 
potential or impairment of fertility. A study in rats noted inhibition of reproductive function 
like natural ACTH. 
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Pregnancy 
Pregnancy Category C. Animal reproduction studies have not been conducted with 
CORTROSYN™ (cosyntropin) for Injection. It is also not known whether CORTROSYN™ 
can cause fetal harm when ad-ministered to a pregnant woman or can affect reproduction 
capacity. CORTROSYN™ should be given to a pregnant woman only if clearly needed. 
Nursing Mothers 
It is not known whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk, caution should be exercised when CORTROSYN™ (cosyntropin) for 
Injection is administered to a nursing woman. 
Pediatric Use 
(See DOSAGE AND ADMINISTRATION section.) 
ADVERSE REACTIONS 
Since CORTROSYN®™ (cosyntropin) for Injection is intended for diagnostic and not 
therapeutic use, adverse reactions other than a rare hypersensitivity reaction are not 
anticipated. A rare hypersensitivity reaction usually associated with a pre-existing allergic 
disease and/or a previous reaction to natural ACTH is possible. Symptoms may include slight 
whealing with splotchy erythema at the injection site. There have been rare reports of 
anaphylactic reaction. The following adverse reactions have been reported in patients after the 
administration of CORTROSYN®™ and the association has been neither confirmed nor 
refuted: 
o bradycardia
o tachycardia
o hypertension
o peripheral edema
o rash
DOSAGE AND ADMINISTRATION 
CORTROSYN™ (cosyntropin) for Injection may be administered intramuscularly or as a 
direct intravenous injection when used as a rapid screening test of adrenal function. It may 
also be given as an intravenous infusion over a 4 to 8 hour period to provide a greater 
stimulus to the adrenal glands. Doses of CORTROSYN™ 0.25 to 0.75 mg have been used in 
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clinical studies and a maximal response noted with the smallest dose. 
A suggested method for a rapid screening test of adrenal function has been described by Wood 
and Associates (1). A control blood sample of 6 to 7 ml is collected in a heparinized tube. 
Reconstitute 0.25 mg of CORTROSYN™ with 1mL of 0.9% Sodium Chloride Injection, USP 
and inject intramuscularly. The reconstituted drug product should be inspected visually for 
particulate matter and discoloration prior to injection. Reconstituted CORTROSYN™ should 
not be retained. In the pediatric population, aged 2 years or less, a dose of 0.125 mg will often 
suffice. A second blood sample is collected exactly 30 minutes later. Both blood samples 
should be refrigerated until sent to the laboratory for determination of the plasma cortisol 
response by some appropriate method. If it is not possible to send them to the laboratory or 
perform the fluorimetric procedure within 12 hours, then the plasma should be separated and 
refrigerated or frozen according to need. 
Two alternative methods of administration are intravenous injection and infusion. 
CORTROSYN™ can be injected intravenously in 2 to 5 mL of saline over a 2-minute period. 
When given as an intravenous infusion: CORTROSYN™, 0.25 mg may be added to glucose 
or saline solutions and given at the rate of approximately 40 micrograms per hour over a 6- 
hour period. It should not be added to blood or plasma as it is apt to be inactivated by 
enzymes. Adrenal response may be measured in the usual manner by determining urinary 
steroid excretion before and after treatment or by measuring plasma cortisol levels before and 
at the end of the infusion. The latter is preferable because the urinary steroid excretion does 
not always accurately reflect the adrenal or plasma cortisol response to ACTH. 
The usual normal response in most cases is an approximate doubling of the basal level, 
provided that the basal level does not exceed the normal range. Patients receiving cortisone, 
hydrocortisone or spironolactone should omit their pre-test doses on the day selected for 
testing. Patients taking inadvertent doses of cortisone or hydrocortisone on the test day and 
patients taking spironolactone or women taking drugs which contain estrogen may exhibit 
abnormally high basal plasma cortisol levels. 
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A paradoxical response may be noted in the cortisone or hydrocortisone group as seen in a 
decrease in plasma cortisol values following a stimulating dose of CORTROSYN™. 
In the spironolactone or estrogen group only a normal incremental response is to be expected. 
Many patients with normal adrenal function, however, do not respond to the expected degree 
so that the following criteria have been established to denote a normal response: 
1. The control plasma cortisol level should exceed 5 micrograms/100 ml.
2. The 30-minute level should show an increment of at least 7 micrograms/100 ml above the
basal level.
3. The 30-minute level should exceed 18 micrograms/100 ml. Comparable figures have
been reported by Greig and co-workers
Plasma cortisol levels usually peak about 45 to 60 minutes after an injection of 
CORTROSYN™ and some prefer the 60-minute interval for testing for this reason. While it is 
true that the 60-minute values are usually higher than the 30-minute values, the difference 
may not be significant enough in most cases to outweigh the disadvantage of a longer testing 
period. If the 60-minute test period is used, the criterion for a normal response is an 
approximate doubling of the basal plasma cortisol value. 
In patients with a raised plasma bilirubin or in patients where the plasma contains free 
hemoglobin, falsely high fluorescence measurements will result. The test may be performed at 
any time during the day but because of the physiological diurnal variation of plasma cortisol 
the criteria listed by Wood cannot apply. It has been shown that basal plasma cortisol levels 
and the post CORTROSYN™ increment exhibit diurnal changes. However, the 30-minute 
plasma cortisol level remains unchanged throughout the day so that only this single criterion 
should be used (3). 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
whenever solution and container permit. Reconstituted CORTROSYN™ should not be 
retained. 
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HOW SUPPLIED 
Box of 10 vials of CORTROSYN®™ (cosyntropin) for Injection 0.25 mg 
NDC # 0548-5900-00 
Storage 
Store at 15-30°C (59-86°F). 
CORTROSYN™ is intended as a single dose injection and contains no antimicrobial 
preservative. Any unused portion should be discarded. 
Rx only 
REFERENCES 
1. Wood, J.B. et al. LANCET 1.243, 1965.
2. Greig, W.R. et al. J. ENDOCR 34.411, 1966.
3. McGill, P.E. et al. ANN RHEUM DIS 26.123, 1967.
Amphastar Pharmaceuticals, Inc. 
Rancho Cucamonga, CA 91730 U.S.A. 
REV. 9-05 
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Appendix 3: Summary of Product Characteristics for Synacthen® 
(Tetracosactide) Ampoules 250mcg   
1 NAME OF THE MEDICINAL PRODUCT 
Synacthen Ampoules 250mcg. 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Tetracosactide acetate 250micrograms per ampoule.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM 
Solution for injection or infusion. 
A clear colourless aqueous solution for intramuscular injection or intravenous 
infusion in a 1 mL clear glass ampoule. 
4 CLINICAL PARTICULARS 
4.1 Therapeutic indications 
Diagnostic test for the investigation of adrenocortical insufficiency. 
4.2 Posology and method of administration 
Adults: This preparation of Synacthen is intended for administration for 
diagnostic purposes only as a single intramuscular or intravenous dose; it is 
not to be used for repeated therapeutic administration. 
The 30-minute Synacthen diagnostic test: This test is based on measurement 
of the plasma cortisol concentration immediately before and exactly 30 
minutes after an intramuscular or intravenous injection of 250micrograms 
(1ml) Synacthen. Adrenocortical function can be regarded as normal if the 
post-injection rise in plasma cortisol concentration increases by 200 nmol/litre 
(70 micrograms/litre), i.e. if the value 30 minutes after injection is >500 
nmol/litre (180 micrograms/litre), adrenocortical function is regarded as 
normal. All the plasma samples should be stored in a refrigerator until plasma 
cortisol level estimation. 
Where the 30-minute test has yielded inconclusive results, or where it is 
desired to determine the functional reserve of the adrenal cortex, a 5-hour test 
can be performed with Synacthen Depot (see separate Summary of Product 
Characteristics). Furthermore, a 3-day test with Synacthen Depot may be used 
to differentiate between primary and secondary adrenocortical insufficiency. 
Children: An intravenous dose of 250micrograms/1.73m² body surface area 
has been suggested. Thus for children aged 5 to 7 years, approximately half 
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the adult dose will be adequate. For more accurate dosing of other ages, 
standard body surface area tables should be consulted. 
Elderly: There is no evidence to suggest that dosage should be different in the 
elderly. 
4.3 Contraindications 
Known hypersensitivity to tetracosactide and/or ACTH or to any of the 
excipients listed in section 6.1 List of excipients. 
Synacthen is contra-indicated in patients with allergic disorders (e.g. asthma) 
(see Section 4.4 Special warnings and precautions for use), acute psychosis, 
infectious diseases, peptic ulcer, refractory heart failure, Cushing’s syndrome, 
treatment of primary adrenocortical insufficiency and adrenocongenital 
syndrome. 
4.4 Special warnings and precautions for use 
Before using Synacthen, the doctor should make every effort to find out 
whether the patient is suffering from, or has a history of, allergic disorders (see 
Section 4.3 “Contra-indications”). In particular, he should enquire whether the 
patient has previously experienced adverse reactions to ACTH, Synacthen or 
other drugs. 
Synacthen should only be administered under the supervision of appropriate 
senior hospital medical staff (e.g. consultants). 
If local or systemic hypersensitivity reactions occur after the injection (for 
example, marked redness and pain at the injection site, urticaria, pruritus, 
flushing, faintness, severe malaise or dyspnoea), Synacthen or other ACTH 
preparations must be discontinued and should be avoided in the future. 
Hypersensitivity reactions tend to occur within 30 minutes of an injection. 
The patient should therefore be kept under observation during this time. 
Preparation should be made in advance to combat any anaphylactic reaction 
that may occur after an injection of Synacthen. In the event of a serious 
anaphylactic reaction, the patient should be treated appropriately with 
adrenaline and steroids. 
Synacthen Ampoules should not be used in the presence of active infectious or 
systemic diseases, when the use of live vaccine is contemplated or in the 
presence of a reduced immune response, unless adequate disease specific 
therapy is being given. 
Use with care in patients with hypertension and thromboembolic tendencies. 
Use cautiously in patients with ocular herpes simplex owing to possible 
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corneal perforation. 
The increased production of adrenal steroids may result in corticosteroid type 
effects: 

Psychological disturbances may be triggered (e.g. euphoria, insomnia, mood swings,
personality changes and severe depression, or even frank psychotic manifestations).
Existing emotional instability or psychotic tendencies may be aggravated

Latent infections (e.g. amoebiasis, tuberculosis) may become activated

Ocular effects may be produced (e.g. glaucoma, cataracts)

Dosage adjustments may be necessary in patients being treated for diabetes or
hypertension

If Synacthen is used in any of the following conditions, the risks of treatment should
be weighed against the possible benefits: ulcerative colitis, diverticulitis, recent
intestinal anastomosis, kidney failure, hypertension, predisposition to
thromboembolism, osteoporosis, myasthenia gravis.
The solution for injection contains less than 1 mmol sodium (23 mg) per 
ampoule, i.e. essentially ‘sodium- free’. 
Lack of diagnostic accuracy 
Post administration total plasma cortisol levels during Synacthen test might be 
misleading in some special clinical situations due to altered cortisol binding 
globulin levels. These situations include patients on oral contraceptives, post 
operative patients, critical illness, severe liver disease, nephrotic syndrome. 
Hence in these circumstances, alternative parameters (e.g., salivary cortisol, 
free cortisol index, plasma free cortisol) can be used to assess the integrity of 
HPA axis. 
4.5 Interaction with other medicinal products and other forms of interaction 
Severe jaundice has been observed for concurrent use of Synacthen and 
valproate in paediatric population. Their concurrent use should be avoided. 
Concurrent use of Synacthen and other anticonvulsants (e.g. phenytoin, 
clonazepam, nitrazepam, phenobarbital, primidone) may increase the risk of 
liver damage thus, Synacthen should be used with caution at minimum 
possible doses and for minimum duration for concurrent treatment. 
Endogenous and synthetic oestrogens can cause an increase in total cortisol 
levels and therefore, it is considered appropriate to use alternative methods 
(e.g., salivary cortisol, free cortisol index, plasma free cortisol) for 
interpretation of the results of the HPA axis examination (see Section 4.4 
Special warnings and precaution for use). 
Since Synacthen increases the adrenocortical production of glucocorticoids 
and mineralocorticoids, drug interactions of the type seen with these 
corticosteroids may occur (see Section 4.4 Special warnings and precautions 
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for use). Patients already receiving medication for diabetes mellitus or for 
moderate to severe hypertension must have their dosage adjusted if treatment 
with Synacthen is started. 
4.6 Fertility, pregnancy and lactation 
Pregnancy 
There is limited amount of data in the use of tetracosactide in pregnant women. 
Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 
Preclinical safety data). Synacthen should be used during pregnancy only if the 
expected benefit outweighs the potential risk to the foetus. 
Breast-feeding 
It is not known whether tetracosactide enters breast milk or not. Because many drugs 
are excreted in human milk, caution should be exercised when Synacthen is 
administered to a breastfeeding woman. 
Fertility 
Animal studies are insufficient with respect to reproductive toxicity (see Section 5.3 
Preclinical safety data). 
4.7 Effects on ability to drive and use machines 
Patients should be warned of the potential hazards of driving or operating 
machinery if they experience side effects such as dizziness. 
4.8 Undesirable effects 
Undesirable effects may be related to tetracosactide or to the stimulation of 
glucocorticoids and mineralocorticoid secretion during the use of Synacthen. 
The following undesirable effects have been derived from post-marketing experience 
via spontaneous cases reports and literature cases. Because these reactions are 
reported voluntarily from a population of uncertain size, it is not possible to reliably 
estimate their frequency which is therefore categorised as not known. Undesirable 
effects are listed according to system organ classes in MedDRA. Within each system 
organ class, undesirable effects are presented in order of decreasing seriousness. 
Table 1. Undesirable effects (frequency not known) related to tetracosactide 
Immune system disorders: 
Hypersenstivity* 
Endocrine disorders: 
Adrenal haemorrhage 
*Tetracosactide can provoke hypersensitivity reactions, which tend to be more severe
(anaphylactic shock) in patients susceptible to, allergies (especially asthma).
Hypersensitivity reactions may include skin reactions at the injection site, dizziness,
nausea, vomiting, urticaria, pruritus, flushing, malaise, dyspnoea, angioneurotic
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oedema and Quincke's oedema. 
The undesirable effects related to glucocorticoid and mineralocorticoid effects are 
unlikely to be observed with short-term use of Synacthen as a diagnostic tool, but may 
be reported when Synacthen is used in therapeutic indications. Should information be 
required on the side effects reported with therapeutic use of tetracosactide acetate, see 
Synacthen Depot Ampoules 1 mg/ml Summary of Product Characteristics. 
Table 2 Undesirable effects (frequency not known) related to glucocorticoid and 
mineralocorticoid effects 
Infections and infestations 
Abscess. Infection susceptibility increased 
Blood and the lymphatic system disorders 
Leukocytosis 
Endocrine disorders 
Cushing’s syndrome, secondary adrenocortical and pituitary unresponsiveness, 
particularly in times of stress, e.g. after trauma, surgery or illness; 
menstruation irregular, carbohydrate tolerance decreased, hyperglycaemia, 
manifestations of latent diabetes mellitus, hirsutism 
Metabolism and nutrition disorders 
Hypokalaemia, calcium deficiency, sodium retention, fluid retention, increased 
Appetite 
Psychiatric disorders 
Mental disorder1)
Nervous system disorders 
Convulsions, benign intracranial pressure increased with papilloedema, 
usually after treatment; vertigo, headache 
Eye disorders 
Intraocular pressure increased, glaucoma, posterior sub capsular cataracts , 
Exophthalmoses 
Cardiac disorders 
Cardiac failure congestive 
Reversible cardiac hypertrophy may occur in isolated cases in infants and 
small children treated over a prolonged period with high doses 
Vascular disorders 
Vasculitis necrotising, thromboembolism, hypertension 
Gastrointestinal disorders 
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Pancreatitis, peptic ulcer with possible perforation and haemorrhage, 
oesophagitis ulcerative, abdominal distension 
Skin and subcutaneous tissue disorders 
Skin atrophy, petechiae and ecchymosis, erythema, hyperhidrosis, acne and 
skin hyper pigmentation 
Musculoskeletal and connective tissue disorders 
Aseptic necrosis of femoral and humeral heads, spinal compression fracture, 
muscle atrophy, myopathy , osteoporosis, muscular weakness, pathological 
fracture of long bones, tendon rupture 
General disorders and administration site conditions 
Hypersensitivity reactions 2), growth retardation, weight increased, impaired 
Healing 
Investigations 
Negative nitrogen balance due to protein catabolism, suppression of skin test 
reactions 
1) Also see section 4.4 Special warnings and precautions for use
2) Also see 4.4. Special warnings and precautions for use and Table 1 Undesirable effects related to
tetracosactide.
Reporting of suspected adverse reactions 
Reporting of suspected adverse reactions after authorisation of the medicinal product 
is important. It allows continued monitoring of the benefit/risk balance of the 
medicinal product. Healthcare professionals are asked to report any suspected adverse 
reactions via the Yellow Card Scheme by connecting to the following website: 
www.mhra.gov.uk/yellowcard. 
4.9 Overdose 
Overdosage is unlikely to be a problem when the product is used as a single 
dose for diagnostic purposes. 
5 PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: anterior pituitary lobe hormones and analogues – 
ACTH. 
ATC code: H01AA02. 
Tetracosactide acetate consists of the first 24 amino acids occurring in the 
ACTH sequence and displays the same physiological properties as ACTH. In 
the adrenal cortex, it stimulates the biosynthesis of glucocorticoids, 
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mineralocorticoids, and, to a lesser extent androgens. Prolonged use of 
Synacthen is reported to have minimal suppression of hypothalamic-pituitaryadrenal 
axis as compared to long-term corticosteroids. 
The site of action of ACTH is the plasma membrane of the adrenocortical 
cells, where it binds to a specific receptor. The hormone-receptor complex 
activates adenylate cyclase, stimulating the production of cyclic AMP 
(adenosine monophosphate) and so promoting the synthesis of pregnenolone 
from cholesterol. From pregnenolone the various corticosteroids are produced 
via different enzymatic pathways. 
5.2 Pharmacokinetic properties 
Distribution 
Tetracosactide is rapidly distributed and concentrated in the adrenals and kidneys, 
which lead to rapid decrease in its plasma levels. 
There is no evidence of binding of ACTH to any particular plasma protein, though 
some non-specific interaction with albumin has been reported. Tetracosactide acetate 
has an apparent volume of distribution of approximately 0.4L/kg. 
Biotransformation 
In the serum, tetracosactide acetate is broken down by serum endopeptidases into 
inactive oligopeptides and then by aminopeptidases into free amino acids. The rapid 
elimination from plasma is probably not attributable to this relatively slow cleavage 
process, but rather to the rapid concentration of the active substance in the adrenal 
glands and kidneys. 
Elimination 
Following an intravenous injection, elimination of tetracosactide acetate from the 
plasma consists of 3 phases. The half-lives of these phases are approximately 7 
minutes (0 to 1 hour), 37 minutes (1 to 2 hours) and 3 hours thereafter. 
Following an iv dose of 131I-labelled tetracosactide acetate, 95 to 100% of the 
radioactivity is excreted in the urine within 24 hours. 
5.3 Preclinical safety data 
No studies have been performed to evaluate the mutagenic or carcinogenic 
potential of tetracosactide. No animal studies on fertility and reproduction 
toxicity have been performed with tetracosactide. 
6 PHARMACEUTICAL PARTICULARS 
6.1 List of excipients 
Acetic acid, 
Sodium acetate, 
Sodium chloride, 
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Water for injection. 
6.2 Incompatibilities 
None known. 
6.3 Shelf life 
3 years. 
6.4 Special precautions for storage 
Synacthen should be protected from light and stored in a refrigerator (2 - 8C). 
6.5 Nature and contents of container 
Synacthen Depot comes in cardboard boxes of 1 ampoule and 5 ampoules of 1 ml. 
Not all pack sizes may be marketed. 
6.6 Special precautions for disposal 
Any unused product or waste material should be disposed of in accordance 
with local requirements. 
7 MARKETING AUTHORISATION HOLDER 
Mallinckrodt Specialty Pharmaceuticals Ireland Ltd 
Sandyford Business Centre, Unit 7 
Dublin 18 
Ireland 
8 MARKETING AUTHORISATION NUMBER(S) 
PL 43357/0001 
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
25 June 1998 
10 DATE OF REVISION OF THE TEXT 
08/06/2016 
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Appendix 4: Definitions of Adverse Events and Serious Adverse Events 
Adverse Event Definition 
An adverse event 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 adverse event (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 investigational product. In addition, any laboratory abnormality assessed as
clinically significant by the (sub)investigator must be recorded as an AE.
Serious Adverse Event Definition 
A serious adverse event (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 
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
is a medically important condition. Events that may not be immediately life-
threatening or result in death or hospitalisation but may jeopardise the subject or
may require intervention to prevent one of the other outcomes listed in the
definition above. Examples are intensive treatment in an emergency room or at
home for allergic broncospasm, blood dyscrasias and convulsions that do not result
in hospitalization, development of drug dependency or drug abuse.
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Appendix 5: Classification of Adverse Events 
Severity 
The severity of the AE should be described in terms of mild, moderate or severe according to 
the (sub)investigator’s clinical judgement. 
Mild 
An adverse event 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 adverse event 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 adverse event 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 investigational product 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 
investigational product. 
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 investigational product. 
Disappears or decreases on cessation or reduction in dose of the 
investigational product. 
Reappears or worsens upon re-challenge. 
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Possibly 
related 
Follows a reasonable temporal sequence from the administration of the 
investigational product. 
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 investigational product. 
Not related 
Does not follow a reasonable temporal sequence from administration of the 
investigational product. 
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 investigational product. 
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 
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 (sub)investigator, e.g. subject lost to follow-up. 
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Appendix 6: Contact list of LEO, vendors, trial committees and 
coordinating investigators 
Contact details for the clinical project manager (CPM), national lead CRA (NLCRA), medical 
expert and safety scientist/safety physician are provided to participating trial sites outside the 
protocol on a list of LEO representatives which is included in clinical trial applications. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO’ in this clinical trial protocol) is the sponsor of the 
clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
CRO(s)/vendors 
Larix A/S, Lyskaer 8b, DK-2730 Herlev, Denmark will be responsible for all services related 
to electronic data capture and data management services, as agreed to in a Service 
Agreement/Contract. 
ACM Global Laboratory, 23 Hospital Fields Road, York YO10 4DZ, United Kingdom or 
ACM Medical Laboratory, Inc., 160 Elmgrove Park, Rochester, New York 14624, USA will 
be responsible for all services related to the central laboratory analysis, as agreed to in a 
Service Agreement/Contract. 
DSG, Inc, Great Valley Corporate Center, 325 Technology Drive, Malvern, Pennsylvania 
19355, United States will be responsible for providing IWRS services as agreed to in a 
Service Agreement/Contract. 
Klifo, Smedeland 36, 2600 Glostrup, Denmark will be responsible for drug storage, 
packaging, labeling, distribution and destruction of investigational medicinal product, as 
agreed to in the Service Agreement/Contract. 
CRF Health, Brook House, 229-243 Shepherds Bush Road, Hammersmith, London, W6 7AN, 
United Kingdom will be responsible for all services related to ePRO and eDiary solutions, as 
agreed to in the Service Agreement/Contract. 
Trial Committees  
The Adjudication Panel: 
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Adjudicator 
Expert role 
Affiliation 
 (
, MD) Dermatologist 
Texas Dermatology Associates, 
P.A. & Menter Cosmetic Institute, 
Dallas, Texas 75246, USA 
 (
, 
MD) 
Dermatologist 
Sjællands Universitetshospital, 
4000 Roskilde, Denmark 
 (
, MD) 
Endocrinologist 
Odense University Hospital, 5000 
Odense C, Denmark 
Coordinating Investigators 
International Coordinating Investigator: Dr. Mark Lebwohl 
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Appendix 7: EQ-5D-5L-PSO 
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Appendix 8: DLQI 
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Appendix 9: WPAI:PSO 
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Appendix 10: Psoriasis Symptom Inventory (PSI) – 24 hours recall 
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Appendix 11: Psoriasis Symptom Inventory (PSI) – 7 days recall 
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Appendix 12: Protocol amendment history 
The Protocol amendment summary of changes table for the current amendment is located 
directly before the table of contents.  
Amendment 5 (22-Aug-2017) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of subjects nor the scientific value of the trial. 
Overall rationale for the amendment 
The protocol was updated to include an additional country (Poland). 
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). 
Protocol section number 
Description of change 
Brief rationale 
Section 6.1.1 
Introduction of an additional country 
(Poland)  
To increase the number of 
subjects participating in the 
ACTH challenge part of the 
trial. 
Sections 10.9, 10.9.1.1, and 
10.9.1.5  
Table 1 
Sponsor to provide Synacthen® to Polish 
sites for ACTH challenge. 
Synacthen® is not 
registered in Poland. 
Sections 6.1.3 and 10.2 
Clarification that the first dose of 
investigational product may be applied at 
home.  
To clarify that the first IP 
dose may be taken at home. 
Section 8.12.2 
Clinically significant out-of-range values 
of urine calcium and urine creatinine to be 
reported as adverse events only apply to 
the urine calcium/creatinine ratio, not to 
the individual values. 
Urine calcium and urine 
creatinine values depend on 
the subject’s hydration 
status. 
Note that the changes in this amendment have also been described in an errata sheet (eTMF no. 000031211). 
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Amendment 4 (05-Jul-2017) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
subjects nor the scientific value of the trial.  
Overall rationale for the amendment 
The protocol was updated to meet FDA advice received 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). 
Protocol section number 
Description of change 
Brief rationale 
Section 8.1 
Table 4 
A physical examination has been added 
at Visit 2 for subjects who are not 
eligible for randomisation. Subjects 
attending Visit 2 have been treated with 
open-label IP for 4 weeks and should 
therefore have a physical examination 
done before leaving the trial. 
To meet FDA advice. 
Sections 6.1.1, 6.2 and 11.1 
Due to difficulties in recruiting the 
required number of subjects into the 
HPA-axis part of the trial, the trial will 
remain open at selected sites for 
inclusion of subjects to participate in the 
HPA-axis part after completing 
recruitment of subjects into the main 
trial. The planned date of Last Subject 
Last Visit has been updated to reflect 
this. 
To clarify that more than 
380 subjects may be 
recruited to ensure 
30 subjects in HPA-axis 
substudy. 
Table 4 
Clarification that screening visit and 
Visit 1 (baseline) may be performed on 
the same day if washout is not required. 
Clarification of protocol 
text. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not 
been summarised. 
Note that the changes in this amendment have also been described in an errata sheet (eTMF no. 000025375). 
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Amendment 3 (14-Dec-2016) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The protocol was updated to describe a new treatment principle for non-active lesions during 
relapse treatment. 
Note: The table below describes the main 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). 
Protocol section number 
Description of change 
Brief rationale 
Sections 3.3.2, 3.3.3, 6.1.1, 6.1.4, 
6.1.4.1, 6.1.4.2, 6.1.4.3, 10.2, 10.4, 
and 11  
Figure 1, Figure 2, Figure 3, and 
Figure 4, 
Table 3 
In the previous version of the protocol it 
was specified that during relapse 
treatment, all psoriasis areas were to be 
treated with rescue medication (active 
LEO 90100) once daily for up to 
4 weeks. This amendment introduces a 
new treatment principle so that only 
active areas will be treated with rescue 
medication for 4 weeks (regardless of 
whether the psoriasis clears before 
4 weeks) while non-active psoriasis areas 
will continue twice weekly maintenance 
treatment. 
To change the way psoriasis 
relapses are treated in order 
to better reflect how 
LEO 90100 will be used in 
real life. 
Sections 3.3.3 and 10.2 
Use of trial medication is now 
disallowed on the scalp during 
once-daily treatment periods (initial 
open-label treatment period and relapse 
treatment periods). 
On request from the French 
regulatory authority 
(ANSM). 
Sections 3.3.3, 6.1.4, 6.1.4.2, 
6.1.5, 9.1, 9.5, and 16.2 
Figure 1, Figure 2, Figure 3, and 
Figure 4 
Table 2 
An 8-week follow-up period has been 
added for all subjects after end of the 
maintenance period (or early withdrawal 
during maintenance) to capture if 
subjects develop rebound after twice 
weekly maintenance treatment. 
On request from the French 
regulatory authority 
(ANSM). 
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Protocol section number 
Description of change 
Brief rationale 
Sections 3.3.3, 9.3.6, 9.5, 11.3.6.2, 
and 16.2  
Table 2 
The definition of “rebound” has been 
updated to make it more clear when the 
observational period for rebound starts. 
Clarification of protocol 
text. 
Table 1 
Specification that use of mild topical 
corticosteroids on the scalp is allowed 
during the trial. 
Specification that mild 
topical corticosteroids may 
be used on the scalp. 
Sections 3.3.3, 6.6.1, 6.1.4, 
6.1.4.1, 6.1.4.2, 6.1.4.3, 10.2, and 
10.4 
Table 3 
Terminology for the IP has been changed 
as follows: the term “LEO 90100” will 
be used for the IP used during the initial 
open-label phase, “maintenance IP” for 
the double-blinded IP used during 
maintenance treatment, and “rescue IP” 
for open-label IP used during relapse 
treatment. 
Clarification of terminology 
used for the IP. 
Sections 11.3.3.3, 11.3.3.5, 
11.3.3.6,11.3.4.3, 11.3.4.4, and 
11.3.8 
HPA axis testing has been removed as a 
stratification factor in the statistical 
analyses.  
The HPA axis test is a 
safety parameter which is 
only obtained for a subset 
of subjects. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not 
been summarised. 
Note that the changes in this amendment have also been described in an errata sheet (eTMF no. 00645283). 
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Amendment 2 (07-Sep-2016) 
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental 
integrity of subjects nor the scientific value of the trial.  
Overall rationale for the amendment 
The protocol was updated to allow dermatological assessments to be performed by qualified 
staff who are not dermatologists. 
Note: The table below describes the main 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). 
Protocol section number 
Description of change 
Brief rationale 
Section 7.2 
Removal of inclusion criterion #3: 
3.Attending a hospital out-patient clinic,
the private practice of a qualified,
experienced dermatologist, or the
practice of a general practitioner
experienced in the treatment of psoriasis
vulgaris patients
Inclusion criterion not 
needed as certified 
physician’s assistants and 
advanced registered nurse 
practitioners may now 
perform dermatological 
assessments. 
Sections 8.11 and 8.16 
Certified physician’s assistants and 
advanced registered nurse practitioners 
are allowed to perform dermatological 
assessments. 
The dermatology 
assessments in this protocol 
can be performed as reliably 
by qualified staff that are not 
dermatologists. 
Section 10.1 
The IP description tables (LEO 90100 
and foam vehicle) were updated to 
reflect that LEO releases the final IP. 
Correction of error. 
Throughout 
Minor editorial and document formatting 
revisions. 
Minor, have therefore not 
been summarised. 
Note that the changes in this amendment have also been described in an errata sheet (eTMF no. 00622834). 
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Amendment 1 (19-Aug-2016) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall rationale for the amendment 
The protocol was updated to implement advice from the FDA and the Danish Medicines 
Agency (DMA). 
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 italics and deleted text has a line through it). 
Protocol section 
number 
Description of change 
Brief rationale 
Section 7.2 
Change of inclusion criteria #3 and #12: 
3. Attending a hospital out-patient clinic or, the private
practice of a qualified, experienced dermatologist, or the
practice of a general practitioner experienced in the
treatment of psoriasis vulgaris patients
12. Access to the internet (e.g. computer, tablet or
smartphone) and able to complete online questionnaires about
health status
12. Signed and dated informed consent obtained for having
ACTH challenge tests performed
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 7.3 
Addition of exclusion criteria # 22 and #23 and change of 
exclusion criterion #25:  
22. Subjects in close affiliation with the trial personnel (e.g.
immediate family member or subordinate), subjects being a
member of the clinical trial personnel, or being an employee
of the sponsor or a contract research organisation (CRO)
involved in the trial
23. Subjects who are institutionalised by court order or by
local authority.
25. Known or suspected hypersensitivity to component(s) of
CORTROSYN® (including cosyntropin/tetracosactide) (in the
US) / Synacthen® (including tetracosactide) (in Europe)
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
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Protocol section 
number 
Description of change 
Brief rationale 
Sections 3.3.3, 
6.1.1, 6.1.3, 7.9, 
10.2, 10.6, 11 and 
11.1 
The criterion for entering the maintenance phase of the trial 
has been changed from “a PGA score of clear or almost clear” 
to “a PGA score of clear or almost clear with at least a 2-step 
improvement”. Due to this change, it is expected that more 
subjects will have to leave the trial after the open-label phase. 
Consequently, the number of subjects to be enrolled has been 
increased from 752 to 832. 
To meet FDA advice. 
Sections 6.1.4, 
6.1.4.1, 6.1.4.2, and 
10.2 
Clarification that during maintenance phase, subjects will be 
instructed to continue applying the IP to areas on the trunk 
and limbs where lesions have cleared after initiation of 
treatment at baseline. Subjects will also be instructed to treat 
any new psoriatic lesions. Following confirmation of a 
relapse, subjects will be instructed to apply IP on the affected 
areas (all active psoriatic lesions as well as to areas where 
lesions had cleared after initiation of treatment at baseline) 
once daily for up to 4 weeks. 
To meet FDA advice. 
Section 8.1 
A physical examination at the end of treatment and in case of 
early withdrawal has been added.  
To meet FDA advice. 
Sections 3.3.3, 8.1, 
8.12.3.1, 8.12.4, 
Table 8 
Assessment of vital signs in case of early withdrawal has 
been added. ACTH challenge test and sampling of biomarkers 
at Week 28 have been added and the total blood sampling 
volume to be drawn has been updated. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 3.3.3, 6.2, 
8.12.1, and 16.1 
The number of subjects to be randomised for the HPA 
assessment has been increased from 25 to 30 subjects. 
Furthermore, it has been added that HPA axis assessment will 
also be performed at Week 28 and in case of early 
withdrawal. 
To meet DMA advice. 
Section 11.3.4.4 
Time to first relapse according to m-PASI has been added as 
an exploratory endpoint to be able to make an indirect 
comparison to other studies where this definition is used. 
To meet DMA advice. 
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Protocol section 
number 
Description of change 
Brief rationale 
Section 11.3.3.3 
Update of the primary endpoint:  
The primary endpoint, is time to first relapse during the 
maintenance period, phase, where relapse is an exacerbation 
of psoriasis defined as a PGA of at least ‘mild’. This will be 
calculated as the number of days from randomisation to the 
day where the subject has the first relapse confirmed. For 
subjects who either do not encounter a relapse or are 
withdrawn from the trial, the number of days will be treated 
as a censored observation at the day of end of trial visit. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 10.6, 
11.3.3.5, 11.3.3.6, 
and 11.3.4.3 
Specification that randomisation will also be stratified by 
HPA axis testing; HPA axis testing at baseline has been 
included as factor in the statistical analysis model. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 11.3.5, 
11.3.5.1, 11.3.5.2, 
11.3.5.3, 11.3.5.4, 
11.3.5.5, and 13.2 
Clarification of statistical analyses and data handling of 
PROs. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 11.3.6.3 
and 11.3.6.6  
Statistical analyses of local safety and tolerability and clinical 
safety laboratory evaluations have been specified further. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 12.1 
The following data have been added to the list of data to be 
provided to the adjudication committee: (i) the investigator’s 
assessments of causal relationship of long-term use of 
corticosteroids to the event and (ii) information on the action 
taken with IP. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 10.6.1 
Clarification of how to handle the randomisation files. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
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Protocol section 
number 
Description of change 
Brief rationale 
Section 10.7.3 
Table 8.1 
Additional visits have been added for recording of treatment 
compliance.  
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 7.3, 8.1, 
8.12.1, and 10.9, 
10.9.1.2, 10.9.1.3, 
10.9.1.4, Table 15 
Appendix 3 
French sites have been included in the HPA axis testing and 
Synacthen® has therefore been added for ACTH challenge in 
Europe. 
French site have been 
added. 
Table 1 
Vitamin D supplements > 400 IU/day have been added as 
prohibited medication. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 7.8.2 
Specification that inhaled steroids are disallowed during the 
last 4 weeks prior to ACTH-challenge. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 7.8.2 
In case of use of sunscreen, it has been specified that an 
interval of at least 1 hour is recommended between 
applications. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Table 3 
For permitted concomitant anti-psoriatic treatment, it has 
been added that emollient should not contain alpha-hydroxy 
acids, beta-hydroxy acids, or acetylic acid; emollients 
containing urea acid (≤ 5%) are allowed. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 8.11 and 
8.16 
Specification that all physician’s dermatological assessments 
of the treatment area must be performed by a dermatologist or 
general practitioner experienced in treating psoriasis vulgaris 
(also added as an inclusion criterion; see above). 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
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Protocol section 
number 
Description of change 
Brief rationale 
Section 8.12.1 
Specification that in case a patient discontinues the trial prior 
to Week 56, a follow-up visit has to be scheduled within 
7 days of the last treatment period visit for the purpose of 
performing the ACTH challenge test, if the test has been not 
performed on the same day. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 3.3.3, 8.1, 
and 8.13.3 
Specification that WPAI:PSO will be assessed only at 
Week 28 and Week 56 or at the last treatment visit. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Sections 3.3.3, 8.1, 
and 8.12.1 
Specification that subjects are requested to give a separate 
written consent for having ACTH challenge tests  performed. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 9.1 
Clarification that abnormal findings at screening should be 
recorded as diagnoses in the Concomitant Medication page if 
medication is currently being taken for the condition. If not, 
the diagnosis should be documented as medical history in the 
eCRF. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 9.1.1 
Clarification of when applications site reactions should be 
reported as AEs. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 9.1.2 
Clarification of the requirements for reporting of AEs of 
concern associated with long-term topical corticosteroid use. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 9.3.2 
Definition of overdose has been added. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
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Protocol section 
number 
Description of change 
Brief rationale 
Sections 9.3.2 and 
11.3.6.2 
Specification that relapse of psoriasis during the maintenance 
phase of the trial is not to be reported as an AE. A definition 
of rebound effect has been added. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Section 10.5 
Further instructions on storage requirements of the IPs have 
been added. 
The protocol has been 
updated several places 
due to input received 
from internal and 
external stakeholders. 
Throughout 
Minor editorial and document formatting revisions. 
Minor, have therefore 
not been summarised. 
Note that the changes in this amendment have also been described in an errata sheet (eTMF no. 00626924). 
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