Conditions: Psoriasis Vulgaris
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 125
Healthy volunteers: no

Brief summary:
An international, multi-centre, prospective, non-controlled, open, single-group, 8-week trial in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis.

Detailed description:
A phase 2 trial evaluating the safety and efficacy of once daily use of LEO 80185 gel containing calcipotriol 50 mcg/g plus betamethasone 0.5mg/g (as dipropionate) in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis.

Arms:
arm 1: None

Interventions: intervention 1: LEO 80185 gel
Intervention descriptions: intervention 1: None

Protocol document:
Prot_001.pdf: 
 
 
 
 
Clinical Study Protocol 
 
Effect of Calcipotriol plus Betamethasone Dipropionate Gel on the HPA Axis and 
Calcium Metabolism in Adolescent Subjects (Aged 12 to 16 Years, 11 months) with 
Scalp and Body Psoriasis 
 
A phase 2 trial evaluating the safety and efficacy of once daily use of LEO 80185 gel 
containing calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) in 
adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis 
An international, multi-centre, prospective, non-controlled, open, single-group, 8-week trial 
in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis 
 
 
 
ICH GCP statement:  The clinical trial will be conducted in compliance with the Clinical 
Study Protocol, GCP and the applicable regulatory requirement(s). 
 
 
LEO Pharma A/S 
Protocol Code Number:
LP0076-1017
Global Clinical Operations 
Date: 
17-Apr-2013
 
Version:
1
 
EudraCT Number: 
2013-001538-16
 
 
 
 
 
 
 
 
 
            
eDoc-00341337 - Version 2.0


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2 Protocol Statement 
2.1 Compliance with Good Clinical Practice 
This Clinical Study Protocol is designed to comply with the guideline produced by the 
International Conference on Harmonisation (ICH) on the topic Good Clinical Practice (GCP) 
as well as other relevant guidelines issued by ICH, primarily the efficacy guidelines. 
2.2 Trademarks 
Daivobet®, Dovobet®, Taclonex®, Xamiol®, Daivonex®, and Dovonex® are trademarks owned 
by LEO Pharma A/S (or its subsidiaries). Daivobet® gel is launched in different markets under 
following trademarks Daivobet®, Dovobet®, Taclonex®, and Xamiol®.  The U.S. marketed 
product, Taclonex® topical suspension, is equivalent to Daivobet® gel marketed in other 
markets.  
 
3 Protocol Synopsis 
Name of finished/ 
investigational product: 
LEO 80185 gel 
Taclonex® gel 
Name of active substance: 
Calcipotriol plus betamethasone dipropionate. 
Title of trial/ 
protocol code number: 
Effect of Calcipotriol plus Betamethasone Dipropionate 
Gel on the HPA Axis and Calcium Metabolism in 
Adolescent Subjects (Aged 12 to 16 Years, 11 months) 
with Scalp and Body Psoriasis / LP0076-1017 
Co-ordinating  
investigator(s): 
Lawrence F. Eichenfield, MD, University of California at 
San Diego/Rady Children´s Hospital, California, USA 
Estimated number of trial  
sites and distribution: 
Approximately 30 sites: 
Australia and New Zealand: Approximately 5 sites 
Canada: Approximately 5 sites 
France: Approximately 3 sites 
Germany: Approximately 5 sites 
United Kingdom: Approximately 5 sites 
USA: Approximately 7 sites 
Trial period: 
Planned date of enrolment of first subject: October 2013. 
Planned date of completion of last subject: October 2015. 
Main objectives: 
The primary objective is to evaluate the safety of once 
daily use of calcipotriol (50 mcg/g) plus betamethasone 
 


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(0.5 mg/g) (as dipropionate) gel in adolescent subjects 
(aged 12 to 16 years, 11 months) with scalp and body 
psoriasis. 
 
The secondary objective is to evaluate the efficacy of once 
daily use of calcipotriol (50 mcg/g) plus betamethasone 
(0.5 mg/g) (as dipropionate) gel in adolescent subjects 
(aged 12 to 16 years, 11 months) with scalp and body 
psoriasis. 
Methodology: 
An international, multi-centre, prospective, non-
controlled, open, single-group, 8-week trial in adolescent 
subjects (aged 12 to 16 years, 11 months) with scalp and 
body psoriasis 
 
Psoriatic lesions on the scalp and body will be treated with 
calcipotriol (50 mcg/g) plus betamethasone (0.5 mg/g) (as 
dipropionate) gel applied once daily for up to 8 weeks 
under maximal use conditions on the body. 
 
The duration of the trial for each subject will be a 
maximum of 20 weeks, consisting of a screening period of 
7 days to 8 weeks followed by a 4- or 8-week treatment 
period and, if required, a 2-4-week follow-up period. 
 
Prior to Visit 1 (Day 0), a wash-out period (up to 8 weeks) 
should be completed if the subject is being treated or has 
recently been treated with anti-psoriatic treatments or 
other relevant medication, as defined by the exclusion 
criteria.  
 
During the trial, the subset of subjects performing HPA 
axis assessments will be allowed to use non-steroid topical 
treatments without expected systemic effects to treat 
psoriasis lesions on the face and sensitive areas (armpits, 
groin, under the breasts and in other skin folds around the 
genitals and buttocks).  Subjects not performing HPA axis 
assessments will be allowed to use any topical treatment 
 


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allowed except potent or very potent (WHO groups III-
IV) corticosteroids to treat psoriasis lesions on the face 
and skin folds. Bath oils and moisturizing soaps are 
allowed. Topical vitamin D analogues (calcipotriol, 
calcitriol or tacalcitol) are limited to a maximum of 50 g, 
75 g or 100 g of ointment/gel/cream per week depending 
on the subject’s age and body surface area (BSA).  This 
includes the amount of investigational product used.  
 
The study will consist of a wash-out period (if required), 
2 screening visits; SV1 and SV2 (to be conducted within 
8 and 1 weeks prior to Visit 1, respectively) followed by a 
4-or 8-week treatment period (Days 0-56). Subjects whose 
psoriasis is clear after 4-week treatment will stop the 
investigational product and leave the trial. Subjects who 
have signs of psoriasis after 4 weeks of treatment will 
continue treatment for another 4-week period. During the 
treatment period, the study visits will be on Days 0, 14, 
28, 42 and 56 (Visits 1 to 5).  
 
Each subject will receive the investigational product and 
will be instructed to apply it once daily.  
 
Calcium metabolism evaluation will be performed at SV2 
and after 4 and 8 weeks of treatment (Day 28 and 
Day 56). The evaluation will include measurements of 
serum calcium, albumin, phosphate, plasma parathyroid 
hormone (PTH) level and calculation of the albumin-
corrected serum calcium concentration. Also, 24-hour 
urine will be collected and urinary volume, calcium-, 
phosphate-, and creatinine excretion will be measured and 
the calcium:creatinine and phosphate:creatinine ratios 
calculated.  
 
Pharmacokinetic analysis will be performed to evaluate if 
any potential adverse events could be correlated to the 
investigational product. A blood sample for 
 


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pharmacokinetic analysis will be drawn at Visit 3 (Day 
28) for the measurement of plasma LEO 80185 when the 
investigational product is at a steady state concentration. 
 
In the U.S. only, subjects will perform hypothalamic-
pituitary-adrenal (HPA) axis function assessments until 
30 evaluable subjects are obtained. These subjects will 
have their HPA axis function assessed at SV2 and after 
4 and 8 weeks of treatment (Day 28 and Day 56). The 
adrenal function will be assessed with a rapid standard 
dose synthetic adrenocorticotropic hormone (ACTH) 
(CORTROSYN®) challenge test. The test consists of 
blood sampling starting at 8 a.m. (± 30 minutes). 
Following the blood sample, an intravenous bolus 
injection of 250 mcg CORTROSYN® is given at time zero 
(t=0). Serum cortisol concentration at 30 and 60 minutes 
will reflect the stimulation induced by CORTROSYN®. 
Subjects will not be included in the study if serum cortisol 
concentration at SV2 is 5 mcg/dl or lower before the 
CORTROSYN® injection or if serum cortisol 
concentration, obtained at 30 minutes after 
CORTROSYN® injection, is below or equal to 18 mcg/dl. 
At Week 4, subjects with serum cortisol below or equal to 
18 mcg/dl at 30 min after administration of 
CORTROSYN® will discontinue the treatment and will 
perform a follow-up visit 2 (Visit FU2). 
 
Visit FU2 will be conducted for subjects with possible 
HPA axis suppression 28 days after possible suppression 
is reported (i.e. 28 days after Visit 3 or 5). This follow-up 
will involve a repeat HPA axis suppression test to assess if 
the possible suppression has reversed. 
 
A follow-up visit (Visit FU1) will be conducted 14 days 
after the last on-treatment visit for subjects with any 
ongoing adverse event(s) classified as possibly/probably 
related/not assessable relationship to the investigational 
 


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product. FU1 will also be performed for subjects with 
albumin corrected serum calcium above the reference 
range at the last on-treatment visit. 
 
A window of ± 2 days will be allowed for Visits 2, 3, 4, 5, 
FU1 and FU2. The overall treatment period should be 4 or 
8 weeks (28 or 56 days ± 2 days). 
Number of subjects  
to be enrolled: 
In total, a sufficient number of subjects will be enrolled to 
ensure 100 subjects are evaluable for calcium metabolism.  
Thirty of the 100 subjects will also be evaluable for HPA 
axis suppression. At least 30 subjects will be evaluable for 
pharmacokinetic evaluation. 
 
In the U.S. only, subjects will perform hypothalamic-
pituitary-adrenal (HPA) axis function assessments until 
30 evaluable subjects are obtained.   
 
Power of the study 
No formal sample size calculation evaluating the power of 
the study has been performed, but further considerations 
regarding sample size have been made as described 
below. 
 
The upper limit of an exact two-sided 95% confidence 
interval for the probability of observing a specific adverse 
event, when 0 out of 100 possible events have been 
observed, is approximately 4% assuming a binomial 
distribution. 
 
With 100 subjects and an assumed response rate 
(percentage of subjects who achieve “Clear” or “Almost 
clear” according to the Investigator’s Global Assessment 
(IGA) of disease severity on the body at end of treatment) 
of approximately 30%, the 95% confidence interval for 
the estimated response rate will be approximately ± 9%. 
Main criteria for inclusion for 
all subjects: 
1. Signed informed consent given by parent(s), or legal 
guardian(s), or by the subject (according to national 
 


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law) following their receipt of verbal and written 
information about the trial. 
2. Subjects will receive verbal and written information 
and will provide written assent to the trial.  
3. Subjects 12 to 16 years, 11 months of age. 
4. Either sex. 
5. Any race or ethnicity. 
6. Clinical signs of psoriasis vulgaris on both the scalp 
and body (trunk and/or limbs). 
7. At SV2 and Visit 1, a clinical diagnosis of scalp and 
body (trunk and/or limbs) psoriasis which is: 
a. of an extent of 10 to 35% of the body surface 
area (excluding psoriatic lesions of the face 
and sensitive areas.  Sensitive areas include 
armpits, groin, under the breasts and in other 
skin folds around the genitals and buttocks), 
and 
b. of at least moderate severity according to the 
investigator’s global assessment of disease 
severity on the body, and 
c. for subjects aged 12 to 14 years with a BSA 
≤ 1.3 m2, amenable to topical treatment with a 
maximum of 50 g of investigational product 
per week, and 
d. for subjects aged 12 to 14 years with a BSA 
> 1.3 m2, amenable to topical treatment with a 
maximum of 75 g of investigational product 
per week, and 
e. for subjects aged 15 to 16 years, 11 months 
with a BSA ≤ 1.7 m2, amenable to topical 
treatment with a maximum of 75 g of 
investigational product per week, and 
f. for subjects aged 15 to 16 years, 11 months 
with a BSA > 1.7 m2, amenable to topical 
treatment with a maximum of 100 g of 
investigational product per week. 
8. A serum albumin-corrected calcium below the upper 
 


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reference limit at SV2. 
9. Females of child-bearing potential must have a 
negative urine pregnancy test result and must agree to 
use a highly effective method of contraception during 
the trial. Highly effective methods are defined as ones 
which result in a low failure rate (less than 1% per 
year) such as progestin-only formulations (implants, 
injectables, or “mini-pill” in combination with a 
barrier method), some intra-uterine devices, double 
barrier methods (e.g. cervical cap and condom), tubal 
ligation/section, sexual abstinence or vasectomised 
partner. The patients must have used the contraceptive 
method 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 
investigational product. A female is defined as not of 
child-bearing potential if she is premenarchal, 
postmenopausal or surgically sterile (hysterectomy or 
bilateral ovariectomy). 
10. Subjects fulfilling national requirements/law for 
participation in this trial. 
Additional inclusion criteria 
for subjects performing HPA 
axis assessments (U.S. only): 
1. At SV2 and Visit 1, a clinical diagnosis of scalp 
psoriasis which is:  
a. more than or equal to 20% of the scalp area, 
and 
b. of at least moderate severity according to the 
investigator’s global assessment of disease 
severity on the scalp. 
2. Subjects with a normal HPA axis function at SV2 
including serum cortisol concentration above 
5 mcg/dl before ACTH challenge and serum cortisol 
concentration above 18 mcg/dl 30 minutes after 
ACTH challenge. 
Additional inclusion criteria 
for subjects not performing 
HPA axis assessments: 
1. At SV2 and Visit 1, a clinical diagnosis of scalp 
psoriasis which is:  
a. more than or equal to 10% of the scalp area, 
and 
 


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b. of at least moderate severity according to the 
investigator’s global assessment of disease 
severity on the scalp. 
Main exclusion criteria for all 
subjects: 
1. A history of hypersensitivity to any component of the 
LEO 80185 gel 
2. Systemic treatment with biological therapies 
(marketed or not marketed), with a possible effect on 
scalp and/or body psoriasis within the following time 
period prior to Visit 1 and during the trial: 
a. etanercept – within 4 weeks prior to Visit 1 
b. adalimumab, infliximab – within 2 months 
prior to Visit 1 
c. ustekinumab – within 4 months prior to Visit 1 
d. experimental products – within 4 weeks/5 half-
lives (whichever is longer) prior to Visit 1 
3. Systemic treatment with therapies other than 
biologicals, with a possible effect on scalp and/or 
body psoriasis (e.g., retinoids, immunosuppressants, 
PUVA) within 4 weeks prior to Visit 1 (Day 0) or 
during the trial. 
4. UVB therapy within 2 weeks prior to Visit 1 or during 
the trial. 
5. Any topical treatment on the scalp and body (except 
for emollients and non-steroid medicated shampoos) 
within 2 weeks prior to Visit 1 or during the trial. 
6. Systemic calcium, vitamin D supplements, antacids, 
diuretics, antiepileptics, diphosphonates or calcitonin 
within 4 weeks prior to SV2 or during the trial. 
7. Planned initiation of, or changes to, concomitant 
medication that could affect psoriasis (e.g., 
betablockers, chloroquine, lithium, ACE inhibitors) 
during the trial. 
8. Current diagnosis of guttate, erythrodermic, 
exfoliative or pustular psoriasis. 
9. Subjects with any of the following conditions present 
on the treatment areas on scalp and/or body: viral 
(e.g., herpes or varicella) lesions of the skin, fungal 
 


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and bacterial skin infections, parasitic infections, skin 
manifestations in relation to syphilis or tuberculosis, 
rosacea, acne vulgaris, acne rosacea, atrophic skin, 
striae atrophicae, fragility of skin veins, ichthyosis, 
ulcers and wounds. 
10. Other inflammatory skin diseases that may confound 
the evaluation of scalp and/or body psoriasis. 
11. Planned excessive exposure to sun during the trial that 
may affect scalp and/or body psoriasis. 
12. Known or suspected severe renal insufficiency or 
severe hepatic disorders. 
13. Known or suspected disorders of calcium metabolism 
associated with hypercalcaemia. 
14. Any clinically significant abnormality following 
review of screening laboratory tests (blood and urine 
samples), physical examination or blood 
pressure/heart rate measurement performed at SV2. 
15. Current participation in any other interventional 
clinical trial. 
16. Previously enrolled in this trial. 
17. Subjects who have received treatment with any non-
marketed drug substance (i.e., an agent which has not 
yet been made available for clinical use following 
registration) within a month prior to SV1 or longer, if 
the class of substance required a longer wash-out as 
defined above (e.g., biological treatments). 
18. Subjects or parent(s) or legal guardian(s) known or 
suspected of being unlikely to comply with the 
Clinical Trial Protocol (e.g., alcoholism, drug 
dependency or psychotic state). 
19. Females who are pregnant, or of child-bearing 
potential and wishing to become pregnant during the 
trial, or who are breast-feeding. 
20. Females of child-bearing potential with positive 
pregnancy test at SV2. 
21. Subject (or their partner) not using an adequate 
method of contraception according to national 
 


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requirements. 
Additional exclusion criteria 
for subjects performing HPA 
axis assessments (U.S. only): 
1. A history of serious allergy, allergic asthma or serious 
allergic skin rash. 
2. Known or suspected hypersensitivity to any 
component of CORTROSYN® (including 
ACTH/cosyntropin/tetracosactide). 
3. Systemic treatment with corticosteroids (including 
inhaled and nasal steroids) within 12 weeks prior to 
SV2 or during the trial. 
4. Topical treatment with corticosteroids within 2 weeks 
prior to SV2 or during the trial. 
5. Oestrogen therapy (including contraceptives) or any 
other medication known to affect cortisol levels or 
HPA axis integrity within 4 weeks prior to SV2 or 
during the trial. 
6. Enzymatic inductors (e.g., barbiturates, phenytoin, 
rifampicin) within 4 weeks prior to SV2 or during the 
trial. 
7. Systemic or topical cytochrome P450 inhibitors (e.g., 
ketoconazole, itraconazole, metronidazole) within 
4 weeks prior to SV2 or during the trial. Topical 
ketoconazole 2 weeks prior to SV2. 
8. Hypoglycemic sulfonamides within 4 weeks prior to 
SV2 or during the trial. 
9. Antidepressive medications within 4 weeks prior to 
SV2 or during the trial. 
10. Known or suspected endocrine disorder that may 
affect the results of the ACTH challenge test. 
11. Clinical signs or symptoms of Cushing’s disease or 
Addison’s disease. 
12. Subjects with diabetes mellitus. 
13. Known or suspected cardiac condition. 
14. Not following nocturnal sleep patterns. 
Additional exclusion criteria 
for subjects not performing 
HPA axis assessments: 
1. Topical treatment on the trunk and/or limbs with very 
potent (WHO group IV) corticosteroids within 
2 weeks prior to Visit 1 or during the trial. 
2. Topical treatment on the face and/or sensitive areas 
 


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(armpits, groin, under the breasts and in other skin 
folds around the genitals and buttocks) with potent or 
very potent (WHO groups III-IV) corticosteroids 
within 2 weeks prior to Visit 1 or during the trial. 
Investigational product: 
Calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as 
dipropionate) gel (LEO 80185 gel). 
CORTROSYN® will be used only as a test product for the 
ACTH challenge testing. 
Reference product: 
Not applicable 
Duration of treatment: 
The screening period including any washout period will 
last for 7-56 days, depending on the prior use of excluded 
treatments. The treatment period will be up to 8 weeks. 
The follow-up period will last for up to 4 weeks, 
depending on whether the subject has potential adrenal 
suppression and/or ongoing adverse event(s) classified as 
possibly/probably related/not assessable relationship to 
the investigational product. 
Assessments: 
Safety Assessment 
Calcium metabolism evaluation will include serum 
albumin-corrected calcium, phosphate and plasma PTH on 
a blood sample taken at SV2 and after 4 and 8 weeks of 
treatment. 24-hour urine will be collected at SV2 and after 
4 and 8 weeks of treatment and urinary volume, calcium-, 
phosphate-, and creatinine excretion will be measured and 
calcium:creatinine and phosphate:creatinine ratios will be 
calculated. 
 
Dietary calcium intake will be monitored 3 days prior to 
and during collection of 24-hour urine. Subjects will be 
instructed to keep a diary of daily intake of calcium-rich 
nutrients in these periods. 
 
Blood pressure will be measured at SV2, Visit 3 (Day 28) 
and Visit 5 (Day 56). 
 
Laboratory screening: the following laboratory tests will 
 


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be taken at SV2, Visit 3 (Day 28) and Visit 5 (Day 56): 
• 
haematology: hemoglobin, haematocrit, red blood 
cells (RBC), mean corpuscular volume (MCV), white 
blood cells (WBC) including differential count and 
platelets. 
• 
biochemistry (serum/plasma): cortisol, urea, 
creatinine, albumin, sodium, potassium, chloride, 
calcium, phosphate and PTH. 
• 
urinalysis on 24-hour urine: calcium, phosphate, 
creatinine, volume. 
• 
urinalysis on spot urine: glucose and ketones. 
 
A PK sample will be collected at Visit 3 prior to the 
application of investigational product on the day of the 
visit. 
 
Urinary pregnancy test will be performed at SV2, Visit 3 
(Day 28), Visit 5 (Day 56) and at FU2 (if applicable) in 
females of childbearing potential. 
 
Adverse events will be recorded at all visits after SV1 (if 
applicable). 
 
For subjects performing HPA axis assessments: the 
ACTH challenge test will be performed on 3 occasions: 
At SV2, Visit 3 (Day 28) and Visit 5 (Day 56). In 
addition, an ACTH challenge test will be performed at 
Visit FU2 for subjects with possible HPA axis suppression 
at Visit 3 or Visit 5.  
 
Efficacy Assessment 
At SV2 and at all on-treatment visits the following will be 
performed:  
• 
Investigator’s Global Assessment (IGA) of disease 
severity on the body (ranging from “Clear” to 
“Severe”) 
• 
Investigator’s Global Assessment of disease severity 
 


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on the scalp (ranging from “Clear” to “Severe”) 
• 
Investigator’s assessment of the extent and severity of 
clinical signs of psoriasis vulgaris (redness, thickness 
and scaliness) 
• 
Patient’s global assessment of disease severity on the 
body (ranging from “Clear” to “Severe”) 
• 
Patient’s global assessment of disease severity  on the 
scalp (ranging from “Clear” to “Severe”) 
• 
Patient’s assessment of itching on the scalp and body  
• 
Patient’s assessment of sleep 
Safety Evaluation: 
Primary response criteria: 
•  Adverse drug reactions (ADRs) 
• 
Subjects with serum cortisol concentration of 
≤18 mcg/dl at 30 minutes after ACTH-challenge at 
Week 4 and at Week 8 
• 
Change in albumin-corrected serum calcium from 
baseline (SV2) to Week 4,  Week 8, and end of 
treatment 
• 
Change in 24-hour urinary calcium excretion from 
baseline (SV2) to Week 4,  Week 8, and end of 
treatment 
Secondary response criteria: 
 
 
 
 
 
 
Efficacy Evaluation: 
Secondary response criteria: 
• 
Adverse events (AEs) 
• 
Subjects with serum cortisol concentration of 
≤18 mcg/dl at both 30 and 60 minutes after ACTH-
challenge at Week 4 and at Week 8 
• 
Change in urinary calcium:creatinine ratio from 
baseline (SV2) to Week 4 and Week 8  
• 
Subjects with “Controlled disease” (i.e., “Clear” or 
“Almost clear”) according to the investigator’s global 
assessment of disease severity on the body at end of 
treatment. 
• 
Percentage change in PASI from baseline to end of 
treatment. 
• 
Subjects with “Controlled disease” (i.e., “Clear” or 
“Very mild”) according to the patient’s global 
assessment of disease severity on the body at end of 
treatment. 
 


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Statistical methods: 
The percentages of subjects with a serum cortisol 
concentration ≤18 mcg/dl at 30 minutes, and at both 30 
and 60 minutes, after the ACTH-challenge at Week 4 and 
Week 8 will be calculated. The mean serum cortisol 
concentration at time 0 and at 30 and 60 minutes after 
ACTH-challenge at baseline (SV2), Week 4 and Week 8, 
respectively, will be calculated. 
 
The number of subjects experiencing each type of adverse 
event and each type of adverse drug reaction will be 
tabulated. 
 
The mean change from baseline (SV2) to Week 4 and 
Week 8 in haematology, biochemistry and urinalysis 
parameters except in the urinary glucose and ketones will 
be calculated. For the albumin-corrected serum calcium 
and 24-hour urinary calcium excretion, the mean change 
from baseline to end of treatment will also be calculated 
and the 95% confidence interval of mean change from 
baseline to Week 4 and Week 8 and end of treatment will 
be presented. For the urinary calcium:creatinine ratio, the 
95% confidence interval of mean change from baseline to 
Week 4 and Week 8 will be presented. Laboratory 
parameters will also be categorised according to the 
reference range, and shift tables will be produced. 
 
The following will be presented with the 95% confidence 
interval: 
- 
the percentage of subjects with “Controlled disease” 
according to the investigator’s global assessment of 
disease severity on the body at end of treatment 
- 
the percentage change in PASI from baseline to end of 
treatment 
- 
the percentage of subjects with “Controlled disease” 
according to the patient’s global assessment of disease 
severity on the body at end of treatment 
 
 


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3.1 Schedule/Chart of Trial Procedures 
Visit 
SV1 1 
SV2 1,2
1 
2 
3 
4 
53 
FU14 
FU25 
Day 
-56 to -7 
-7 to -3 
0 
14 ± 2 
28 ± 2 
42 ± 2 
56 ± 2 
+ 14 
± 2 
+ 28 
± 2 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Height, weight and BSA 
X 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X
X 
 
 
 
 
 
 
Vital signs (blood pressure, 
heart rate)  
 
X 
 
 
X 
 
X 
 
 
Haematology/biochemistry/ 
urinalysis 6 
 
X 
 
 
X 
 
X 
X 7 
 
Pharmacokinetic blood 
sample 8 
 
 
 
 
X 
 
 
 
 
ACTH challenge test 9 
 
X 
 
 
X 
 
X 
 
X 
Instruction for 24-hour urine 
collection and dietary 
calcium intake diary 
X 
 
 
X 
 
X 
 
 
 
Review of dietary calcium 
 
X 
 
X 
 
X 
 
 
Collection of 24-hour urine 10 
 
X 
 
X 
 
X 
 
 
Urine pregnancy test 11, 12 
 
X 
 
X 
 
X 
 
 
Adverse events 
 
X
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X
X 
X 
X 
X 
X 
X 
 
Investigator’s assessment of 
extent of psoriasis (BSA) and 
extent of scalp psoriasis 
 
X 
X 
 
 
 
 
 
 
Investigator ’s global 
assessment of disease 
severity on the scalp and on 
the body 
 
X 
X 
X 
X 
X 
X 
 
 
Patient’s global assessment 
of disease severity on the 
scalp and on the body 
 
X 
X 
X 
X 
X 
X 
 
 
Investigator’s assessment of 
the extent and severity of 
clinical signs of psoriasis 
vulgaris (for PASI) 
 
X 
X 
X 
X 
X 
X 
 
 
Patient’s assessment of 
itching and sleep 
 
X 
X 
X 
X 
X 
X 
 
 
Dispensing of IP 
 
 
X
X
X 
X 
 
 
 
Return of IP 
 
 
 
X 
X 
X 
X 
 
 
IP Compliance 
 
 
 
X 
X 
X 
X 
 
 
 
1. There should be at least 4 days between SV1 and SV2 so dietary information (diary) can be 
collected. 
 


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2. It will be acceptable that the following assessments are done on the day prior to the ACTH 
challenge: vital signs, spot urine collection, pregnancy test, AEs, concomitant medication and 
assessments of psoriasis.  
3. In case of early withdrawal prior to Visit 5, the additional tests scheduled for Visit 5 should be 
done at the end of treatment, with the exception of the ACTH-challenge test and the 24-hour urine 
collection. 
4. Follow-up Visit 1 is only applicable for subjects who at the last on-treatment visit have ongoing 
(serious or non-serious) adverse event(s) classified as possibly/probably related/not assessable 
relationship to the investigational product and for subjects with albumin corrected serum calcium 
above reference range at the last on-treatment visit. 
5. Applicable only to subjects in the U.S. performing HPA axis assessments.  Follow-up Visit 2 is 
only applicable if serum cortisol is ≤18 mcg/dl at 30 min after the ACTH challenge test at Visit 3 
or Visit 5. 
6. Blood and spot urine samples should be collected at the end of treatment for subjects who are 
withdrawn from trial prior to Visit 5. 
7. If laboratory results suggest albumin corrected serum calcium above reference range at the last on-
treatment visit, a follow-up test will be performed. 
8. PK sample to be taken prior to the application of investigational product on the day of the visit. 
9. Applicable only to subjects in the U.S. 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. It will be acceptable that the 24-hour urine sample is collected up to three days prior to the trial 
visit. 
11. For female subjects of childbearing potential. 
12. In case of early withdrawal there will be a pregnancy test if possible at their last on treatment visit. 
 
 
 


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Table of Contents 
1 Clinical Study Protocol Approval/Acknowledge .................................................................. 2 
1.1 Approval Statement LEO Pharma A/S .............................................................................. 2 
1.2 Approval Statement International Co-ordinating Investigator .......................................... 2 
1.3 Acknowledge Statement Investigator(s) ........................................................................... 2 
2 Protocol Statement ................................................................................................................. 3 
2.1 Compliance with Good Clinical Practice .......................................................................... 3 
2.2 Trademarks ........................................................................................................................ 3 
3 Protocol Synopsis .................................................................................................................. 3 
3.1 Schedule/Chart of Trial Procedures ................................................................................. 17 
Table of Contents ..................................................................................................................... 19 
4 List of Abbreviations and Definition of Terms .................................................................... 24 
4.1 List of Abbreviations ....................................................................................................... 24 
4.2 Definition of Terms ......................................................................................................... 25 
5 Ethics ................................................................................................................................... 27 
5.1 Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs) ............ 27 
5.2 Ethical Conduct of the Trial ............................................................................................ 28 
5.3 Ethical Consideration Statement ..................................................................................... 28 
5.4 Subject Information and Informed Consent .................................................................... 31 
5.5 Handling of Personal Data .............................................................................................. 31 
6 Trial Administrative Structure ............................................................................................. 31 
6.1 Sponsor ............................................................................................................................ 32 
6.2 LEO Pharma A/S Affiliates and CRO(s) ......................................................................... 32 
6.3 LEO Pharma A/S Personnel ............................................................................................ 32 
6.3.1 
International Clinical Trial Manager (ICTM) ............................................................. 32 
6.3.2 
National Lead CRA (NLCRA) .................................................................................... 33 
6.3.3 
Sponsor’s Medical Expert ........................................................................................... 33 
6.3.4 
Safety Scientist, Global Pharmacovigilance................................................................ 33 
6.3.5 
Study Statistician ......................................................................................................... 33 
6.3.6 
Study Data Manager .................................................................................................... 33 
6.4 Protocol Authors .............................................................................................................. 33 
6.5 Investigators and Trial Committees ................................................................................. 34 
6.5.1 
International Co-ordinating Investigator ..................................................................... 34 
 


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6.5.2 
National Co-ordinating Investigator(s)........................................................................ 34 
6.5.3 
Investigators ................................................................................................................ 34 
6.5.4 
Trial Committees ......................................................................................................... 34 
6.6 Agreements ...................................................................................................................... 34 
7 Insurance .............................................................................................................................. 35 
8 Introduction and Rationale .................................................................................................. 35 
8.1 Psoriasis ........................................................................................................................... 35 
8.2 Investigational Product Description ................................................................................ 36 
8.3 Trial Rationale ................................................................................................................. 36 
9 Trial Objectives ................................................................................................................... 41 
9.1 Primary Objective ............................................................................................................ 41 
9.2 Secondary Objectives ...................................................................................................... 41 
10 Investigational Plan ............................................................................................................. 41 
10.1 Trial Design ..................................................................................................................... 41 
10.1.1 Overall Chart ............................................................................................................... 43 
10.2 Time Schedule ................................................................................................................. 43 
10.3 Number of Subjects/Sample Size .................................................................................... 43 
10.4 Criteria for Subject Selection (In- and Exclusion) .......................................................... 44 
10.4.1 Inclusion Criteria ......................................................................................................... 45 
10.4.1.1 Inclusion Criteria for All Subjects ........................................................................... 45 
10.4.1.2 Additional Inclusion Criteria for Subjects Performing HPA Axis Assessments (U.S. 
only) ......................................................................................................................... 46 
10.4.1.3 Additional Inclusion Criteria for Subjects Not Performing HPA Axis Assessments 46 
10.4.2 Exclusion Criteria ........................................................................................................ 46 
10.4.2.1 Exclusion Criteria for All Subjects .......................................................................... 46 
10.4.2.2 Additional Exclusion Criteria for Subjects Performing HPA Axis Assessments (U.S. 
Only) ........................................................................................................................ 48 
10.4.2.3 Additional Exclusion Criteria for Subjects Not Performing HPA Axis Assessments
 ................................................................................................................................. 48 
10.4.3 Subject Screening Log ................................................................................................. 49 
10.4.4 Subject Registration .................................................................................................... 49 
10.5 Withdrawal Criteria ......................................................................................................... 49 
10.6 Investigational Products .................................................................................................. 50 
10.6.1 LEO 80185 .................................................................................................................. 50 
10.6.2 Packaging of Investigational Products ........................................................................ 50 
 


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10.6.3 Storage of Investigational Products ............................................................................. 51 
10.6.4 Administration of Investigational Products ................................................................. 51 
10.6.4.1 LEO 80185 ............................................................................................................... 51 
10.6.5 Precautions/Overdosage .............................................................................................. 52 
10.6.6 Treatment Assignment ................................................................................................. 52 
10.6.6.1 Randomisation Code List ........................................................................................ 53 
10.6.6.2 Subject Identification List ........................................................................................ 53 
10.6.7 Blinding of the Trial .................................................................................................... 53 
10.6.8 Breaking the Randomisation Code .............................................................................. 53 
10.6.8.1 Un-blinding of Individual Subject Treatment .......................................................... 53 
10.6.8.2 Un-blinding of the Clinical Trial ............................................................................. 53 
10.6.9 Drug Accountability and Compliance Checks ............................................................ 53 
10.6.9.1 Sponsor-Investigator Drug Accountability .............................................................. 53 
10.6.9.2 Investigator-Subject Drug Accountability ............................................................... 54 
10.6.9.3 End of Trial Drug Accountability ............................................................................ 54 
10.6.9.4 Treatment Compliance ............................................................................................. 54 
10.6.10 Prior and Concomitant Treatment ............................................................................... 54 
10.7 Non-Investigational Medicinal Products ......................................................................... 57 
10.7.1 CORTROSYN® (cosyntropin) for injection ................................................................ 57 
10.7.1.1 Packaging and Labelling .......................................................................................... 57 
10.7.1.2 Storage ..................................................................................................................... 57 
10.7.1.3 Reconstitution and Administration .......................................................................... 58 
10.7.1.4 Precautions ............................................................................................................... 58 
10.7.1.5 Drug Accountability ................................................................................................. 58 
10.7.2 0.9% Sodium Chloride Injection, USP ........................................................................ 59 
10.7.2.1 Packaging and Labelling .......................................................................................... 59 
10.7.2.2 Storage ..................................................................................................................... 59 
10.7.2.3 Precautions ............................................................................................................... 59 
10.7.2.4 Drug Accountability ................................................................................................. 59 
10.8 Trial Procedures ............................................................................................................... 60 
10.8.1 Schedule of Trial Procedures ....................................................................................... 60 
10.8.2 Subject Eligibility ........................................................................................................ 62 
10.8.3 Clinical Assessment ..................................................................................................... 64 
10.8.3.1 Investigator Assessments ......................................................................................... 64 
10.8.3.2 Subject Assessments ................................................................................................ 67 
10.8.3.3 Imaging Assessments ............................................................................................... 68 
10.8.4 Laboratory Assessments .............................................................................................. 68 
10.8.4.1 Central Analysis ....................................................................................................... 68 
 


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10.8.4.2 Local Analysis ......................................................................................................... 72 
10.8.5 Adverse Events ............................................................................................................ 72 
10.8.5.1 Reporting of Adverse Events ................................................................................... 73 
10.8.5.2 Other Events to Be Reported ................................................................................... 76 
10.8.6 Serious Adverse Events ............................................................................................... 76 
10.8.6.1 Reporting of Serious Adverse Events ...................................................................... 76 
10.8.7 Source Data ................................................................................................................. 78 
10.9 Safety Evaluation ............................................................................................................ 79 
10.9.1 Primary Response Criteria ........................................................................................... 79 
10.9.2 Secondary Response Criteria ....................................................................................... 79 
10.9.3 Evaluation of (Serious) Adverse Events ...................................................................... 80 
10.9.4 Evaluation of Laboratory Data .................................................................................... 80 
10.9.5 Evaluation of Other Observations ............................................................................... 80 
10.10 Efficacy Evaluation ..................................................................................................... 80 
10.10.1 Secondary Response Criteria ....................................................................................... 80 
10.11 Statistical Analysis .......................................................................................................... 80 
10.11.1 Subject Qualification for Analysis .............................................................................. 80 
10.11.2 Reasons for Leaving the Trial ..................................................................................... 81 
10.11.3 Baseline Characteristics .............................................................................................. 81 
10.11.4 Compliance .................................................................................................................. 81 
10.11.5 Analysis of Safety ....................................................................................................... 81 
10.11.5.1 Adverse Events ........................................................................................................ 81 
10.11.5.2 ACTH-Challenge Test ............................................................................................. 83 
10.11.5.3 Exposure .................................................................................................................. 83 
10.11.5.4 Drug Accountability ................................................................................................. 83 
10.11.5.5 Laboratory Examinations ......................................................................................... 83 
10.11.5.6 Other Observations .................................................................................................. 84 
10.11.6 Analysis of Efficacy .................................................................................................... 84 
10.11.7 General Principles ....................................................................................................... 85 
10.12 Trial Committees ......................................................................................................... 86 
10.13 Quality Assurance/Audit ............................................................................................. 87 
10.13.1 Trial Monitoring .......................................................................................................... 87 
10.14 Case Report Form Books and Data Handling ............................................................. 88 
10.14.1 Case Report Forms (CRFs) ......................................................................................... 88 
10.14.2 Data Handling .............................................................................................................. 89 
10.15 Protocol Amendments ................................................................................................. 89 
10.16 Completion of Trial ..................................................................................................... 89 
 


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10.16.1 Trial Completion Procedures ....................................................................................... 89 
10.16.2 Provision for Subject Care Following Trial Completion ............................................. 90 
10.16.3 Archiving of Trial Documents ..................................................................................... 90 
11 Use of information ............................................................................................................... 91 
12 Publication ........................................................................................................................... 91 
13 References ........................................................................................................................... 92 
14 List of Appendices ............................................................................................................... 95 
 


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4  List of Abbreviations and Definition of Terms 
4.1 List of Abbreviations 
ACE 
Angiotensin-converting enzyme 
ACTH 
Adrenocorticotropic hormone 
ADR 
Adverse drug reaction 
AE 
Adverse event 
BSA 
Body surface area 
CI 
Confidence interval 
CRF 
Case report form (the CRF could be electronic) 
CRO 
Contract research organisation 
eCRF 
Electronic CRF 
EMEA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FU 
Follow-up 
GCP 
Good Clinical Practice 
HPA 
Hypothalamic-pituitary-adrenal 
ICH 
International Conference on Harmonisation 
ICTM 
International clinical trial manager 
IEC 
Independent ethics committee 
IGA 
Investigator’s global assessment 
IP 
Investigational product 
IRB 
Institutional Review Board 
LEO 
LEO Pharma A/S 
MCV 
Mean corpuscular volume 
Mcg 
Microgram 
MedDRA® 
Medical Dictionary for Regulatory Activities 
NLCRA 
National lead clinical research associate 
PK 
Pharmacokinetics 
PUVA 
Psoralen-ultraviolet A 
PTH 
Parathyroid hormone 
RBC 
Red blood cells 
SAE 
Serious adverse event 
SD 
Standard deviation  
SDV 
Source data verification 
SOP 
Standard operating procedure 
SV  
Screening visit 
 


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UVA 
Ultraviolet A light 
UVB 
Ultraviolet B light 
U.S. 
United States 
WBC 
White blood cells 
WHO 
World Health Organisation 
 
4.2 Definition of Terms 
Assessment 
A (cluster of) characteristic(s) measured and/or recorded for a subject. 
Certified Copy 
A certified copy is a copy of original information that has been verified, as indicated by a 
dated signature, as an exact copy having all of the same attributes and information as the 
original (FDA Guidance for Industry, Computerized Systems Used in Clinical Investigations, 
May 2007). 
Concomitant Medication 
Any medication taken by a subject during the clinical trial apart from the investigational 
product. 
Enrolled Subject 
A subject for whom informed consent has been obtained and a CRF number assigned. 
Fraud 
Fabrication of data, selective and undisclosed rejection of undesired results, substitution with 
fictitious data, deliberately incorrect use of statistical methods for the purposes of reaching 
other conclusions than those warranted by the data, misinterpretation of results and conclu-
sions, plagiarism of results or entire articles from other researchers, misrepresentation of other 
researchers’ results, unwarranted authorship, and misleading application for positions or 
funds. 
International Clinical Trial Manager (ICTM) 
The person appointed by LEO Pharma A/S to be the main international representative 
responsible for all aspects of a clinical trial as outlined in Global Clinical Operations SOPs. 
 


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Clinical trial agreement 
A contract between on the one hand LEO Pharma A/S and/or a Contract Research Organisa-
tion (CRO) and on the other hand an investigator and/or the institution specifying the 
conditions for the co-operation in the clinical trial and the investigator’s and/or the institu-
tion‘s responsibilities. 
Investigator Staff Signature Form 
A form used: 
1. for the investigator to delegate trial related tasks/duties 
2. for trial site staff to sign and date to accept delegation 
3. for trial site staff to document signature and initials 
4. for the investigator to authorise tasks/duties delegated 
 
Investigator Trial File 
The collection of trial documents required by Global Clinical Operations SOPs LEO Pharma 
A/S, ICH Guidelines and/or regulatory requirements to be on file at the trial site. 
LEO Pharma A/S 
LEO Pharma A/S refers to the sponsor of the clinical trial. 
LEO Pharma A/S affiliate 
An affiliated company of LEO Pharma A/S authorised to manage certain clinical trial related 
activities for LEO Pharma A/S. 
Monitor 
A person appointed by LEO Pharma A/S to carry out monitoring of a clinical trial. 
National Lead CRA (NLCRA) 
The person appointed by LEO Pharma A/S to be the national representative responsible for all 
aspects of a clinical trial within a country as outlined in Global Clinical Operations SOPs. 
Response Criterion 
 


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An assessment or a transformation of the assessment(s) described on a subject level for which 
a statistical analysis is performed, i.e. a p-value or a confidence interval is stated, or for which 
tabulation serves as important supportive evidence of efficacy/safety. 
Subject Identification List 
A summary list kept by the investigator in the Investigator Trial File which records the names 
of all subjects enrolled and the date of enrolment in the trial at that trial site. The list includes 
each subject’s corresponding CRF number to allow the investigator/institution to reveal the 
identity of any subject if required. 
Subject Screening Log 
A document kept by the investigator which identifies patients/subjects who entered pre-trial 
screening. 
Subject Screening Log is synonymous with Patient Screening Log. 
Subject Study Card 
A card given to a subject by the trial site at the time investigational product is first dispensed 
to a subject to identify that the subject is having treatment with an investigational product. 
Writing committee 
An appointed committee participating in the writing of a multi-centre publication. 
5 Ethics 
5.1 Independent Ethics Committees (IECs) or Institutional Review Boards 
(IRBs) 
The clinical trial must be approved by/receive favourable opinion from relevant Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) prior to the enrolment of 
subjects. 
Any amendments to the approved clinical trial must likewise, as required, be approved 
by/receive favourable opinion from relevant IRBs/IECs prior to implementation. 
The appropriate regulatory authority(ies) must be notified of/approve the clinical trial, as 
required. 
 


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5.2 Ethical Conduct of the Trial 
This clinical trial will be conducted to conform to the principles of the World Medical 
Association (WMA), Declaration of Helsinki, Ethical Principles for Medical Research 
Involving Human Subjects adopted by the 18th WMA General Assembly, Helsinki, Finland, 
June 1964 and last revised in Seoul in October 2008 by the WMA General Assembly (see 
Appendix II). 
5.3 Ethical Consideration Statement 
Psoriasis vulgaris is a chronic and recurrent skin disorder. At present, no curative treatment is 
available for the disease. Psoriasis is a disabling disease, with a significant impact on the 
quality of life comparable with that observed in other chronic medical conditions such as 
diabetes and depression (1) (2).  
Approximately 35% of patients with psoriasis develop the disease before the age of 20 and 
25% are diagnosed between 10 and 19 years of age (3). Involvement of the scalp is more 
common in children (4) (5). Based on this, it is evident that scalp psoriasis is also prevalent in 
the adolescent age group (12-17 years).  
Most preparations are greasy and messy to apply, have an unpleasant smell and may cause 
staining of clothes and fabrics and skin irritation (6). Patient’s compliance is therefore often 
poor, leading to a bad therapeutic result. Therefore, there is a need for a patient acceptable 
topical treatment in this age group. 
LEO 80185 gel is a fixed combination product containing the vitamin D3 analogue 
calcipotriol and betamethasone dipropionate, for topical treatment of psoriasis vulgaris on 
scalp and body in subjects aged 18 years and above.  
Daivobet® gel was approved for the treatment of scalp psoriasis in adults in several countries 
in the EU and the US in 2008 and is launched under the trademarks Daivobet®, Dovobet®, 
Taclonex®, and Xamiol®. Since then it has been approved in the remaining EU countries 
(2009) and in several other countries in the rest of the world (more than 40 countries outside 
EU), including Canada and Australia; approvals are pending in several countries in the rest of 
the world. The product has been launched with the indication scalp psoriasis in adults since 
2008. 
 


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The marketing authorisation application for treatment of ‘non-scalp’ psoriasis vulgaris in 
adults was approved in several countries in the EU in July 2009. Since then, the indication of 
non-scalp psoriasis vulgaris in adults has been approved in the remaining EU countries 
(Dec 2011), in US October 2012, and in several other countries in the rest of the world. 
Approvals are pending in several countries in the rest of the world. The product was launched 
in the first European country, Denmark, in March 2010 under the trademark Daivobet® gel. 
Two non-controlled trials, MBL 0801 and MBL0412 INT, in adolescent subjects (aged 12-
17 years) with psoriasis on the scalp have recently been completed. In a total of 
109 adolescent subjects using up to 69 g/week, LEO gel was safe and effective in the 
treatment of psoriasis vulgaris on the scalp.  The effects on calcium metabolism were 
investigated; no cases of hypercalcaemia and no clinically relevant changes in urinary calcium 
were reported. The adrenal response to ACTH challenge was assessed in a subset of 30 
patients; one patient showed a decrease in cortisol response to ACTH challenge after 4 weeks 
of treatment which was considered mild (7) (8). 
All subjects in the trial will receive LEO 80185 gel to use once-daily for up to 8 weeks. This 
application frequency and treatment duration have been shown to be safe and effective in 
adults for the approved products Taclonex® and Xamiol®.  
At the end of the trial, subjects will have received treatment with LEO 80185 gel for up to 8 
weeks. Continued use of LEO 80185 gel at the end of the trial will not be available to the 
subjects.   
Following the 4-week or 8-week treatment period and the follow-up examinations, subjects 
will leave the trial and, if required, resume the treatment they received prior to the wash-out 
period or start a treatment according to the investigator’s discretion, whichever is most 
appropriate. 
The parent(s)/legal guardian(s) of the subjects will give informed consent, and subjects must 
give their assent, or subjects may give informed consent as appropriate and according to 
national laws and regulations. 
Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment 
has been reported (9), due to systemic absorption of the corticosteroid.  LEO 80185 gel 
contains the corticosteroid betamethasone dipropionate and is why adrenal function will be 
assessed in the present trial, although the risk of adrenal suppression with LEO 80185 gel is 
expected to be low. 
 


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In this trial, treatment for up to 8 weeks is expected to be safe. The application area of LEO 
80185 gel for subjects in the trial is expected to decrease with time as their psoriasis decreases 
in severity. Thus, the amount of investigational product required is expected to be less by the 
end of the trial. Adrenal function will be assessed by an ACTH-challenge test before, during, 
and at the end of trial treatment. This test involves injecting a synthetic subunit of ACTH 
(CORTROSYN®) into the subject, and measuring the cortisol produced by the adrenal glands 
30 and 60 minutes after the injection.  
The use of CORTROSYN® in this trial will be in keeping with that detailed in the US 
Prescribing Information (Appendix III); therefore this is expected to be of low risk.   
The risk of hypercalcemia due to systemic absorption of the calcipotriol component of LEO 
80185 gel is expected to be low when the medication is used in the doses specified in the trial. 
Any potential effects of LEO 80185 gel on calcium metabolism will be assessed by 
measurement of the concentrations of serum calcium and -phosphate and plasma parathyroid 
hormone (PTH) and the urinary calcium-, phosphate-, and creatinine excretion based on 
collection of 24-hour urine and the calcium:creatinine and phosphate:creatinine, ratios will be 
calculated before, during and at the end of treatment.  
The expected total blood volume collected will be approximately 46.5 ml for subjects 
performing HPA axis assessments and 31.5 ml for subjects not performing HPA axis 
assessments. This excludes any follow-up assessment of abnormal values. Topical anaesthetic 
will be provided at study sites to decrease discomfort and pain for the subjects when having 
placed catheters at the (sub)investigator’s discretion. 
Recruitment for the trial will be continued until 100 subjects are available for evaluation of 
calcium metabolism.  This includes the 30 subjects (in the US) without adrenal suppression at 
baseline who is to undergo ACTH-challenge test at end of treatment (Visit 3 or 5). 
Since all subjects will receive the LEO 80185 gel, the prospect of subjects experiencing an 
improvement of their psoriasis during the trial will be good. Subjects will be under the careful 
supervision of a dermatologist with paediatric experience during the entire course of the trial. 
Subjects performing HPA axis assessments will be allowed to use non-steroid topical 
treatments without expected systemic effects to treat psoriasis lesions on the face and skin 
folds.  Subjects not performing HPA axis assessments will be allowed to use any topical 
treatment allowed except potent or very potent (WHO groups III-IV) corticosteroids to treat 
psoriasis lesions on the face and skin folds. Bath oils and moisturizing soaps are allowed.  
 


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The results from this trial could help make LEO 80185 gel available to adolescent subjects 
suffering from psoriasis. It is therefore concluded that the expected benefits of conducting this 
trial will compensate for the inconveniences for the participating subjects. 
5.4 Subject Information and Informed Consent 
The parent(s)/legal guardian(s) of subjects will receive written and verbal information 
concerning the trial or subjects may give informed consent as appropriate and according to 
national laws or regulations. This information will emphasise that participation in the trial is 
voluntary and that the subject may withdraw from the trial at any time and for any reason. The 
parent(s)/legal guardian(s) will be given an opportunity to ask questions and will be given 
sufficient time to consider before consenting. Signed and dated informed consent for the 
subject to participate in the trial will be obtained from the parent(s)/legal guardian(s), or by 
the subject in accordance with national laws or regulations, prior to any trial related procedure 
being carried out. 
 
All subjects will also receive appropriate written and verbal information, be given an 
opportunity to ask questions and sufficient time to consider, before providing written assent. 
The subject’s decision not to participate or to withdraw will be respected, even if consent is 
given by the parent(s)/legal guardian(s). 
 
If during the trial a subject who has previously given assent becomes legally emancipated i.e. 
ceases to be a minor, the subject should be asked to provide their written consent. 
 
All Investigators will sign an “Investigator’s Agreement” to confirm the above. 
5.5 Handling of Personal Data 
Subjects (or their legally acceptable representative) shall be asked to consent that their 
personal data are recorded, collected, processed and may be transferred to EU and non-EU 
countries in accordance with any national legislation regulating privacy and data protection. 
Personal data shall be handled and processed by all relevant parties involved in the clinical 
trial in accordance with any national legislation regulating privacy and data protection as well 
as in accordance with the general terms and conditions of the authorisation granted by the 
Danish Data Protection Agency to LEO Pharma A/S as set forth in the attached Appendix I. 
LEO Pharma A/S is considered data controller for this clinical trial. 
6 Trial Administrative Structure 
 


L P 0 0 7 6- 1 0 1 7  
1 7- A pr- 2 0 1 3 
Pa ge 3 2 of 1 2 3
 
 
 
6. 1  S p o ns or 
L E O P har ma A/ S is t he s p o ns or of t he cli nical trial. 
6. 2  L E O P h ar m a A/ S Affili ates a n d C R O(s) 
L E O P har ma A/ S has tra nsferre d ce rtai n cli nical trial relate d acti vities t o t he L E O P har ma A/ S 
affiliate(s) a n d/ or t o t he C R O(s) rele va nt f or t he c o n d uct of t he cli nical trial. 
 
L E O P h ar m a A/ S affili ates  
 
L E O P h ar m a I nc. 1 S yl va n Wa y, Parsi p pa n y, NJ 0 7 0 5 4, U S A. 
L E O P h ar m a I nc. 1 2 3 C o m merce Valle y Dri ve East, S u ite 4 0 0, T h or n hill, O ntari o, L 3 T 
7 W 8, Ca na da. 
L E O P h ar m a. 2 R ue Re ne Ca u dr o n, 7 8 9 6 0 Vois i ns-le- Bret o n ne u x, Fra nce. 
L E O P h ar m a. L o n g wic k R oa d, Pri nces Ris b or o u g h, H P 2 7 9 R R, B uc ki n g ha ms hire, U nite d 
Ki n g d o m. 
L E O P h ar m a G m b H. Fra n kf urter Strasse 2 3 3, A 3, 6 3 2 6 3 Ne u-Ise n b ur g, Ger ma n y. 
L E O P h ar m a Pt y Lt d, Le vel 3, T o wer O ne, 2 5 M o nt pelier R d, B o we n Hills Q L D 4 0 0 6, 
A ustralia. 
 
Cli nic al Rese arc h Or g a niz ati o ns  
 
, 
,  
,  
,  
A. 
 
T he C R O will be res p o nsi ble f or all ser vices relate d t o t he ce ntral la b orat or y a nal ysis 
( hae mat ol o g y, bi oc he mistr y, uri nal ysis) as a gree d t o i n a Ser vice A gree me nt/ C o ntract. 
 
, 
,  
,  
,  
. 
 
T he C R O will be res p o nsi ble f or all ser vices relate d t o t he la b orat or y P K a nal ysis as a gree d t o 
i n a Ser vice A gree me nt/ C o ntract. 
 
6. 3  L E O P h ar m a A/ S Pers o n nel 
6. 3. 1  I nter n ati o n al Cli nic al Tri al M a n a ger (I C T M) 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


L P 0 0 7 6- 1 0 1 7  
1 7- A pr- 2 0 1 3 
Pa ge 3 3 of 1 2 3
 
 
 
, Cli nical Pr oject Ma na ger, L E O P har ma I nc., 1 2 3 C om merce Valle y Dri ve East, 
S uite 4 0 0, T h or n hill, O ntari o, L 3 T 7 W 8, Ca na da.  Tel.: + 1-
, Fa x: + 1-
, e- mail:  
@le o- p har ma.c o m 
6. 3. 2  N ati o n al Le a d C R A ( N L C R A) 
, Se ni or Cli nical Researc h Ass ociate,  1 S yl va n Way, Parsi p pa n y, NJ 0 7 0 5 4, 
U S A, Tel: + 1 
, Fa x: + 1 
, e mail: 
@le o- p har ma.c o m 
Ot her N L C R A c o ntact details t o be pr o vi de d o utsi de pr ot oc ol. 
6. 3. 3  S p o ns or’s Me dic al E x pert 
, M D, Me dical E x pert, L E O P har ma A/ S, I n d ustri par ke n 5 5, D K- 2 7 5 0 
Baller u p, De n m ar k. Tel: + 4 5  
, e mail: 
@le o- p har ma.c o m 
6. 3. 4  S afet y Scie ntist, Gl o b al P h ar m ac o vi gil a nce 
, P har mac o vi gila nce Scie ntist, L E O P har ma A/ S, I n d ustri par ke n 5 5, D K-
2 7 5 0 Baller u p, De n mar k, Tel: + 4 5  
, e mail: 
@le o- p har ma.c o m 
6. 3. 5  St u d y St atistici a n 
, M Sc, Pri nci pal Statisticia n, L E O P har ma  A/ S, I n d ustri par ke n 5 5, D K- 2 7 5 0 
Baller u p, De n mar k. Tel.: + 4 5  
,  e- mail: 
@le o- p har ma.c o m 
6. 3. 6  St u d y D at a M a n a ger 
, P h D, Cli nical A p plicati o n S pecialist, L E O P har ma I nc., 1 2 3 
C o m merce Valle y Dri ve East, S uite 4 0 0, T h or n hill,  O ntari o, L 3 T 7 W 8, Ca na da.  Tel.: + 1-
, Fa x: + 1-
, e- mail: 
@le o- p har ma.c o m 
6. 4  Pr ot oc ol A ut h ors 
, M D, U ni versit y of Calif or nia at Sa n Die g o/ Ra d y C hil dre n´s 
H os pital, Calif or nia, U S A  
, M Bi otec h, P M P, Cli nical Pr oject Mana ger, L E O P har ma I nc., 1 2 3 C o m merce 
Valle y Dri ve East, S uite 4 0 0, T h or n hill, O ntari o, L 3 T 7 W 8, Ca na da.  Tel.: + 1-
, 
Fa x: + 1-
, e- mail:  
@le o- p har ma.c o m 
, M D, P h D, Me dical E x pert, L E O P har ma A/ S, I n d ustri par ke n 5 5, D K-
2 7 5 0 Baller u p, De n mar k. Tel: + 4 5  
, e mail: 
@le o- p har ma.c o m 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


L P 0 0 7 6- 1 0 1 7  
1 7- A pr- 2 0 1 3 
Pa ge 3 4 of 1 2 3
 
 
 
, M Sc, Pri nci pal Statisticia n, L E O P har ma  A/ S, I n d ustri par ke n 5 5, D K- 2 7 5 0 
Baller u p, De n mar k. Tel.: + 4 5  
,  e- mail: 
@le o- p har ma.c o m 
, M Sc, P har mac o vi gila nce Scie ntist, L E O P har ma A/ S, I n d ustri par ke n 5 5, 
D K- 2 7 5 0 Baller u p, De n mar k, Tel: + 4 5  
, e mail: 
@le o- p har ma.c o m 
6. 5  I n vesti g at ors a n d Tri al C o m mittees 
6. 5. 1  I nter n ati o n al C o- or di n ati n g I n vesti g at or 
T he i nter nati o nal c o- or d i nati n g i n vesti gat or is res p o nsi ble f or a p pr o val of t he ( C o ns oli date d) 
Cli nical St u d y Pr ot oc ol, Cli nical St u d y Pr ot oc ol A d de n d u m(s), ( C o ns oli date d) C R F a n d t he 
Cli nical St u d y Re p ort o n be half of all trial i n ve sti gat ors a n d as a gree d t o i n a n I nter nati o nal 
C o- or di nati n g I n vesti gat or A gree me nt. 
L a wre nce F. Eic he nfiel d , M D, U ni versit y of Calif or nia at Sa n Die g o/ Ra d y C hil dre n’s 
H os pital, Pe diatric a n d A d olesce nt Der mat ol o g y, 8 0 1 0 Fr ost Street- S uite 6 0 2, Sa n Die g o, 
Calif or nia C A 9 2 1 2 3, U S A, Tel.: + 1 8 5 8 5 7 6 1 7 0 0, Fa x: + 1 8 5 8 9 6 6 4 0 4 0, e- mail: 
leic he nfiel d @rc hs d. or g 
6. 5. 2   N ati o n al C o- or di n ati n g I n vesti g at or(s) 
T he Nati o nal C o- or di nati n g I n ves ti gat ors are res p o nsi ble f or nati o nal iss ues relati n g t o t he 
cli nical trial as a gree d t o i n a Nati o na l C o- or di nati n g I n vesti gat or A gree me nt. 
T he c o ntact details of Nati o nal C o- or di nati n g I n vesti gat ors are pr o vi de d o utsi de t he pr ot oc ol. 
6. 5. 3  I n vesti g at ors 
Eac h partici pati n g i n vesti gat or is res p o nsi ble f or all as pects of t he cli nical trial c o n d uct at 
his/ her trial site as a gree d t o i n a cli nical trial a gree me nt. 
T he c o ntact details of eac h part ici pati n g i n vesti gat or are pr o vi de d o utsi de t he pr ot oc ol a n d i n 
t he nati o nal cli nical trial a p plicati o ns. 
6. 5. 4  Tri al C o m mittees 
N ot A p plica ble 
6. 6  A gree me nts 
 
P P D
P P D
P P D
P P D
P P D
P P D


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Before the initiation of any clinical trial related activities by the investigators/clinical trial 
committee(s)/LEO Pharma A/S affiliate(s)/CRO(s) listed above, the relevant parties must 
have entered into a written agreement regulating those activities. 
7 Insurance 
LEO Pharma A/S has taken out relevant insurances covering the subjects in the present 
clinical trial in accordance with applicable laws and regulations. 
8 Introduction and Rationale 
8.1 Psoriasis 
Psoriasis is one of the most common chronic skin diseases, with a prevalence generally 
estimated at between 1 to 3% of the world’s population (10). Psoriasis is characterised by 
sharply marginated areas of affected skin which appear thickened, red and scaly, and may 
itch. This appearance is produced by a greatly increased rate of epidermal proliferation with 
impaired differentiation of keratinocytes. Dermal blood vessels are dilated and there is 
infiltration of the skin with immunologically active cells (11) (12). The pathogenesis is 
incompletely understood, but the disease is thought to be triggered by activation of the 
cellular immune system with involvement of T cells, dendritic cells, and various cytokines 
and chemochines (13). 
 
The most common clinical type of psoriasis, affecting 80-90% of patients, is psoriasis 
vulgaris (plaque-type psoriasis) (14). Sites of predilection are the hairy scalp (30% initially 
and 75% over the course of the disease), the extensor surfaces of the elbows and knees and 
the sacral region (15). The nails are involved in about 30% of patients with psoriasis and in 
about 20% psoriatic arthritis arises, usually many years after the initial cutaneous 
manifestation. 
 
Psoriasis can be treated either by topical therapy, phototherapy, or by systemic methods (10) 
(16). Systemic treatments and phototherapy are generally reserved for extensive disease 
unresponsive to topical treatments due to concerns over toxicity (13) (16). 
 
Most preparations are greasy and messy to apply, have an unpleasant smell and may cause 
staining of clothes and fabrics and skin irritation (6). Patient’s compliance is therefore often 
poor, leading to a bad therapeutic result. 
 
There is a need for a patient acceptable topical treatment. 
 


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8.2 Investigational Product Description 
LEO 80185 (Calcipotriol plus Betamethasone Dipropionate) Gel  
LEO 80185 gel, containing calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as 
dipropionate), is a topical therapy indicated for treatment of psoriasis vulgaris on the scalp 
and body. It obtained marketing approval in 2008 in the U.S., Canada, and 16 European 
countries, and since then has been marketed in the U.S. and Europe under the trade names 
Taclonex® Scalp Topical Suspension and Daivobet®/Dovobet®/Xamiol® gel, respectively. In 
this Clinical Study Report, ‘LEO 80185 gel’ is used in text ‘LEO 80185’ is used in the tables, 
figures, and listings. 
 
Calcipotriol is a vitamin D3 analogue and betamethasone dipropionate is a topical 
corticosteroid. Both the active components in LEO 80185 gel have been widely available 
world-wide for many years and their efficacy and safety profiles in the treatment of psoriasis 
are well-known. 
 
Numerous trials have been conducted with LEO 80185 gel as described in the Investigator’s 
Brochure. Overall, it can be concluded that LEO 80185 gel is considered to be effective and 
safe in the treatment of psoriasis vulgaris on scalp and body. 
 
8.3 Trial Rationale 
The FDA has approved Taclonex® Gel for the treatment of body psoriasis in adults. The 
objective of the present phase 2 trial is to evaluate the safety and efficacy of LEO 80185 gel 
for the treatment of both body and scalp psoriasis in adolescent subjects and has been 
undertaken as a post-marketing commitment to the FDA (for NDA 22-185). The FDA requires 
the trial to be conducted in 100 evaluable paediatric patients (ages 12 to 16 years, 11 months) 
with psoriasis vulgaris on the scalp and body, to evaluate the safety and effect of Taclonex® 
Gel on calcium metabolism. In a subset of a least 30 patients treated under maximal use 
conditions, evaluation of the hypothalamic-pituitary axis and pharmacokinetics is required. 
LEO 80185 gel has marketing approval in many countries for the treatment of scalp psoriasis 
in adults. Two non-controlled trials, MBL 0801 and MBL 0412 INT, in adolescent subjects 
(aged 12-17 years) have recently been completed. In these trials in a total of 109 adolescent 
subjects, LEO gel was safe and effective in the treatment of psoriasis vulgaris on the scalp (7) 
(8). 
 
 


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Approximately 35% of patients with psoriasis develop the disease before the age of 20 and 
25% are diagnosed between 10 and 19 years of age (3). Involvement of the scalp is more 
common in children (4) (5). Based on this, it is evident that scalp psoriasis is also prevalent in 
the adolescent age group (12-17 years).  
Only 10% of psoriasis patients develop psoriasis before the age of ten (3). The clinical 
appearance of psoriasis in children (ages 2-11 years) may differ from the classical picture 
seen in older patients. Facial psoriasis is more common in children than in adults and may be 
the only site affected; guttate and flexural forms are particularly common in children (20) (21) 
(22) (23). Children have a higher body surface area (BSA) to body mass ratio than 
adolescents and adults which increases the potential for adverse drug reactions due to 
absorption of topically applied compounds through the skin (24). This limits the use of potent 
topical corticosteroids in this age group (25). Hence children below 12 years of age will not 
be enrolled into this study. 
 
To evaluate the safety of the LEO 80185 gel in this trial, all adverse events reported by the 
subject or observed by the investigator will be recorded. In addition, any effects resulting 
from systemic absorption of the active components, betamethasone dipropionate and 
calcipotriol, will be evaluated by assessing adrenal function and calcium metabolism, 
respectively. 
 
Laboratory evidence of adrenal insufficiency due to the use of topical corticosteroid treatment 
has been reported (9).  This is due to systemic absorption of the corticosteroid, which then 
induces suppression of the hypothalamic-pituitary-adrenal (HPA) axis due to a negative 
feedback effect on the pituitary gland and the hypothalamus (9) (26). This results in a 
decrease in the secretion of ACTH from the pituitary gland. The adrenal glands depend on 
ACTH as a tropic hormone in such a way that ACTH deficiency results in a reversible 
inability to produce cortisol (27). Hence, the adrenal glands lose the capacity to produce 
cortisol in response to an ACTH-challenge. Adrenal function can therefore be measured by 
injection of a synthetic subunit of ACTH into the subject, and then measuring the production 
of cortisol by the adrenal glands in response to this. A serum cortisol concentration of 
18 mcg/dl or less at 30 and 60 minutes after the injection indicates possible adrenal 
suppression (26). 
 
 


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The effect of LEO 80185 gel on adrenal function in adult subjects has been assessed by the 
ACTH-challenge test in a previous trial (28). The subjects included in the trial had extensive 
psoriasis on both scalp (at least 30% of scalp affected) and non-scalp regions of the body (15-
30% of body surface area). Subjects applied LEO 80185 gel to lesions on the scalp and the 
corresponding ointment product Daivobet®/Taclonex® ointment to the lesions on the trunk 
and limbs. After a total of 32 subjects had received treatment with LEO 80185 gel for 4 
weeks, 5 had a serum cortisol concentration ≤18mcg/dl at 30 minutes after ACTH-challenge, 
and out of 11 subjects who continued treatment for 8 weeks, 2 subjects had a serum cortisol of 
≤18 mcg/dl at 30 minutes after ACTH challenge. The cortisol value was >18mcg/dl at 60 
minutes after ACTH-challenge for all subjects.  
 
In the two trials MBL 0801 and MBL 0412 INT, no cases of hypercalcaemia and no clinically 
relevant changes in urinary calcium were reported.  The adrenal response to ACTH challenge 
was measured in 30 patients; one patient showed a decrease in cortisol response to ACTH 
challenge after 4 weeks of treatment which was considered to be mild (7) (8). 
 
In the present study LEO 80185 gel will be applied to lesions on both scalp and body. The 
risk of adrenal suppression with LEO 80185 gel is expected to be low with LEO 80185 being 
applied under maximal use conditions as systemic exposure is known to be low and the drug 
concentration is expected to be below the limit of quantification (Investigator’s Brochure). 
 
Subjects participating in the present study will perform ACTH-challenge test before and after 
treatment. The pre-treatment test is to ensure that adrenal function is normal before starting 
investigational product. Serum cortisol concentrations at 30 and 60 minutes after injection 
will be measured in order to show the maximum cortisol level achieved (26). 
 
Overdosage with topical calcipotriol can cause hypercalcemia (27), due to the systemic 
absorption of calcipotriol, which then affects calcium metabolism as it is a vitamin D 
analogue. However, extensive experience with topical use of calcipotriol in psoriasis has 
demonstrated no significant impact on calcium metabolism when used in the recommended 
amounts (maximum weekly dose in adults of 100 g of a 50 mcg/g concentration). Doses up to 
300 g have been used with serum calcium remaining within the normal range (29). 
 
Two studies with calcipotriol ointment have been conducted in children 2-14 years of age and 
did not show effects on calcium metabolism (30) (31). One trial with Daivobet® Ointment, 
MCB 0501 INT, has been conducted in adolescent subjects and did not show any effects on 
calcium or HPA axis. 
 


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Calcium metabolism will be evaluated in the present study by 24-hour urinary collection and 
measurement of serum calcium, -phosphate and plasma PTH before, during and/or after 
treatment. 24-hour urine will be collected and the urinary calcium-, phosphate- and creatinine 
excretion will be measured and the calcium:creatinine and phosphate:creatinine ratios 
calculated. Subjects who report an incomplete 24-hour urinary collection will be excluded 
from the analyses of 24-hour urinary calcium and phosphate excretion but will still be 
analysed for calcium:creatinine and phosphate:creatinine. To identify any severe, non-
reported sampling errors the daily creatinine excretion/kg body weight will be calculated as 
proposed by Remer et al. (32).   
 
It is well established that there is a relationship between dietary calcium intake and the 
urinary calcium excretion in adults. However, in rapidly growing adolescents, it appears that 
only dietary calcium intake above a certain threshold of approximately 1500 mg/day will 
result in an increase in urinary calcium excretion (33). As this study includes adolescents 12 
to 16 years, 11 months of age, some of the subjects may not be in phase of rapid growth and 
some subjects might consume large amounts of dairy products. Therefore, there is a 
possibility of an effect of the diet on the calcium excretion.  
 
A review of the subject’s normal diet will be done. As dairy products account for 
approximately 73% of the total dietary calcium content, and as the calcium from other sources 
such as vegetables and grains are less easily absorbed (34), the review will focus on the intake 
of dairy products. The subjects will be asked to keep a diary of the daily intake of dairy 
products and calcium-fortified products (e.g. bread, cereals, orange juice or soy milk). The 
number of daily servings of calcium defined as one cup (240 ml) or 1.5 ounces of cheese 
(43 g) in dairy products such as milk, yoghurt or cheese or of a calcium-fortified product with 
corresponding calcium content (300 mg calcium/cup) will be estimated (35). The subjects will 
be asked to keep the same number of daily servings three days prior to and during each 24-
hour urine collection. The number of daily calcium servings should not exceed five (i.e. 
1500 mg calcium). 
 
The combination of high calcium intake with vitamin D supplementation, or extreme calcium 
intake alone, has been shown to significantly increase urinary calcium in adults (36). Hence, 
the use of calcium or vitamin D supplements will be excluded in this study. 
 
 


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Subjects will apply the LEO 80185 gel once daily for up to 8 weeks. This application 
frequency and treatment duration has been shown to be safe and effective in adults with 55-
70% of subjects achieving controlled disease after 4-week treatment (37) (38). Only subjects 
who have signs of scalp and/or body psoriasis after 4 weeks of treatment will continue 
treatment in the study. As the application area and the amount of investigational product 
required is expected to decrease with time as lesions heal, continued treatment for up to 8 
weeks is expected to be safe in those subjects who need it.   
 
The maximum weekly dosage approved for adults is 100 g. In the present trial, the maximum 
weekly dose will be determined by age and BSA at baseline. For subjects aged 12 to 14 years 
with a BSA ≤ 1.3 m2, the maximum weekly dosage will be 50 g of LEO 80185 gel per week. 
For subjects aged 12 to 14 years with a BSA > 1.3 m2 and subjects aged 15 to 16 years, 11 
months with a BSA ≤ 1.7 m2, the maximum weekly dosage will be 75 g of LEO 80185 gel per 
week. For subjects aged 15 to 16 years, 11 months with a BSA > 1.7 m2, the maximum 
weekly dosage will be 100 g of LEO 80185 gel per week.  
 
To be eligible for the study, all subjects are to have an extent of scalp and body (trunk and /or 
limbs) psoriasis of 10-35% BSA.  In addition, subjects performing HPA axis assessments are 
to have an extent of scalp psoriasis that is more than or equal to 20% of the scalp area.  
Subjects not performing HPA axis assessments are to have an extent of scalp psoriasis that is 
more than or equal to 10% of the scalp area. The disease severity of body psoriasis and scalp 
psoriasis is to at least moderate according to the investigator’s global assessment. It is 
expected that many adolescent subjects with psoriasis will have less extensive and less severe 
disease. However, since the main purpose of the present study is to evaluate the safety of the 
investigational product, the exposure to treatment has to be as close to maximum as possible. 
 
A total of 100 subjects will be enrolled in this study.  All subjects will undergo assessments 
on safety, pharmacokinetic analysis, calcium metabolism and efficacy. A subgroup of 30 
subjects providing data for the ACTH-challenge test at the end of treatment will be included 
in the study.  This number of subjects has been requested by the FDA for an HPA axis 
evaluation.  Pharmacokinetic analysis will be performed to evaluate if any adverse events 
could be correlated to the investigational product. A blood sample (2 x 6mL) for 
pharmacokinetic evaluation will be drawn at Visit 3 (4 weeks of treatment) prior to the 
application of LEO 80185 on the day of the visit.  Validated bioanalytical assays will be used 
for quantification of calcipotriol, betamethasone dipropionate and the metabolites MC1080  
and betamethasone 17-propionate in the plasma sample. 
 
 


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Subjects will have a washout period of up to 8 weeks if they are using treatments which could 
have an effect on (or be affected by) the ACTH-challenge test (e.g., corticosteroids, enzymatic 
inductors, cytochrome P450 inhibitors, hypoglycemic sulfonamides, antidepressive medica-
tions, estrogen), calcium metabolism (e.g., vitamin D, calcium supplements, antacids, 
diuretics and antiepileptics) or the psoriasis to be treated with investigational product (e.g., 
systemic/topical/ ultraviolet anti-psoriatic therapy, although emollients are allowed). 
 
9 Trial Objectives 
9.1 Primary Objective 
The primary objective is to evaluate the safety of once daily use of calcipotriol (50 mcg/g) 
plus betamethasone (0.5 mg/g) (as dipropionate) gel in adolescent subjects (aged 12 to 16 
years, 11 months) with scalp and body psoriasis. 
9.2 Secondary Objectives 
The secondary objective is to evaluate the efficacy of once daily use of calcipotriol (50 
mcg/g) plus betamethasone (0.5 mg/g) (as dipropionate) gel in adolescent subjects (aged 12 to 
16 years, 11 months) with scalp and body psoriasis. 
10 Investigational Plan 
10.1 Trial Design 
This will be an international, multi-centre, prospective, non-controlled, open, single-group, 8-
week trial in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body 
psoriasis. 
 
The subjects will receive topical treatment with calcipotriol 50 mcg/g plus betamethasone 0.5 
mg/g (as dipropionate) gel once daily for up to 8 weeks. 
 
Washout/Screening Period 
Depending on the prior use of disallowed treatments, the washout/screening period will last 
for 7 to 56 days prior to the first administration of LEO 80185 gel (Visit 1).  
 
 


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Prior to attending any study procedure, a signed informed consent must be obtained from the 
parent(s)/legal guardian(s) of the subject, or by the subject (as appropriate and according to 
national laws and regulations). Written assent should also be obtained from the subject. There 
are two screening visits: Screening visit 1 (SV1) and screening Visit 2 (SV2). Depending on 
the subjects’ use of excluded treatments, SV1 is performed up to 7 weeks before SV2; SV2 is 
performed at 3 to 7 days before Visit 1. 
 
Treatment Period 
The treatment period will last for up to 8 weeks. There are up to 5 visits: Visit 1 (day 0), Visit 
2 (day 14), Visit 3 (day 28), Visit 4 (day 42) and Visit 5 (day 56). Visits 2-5 should be 
performed within ±2 days of the scheduled time relative to Visit 1; if they are outside this 
window, the (sub)investigator should record the reason in the subject’s medical record.   
 
LEO 80185 gel will be applied once daily to scalp psoriasis lesions. Subjects should be 
instructed to discontinue treatment on individual lesions if/when a lesion has cleared. Subjects 
whose psoriasis clears after 4-week treatment will stop the investigational product and leave 
the trial.  
 
Subjects who have psoriasis after 4 weeks of treatment will continue treatment for another 4-
week period. 
 
Subjects whose psoriasis clears at Visit 2 or Visit 4 according to the (sub)investigator should 
discontinue treatment but will stay in the study. During periods of discontinuation of 
treatment the subject should restart the treatment if psoriasis reappears. 
 
Follow-up 
If applicable, the treatment period will be followed by a follow-up (FU) period consisting of 
visit FU1 and/or visit FU2.  
 
Visit FU1 will take place 14 days after the last visit in the treatment period, but only if there 
was an ongoing adverse event at this time of possible/probable/not assessable relationship to 
the investigational product. At the (sub)investigator’s discretion, the information required at 
this visit may be obtained over the telephone, and the subject need not make the visit. FU1 
should also be performed if albumin corrected serum calcium is above the reference range at 
the last on-site visit. A new blood sample should then be collected. 
 
 


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Visit FU2 will take place 28 days after the ACTH-challenge test performed at Visit 3 or Visit 
5, but only if this test showed a serum cortisol concentration ≤18 mcg/dl at 30 minutes after 
ACTH-challenge. 
 
Visits FU1 and FU2 should be performed within ±2 days of the scheduled time; if they are 
outside this window, the qualified site staff person should record the reason in the subject’s 
medical record/source document. 
 
For details, see Section 10.8 for the schedule of trial procedures.   
10.1.1 Overall Chart 
 
There should be at least 4 days between SV1 and SV2 so dietary information (diary) can be 
collected. 
 
10.2 Time Schedule 
Planned date of enrolment of first subject: October 2013 
Planned date of enrolment of last subject: August 2015 
Planned date of completion of last subject: October 2015 
10.3 Number of Subjects/Sample Size  
Treatment period
 0 
28 
56 
+14 
 1 
   5 
FU1 
    FU2
Washout/ screening 
period 
Follow-up period  
(if applicable) 
+28
-3 to -7 
SV2 
SV1 
-56  to -7 
before Visit 1 
  2
42
    4 
 3 
14 
 


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Enrolment of subjects will continue until data from 100 subjects are available for evaluation 
of the effect of LEO 80185 on calcium metabolism (i.e. the measurement of the serum 
calcium concentration and the 24-hour urinary calcium excretion and/or the urinary 
calcium:creatinine ratio is available before and at Visit 3 and/or Visit 5). Therefore, the 
number of enrolled subjects can exceed 100 subjects.  
 
The 100 subjects include the enrolment of 30 evaluable subjects in the U.S. without adrenal 
suppression at baseline who undergo the ACTH-challenge test at end of treatment (Visit 3 or 
Visit 5). At the time the sponsor confirms 30 evaluable subjects has been obtained, there may 
be other subjects ongoing in the trial that have not yet had the ACTH-challenge test. Such 
subjects will be allowed to complete the trial without the ACTH-challenge test. 
 
The primary objective of the trial is to evaluate the safety of LEO 80185 gel. No formal 
sample size calculation evaluating the power of the trial has been performed. However, a few 
considerations regarding the sample size have been made as described below. 
 
The upper limit of an exact two-sided 95% confidence interval for the probability of 
observing a specific adverse event, when 0 out of 100 possible events have been observed, is 
approximately 4% assuming a binomial distribution. 
 
With 100 subjects and an assumed response rate (percentage of subjects who achieve “Clear” 
or “Almost clear” according to the investigator’s global assessment of disease severity on the 
body at end of treatment) of approximately 30%, the 95% confidence interval for the 
estimated response rate will be approximately ± 9%. 
 
Each centre should aim to enroll a minimum of three subjects. As the subjects are anticipated 
to be difficult to recruit, the suggested minimum number of subjects per centre is based on 
practical considerations rather than statistical robustness of estimates given per centre.  
10.4 Criteria for Subject Selection (In- and Exclusion) 
Following receipt of verbal and written information about the trial, the parent(s) or legal 
guardian(s) or the subject (as appropriate and according to national laws or regulations) must 
provide signed and dated informed consent before any trial related activity is carried out, 
including activities relating to washout periods. 
 
Any implementation of national requirements/law for the trial subject’s participation in the 
clinical trial will be ensured and will be described in submission documentation to 
authorities/ethics committees, as applicable. 
 


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10.4.1 Inclusion Criteria 
10.4.1.1 Inclusion Criteria for All Subjects 
1. Signed informed consent given by parent(s), or legal guardian(s), or by the subject 
(according to national law) following their receipt of verbal and written information about 
the trial. 
2. Subjects will receive verbal and written information and will provide written assent to the 
trial.  
3. Subjects 12 to 16 years, 11 months of age. 
4. Either sex. 
5. Any race or ethnicity. 
6. Clinical signs of psoriasis vulgaris on both the scalp and body (trunk and/or limbs). 
7. At SV2 and Visit 1, a clinical diagnosis of scalp and body (trunk and/or limbs) psoriasis 
which is: 
a. of an extent of 10 to 35% of the body surface area (excluding psoriatic lesions of 
the face and sensitive areas.  Sensitive areas include armpits, groin, under the 
breasts and in other skin folds around the genitals and buttocks),  and 
b. of at least moderate severity according to the investigator’s global assessment of 
disease severity on the body, and 
c. for subjects aged 12 to 14 years with a BSA ≤ 1.3 m2, amenable to topical 
treatment with a maximum of 50 g of investigational product per week, and 
d. for subjects aged 12 to 14 years with a BSA > 1.3 m2, amenable to topical 
treatment with a maximum of 75 g of investigational product per week, and 
e. for subjects aged 15 to 16 years, 11 months with a BSA ≤ 1.7 m2, amenable to 
topical treatment with a maximum of 75 g of investigational product per week, and 
f. for subjects aged 15 to 16 years, 11 months with a BSA > 1.7 m2, amenable to 
topical treatment with a maximum of 100 g of investigational product per week. 
8. A serum albumin-corrected calcium below the upper reference limit at SV2. 
 


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9. Females of child-bearing potential must have a negative urine pregnancy test result and 
must agree to use a highly effective method of contraception during the trial. Highly 
effective methods are defined as ones which result in a low failure rate (less than 1% per 
year) such as progestin-only formulations (implants, injectables, or “mini-pill” in 
combination with a barrier method), some intra-uterine devices, double barrier methods 
(eg. cervical cap and condom), tubal ligation/section, sexual abstinence or vasectomised 
partner. The patients must have used the contraceptive method 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 investigational product. A female is defined as not of child-
bearing potential if she is premenarchal, postmenopausal or surgically sterile 
(hysterectomy or bilateral ovariectomy). 
10. Subjects fulfilling national requirements/law for participation in this trial. 
10.4.1.2 Additional Inclusion Criteria for Subjects Performing HPA Axis 
Assessments (U.S. only) 
1. At SV2 and Visit 1, a clinical diagnosis of scalp psoriasis which is:  
a. more than or equal to 20% of the scalp area, and 
b. of at least moderate severity according to the investigator’s global assessment of 
disease severity on the scalp. 
2. Subjects with a normal HPA axis function at SV2 including serum cortisol concentration 
above 5 mcg/dl before ACTH challenge and serum cortisol concentration above 18 mcg/dl 
30 minutes after ACTH challenge. 
10.4.1.3 Additional Inclusion Criteria for Subjects Not Performing HPA 
Axis Assessments 
1. At SV2 and Visit 1, a clinical diagnosis of scalp psoriasis which is:  
a. more than or equal to 10% of the scalp area, and 
b. of at least moderate severity according to the investigator’s global assessment of 
disease severity on the scalp. 
10.4.2 Exclusion Criteria 
10.4.2.1 Exclusion Criteria for All Subjects 
1. A history of hypersensitivity to any component of the LEO 80185 gel 
2. Systemic treatment with biological therapies (marketed or not marketed), with a possible 
effect on scalp and/or body psoriasis within the following time period prior to Visit 1 and 
during the trial: 
a. etanercept – within 4 weeks prior to Visit 1 
 


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b. adalimumab, infliximab – within 2 months prior to Visit 1 
c. ustekinumab – within 4 months prior to Visit 1 
d. experimental products – within 4 weeks/5 half-lives (whichever is longer) prior to 
Visit 1 
3. Systemic treatment with therapies other than biologicals, with a possible effect on scalp 
and/or body psoriasis (e.g., retinoids, immunosuppressants, PUVA) within 4 weeks prior 
to Visit 1 (Day 0) or during the trial. 
4. UVB therapy within 2 weeks prior to Visit 1 or during the trial. 
5. Any topical treatment on the scalp and body (except for emollients and non-steroid 
medicated shampoos) within 2 weeks prior to Visit 1 or during the trial. 
6. Systemic calcium, vitamin D supplements, antacids, diuretics, antiepileptics, 
diphosphonates or calcitonin within 4 weeks prior to SV2 or during the trial. 
7. Planned initiation of, or changes to, concomitant medication that could affect psoriasis 
(e.g., betablockers, chloroquine, lithium, ACE inhibitors) during the trial. 
8. Current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis. 
9. Subjects with any of the following conditions present on the treatment areas on scalp 
and/or body: 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, 
rosacea, acne vulgaris, acne rosacea, atrophic skin, striae atrophicae, fragility of skin 
veins, ichthyosis, ulcers and wounds. 
10. Other inflammatory skin diseases that may confound the evaluation of scalp and/or body 
psoriasis. 
11. Planned excessive exposure to sun during the trial that may affect scalp and/or body 
psoriasis. 
12. Known or suspected severe renal insufficiency or severe hepatic disorders. 
13. Known or suspected disorders of calcium metabolism associated with hypercalcaemia. 
14. Any clinically significant abnormality following review of screening laboratory tests 
(blood and urine samples), physical examination or blood pressure/heart rate measurement 
performed at SV2. 
15. Current participation in any other interventional clinical trial. 
16. Previously enrolled in this trial. 
17. Subjects who have received treatment with any non-marketed drug substance (i.e., an 
agent which has not yet been made available for clinical use following registration) within 
a month prior to SV1 or longer, if the class of substance required a longer wash-out as 
defined above (e.g., biological treatments). 
18. Subjects or parent(s) or legal guardian known or suspected of being unlikely to comply 
with the Clinical Trial Protocol (e.g., alcoholism, drug dependency or psychotic state). 
 


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19. Females who are pregnant, or of child-bearing potential and wishing to become pregnant 
during the trial, or who are breast-feeding. 
20. Females of child-bearing potential with positive pregnancy test at SV2. 
21. Subject (or their partner) not using an adequate method of contraception according to 
national requirements. 
10.4.2.2 Additional Exclusion Criteria for Subjects Performing HPA Axis 
Assessments (U.S. Only) 
1. A history of serious allergy, allergic asthma or serious allergic skin rash. 
2. Known or suspected hypersensitivity to any component of CORTROSYN® (including 
ACTH/cosyntropin/tetracosactide) 
3. Systemic treatment with corticosteroids (including inhaled and nasal steroids) within 12 
weeks prior to SV2 or during the trial. 
4. Topical treatment with corticosteroids within 2 weeks prior to SV2 or during the trial. 
5. Oestrogen therapy (including contraceptives) or any other medication known to affect 
cortisol levels levels or HPA axis integrity within 4 weeks prior to SV2 or during the trial. 
6. Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin) within 4 weeks prior to 
SV2 or during the trial. 
7. Systemic or topical cytochrome P450 inhibitors (e.g., ketoconazole, itraconazole, 
metronidazole) within 4 weeks prior to SV2 or during the trial. Topical ketoconazole 2 
weeks prior to SV2. 
8. Hypoglycemic sulfonamides within 4 weeks prior to SV2 or during the trial. 
9. Antidepressive medications within 4 weeks prior to SV2 or during the trial. 
10. Known or suspected endocrine disorder that may affect the results of the ACTH challenge 
test. 
11. Clinical signs or symptoms of Cushing’s disease or Addison’s disease. 
12. Subjects with diabetes mellitus. 
13. Known or suspected cardiac condition. 
14. Not following nocturnal sleep patterns. 
10.4.2.3 Additional Exclusion Criteria for Subjects Not Performing HPA 
Axis Assessments 
1. Topical treatment on the trunk and/or limbs with very potent (WHO group IV) 
corticosteroids within 2 weeks prior to Visit 1 or during the trial 
2. Topical treatment on the face and/or sensitive areas (armpits, groin, under the breasts and 
in other skin folds around the genitals and buttocks) with potent or very potent (WHO 
groups III-IV) corticosteroids within 2 weeks prior to Visit 1 or during the trial 
 


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10.4.3 Subject Screening Log 
All subjects screened for this study will be logged on a screening log. This log will list 
whether subjects were included or not. If a subject is not enrolled, the main reason will be 
listed. The list will be prepared according to local regulations about personal data protection. 
10.4.4 Subject Registration 
At SV1, each subject will be assigned the next (ascending) CRF book number available at the 
trial site. The CRF book number is a unique subject identifier used throughout the trial, in lieu 
of the subject’s name. 
10.5 Withdrawal Criteria 
Subjects may withdraw for any of the following reasons: 
1. Unacceptable treatment efficacy: the investigator is free to withdraw the subject at any 
time for medical reasons. 
2. Unacceptable adverse events: any adverse event that the investigator or the subject 
considers unacceptable. 
3. Exclusion criteria: any exclusion criteria which emerge/become apparent during the 
subject’s participation in the clinical trial. 
4. Voluntary withdrawal: subjects will be free to withdraw from the clinical trial at any 
time and for any reason. 
5. Other reasons: other reasons than stated above which requires the subject to (be) with-
draw(n) should be specified. 
Subjects must be withdrawn if they are found to have become pregnant or experience an 
allergic reaction to CORTROSYN®. 
Subjects who are discovered, after enrolment, not to have fulfilled all in-/exclusion criteria at 
time of enrolment, should be withdrawn from treatment unless the investigator, based on 
clinical and ethical evaluation, finds withdrawal inappropriate.  The final efficacy assessment 
(at the correct scheduled time) should, however, be attempted to be completed for all subjects.  
Such deviation(s) from the (Consolidated) Clinical Study Protocol must be reported to LEO 
Pharma A/S (and IEC/IRB, as appropriate) and recorded in the Clinical Study Report. 
In case of premature withdrawal prior to visit 5, the additional tests scheduled for visit 5 
should be done at the end of treatment, with the exception of the 24-hour urine collection. 
Reason(s) for withdrawal will be recorded in the CRF. 
 


L P 0 0 7 6- 1 0 1 7  
1 7- A pr- 2 0 1 3 
Pa ge 5 0 of 1 2 3
 
 
 
S u bjects wit h dra w n will n ot be s u bstit ute d. 
1 0. 6  I n vesti g ati o n al Pr o d ucts 
1 0. 6. 1  L E O 8 0 1 8 5 
Fi nis he d pr o d uct ( bra n d) na me 
(if a vaila ble)/ na me 
i n vesti gati o nal pr o d uct 
L E O 8 0 1 8 5 gel  
 
F or m ulati o n
 Gel
 
Acti ve i n gre die nt 
na me/c o nce ntrati o n 
Calci p otri ol 5 0 mc g/ g (as h y drate) 
Beta met has o ne 0. 5 m g/ g (as di pr o pi o nate) 
E xci pie nts ( n ot q ua ntitati ve) 
Paraffi n, li q ui d  
P ol y o x y pr o p yle ne- 1 5 stear yl et her  
Cast or oil, h y dr o ge nate d  
B ut yl h y dr o x yt ol ue ne ( E 3 2 1) (a d de d t o 
P ol y o x y pr o p yle ne- 1 5 stear yl et her b y t he s u p plier) 
All-rac- α -t oc o p her ol (a d de d t o Paraffi n, li q ui d b y t he 
s u p plier) 
Pac k size(s) 
6 0 g i n 1 2 0 ml b ottle 
Ma n ufact urer’s na me of b ul k 
me dicati o n (I P) 
L E O P har ma A/ S 
Certifier’s na me of b ul k 
me diati o n (I P) 
L E O P har ma A/ S 
S u p plier’s na me 
L E O P har ma A/ S 
Ma n ufact urer’s na me of s u bject 
treat me nt  pac ka ges 
 
 
Certifier’s na me of s u bject 
treat me nt  pac ka ges 
 
 
 
1 0. 6. 2  P ac k a gi n g of I n vesti g ati o n al Pr o d ucts 
L E O 8 0 1 8 5 
I n di vi d ual b ottles c o ntai ni n g L E O 8 0 1 8 5 gel will be dis pe nse d at eac h visit b y t he site.  T he 
n u m ber of b ottles dis pe nse d at e ac h visit is de pe n de nt o n t he s u bj ect’s a ge a n d B S A at Visit 1.  
T he i n di vi d ual b ottles will be la bele d i n c o m plia nce wit h nati o nal la ws a n d re g ulati o ns of t he 
partici pati n g c o u ntries. 
 
 
C CI
C CI


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Each individual bottle of investigational product will be packed in a separate bottle container. 
This bottle container serves to protect the bottle from sunlight and must be used for storage of 
the bottle at all times. 
 
The individual bottle container and individual bottles will be identified by a label in 
compliance with national laws and regulations of the participating countries. 
 
10.6.3 Storage of Investigational Products 
The investigational product, LEO 80185, should be stored in a safe and secure place 
inaccessible for children. Do not store above 25°C. Do not refrigerate.  Keep the bottle in 
outer carton and away from sunlight. 
10.6.4 Administration of Investigational Products 
10.6.4.1 LEO 80185 
Route of Administration 
Topical 
Dosing Range (g) 
Up to 100 g gel per week 
Dosing frequency 
Once daily application 
Weekly Maximum (g) 
Up to 100  g 
Time of day for dosing 
No specific requirements 
Relation of time of dosing to dietary intake 
No specific requirements 
 
The investigational product will be dispensed by the (sub)investigator/investigational staff at 
Visit(s) 1, 2, 3 and 4. The dispenser should ensure that the subject and/or parents/legal 
guardian is/are familiar with the procedures for administration of the LEO 80185 gel. The 
subject should be instructed to return all dispensed investigational product at the following 
visit. 
The number of bottles dispensed at each dispensing visit (Visit 1, 2, 3 and 4) is dependent on 
the subject’s age and BSA at Visit 1.  
• For subjects aged 12 to 14 years with a BSA ≤ 1.3 m2, the maximum weekly dosage 
will be 50 g of LEO 80185 gel per week.  These subjects will be dispensed 2 bottles at 
each dispensing visit. 
 


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• For subjects aged 12 to 14 years with a BSA > 1.3 m2 and subjects aged 15 to 16 
years, 11 months with a BSA ≤ 1.7 m2, the maximum weekly dosage will be 75 g of 
LEO 80185 gel per week.  These subjects will be dispensed 3 bottles at each 
dispensing visit. 
• For subjects aged 15 to 16 years, 11 months with a BSA > 1.7 m2, the maximum 
weekly dosage will be 100 g of LEO 80185 gel per week.  These subjects will be 
dispensed 4 bottles at each dispensing visit. 
 
At Visit 1, a treatment instruction will be handed over to the subject/parent(s)/legal 
guardian(s) of the subject. On this sheet, the subject/parent(s)/legal guardian (s) will be 
instructed how to apply the investigational product. 
 
10.6.5 Precautions/Overdosage 
LEO 80185 
Overdosage with calcipotriol may be associated with hypercalcaemia. In such cases 
administration of the investigational product will be stopped and the subject will be 
withdrawn from the trial. Clinically important hypercalcaemia will be managed at the 
investigator’s discretion with rehydration, biphosphonate administration or according to local 
instructions. Hypercalcaemia should rapidly subside when treatment is discontinued. 
 
Overdosage with betamethasone dipropionate may result in suppression of the pituitary 
adrenal function causing secondary adrenal insufficiency which is usually reversible. In such 
cases symptomatic treatment is indicated. In case of chronic toxicity the corticosteroid 
therapy must be discontinued gradually. 
 
If severe skin irritation or skin infections develop, LEO 80185 gel should be discontinued and 
appropriate therapy instituted. 
 
Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to 
heal rather than by noting any clinical exacerbation as with most topical products not 
containing corticosteroids. Such an observation should be corroborated with appropriate 
diagnostic patch testing. 
10.6.6 Treatment Assignment 
Subjects who have been found to comply with all the protocol’s inclusion and exclusion 
criteria will start treatment and be dispensed investigational product at Visit 1.  Each bottle 
 


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will have a unique identification number.  When a bottle is dispensed to the subject, the 
unique identification number for that bottle will be recorded in the subject’s medical record 
and the CRF. 
10.6.6.1 Randomisation Code List 
Not applicable 
10.6.6.2 Subject Identification List 
The investigator will maintain a list of all subjects included in the trial at the trial site 
including each subject's identity, date of enrolment and corresponding CRF book number so 
that any subject may be identified if required for any reason. The list is kept by the 
investigator and will not be copied to LEO Pharma A/S. 
10.6.7 Blinding of the Trial 
Not applicable 
10.6.8 Breaking the Randomisation Code 
Not applicable 
10.6.8.1 Un-blinding of Individual Subject Treatment 
Not Applicable. 
10.6.8.2 Un-blinding of the Clinical Trial 
Not Applicable. 
10.6.9 Drug Accountability and Compliance Checks 
The investigator is fully responsible for the investigational products at the trial site. 
Dispensing of investigational products may be delegated to, e.g. a hospital pharmacy as 
locally applicable. 
The person responsible for dispensing the investigational products will be responsible for 
maintaining adequate control of the investigational products and for documenting all transac-
tions with them. Investigational products must be stored in a safe and secure place, and proper 
dispensing arrangements must be made. 
10.6.9.1 Sponsor-Investigator Drug Accountability 
 


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All investigational products supplied by the Contract Manufacturing Organisation (CMO) on 
behalf of LEO Pharma A/S will be returned to the CMO and be fully accounted for by the 
monitor with the help of the person responsible for dispensing the investigational products. 
Accountability will be documented by use of drug accountability forms. 
Investigational products may be returned from the trial site either to the CMO directly or via 
the LEO Pharma A/S affiliate/ CRO responsible for the running of the clinical trial. 
10.6.9.2 Investigator-Subject Drug Accountability 
At each visit, investigational product, including (empty) containers, dispensed at the previous 
visit must be returned by the subject. An inventory (Individual Drug Accountability Form) 
will be kept of all investigational product given to and returned by each subject enrolled 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 investigational product. 
10.6.9.3 End of Trial Drug Accountability 
All investigational product supplies returned to the CTS CMO will be reconciled with the 
Individual Drug Accountability Forms. All returned bottles will subsequently be weighed by 
the CTS CMO to determine the amount of investigational product used. 
10.6.9.4 Treatment Compliance 
At all on-treatment visits, the subject will be asked if she/he has used the medication as 
prescribed. If this is not the case, the degree and nature of non-compliance will be specified. 
10.6.10 
Prior and Concomitant Treatment 
Use of concomitant treatment should be recorded in the subject’s medical record and the CRF 
(treatment/drug name, dose, indication and dates of start and stop). 
Use of non-marketed/other investigational products one month prior to SV1 and during the 
trial is not permitted. 
 
Changes of doses (including starting) of drugs that, while not specifically indicated for 
treatment of the indication being studied, are known to have an effect (positive or negative) 
on the indication, are not permitted. 
 
For all subjects, treatments requiring washout before SV2/Visit 1 are listed below, with the 
required individual washout periods indicated in brackets: 
 


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• Topical treatment with corticosteroids (2 weeks prior to SV2) 
• Systemic treatment with biological therapies (marketed or not marketed), with a 
possible effect on scalp or body psoriasis (etanercept) (4 weeks prior to Visit 1), 
adalimumab, infliximab (2 months prior to Visit 1)*, ustekinumab (4 months prior to 
Visit 1)* or experimental products (4 weeks/5 half-lives (whichever is longer) prior to 
Visit 1)  
• Systemic treatment with therapies other than biologicals, with a possible effect on 
scalp or body psoriasis (e.g., retinoids, immunosuppressants, PUVA) within 4 weeks 
prior to Visit 1 
• UVB therapy within 2 weeks prior to Visit 1 
• Any topical treatment on the scalp or body (except for emollients and non-steroid 
medicated shampoos) within 2 weeks prior to Visit 1 
• Systemic calcium, vitamin D supplements, antacids, diuretics, antiepileptics, 
diphosphonates or calcitonin (4 weeks prior to SV2) 
 
* Note: the time between SV1 and Visit 1 cannot be longer than 8 weeks, and between SV1 
and SV2 not longer than 7 weeks, therefore subjects receiving, or having recently 
received, these treatments at SV1 cannot be enrolled. 
 
For subjects performing HPA axis assessments, additional treatments requiring washout 
before SV2/Visit 1 are listed below, with the required individual washout periods indicated in 
brackets: 
 
• Systemic treatment with corticosteroids (including inhaled and nasal steroids) (12 
weeks prior to SV2)* 
• Oestrogen therapy (including contraceptives) or any other medication known to affect 
cortisol levels or HPA axis integrity (4 weeks prior to SV2) 
• Enzymatic inductors (e.g., barbiturates, phenytoin, rifampicin), systemic or topical 
cytochrome P450 inhibitors (e.g., ketoconazole, itraconazole, metronidazole), 
hypoglycaemic sulfonamides, antidepressive medications (4 weeks prior to SV2). 
Topical ketoconazole (2 weeks prior to SV2). 
 
Treatments which cannot be used during the treatment period (Visits 1-5) are the same as 
those requiring a washout period, as listed previously, with the addition that the following are 
not allowed: 
 
 


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• Initiation of, or changes to, concomitant medication that could affect scalp or body 
psoriasis (e.g. beta-blockers, lithium, anti-malaria drugs, ACE inhibitors). 
• Excessive exposure of treated areas to either natural or artificial sunlight (including 
tanning booths, sunlamps, etc.). 
 
The following concomitant anti-psoriatic treatments are allowed during the trial: 
 
Scalp: 
No other treatment allowed. Non-medicated shampoo is allowed. 
Trunk/limbs: 
No other treatment allowed.  Bath oils and moisturizing soaps are 
allowed.  
Face and  
For subjects performing HPA axis assessments:  Any topical treatment  
sensitive areas: 
allowed except corticosteroids.  Bath oils and moisturizing soaps are 
allowed.  For subjects not performing HPA axis assessments:  Any 
topical treatment allowed except potent or very potent (WHO groups 
III-IV) corticosteroids. Bath oils and moisturizing soaps are allowed.  
 
Sensitive areas refers to armpits, groin, under the breasts and in other skin folds around the 
genitals and buttocks. 
The maximum amount of topical treatment containing vitamin D analogues (calcipotriol, 
calcitriol or tacalcitol) is limited to the following including the amount of investigational 
product used: 
• 50 g ointment/gel/cream per week for subjects aged 12 to 14 years with a BSA ≤ 1.3 
m2 . 
• 75 g ointment/gel/cream per week for subjects aged 12 to 14 years with a BSA > 1.3 
m2 and subjects aged 15 to 16 years, 11 months with a BSA ≤ 1.7 m2 . 
• 100 g ointment/gel/cream per week for subjects aged 15 to 16 years, 11 months with a 
BSA > 1.7 m2. 
During the follow-up period, subjects who require a repeat ACTH-challenge test at FU2 
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. 
Otherwise, there are no restrictions on the use of concomitant treatment during the follow-up 
period. 
 


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10.7 Non-Investigational Medicinal Products 
10.7.1 CORTROSYN® (cosyntropin) for injection 
CORTROSYN® 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). 
 
CORTROSYN® will be sourced by the investigational sites. 
CORTROSYN® will be used in accordance with the U.S. Prescribing Information for the 
marketed product (see Appendix III).  
 
CORTROSYN® 
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 . 
 
10.7.1.1 Packaging and Labelling 
The marketed product, as available in the U.S. will be used for this study without any re-
labelling or re-packaging of the product. 
10.7.1.2 Storage 
 


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CORTROSYN® should be stored in a safe and secure place inaccessible for children. The 
temperature for storage should be at 15 to 30°C. The Investigator is responsible for ensuring 
that the storage of CORTROSYN® is in accordance with these conditions. Should there be 
any evidence that these conditions have not been maintained the product should be destroyed 
and spoiled stock replaced.  
10.7.1.3 Reconstitution and Administration 
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. 
 
The timing of administration of CORTROSYN® during the study is detailed in Section 
10.8.4.1. 
10.7.1.4 Precautions 
Prior to injection of CORTROSYN®, the investigator and staff must be prepared to treat any 
possible anaphylactic/allergic/hypersensitivity reaction. Severe anaphylactic reactions to 
CORTROSYN® can be minimised by discontinuing the IV injection at the earliest sign of any 
local or general reaction such as redness, urticaria, pruritus, flushing of the face, malaise or 
dyspnoea. In the rare event of a serious allergic/anaphylactic reaction, local procedures should 
be followed and IM/IV epinephrine (adrenaline), IV high dose corticosteroids, IV 
antihistamines and intravenous fluids must be readily available and immediately used as 
appropriate. Protection of the airway must also be considered and managed appropriately.  
Because of the risk of an allergic reaction, the injections should be given under medical 
supervision and the subject kept under observation for approximately one hour. If subjects 
experience an allergic reaction to CORTROSYN® they should be withdrawn from the trial. 
Repeat administration may increase the risk of hypersensitivity. Subjects should be instructed 
to inform subsequent physicians of previous use of corticotropic hormones. See the 
Prescribing Information for CORTROSYN® in Appendix III for further details. 
10.7.1.5 Drug Accountability 
The investigator is fully responsible for the CORTROSYN® at the trial site. Dispensing of 
CORTROSYN® may be delegated, e.g. to a hospital pharmacy, as locally applicable.  
 


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The person responsible for dispensing the CORTROSYN® will be responsible for maintaining 
adequate control and for documenting all transactions. All CORTROSYN® 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 CORTROSYN® dispensed for each 
subject in the trial. The batch number/lot number and expiry date of the CORTROSYN® 
dispensed will be recorded. This inventory must be available for inspection at monitoring 
visits and will be checked to ensure correct dispensing of CORTROSYN®.  
 
10.7.2 0.9% Sodium Chloride Injection, USP 
0.9% Sodium Chloride Injection, USP will be sourced by the investigational sites in the U.S. 
and reimbursed by LEO Pharma A/S. There is no requirement for a specific brand or 
manufacturer to be used. 
 
0.9% Sodium Chloride Injection, USP will be used in accordance with the product 
monograph specific to the chosen product. 
10.7.2.1 Packaging and Labelling 
The marketed product, as available in the U.S. will be used for this study without any re-
labelling or re-packaging of the product. 
10.7.2.2 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. 
10.7.2.3 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 
10.7.2.4 Drug Accountability 
The investigator is fully responsible for the 0.9% Sodium Chloride Injection, USP at the trial 
site.  
 


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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.  
10.8 Trial Procedures 
10.8.1 Schedule of Trial Procedures 
Visit 
SV1 1 
SV2 1,2
1 
2 
3 
4 
53 
FU14 
FU25 
Day 
-56 to -7 
-7 to -3 
0 
14 ± 2 
28 ± 2 
42 ± 2 
56 ± 2 
+ 14 
± 2 
+ 28 
± 2 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Height, weight and BSA 
X 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X
X 
 
 
 
 
 
 
Vital signs (blood pressure, 
heart rate)  
 
X 
 
 
X 
 
X 
 
 
Haematology/biochemistry/ 
urinalysis 6 
 
X 
 
 
X 
 
X 
X 7 
 
Pharmacokinetic blood 
sample 8 
 
 
 
 
X 
 
 
 
 
ACTH challenge test 9 
 
X 
 
 
X 
 
X 
 
X 
Instruction for 24-hour urine 
collection and dietary 
calcium intake diary 
X 
 
 
X 
 
X 
 
 
 
Review of dietary calcium 
 
X 
 
X 
 
X 
 
 
Collection of 24-hour urine 10 
 
X 
 
X 
 
X 
 
 
Urine pregnancy test 11, 12 
 
X 
 
X 
 
X 
 
 
Adverse events 
 
X
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X
X 
X 
X 
X 
X 
X 
 
Investigator’s assessment of 
extent of psoriasis (BSA) and 
extent of scalp psoriasis 
 
X 
X 
 
 
 
 
 
 
Investigator ’s global 
assessment of disease 
severity on the scalp and on 
the body 
 
X 
X 
X 
X 
X 
X 
 
 
 


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Visit 
SV1 1 
SV2 1,2
1 
2 
3 
4 
53 
FU14 
FU25 
Day 
-56 to -7 
-7 to -3 
0 
14 ± 2 
28 ± 2 
42 ± 2 
56 ± 2 
+ 14 
± 2 
+ 28 
± 2 
Patient’s global assessment 
of disease severity on the 
scalp and on the body 
 
X 
X 
X 
X 
X 
X 
 
 
Investigator’s assessment of 
the extent and severity of 
clinical signs of psoriasis 
vulgaris (for PASI) 
 
X 
X 
X 
X 
X 
X 
 
 
Patient’s assessment of 
itching and sleep 
 
X 
X 
X 
X 
X 
X 
 
 
Dispensing of IP 
 
 
X
X
X 
X 
 
 
 
Return of IP 
 
 
 
X 
X 
X 
X 
 
 
IP Compliance 
 
 
 
X 
X 
X 
X 
 
 
 
1. There should be at least 4 days between SV1 and SV2 so dietary information (diary) can be 
collected. 
2. It will be acceptable that the following assessments are done on the day prior to the ACTH 
challenge: vital signs, spot urine collection, pregnancy test, AEs, concomitant medication and 
assessments of psoriasis  
3. In case of early withdrawal prior to visit 5, the additional tests scheduled for visit 5 should be done 
at the end of treatment, with the exception of the ACTH challenge test and the 24-hour urine 
collection. 
4. Follow-up Visit 1 is only applicable for subjects who at the last on-treatment visit have ongoing 
(serious or non-serious) adverse event(s) classified as possibly/probably related/not assessable 
relationship to the investigational product and for subjects with albumin corrected serum calcium 
above reference range at the last on-treatment visit. 
5. Applicable only to subjects in the U.S. performing HPA axis assessments.  Follow-up Visit 2 is 
only applicable if serum cortisol is ≤18 mcg/dl at 30 min after the ACTH challenge test at Visit 3 
or Visit 5. 
6. Blood and spot urine samples should be collected at the end of treatment for subjects who are 
withdrawn from trial prior to Visit 5. 
7. If laboratory results suggest albumin corrected serum calcium above reference range at the last on-
treatment visit, a follow-up test will be performed. 
8. PK sample to be taken prior to the application of investigational product on the day of the visit 
9. Applicable only to subjects in the U.S. 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. It will be acceptable that the 24 hour urine sample is collected up to three days prior to the trial 
visit. 
11. For female subjects of childbearing potential. 
12. In case of early withdrawal there will be a pregnancy test if possible at their last on treatment visit. 
 


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10.8.2 Subject Eligibility 
Subject’s eligibility for the clinical trial will be checked according to the inclusion and 
exclusion criteria at visits specified in the flowchart, cf. 10.8.1. Subjects’ demographic details 
and duration of scalp psoriasis will be recorded. 
 
Concomitant medication and medical history are recorded at SV1 and changes in concomitant 
medication are recorded at all subsequent visits. 
 
Demographic Data  
Demographic data will comprise of:  
Date of birth 
Sex  
Ethnic origin 
Race  
Skin type  
 
The 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). 
 
The skin type of the subject will be recorded according to the following classification and can 
be assessed by the (sub)investigator or research nurse: 
 
Fitzpatrick Skin Type 
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 
 
 
 
 


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Height and Weight 
The subject’s weight (with indoor clothing and without shoes) will be recorded in kg and the 
height (without shoes) will be recorded in cm. 
 
Duration of psoriasis vulgaris 
The duration of psoriasis vulgaris will be recorded to the nearest whole year. 
 
Relevant Medical History, Concomitant Medication and Concurrent Diagnoses 
Relevant medical history, concomitant medication and concurrent diagnoses will be recorded. 
 
Physical Examination 
Physical examination will consist of: Routine medical examination including gross 
neurological assessment and other appropriate system.   
 
Vital Signs 
Recording of vital signs comprises: 
• Heart rate (beats per minute), supine after 5 min rest 
• Blood pressure, systolic and diastolic (mmHg), supine after 5 min rest 
 
The same arm will be used for all measurements. The arm (right or left) used for 
measurement will be recorded in the CRF.  
 
Assessment of vital signs resulting in abnormal values will be repeated in order to exclude an 
erroneous assessment. Individual results will be classified as “normal”, “abnormal with no 
clinical significance” or “abnormal with clinical significance”. 
 
Dietary calcium intake – diary instructions 
The (sub)investigator/site staff should perform a review of the subject’s normal dietary intake 
of calcium-rich nutrients – mainly milk and dairy products, but also a high intake of calcium-
fortified products. The subject will be instructed to keep a diary of the daily intake of calcium-
rich nutrients in the 4-day period prior to SV2 (3 days prior to and during the baseline 24-hour 
urinary collection).  
 


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At SV2, the number of daily servings of dairy (or calcium fortified) products defined as one 
cup (240 ml) of milk or yoghurt, 1.5 ounces (43 g) of cheese or any calcium-fortified product 
with a calcium content of 300 mg/cup will be estimated. The subject will be instructed that the 
number of daily calcium servings should not exceed five. Also the subject should keep the 
intake of calcium-rich nutrients the same three days prior to and during each subsequent 24-
hour urine collection. At the following visit, i.e. Visit 3 and Visit 5 respectively, the 
(sub)investigator/site staff should review the intake of calcium-rich nutrients with the subject. 
Based on the diary entries the (sub)investigator/site staff should estimate the number of daily 
calcium servings for each day and these will be recorded in the CRF. 
 
Instruction on 24-hour urine collection 
In addition to the instructions on dietary calcium intake, the (sub)investigator/site staff should 
instruct the subject on how to perform the 24-hour urine collection. The procedure for 
collecting a 24 hour urine sample should be for subject to pass their first urine of the day as 
normal and then to collect all urine passed in the next 24 hours which should include their 
first urine on the second morning.  
 
10.8.3 Clinical Assessment 
10.8.3.1 Investigator Assessments 
The (sub)investigator will make the clinical assessments listed below. Ideally, all assessments 
for a subject should be made by the same (sub)investigator. 
Investigator’s Global Assessment (IGA) of Disease Severity – Scalp Psoriasis and Body 
Psoriasis 
At SV2 and Visits 1 to 5, and early withdrawal (if applicable), the (sub)investigator will make 
a global assessment of the disease severity of the scalp psoriasis and body psoriasis 
(separately) by use of the 5-point scale below. 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. 
(0) Clear 
Plaque thickening = no elevation or thickening over normal skin 
Scaling = no evidence of scaling 
Erythema = none (no residual red coloration but post-inflammatory 
hyperpigmentation may be present) 
 
(1) Almost 
clear 
Plaque thickening = none or possible thickening but difficult to ascertain 
whether there is a slight elevation above normal skin level 
 


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Scaling =  none or residual surface dryness and scaling  
Erythema = light pink coloration 
 
(2) Mild 
Plaque thickening = slight but definite elevation  
Scaling = fine scales partially or mostly covering lesions  
Erythema = light red coloration 
 
(3) Moderate 
Plaque thickening = moderate elevation with rounded or sloped edges  
Scaling = most lesions at least partially covered  
Erythema = definite red coloration 
 
(4) Severe 
Plaque thickening = marked or very marked elevation typically with hard 
or sharp edges  
Scaling = non-tenacious or thick tenacious scale, covering most or all of 
the lesions  
Erythema = very bright red coloration; extreme red coloration; or deep red 
coloration 
 
Note: IGA of the scalp should include all scalp psoriasis lesions, defined as those areas of the 
scalp where there are any signs of redness, thickness or scaliness caused by psoriasis. 
The scalp is defined by the hair line. Parts of scalp psoriasis lesions that extend outside the 
defined area of the scalp should not be included in the assessments.  
At SV2 and Visit 1 the disease severity of scalp psoriasis and the disease severity of body 
psoriasis must be graded at least as moderate in order to meet the inclusion criteria.  
 
Subjects with disease severity classified as “Clear” or “Almost clear” disease after the 
treatment period will be rated as having “Controlled disease”. 
 
Investigator’s Assessment of the Extent of Psoriasis Vulgaris 
In order to obtain baseline data of psoriatic severity for all the subjects enrolled in the trial, 
the (sub)investigator will also assess the extent of the subject’s total psoriatic involvement at 
SV2 and Visit 1. 
 
The total psoriatic involvement (e.g., the arms, the legs, the trunk, the scalp and the face) will 
be recorded as a percentage of the total BSA, estimating that the surface of the subject’s full, 
flat palm (including the five fingers) correlates to approximately 1% of the BSA. 
 


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Investigator’s Assessment of the Extent of Scalp Psoriasis 
A baseline assessment of the extent of scalp psoriasis as percentage of the total scalp area will 
be done at SV2 and Visit 1, estimating that the surface of the subject’s full, flat palm 
(including the five fingers) correlates to approximately 25% of the scalp area. 
 
Investigator’s assessment of the extent and severity of clinical signs of psoriasis vulgaris 
(Redness, Thickness, Scaliness) 
At SV2 and Visits 1 to 5 and early withdrawal (if applicable), the (sub) investigator will make 
assessments of the extent and severity of clinical signs of the subject’s psoriasis on specific 
areas of the body in terms of three clinical signs: redness, thickness and scaliness.  
 
The extent of psoriatic involvement will be recorded for each of the four areas: head*, 
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% 
 
*) head includes the neck  
**) arms include hands 
***) trunk includes flexures 
****) legs include buttocks and feet 
 
The severity of the psoriatic lesions in each of the four areas will be recorded for each of the 
signs of redness, thickness and scaliness. For each clinical sign, a single score, reflecting the 
average severity of all psoriatic lesions on the given body region, will be determined 
according to the scale below:  
 
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) 
 


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4 
= 
very severe (very dark red erythema) 
 
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 is calculated using the formula given below based on the Investigator’s assessment of 
the extent and severity of the disease locally (head, trunk, arms, legs). 
The following formula will be used to calculate the PASI: 
 
Head 
0.1 (R + T + S)E = W 
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 W+X + Y + Z gives the total PASI, which can range from 0 to 72. 
 
10.8.3.2 Subject Assessments 
The subjects will make the following clinical assessments: 
Patient’s Global Assessment of Disease Severity – Scalp Psoriasis and Body Psoriasis 
At SV2 and Visits 1 to 5, and early withdrawal (if applicable), the subject will make a global 
assessment of the disease severity of scalp psoriasis and body psoriasis (separately) by use of 
the 5-point scale below.  
 


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The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit. 
 
The qualified site staff person will explain the categories of the scale to the subject and the 
subject will tell the qualified site staff person which category to tick. This assessment must be 
made prior to the investigator’s assessments. 
Patient’s Global Assessment of Disease Severity Scale 
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 or restricts daily life very 
frequently 
 
Note: Subjects with disease severity classified as “Clear” or “Very Mild” disease after the 
treatment period will be rated as having “Controlled disease”. 
Patient’s Assessment of Itch and Sleep 
At SV2 and Visits 1 to 5 and early withdrawal (if applicable), subjects will complete the itch 
and sleep questionnaire consisting of three questions (Appendix V).  Subjects will be asked to 
rate the intensity of their itch and sleep loss during the last 24 hours by marking a line on the 
scale. 
10.8.3.3 Imaging Assessments 
Not Applicable 
10.8.4 Laboratory Assessments 
10.8.4.1 Central Analysis 
 


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Samples for analysis of the parameters listed below will be taken as scheduled in the 
flowchart (cf. 10.8.1) or at early withdrawal from the treatment period of the study. 
 
It is recommended that indwelling catheters introduced under topical anaesthesia are used for 
the repeated blood sampling, to minimise discomfort for the subject, unless the 
(sub)investigator judges that there are reasons for not doing it. 
 
A 6.5 ml sample of venous blood and a 30 ml spot urine sample will be taken at SV2, Visit 3 
and Visit 5. The 6.5 ml sample of blood will consist of 2 ml for haematology analysis, 2.5 ml 
for serum biochemistry analysis and 2 ml for analysis of plasma parathyroid hormone. The 
samples will be taken before the ACTH-challenge test that is also scheduled for these visits 
(for U.S. only). Measurement of serum cortisol concentration will be included in the 
biochemistry analysis, and this value will be the baseline serum cortisol concentration for the 
ACTH-challenge test. 
 
At Visit 3, a 12mL (2 x 6 mL) blood sample will be taken for pharmacokinetic analysis. 
 
Prior to SV2, Visit 3 and Visit 5, subjects will collect 24 hour urine. It is allowed to collect the 
24-hour urinary sample up to three days prior to the study visit. 
 
The Central Laboratory will provide the materials and instructions necessary for the collection 
and transport of the samples.   
 
The following analyses will be performed on the blood samples: 
 
Haematology 
Haemoglobin 
Haematocrit 
Red blood cell (RBC) count 
Mean corpuscular volume (MCV) 
White blood cell (WBC) count, including differential count 
Platelet count 
 
Serum/plasma Biochemistry 
Cortisol 
Urea 
Creatinine 
 


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Albumin 
Sodium 
Potassium 
Chloride 
Calcium 
Phosphate 
Parathyroid hormone (plasma)  
 
Urinalysis 
The following will be analysed quantitatively in the collected 24 hour urine: 
Calcium 
Phosphate 
Creatinine 
Volume 
 
The following analyses will be performed on the spot urine sample by dipstick test: 
Glucose 
Ketones 
 
The laboratory will also report: 
Albumin-corrected serum calcium in mmol/l using the formula: 
serum calcium (total) in mmol/l + (0.02 x [40-serum albumin in g/l]) 
 
For the 24 hour urine sample the following will be calculated: 
Total calcium excretion 
Total phosphate excretion 
Total creatinine excretion 
Calcium: creatinine ratio 
Phosphate: creatinine ratio 
 
If any laboratory results are abnormal, the (sub)investigator should follow-up the subject as 
clinically appropriate. 
 
Pharmacokinetic Analysis 
A 12 mL (2 x 6mL) blood sample for PK analysis will be collected Visit 3 prior to the 
application of investigational product on the date of the visit. 
 
 


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A blood sample (2 x 6mL) for pharmacokinetic evaluation will be drawn at Visit 3 (4 weeks 
of treatment) prior to the application of LEO 80185 on the day of the visit.  Validated 
bioanalytical assays will be used for quantification of calcipotriol, betamethasone 
dipropionate and the metabolites MC1080 and betamethasone 17-propionate in the plasma 
sample. Full details for taking, storing and shipping the samples for PK analysis will be 
provided separately.  
 
ACTH Challenge test 
The ACTH-challenge test will be performed at SV2, Visit 3 and Visit 5. If the subject 
withdraws prior to completing treatment, the ACTH-challenge test should not be performed at 
early withdrawal.   
 
If the result of the ACTH-challenge test at Visit 3 or Visit 5 shows a serum cortisol 
concentration ≤18 mcg/dl at 30 minutes after the ACTH-challenge, a further ACTH-challenge 
test is required 28 days later at visit FU2. If the results of the ACTH-challenge test at Visit 
FU2 continue to show a serum cortisol concentration ≤18mcg/dl at 30 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 after the ACTH-challenge). 
 
The following procedures should be performed prior to the ACTH-challenge tests at SV2 and 
Visit 3 and 5: Blood pressure/heart rate measurement, blood/urine sampling for central 
laboratory analysis (haematology/biochemistry/urinalysis) 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. After this, CORTROSYN® is injected, as described in Section 
10.7. Two further 2.5 ml 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 time of injection and of blood sampling will be recorded in the CRF.  
 
The following blood volumes will be drawn per subject performing HPA axis assessments:  
6 ml for Haematology;  
 


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13.5 ml for Biochemistry  
15 ml for ACTH challenge testing 
12 ml for PK analysis 
Total amount of blood drawn per subject, for central analysis: 46.5 ml 
 
The following blood volumes will be drawn per subject not performing HPA axis 
assessments:  
6 ml for Haematology;  
13.5 ml for Biochemistry  
12 ml for PK analysis 
Total amount of blood drawn per subject, for central analysis: 31.5 ml 
 
Follow-up testing: 
A 7.5 ml sample will be collected from subjects requiring additional ACTH challenge testing 
at FU2 if HPA-axis suppression is observed at Visit 3.  A 2.5 ml sample will be collected from 
subjects at FU1 if laboratory results suggest albumin corrected serum calcium above reference 
range at the last on-treatment visit. 
 
10.8.4.2 Local Analysis 
A urine pregnancy test will be performed at the trial site at SV2, Visit 3 and 5, and, if 
applicable, at FU2, in female subjects of child-bearing potential. The test kits will be provided 
by the Central Laboratory. 
10.8.5 Adverse Events 
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)).  
A Serious Adverse Event (SAE) is any untoward medical occurrence that 
• results in death 
• is life-threatening 
 


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• requires inpatient hospitalisation or prolongation of existing hospitalisation 
• results in persistent or significant disability/incapacity  
• is a congenital anomaly/birth defect 
or  
• other medically important conditions*) 
*) 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 of such events are allergic broncospasm, blood 
dyscrasias and convulsions. 
Global Pharmacovigilance, LEO Pharma A/S is responsible for the assessment of headquarter 
expectedness according to LEO Pharma A/S procedures. The relevant reference document for 
this clinical trial is Investigator’s Brochure, edition 12 and subsequent updates as agreed 
between the head of Medical Department, and the medical director, Global 
Pharmacovigilance, LEO Pharma A/S.  
At all visits, the subject will be asked a non-leading question by the investigator: “How have 
you felt since I saw you last?” No specific symptoms will be asked for. 
If there are no AEs to record, no further questions will be asked and “NO” should be stated. In 
case there are one or more AEs to record, “YES” should be stated and the investigator will 
record the event term, intensity, duration, suspected causal relationship to the investigational 
product and outcome. 
It is important that the investigator also observes the subject for any changes not reported by 
the subject and records these changes. 
Only medically qualified personnel must assess AEs. 
10.8.5.1 Reporting of Adverse Events 
Events reported by the subject or observed by the (sub)investigator and that fall into any of 
the above definitions must be recorded on the adverse event page of the CRF and should be 
described in the following manner: 
 
The nature of the event will be described 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). 
 


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For cutaneous adverse events the location must be part of the adverse event description and 
may be described as either the face, scalp or trunk/limbs. Additionally, the location will be 
described using the following terminology:  
 
• lesional/perilesional (≤2 cm from the border of lesion(s) treated with investigational 
product) or  
• distant (>2 cm from the lesion border) 
 
The intensity of the event will be described in terms of mild, moderate or severe according to 
the investigator’s clinical judgement. 
 
• Mild: The adverse event does not interfere in a significant manner with the subject’s 
normal functioning level and requires no medical intervention. 
• Moderate: The adverse event interferes with the subject’s normal functioning level and 
may or may not require medical intervention. 
• Severe: The adverse event produces significant impairment of the subject’s functioning or 
requires medical intervention. 
 
The duration of the event will be reported as the start date and stop date of the event. 
 
The causal relation of the event to the use of the investigational product will be described in 
terms of probable, possible, not related or not assessable 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 
 
Possibly related 
• Follows a reasonable temporal sequence from administration of the investigational 
product 
 


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• 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 follow a known pattern of response to the investigational product 
 
Not assessable 
• The adverse event cannot yet be judged otherwise because present information is 
insufficient or contradictory. A final assessment (i.e. probably, possibly or not related) 
shall be made as more information becomes available, at the latest when the subject has 
completed the trial. 
 
The outcome of the event will 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, however, not yet completely resolved. 
Follow-up on the event is required until final 
outcome is established. 
Not recovered/not resolved 
Event is still ongoing.  
Follow-up on the event is required until final 
outcome is established. 
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. 
Fatal 
The subject has died as a consequence of the event.  
Date of death is recorded as stop date for the 
adverse event. 
 


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Unknown 
Unknown to investigator, e.g. subject lost to follow-
up. 
 
Once a subject has completed the clinical trial, the investigator should follow up for outcome 
on all non-serious adverse events classified as possibly/probably related to the investigational 
product or not assessable for 14 ± 2 or until final outcome is determined, whichever comes 
first. 
10.8.5.2 Other Events to Be Reported 
Pregnancy 
Pregnancy which occurs during a clinical trial with an investigational product must be 
reported to LEO Pharma A/S within one calendar day of first knowledge using the Pregnancy 
Follow-up Form supplied by LEO Pharma A/S. All pregnancies must be followed up until 
delivery or termination. 
Please also confer with chapter 10.5, withdrawal criteria. 
Overdose 
Any overdose defined as any higher dose than prescribed for the individual subject must be 
reported on the adverse event form of the CRF book. AEs originating in the overdose must be 
documented on a separate line. 
Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of the initially treated 
condition compared to baseline, judged by an overall medical assessment, must be reported as 
an AE. 
10.8.6 Serious Adverse Events 
10.8.6.1 Reporting of Serious Adverse Events 
Any Serious Adverse Event (SAE), related or unrelated to the investigational product or any 
trial procedure after signature of the Informed Consent Form must be reported to LEO 
Pharma A/S on the (paper) Serious Adverse Event Form – Clinical Trial within 24 hours.  
Note:  Planned hospitalisation or planned prolonged hospitalisation do not fulfil the criteria 
for being an SAE. The elective nature of the event must be clearly documented in the 
subject’s medical record. 
 


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SAEs must be reported on the adverse event form of the CRF book. Additionally reports must 
be made using the paper Serious Adverse Event Form – Clinical Trial, supplied by LEO 
Pharma A/S. Apart from the assessment of the intensity, causal relationship to the investiga-
tional product(s) and/or trial procedures, the action taken and the outcome to date, this report 
must contain a comprehensive narrative description of the course of the event. 
The completed Serious Adverse Event Form – Clinical Trial must be faxed or scanned and e-
mailed to the following local LEO Pharma A/S affiliates: 
For sites in Australia and New Zealand: 
LEO Pharma Pty Ltd: 
Fax: +61 7 3250 1299 
email: drug.safetyau@leo-pharma.com 
For sites in Canada: 
LEO Pharma Inc.:  
Fax: +1 905 886 6639 
email: drug.safety.ca@leo-pharma.com 
For sites in France: 
LEO Pharma:  
Fax: + 33 1 30144613 
email: pharmacovigilance.fr@leo-
pharma.com 
For sites in Germany: 
LEO Pharma GmbH:  
Fax: +49 6102 201 100 
email: drug.safety.de@leo-pharma.com 
For sites in the United Kingdom: 
LEO Pharma:  
Fax: +44 1844 276385 
email: ukdrug.safety@leo-pharma.com 
For sites in the U.S.: 
LEO Pharma Inc.:  
Fax: +1 973 637 8398 
email: usdrugsafety@leo-pharma.com   
All other relevant reports of diagnostic procedures, hospital records, autopsy reports etc. must 
be included, as applicable or upon request from Global Pharmacovigilance. 
The IRB(s)/IEC(s), regulatory authorities and concerned investigators will be notified of 
SAEs according to current regulation and local requirements. 
All Suspected, Unexpected Serious Adverse Reactions (SUSARs) are subject to expedited 
reporting to regulatory authorities.  
 


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SAEs must be followed indefinitely until a final outcome has been established, i.e. the follow-
up may continue beyond the end of the clinical trial. 
10.8.7 Source Data 
Source data: All information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the recon-
struction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). (ICH E6, 1.51). 
Source documents: Original documents, data, and records (e.g., hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories and at medico-technical departments involved in the clinical 
trial). (ICH E6, 1.52). 
Source Data Verification (SDV) is a key function in assuring the sponsor that clinical trial 
information is recorded and handled in a way that allows its accurate reporting, interpretation 
and verification. Monitors will, during the conduct of the clinical trial, perform SDV to 
confirm the accuracy and completeness of CRFs by verifying selected (as specified below) 
data recorded in the CRF against data recorded in source documents to ensure such records 
are consistent.  
To enable SDV, it is essential that what constitutes source data/documents (see definition 
above) for the clinical trial data to be collected in the CRF as well as where such data can be 
found at the trial site is established and agreed with the investigator at each trial site and 
documented prior to initiation of the clinical trial.  
Source data cannot be entered directly into the CRF. 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 may be entered on a worksheet only if the clinical trial requires capture of 
data, which are normally not part of the subject’s medical record. 
For this clinical trial, the following parameters collected in the CRF should be verifiable from 
source documents available at the trial site: 
• Date of trial visits and date leaving the clinical trial 
• Relevant medical history and diagnosis 
 


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• Nature of contraception used  by the subject and result of pregnancy test(s), when 
applicable 
• Data for evaluation of eligibility criteria 
• Dispensation/administration of investigational product 
• Concomitant medication (including changes) and diagnoses 
• Subject demographics (sex, date of birth) 
• Adverse events, (nature, dates) 
In addition to the above, the following should be added to the subject’s medical record in 
chronological order, i.e. when these are allocated to the subject: 
• Date(s) of conducting the informed consent process including date of provision of subject 
information 
• Date of enrolment 
• CRF book number 
• The fact that the subject is participating in a clinical trial in psoriasis with a treatment arm 
of calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g gel for up to 8 weeks. 
After un-blinding the clinical trial, the investigators will be notified of the actual treatment 
allocation and be asked to record this in the subject’s medical record. 
10.9 Safety Evaluation 
10.9.1 Primary Response Criteria 
• 
Adverse drug reactions (ADRs) 
• 
Subjects with serum cortisol concentration of ≤18 mcg/dl at 30 minutes after ACTH-
challenge at Week 4 and at Week 8 
• 
Change in albumin-corrected serum calcium from baseline (SV2) to Week 4, Week 8, 
and end of treatment 
• 
Change in 24-hour urinary calcium excretion from baseline (SV2) to Week 4, Week 8, 
and end of treatment 
10.9.2 Secondary Response Criteria 
• 
Adverse events (AEs) 
• 
Subjects with serum cortisol concentration of ≤18 mcg/dl at both 30 and 60 minutes after 
ACTH-challenge at Week 4 and at Week 8 
 


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• 
Change in urinary calcium:creatinine ratio from baseline (SV2) to Week 4 and Week 8  
10.9.3 Evaluation of (Serious) Adverse Events 
Refer to Section 10.9.1 and 10.9.2. 
10.9.4 Evaluation of Laboratory Data 
Refer to Section 10.9.1. and 10.9.2. 
10.9.5 Evaluation of Other Observations 
• PK evaluation 
10.10 
Efficacy Evaluation 
10.10.1 
 Secondary Response Criteria 
• 
Subjects with “Controlled disease” (i.e., “Clear” or “Almost clear”) according to the 
investigator’s global assessment of disease severity on the body at end of treatment. 
• 
Percentage change in PASI from baseline to end of treatment. 
• 
Subjects with “Controlled disease” (i.e., “Clear” or “Very mild”) according to the patient’s 
global assessment of disease severity on the body at end of treatment. 
10.11 
Statistical Analysis 
10.11.1 
Subject Qualification for Analysis 
All subjects enrolled into the trial (i.e., signed informed consent obtained and a CRF number 
assigned) will be accounted for in the clinical study report. 
 
All subjects who apply any IP will be included in the full analysis set and analysed for 
efficacy. Exclusion from the full analysis set will be carefully considered for subjects who 
apply no IP or who provide no efficacy data following start of treatment. 
 
All subjects who apply any IP and for whom the presence or confirmed absence of adverse 
events is available will be included in the safety analysis set and analysed for safety, except 
the analysis of the results from the ACTH-challenge test. 
 
For the analysis of the results from the ACTH-challenge test a per protocol analysis set will be 
defined by including the subjects performing HPA axis assessments from the full analysis set, 
however excluding the subjects who do not: 
• apply any IP  
 


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• meet the inclusion criterion concerning evidence of adrenal function at baseline 
• provide any results for the ACTH-challenge test after receiving IP 
 
The decisions regarding inclusion/exclusion of subjects and/or subject data from the trial 
analysis sets will be documented in the clinical study report. 
10.11.2 
Reasons for Leaving the Trial 
The reasons for leaving the trial will be presented separately for subjects who apply any IP 
and for enrolled subjects not assigned to treatment. 
10.11.3 
Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all subjects in the safety analysis set and per protocol analysis set as these are the datasets 
used for primary response criteria. 
 
Demographics include age, sex, ethnicity, race and skin type. Other baseline characteristics 
include duration of psoriasis vulgaris, physical examination, investigator’s global assessment 
of disease severity on body, PASI (calculated from the investigator’s assessment of extent and 
severity of the clinical signs) , investigator’s assessment of extent of psoriasis (BSA and 
scalp) , patient’s global assessment of disease severity on body, concomitant medication and 
concurrent diagnoses. 
 
Age and sex will also be presented by centre. 
10.11.4 
Compliance 
Compliance with treatment instructions will be tabulated for all subjects who apply any IP. 
The number and percentage of subjects who comply and who do not comply with the trial 
treatment regimen will be summarised. The extent of non-compliance as categories of the 
percentage of applications missed (e.g. ≤ 10%, > 10 to 20%, etc.) will also be presented. 
10.11.5 
Analysis of Safety 
The analysis of safety will be based on the safety analysis set according to the defined 
response criteria, except the analysis of the results from the ACTH-challenge test which will 
be based on the per protocol analysis set. 
10.11.5.1 Adverse Events 
 


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Adverse events will be coded in accordance with the current version of the MedDRA 
dictionary. 
 
All adverse events 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 it started after the 
first application of the investigational product or if it started before this and increased in 
intensity after the first application of investigational product. The tabulations described below 
will only include the events that are emergent with the trial treatment. 
 
The number of subjects experiencing each type of adverse event (according to MedDRA 
Preferred Terms within Primary System Organ Class) will be tabulated regardless of the 
number of times each adverse event is reported by each subject.  
 
An overview summary of the number of subjects with any adverse events, adverse drug 
reactions, lesional/perilesional adverse events, serious adverse events and adverse events 
leading to withdrawal from the trial will be produced. 
 
The causal relationship to IP for each type of adverse event (according to the Preferred Term) 
will be tabulated. Where there are several recordings of causal relationship to IP for a given 
type of adverse event, causal relationship will be taken as the most-related recording from the 
last report of that adverse event, since that is when the investigator will be in possession of 
most information and so best able to judge causal relationship.  
 
The intensity for each type of adverse event (according to the Preferred Term) will be 
presented. Where there are several recordings of intensity for a given type of adverse event 
the most severe intensity will be selected.  
 
Adverse drug reactions are defined as adverse events for which the investigator has not 
described the causal relationship to IP as “not related”. The number of subjects experiencing 
each type of adverse drug reaction (according to the Preferred Term) will be tabulated. The 
intensity for each type of adverse drug reaction will be presented.  
 
The number of subjects experiencing each type of lesional/perilesional adverse event, 
lesional/perilesional adverse event on the body and lesional/perilesional adverse event on the 
scalp (according to the Preferred Term) will be tabulated. 
 
 


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Serious adverse events and adverse events leading to withdrawal from the trial will be 
evaluated separately, and a narrative for each will be given. 
10.11.5.2 ACTH-Challenge Test 
The following percentages will be calculated: 
• Percentage of subjects with a serum cortisol concentration ≤18 mcg/dl at 30 minutes 
after ACTH-challenge at Week 4 and at Week 8. 
• Percentage of subjects with a serum cortisol concentration ≤18 mcg/dl at both 30 and 
60 minutes after ACTH-challenge at Week 4 and at Week 8. 
 
The serum cortisol concentration at time 0 (just before the ACTH challenge) and at 30 and 60 
minutes after ACTH-challenge at baseline (SV2), Week 4 and Week 8, respectively, will be 
summarised for the per protocol analysis set. 
 
The serum cortisol concentration at time 0 (just before the ACTH challenge) and at 30 and 60 
minutes after ACTH-challenge and also the change in serum cortisol from time 0 to 30 
minutes and 60 minutes recorded at baseline (SV2), Week 4, Week 8 and FU2 respectively, 
will be listed for each subject with a value ≤18 mcg/dl at either 30 or 60 minutes after ACTH-
challenge for the per protocol analysis set. Values ≤ 18 mcg/dl at 30 or 60 minutes after 
ACTH-challenge will be flagged. 
10.11.5.3 Exposure 
The duration of exposure (weeks) and extent of exposure (subject-treatment-weeks) to IP will 
be summarised. 
10.11.5.4 Drug Accountability 
The amount of IP used (g) and the average weekly amount of IP used (g) will be summarized 
for three different treatment periods (first four weeks, second four weeks and the total 
treatment period). 
10.11.5.5 Laboratory Examinations 
For the haematology, biochemistry and urinalysis parameters except the urinary glucose and 
ketones, the absolute value by visit and the change from baseline (SV2) to Week 4 and Week 
8 will be summarised. In addition, the values will be categorised as “low”, “normal” or “high” 
depending on whether they are below, within or above the laboratory reference range, 
respectively. Shift tables will be produced showing the categories at baseline (SV2) against 
those at Week 4 and Week 8. 
 
 


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For the urinary calcium:creatinine ratio, the 95% confidence interval of mean change from 
baseline to Week 4 and Week 8 will also be presented. 
 
For the albumin-corrected serum calcium and 24-hour urinary calcium excretion, the end of 
treatment values and the change from baseline to end of treatment will also be summarised 
and the 95% confidence interval of mean change from baseline to Week 4 and Week 8 and 
end of treatment will be presented. For these two parameters the end of treatment category 
will also be included in the shift tables. 
 
The albumin-corrected serum calcium and 24-hour urinary calcium will be listed by visit for 
all subjects with any of these values out of reference range at any visit. Values outside the 
reference range will be flagged. 
 
For the urinary glucose and ketones, the values will be categorised by visit as absent or 
present. Shift tables will be produced showing the presence/absence at baseline (SV2) against 
presence/absence at Week 4 and Week 8. 
 
The 24-hour urinary calcium excretion will be presented also for the subjects with complete 
urinary collection. A 24-hour urinary collection is considered incomplete if it is either 
reported to be incomplete by the subject or if the creatinine excretion is below 0.1 mmol per 
kg body weight as proposed by Remer et al (32). 
10.11.5.6 Other Observations 
PK evaluation 
The plasma concentrations above the lower limit of quantification will be presented. 
Vital signs 
For systolic and diastolic blood pressure and heart rate, the absolute value by visit and change 
from baseline (SV2) to Week 4 and Week 8 will be summarised.  
 
Clinically significant abnormalities in the vital signs at baseline (SV2), Week 4 and/or Week 8 
will be presented. Any abnormalities at Week 4 and/or Week 8 that were not present at 
baseline will be highlighted. 
10.11.6 
Analysis of Efficacy 
The statistical analysis of efficacy will be based on the full analysis set according to the 
defined response criteria. 
 


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The percentage of subjects who achieve “Controlled disease” according to the investigator’s 
global assessment of disease severity on the body will be presented by visit and at end of 
treatment. The 95% confidence interval (CI) which is based on a binomial distribution will be 
presented for the proportion of subjects with “Controlled disease” at end of treatment.  
 
The percentage of subjects who achieve “Controlled disease” according to the investigator’s 
global assessment of disease severity on the body at end of treatment will also be tabulated by 
age-group, sex, centre and baseline disease severity according to the investigator’s assessment 
of body psoriasis.  
 
The percentage change in PASI from baseline to each visit and to end of treatment will be 
summarised. The 95% CI for mean percentage change in PASI based on a normal distribution 
will be calculated for end of treatment. 
 
The percentage of subjects who achieve “Controlled disease” according to the patient’s global 
assessment of disease severity on the body will be presented by visit and at end of treatment. 
The 95% CI based on a binomial distribution will be calculated for the proportion of subjects 
with “Controlled disease” at end of treatment. 
 
The percentage of subjects who achieve “Controlled disease” according to the investigator’s 
global assessment of disease severity on the scalp will be presented by visit and at end of 
treatment.  
 
The percentage of subjects who achieve “Controlled disease” according to the patient’s global 
assessment of disease severity on the scalp will be presented by visit and at end of treatment.  
 
The investigator’s global assessment of disease severity on the body and on the scalp, PASI 
and patient’s global assessment of disease severity on the body and on the scalp will be 
summarised by visit and at end of treatment. 
 
Patient’s assessment of itching and sleep will be summarised by visit and at end of treatment. 
In addition, the change from baseline to each visit and end of treatment will be summarised. 
10.11.7 
General Principles 
Categorical data will be summarised using the number and percentage of subjects in each 
category. Continuous data will be summarised using the mean, standard deviation (SD), 
median, minimum and maximum values. 
 


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All confidence intervals will be two-sided and presented with 95% degree of confidence, 
unless otherwise stated.  
 
The data recorded during the course of the trial will be presented in individual data listings, 
according to ICH E3. 
 
For tabulations on changes from baseline, baseline will be defined as the last assessment 
performed before application of IP. 
 
The end of treatment value for a particular parameter will be defined as the last value 
recorded for that parameter up to and including Visit 5 (Week 8). However, for laboratory 
parameters this will be the last value recorded after baseline (SV2) up to and including Visit 5.  
 
All efficacy data will be tabulated by visit using an observed cases approach (i.e. involving 
only those subjects who attended each specific visit) except for the tabulation of end of 
treatment values.  
 
All laboratory data will be tabulated by visit using an observed cases approach except for the 
tabulation of end of treatment values which will be presented for the primary response 
criteria.  
10.12 
Trial Committees 
LEO 80185 gel has obtained marketing authorisation in 2008 and has been marketed in the 
U.S., several European countries and more than 40 other countries worldwide, including 
Canada and Australia. The clinical trial programme for LEO 80185 gel has so far included 
more than 6000 psoriasis patients, of whom more than 3000 were treated with LEO 80185 
gel. LEO 80185 gel has since launch in 2008 to December 2012, been prescribed for 
approximately 4.8 million treatment courses.  
Two non-controlled trials, MBL 0801 and MBL 0412 INT, in adolescent subjects (aged 12-
17 years) with psoriasis on the scalp have recently been completed. In a total of 
109 adolescent subjects using up to 69 g/week, LEO gel was safe and effective in the 
treatment of psoriasis vulgaris on the scalp.  The effects on calcium metabolism were 
investigated; no cases of hypercalcaemia and no clinically relevant changes in urinary calcium 
were reported. The adrenal response to ACTH challenge was assessed in a subset of 30 
patients; one patient showed a decrease in cortisol response to ACTH challenge after 4 weeks 
of treatment which was considered mild (7) (8). 
 


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In this trial, patients 12-14 years with a BSA of ≤ 1.3 m2 will receive up to 50 g/week.  
Patients 12-14 years with a BSA > 1.3 m2  and patients 15-16 years, 11 months with a BSA ≤ 
1.7 m2 will receive up to 75 g/week.  Patients 15-16 years, 11 months with a BSA > 1.7 m2 
will receive up to 100 g/week.  The maximum approved dose in adults is 100g/week. 
The use of CORTROSYN® in this trial will be entirely in keeping with the licensed conditions 
for use as described in the U.S. Prescribing Information, therefore its use in this trial is also 
not expected to reveal any new safety findings. 
It is hence not considered necessary to have a Data Monitoring Committee for this trial. 
10.13 
Quality Assurance/Audit 
LEO Pharma A/S has implemented a system of quality assurance, including all elements 
described in this protocol. Within this system company Standard Operating Procedures 
(SOPs) are implemented to ensure that clinical trials are conducted in compliance with 
regulatory requirements and Good Clinical Practice (GCP). Quality control is applied to each 
stage of data handling to ensure that data are accurate, reliable and processed correctly. 
Trial sites, facilities, laboratories and all data (including sources) and documentation must be 
available for GCP audit by LEO Pharma A/S or inspection by competent authorities. 
Any aspect of the clinical trial may be subject to audit by LEO Pharma A/S and/or inspection 
by regulatory authorities (national or foreign) or IEC/IRB. Such audits/inspections may take 
place at the sponsor’s site(s) or at any trial site including laboratories, pharmacies etc. 
The monitor will, in case of audit, announce this in advance to the (sub)investigator and be 
present at the particular trial site during the audit. 
The site staff should assist in all aspects of audit/inspection. 
10.13.1 
Trial Monitoring 
LEO Pharma A/S, as sponsor of this clinical trial, is responsible to the regulatory authorities 
for assuring the proper conduct of the clinical trial with regard to protocol adherence and 
validity of the data recorded in the CRFs. The company has therefore assigned persons to 
monitor this trial. Their duties are to serve as the principal link between (sub)investigators and 
 


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LEO Pharma A/S and advise the investigator on the collection and maintenance of accurate, 
complete, legible, well organised and easily retrievable data for the clinical trial. In addition, 
they will explain to the investigators any aspect of the (conduct of the) clinical trial, including 
interpretation of the protocol, the purpose of collecting the specified data and reporting 
responsibilities. 
In order to perform their role effectively, monitors and persons involved in quality assurance 
and inspections (see above) will need direct access to primary subject data, e.g. medical 
records, laboratory reports, appointment books etc. Because this affects the subject’s confi-
dentiality, this fact is included on the Subject Information Sheet and Informed Consent Form. 
This clinical trial is organised by LEO Pharma A/S and all enquiries should be made to a 
member of LEO Pharma A/S staff (see section [6.3], LEO Pharma A/S Personnel).  
10.14 
Case Report Form Books and Data Handling 
10.14.1 
Case Report Forms (CRFs) 
In this clinical trial data will be collected by means of Remote Data Capture (RDC). The 
investigator or staff authorised by the investigator will enter subject data into electronic CRFs 
designed by LEO Pharma A/S. A uniquely numbered CRF book will be used for each subject 
enrolled. Data recorded in the electronic CRFs will be accessible to site staff through a secure 
internet connection immediately after entry. The CRFs must be maintained in an up-to-date 
condition at all times by the investigator.  
The investigator, or sub-investigator(s) authorised by the investigator, will electronically sign 
all sections of CRFs used. This signature information (incl. date of signature) will be kept in 
the audit trail and cannot be altered. Only medically qualified (sub)investigators can sign data 
on clinical assessments/safety. Any correction(s) made by the investigator or authorised site 
staff to the CRF after original entry will be documented in the audit trail. Changes to data 
already approved, requires the re-signature of the investigator or authorised staff. The person 
making the change and the date, time and reason for the change will be identified in the audit 
trail.  
The trial monitor will check the CRFs for accuracy and completeness and perform source data 
verification preferably no later than eight weeks after each subject visit. For archiving 
purposes each investigator will be supplied with a copy of the CRFs, for all subjects enrolled 
 


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at the trial site, via an electronic medium at completion of the trial. Audit trail information 
will be included. CRFs will be available for inspection by authorised representatives from 
LEO Pharma A/S (e.g. audit by the quality assurance department), from regulatory authorities 
and/or IEC/IRBs. 
10.14.2 
Data Handling 
Subject data should be entered into the electronic CRF in a timely manner by authorised site 
staff. Data will be entered by site staff and systematic data validation will be performed 
through the discrepancy management system within the data collection software. Queries for 
discrepant data may be generated automatically by the system upon entry or generated 
manually by the monitor or the study 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.  
10.15 
Protocol Amendments 
Neither the investigator(s) nor LEO Pharma A/S will change the Clinical Study Protocol 
without written agreement between LEO Pharma A/S and the international co-ordinating 
investigator. Any modification considered substantial requires approval/favourable opinion by 
the appropriate regulatory authority and IEC/IRB. 
Protocol amendments are issued as Consolidated Clinical Study Protocols comprising all 
current amendments. Consolidated Clinical Study Protocols become effective when written 
approval has been provided by the international co-ordinating investigator, the head of 
Medical Department and the head of Biostatistics and Data Management, LEO Pharma A/S, 
and approval/favourable opinion from regulatory authorities and/or IEC/IRB has been 
obtained, as required. 
Alternatively, a protocol addendum may be issued to comply with national/regional specific 
requirements. A protocol addendum becomes effective when written approval has been 
provided by the international co-ordinating investigator, the head of Medical Department and 
the head of Biostatistics and Data Management, LEO Pharma A/S, and the and 
approval/favourable opinion from the relevant regulatory authorities and/or IEC/IRB has been 
obtained, as required. 
10.16 
Completion of Trial 
10.16.1 
Trial Completion Procedures 
 


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End of trial should be defined. In most cases this will be the date of the last subject’s last visit 
in each participating country and overall (all countries).  
Investigators will be informed when subject recruitment is to cease. 
Trial enrolment will be stopped at a trial site when the total requested number of subjects for 
the clinical trial has been obtained, irrespective of the specific site’s planned inclusion 
number. 
Upon completion of the clinical trial, LEO Pharma A/S will undertake arrangements for 
collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. 
LEO Pharma A/S may stop the clinical trial prematurely after consultation with the interna-
tional co-ordinating investigator, e.g. if the subject recruitment is so slow that the clinical trial 
cannot be completed within a reasonable time frame. Such premature termination/suspension 
of the trial will be notified to regulatory authorities and IECs/IRBs, as required. 
10.16.2 
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. 
10.16.3 
Archiving of Trial Documents 
The investigator at each trial site must make arrangements to store the essential trial docu-
ments, (as defined in Essential Documents for the Conduct of a Clinical Trial (ICH E6, 
Guideline for Good Clinical Practice)) including the Investigator Trial File, until LEO Pharma 
A/S informs the investigator that the documents are no longer to be retained. 
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 completion of the trial (e.g. in 
case of inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents, even if the 
investigator, for example, leaves the clinic/practice or retires before the end of the required 
storage period. 
At present according to ICH Guideline: 
 


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Essential documents should be retained until at least 2 years after last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period however if required by the applicable regulatory 
requirements or by an agreement with the Sponsor. It is the responsibility of the Sponsor to 
inform the investiga-tor/institution as to when these documents no longer need to be 
retained. (ICH E6, 4.9.5) 
11 Use of information 
This Clinical Study Protocol as well as all other information, data and results relating to this 
clinical trial and/or to the investigational product(s) is confidential information of LEO 
Pharma A/S and shall not be used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma A/S may use any and all information, data and 
results from this clinical trial in connection with the development of the investigational 
product(s) and, therefore, may disclose and/or transfer information, data and/or results to 
other investigators, regulatory authorities and/or commercial partners. 
12 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. 
This clinical trial is a multi-centre clinical trial, 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 Pharma A/S and the 
members of a writing committee, which shall be appointed by LEO Pharma A/S. 
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 has been received, defined as data 
base 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. 
 


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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 Pharma A/S a copy of 
all such manuscripts, and LEO Pharma A/S shall have rights to review and comment. Upon 
the request of LEO Pharma A/S 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 Pharma A/S, delay the publica-
tion or presentation to allow LEO Pharma A/S to protect its inventions and other intellectual 
property rights described in any such manuscripts. In case the first multi-centre publication is 
still on-going and has not been made public at the time of notification, LEO Pharma A/S 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 Pharma A/S also subscribes to the joint position of the innovative pharmaceutical 
industry (41) for public disclosure of clinical trial results in a free, publicly accessible 
database, irregardless of outcome. 
13 References 
1. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM.  Psoriasis causes as 
much disability as other major medical diseases.  J Am Acad Dermatol 1999; 41: 401-7. 
2. Gelfand JM, Feldman SR, Stern RS, Thomas J, Rolstad T, Margolis DJ. Determinants of 
quality of life in patients with psoriasis: a study from the US population. J Am Acad 
Dermatol 2004; 51 (5): 704-8. 
3. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica 
1974; 148: 1-18. 
4. Benoit S, Hamm H. Childhood psoriasis. Clin Dermatol 2007; 25(6): 555-562. 
5. Bernard JD. Clinical differences in juvenile vs adult-onset psoriasis. Br J Dermatol 1996; 
135(3): 501-502. 
6. Koo J. Vitamin D and Scalp Psoriasis. Cutis. 2002;70(5):21-24. 
7. Effect of Calcipotriol plus Betamethasone Dipropionate Topical Suspension on the HPA 
Axis and Calcium Metabolism in Adolescent Subjects (Aged 12 to 17 Years) with Scalp 
Psoriasis. Ballerup, Denmark: LEO Pharma, Clinical Development; 2013 Jan 25. 
MBL0801. 
8. Safety and Efficacy of Calcipotriol plus Betamethasone Dipropionate Gel in Adolescent 
Subjects (Aged 12 to 17 Years) with Scalp Psoriasis. Ballerup, Denmark: LEO Pharma, 
Clinical Development; 2013 Mar 2013. MBL0412 INT. 
 


LP0076-1017  
17-Apr-2013 
Page 93 of 123
 
 
 
9. Levin C, Maibach HI. Topical corticosteroid-induced adrenocortical insufficiency. Am J 
Clin Dermatol. 2002;3:141-7. 
10. Greaves MW, Weinstein GD. Treatment of psoriasis. N Engl J Med 1995; 332: 581-8. 
11. Christophers E, Schubert C. Psoriasis. In: Thody AJ, Friedmann PS, editors. Scientific 
basis of dermatology, a physiological approach. London: Churchill Livingstone; 1986. p. 
151-74. 
12. Bos JD. The pathomechanisms of psoriasis; the skin immune system and cyclosporin. Br 
J Dermatol 1988; 118: 141-55. 
13. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 
2007; 445: 866-73. 
14. Menter A, Gottlieb A, Feldman SR, van Voorhees AS, Leonardi CL, Gordon KB et al. 
 Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 1. 
 Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. 
15.  Mrowietz U, Reich K. Psoriasis – New insights to pathogenesis and treatment. Dtsch 
 Arztebl Int 2009; 106 (1-2): 11-19. 
16. Gawkrodger DJ on behalf of the Therapy Guidelines and Audit Subcommittee of the 
British Association of Dermatologists. Current management of psoriasis. J Derm Treat 
1997; 8: 27-55. 
17. Chuang T, Samson C. Clinical efficacy and safety of augmented betamethasone dipropi-
onate ointment and difloresone diacetate ointment for psoriasis, a multicentre, random-
ised, double-blind study. J Dermatol Treat 1991; 2: 63-6.  
18. Roberts DT. Comparison of fluticasone propionate ointment, 0.005%, and 
bethamethasone-17,21-dipropionate ointment, 0.05%, in the treatment of psoriasis. Cutis 
1996; 57(2 Suppl): 27-31. 
19. Shupack JL, Jondreau L, Kenny C, Stiller MJ. Diflorasone diacetate ointment 0.05% 
versus betamethasone dipropionate ointment 0.05% in moderate-severe plaque-type pso-
riasis. Dermatology 1993; 186(2): 129-32. 
20.  Farber EM, Nall L. Childhood psoriasis. Cutis. 1999;64:309-14. 
21.  Rogers M. Childhood psoriasis. Curr Opin Pediatr. 2002;14:404-9. 
22.  Leman J, Burden D. Psoriasis in children. A guide to its diagnosis and management. 
Paediatr Drugs. 2001;3:673-80. 
23. Morris A, Rogers M, Fischer G, Williams K. Childhood psoriasis: A clinical review of 
1262 cases. Pediatr Dermatol. 2001;18:188-98. 
24. Garzon MC. Diagnosis and management of psoriasis and pityriasis lichenoides in 
children. Dermatol Therapy. 1997;2:29-40. 
25. Drake LA, Ceilley RI, Cornelison RL, Dobes WA, Dorner W, Goltz RW, et al. Guidelines 
of care for psoriasis. J Am Acad Dermatol. 1993;28:632-7. 
 


LP0076-1017  
17-Apr-2013 
Page 94 of 123
 
 
 
26. Forest MG. Adrenal function tests. In: Ranke MB (ed):  Diagnostics of endocrine function 
in children and adolescents.  Basel, Karger, 2003, 372-426. 
27. Grinspoon SK, Biller BMK.  Clinical Review 62.  Laboratory assessment of adrenal 
insufficiency.  J Clin Endocrin Metabolism 1994; 79: 923-31. 
28. Clinical Study Report. Effect of DAIVOBET/DOVOBET Gel on the HPA Axis and 
Calcium Metabolism in Patients with Extensive Scalp Psoriasis. Ballerup, Denmark: LEO 
Pharma, Clinical Development; 2007 MAR 23. MBL 0404 FR. 
29. Bourke JF, Berth-Jones J, Iqbal SJ, Hutchinson PE. High-dose topical calcipotriol in the 
treatment of extensive psoriasis vulgaris. Br J Dermatol 1993; 129(1): 74-6.  
30. Oranje AP, Marcoux D, Svensson A, Prendiville J, Krafchik B, Toole J et al. Topical 
calcipotriol in childhood psoriasis. J Am Acad Dermatol 1997; 36(2 Pt 1):203-208. 
31. Darley CR, Cunliffe WJ, Green CM, Hutchinson PE, Klaber MR, Downes N. Safety and 
efficacy of calcipotriol ointment (Dovonex®) in treating children with psoriasis vulgaris. 
Br J Dermatol 1996; 135(3):390-393. 
32. Remer T, Neubert A, Maser-Gluth C. Anthropometry-based reference values for 24-h 
urinary creatinine excretion during growth and their use in endocrine and nutritional 
research1-3. Am J Clin Nutr 2002,75:561-9 
33. Matkovic V, Ilich JZ, Andon MB, Hsieh LL, Tzagoumis MA, Lugger B, et al. Urinary 
calcium, sodium and bone mass of young females. Am J Clin Nutr 1995; 62: 417-25. 
34. Dietary Reference Intakes for Calcium, Phosphorus, Magnesiun, Vitamin D, and Fluoride 
(1997). Institute of Medicine (IOM). The National Academies Press: 81-2 
35. Zemel MB, Donnelly JE, Smith BK, Sullivan DK, Richards J, Morgan-Hanusa D et al. 
Effects of dairy intake on weight maintenance. Nutrition & Metabolism 2008, 5:28 
36. Pacifici R, Vered I, McMurtry C, Smith S, Muckerman J, Delebar C, et al.  Effect of Ca 
and vitamin D supplementation on urinary calcium excretion in an adult female popula-
tion.  J Am Coll Nutr 1987; 6: 430 (Abstr 35). 
37. Kragballe K, Hoffmann V, Tan J, Ortonne JP. Calcipotriene plus betamethasone 
dipropionate gel compared to calcipotriene solution in patients with scalp psoriasis. J Am 
Acad Dermatol 2008; 58(2, Suppl. 2): AB131. 
38. Jemec GBE, Ganslandt C, Ortonne JP, Poulin Y, Burden AD, de Unamuno P, et al. A new 
scalp formulation of calcipotriene plus betamethasone compared with its active 
ingredients and the vehicle in the treatment of scalp psoriasis. J Am Acad Dermatol 2008; 
59(3): 455-63. 
39. De Angelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. 
JAMA 2004; 292(11):1363-4. 
 


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40. De Angelis CD. Is this clinical trial fully registered? A statement from the International 
Committee of Medical Journal Editors, available from: 
http://www.icmje.org/clin_trialup.htm. 
41. Joint Position on the Disclosure of Clinical Trial Registries and Databases, available from: 
http://www.ifpma.org/Documents/NR10990/Revised_Joint_Industry_Position_26Nov08.p
df. 
14 List of Appendices 
Appendix I: 
English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix II: Declaration of Helsinki last amended Seoul 2008 
Appendix III: U.S. Prescribing Information for CORTROSYN® (cosyntronin) for injection  
Appendix IV:  WHO Classification of Corticosteroids 
Appendix V: Itch and Sleep Questionnaire 
 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 96 of 123
 
 
 
Appendix I 
English translation of the Danish Data Protection Agency’s terms and conditions for the 
processing of clinical trial data by medical companies 
 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 97 of 123
 
 
 
English translation of the Danish Data Protection Agency’s terms and conditions for the 
processing of clinical trial data by medical companies1 
Listed below please find an English version of the general terms and conditions, set by the 
Danish Data Protection Agency, in cases involving authorisation for the processing of 
sensitive data by medical companies conducting continuous clinical trials of medical 
products. Circumstances may warrant some variation in the terms and conditions in concrete 
cases. 
AUTHORISATION to process personal data 
The Data Protection Agency hereby grants authorisation for processing of personal data for 
the purpose of the Company's continuous clinical trials, cf. section 50(1)(i) of the Danish Act 
on Processing of Personal Data. In this connection, the Data Protection Agency lays down the 
following terms: 
General terms 
Period of validity: The authorisation is valid until further notice. 
1. LEO Pharma A/S - hereinafter called the "Company" is responsible for compliance 
with these present terms.  
2. The data may be used for the sole purpose of performing clinical trials. 
3. The Company shall once a year to the Data Protection Agency submit an overview of 
new, commenced trials as well as a corresponding overview of which trials have been 
completed in the past year. The overview shall contain as a minimum a title of the trial 
and name and address of the clinically responsible investigator. 
4. Processing of personal data must be performed only by the controller or at the instance 
of the controller and at his responsibility. It is the responsibility of the controller that 
compliance of the terms is always observed when data are processed. 
5. Any person processing personal data must be cognizant of these present terms. 
6. The terms must be complied with also where processing is made by a data processor.  
                                                 
1  Source: Letter dated 07-Mar-2003 from the Danish Data Protection Agency (Datatilsynet) 
to the Danish Association of Pharmaceutical Industries (LIF) 
 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 98 of 123
 
 
 
7. Facilities used for storage and processing of the data must be organized and fitted up in 
order to prevent unauthorized access. 
8. Data processing must be organized in such a manner that data are protected against 
accidental or unlawful destruction, loss or impairment. Furthermore, the necessary con-
trol should be exercised to ensure that no inaccurate or misleading data are processed. 
Inaccurate or misleading data or data processed in contravention of the above Act or of 
these terms shall be rectified or erased. 
9. Data must not be kept in a form that makes it possible to identify the data subject for a 
longer period than is necessary for the implementation of the project.  
10. If results from the clinical trial are published this must be done so that it is impossible 
to identify individual persons. 
11. It is a condition that compliance is made with related terms, if any, laid down in ac-
cordance with other legislation. 
Electronic data 
12. Identification data must be encrypted or replaced by a code number or the like. 
Alternatively, all data can be stored encrypted. Encryption keys, code keys etc. must be 
stored securely and separate from the personal data. 
13. Access to project data can be obtained only through the use of a confidential password. 
A password must be replaced at least once a year and when conditions dictate it. 
14. If personal data are transferred over the Internet or other external network, the neces-
sary security measures must be taken to ensure that the data do not come to the 
knowledge of any unauthorized third parties. As a minimum, the data must be encrypt-
ed during transmission. Transmission of sensitive personal data requires strong encryp-
tion. When using internal networks, it must be ensured that unauthorized persons are 
unable to obtain access to the data. 
15. Removable storage media, safety copies of data etc. must be stored securely and under 
lock and so that unauthorized access is prevented. 
Manual data 
16. Manual clinical trial materials, including print-outs, failure lists and control lists etc., as 
well as other material which may directly or indirectly be linked with specific persons, 
must be stored securely under lock and so that unauthorized access is prevented. 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 99 of 123
 
 
 
Bio-bank and biological material 
17. Samples with biological material and biological material in bio-banks must be stored 
securely under lock so that unauthorized access is prevented and in such a manner that 
it is ensured that the material is not lost, impaired or accidentally or illegally destroyed. 
18. Biological material marked with civil registration number or name must be stored 
subject to special safety requirements. 
19. The Company shall lay down internal guidelines for storage of biological material 
relative to the individual trials, and guidelines for storage of biological material in bio-
banks. The guidelines shall be updated at least once a year. 
Information to be provided to the data subject (trial subject) 
20. Where the personal data are to be obtained from the trial subject (through interviews, 
questionnaires, clinical or para-clinical examination, treatment, observation etc.), de-
tailed data about the project shall be distributed/forwarded to the trial subject. The trial 
subject must be informed of the name of the controller, the purpose of the project and 
of the fact that it is voluntary to participate and that consent may be withdrawn at any 
time. Where the data are to be disclosed to be used for other scientific or statistical 
purposes, the trial subject shall be advised also of the purpose of the disclosure and 
identity of recipients, if applicable.  
The data subject should furthermore be advised that the project is notified to the Data 
Protection Agency in accordance with Act on Processing of Personal Data, and that the 
Agency has laid down specific terms to be complied with for the project for the pur-
pose of protecting the data subject's privacy. 
Disclosure of data 
21. Disclosure of data identifying individuals to a third party may take place for other 
statistical or scientific purposes only. 
22. Disclosure may be made only subject to prior approval of the Data Protection Agency. 
The Data Protection Agency may lay down new terms for the disclosure as well as the 
recipient’s data processing. 
Disclosure of data may, however, take place in accordance with the below-mentioned 
authorisation to disclose data. 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 100 of 123
 
 
 
Right of access to personal data 
23. The subject of the trial i.e. the data subject has no right of access to the data being 
processed concerning himself, cf. Section 32(4) of the Act on Processing of Personal 
Data. This Act does not prevent the grant of access.  
Processing by a data processor 
24. The Data Protection Agency’s conditions shall apply also to processing by a data pro-
cessor. 
25. When data are processed by a data processor, a written agreement shall be made be-
tween the controller and the data processor. The agreement shall stipulate that the data 
processor acts on behalf of the controller only and that the data must not be used for the 
data processor’s own purposes. The controller shall furthermore request sufficient data 
from the data processor to ensure that the Data Protection Agency’s terms can and will 
be complied with. 
26. Where the data processor is established in another Member State it shall, furthermore, 
appear from the agreement that such other regulations on safety measures with regard 
to data processors that may be in force in the Member State in question, shall apply 
also to the data processor in question. 
Erasure of data  
27. Data in the individual trials shall be erased, made anonymous or destroyed no later than 
at the expiry of the storage period stipulated by the GCP-rules.  It must not subsequent-
ly be possible to identify individuals participating in the trial. 
28. Alternatively, the data may be transferred for further storage in archive in accordance 
with the rules of the archive legislation  
29. Erasure of data from electronic media shall take place in such a manner that it is im-
possible to recover the data. 
Transfer of data to third countries 
30. Transfer of data to third countries, including for the purpose of processing by a data 
processor, requires the Data Protection Agency’s prior approval.  
Transfer may take place in accordance with the below-mentioned transfer 
authorisation. 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 101 of 123
 
 
 
31. Transfer may, however, take place without approval of the Data Protection Agency if 
the data subject has given his explicit consent. The data subject can withdraw his con-
sent. 
32. Transfer of data shall take place by courier or registered mail. In case of electronic 
transmission the necessary security measures shall be taken to prevent unauthorized 
access. As a minimum, the data must be safely encrypted during the entire 
transmission. Transfer of sensitive personal data requires strong encryption. 
Changes of the notified data processing  
33. The Data Protection Agency shall prior to implementation be notified of significant 
changes to the data processing (in the form of a change to an existing notification). 
Less significant changes may be notified to the Data Protection Agency subsequently, 
however not later than four (4) weeks after the implementation. 
Discontinuance of notified data processing 
34. The Company shall notify the Data Protection Agency immediately if the company 
discontin-ues carrying out the notified data processing. 
 
AUTHORISATION to disclose data 
In connection with its notification the Company has applied for authorisation to disclose data. 
The Company has applied for authorisation to disclose data to relevant national and interna-
tional health and medicines authorities in connection with an application for marketing 
authorization. 
Furthermore, the Company has applied for authorisation to disclose data concerning adverse 
events to national and international health and medicines authorities according to national and 
international law on reporting of adverse events in clinical trials. 
The Data Protection Agency hereby grants authorisation to the disclosure, cf. Section 
10(3) of Act on Processing of Personal Data. 
The authorisation in granted on the following terms: 
Period of validity: The authorisation is valid until further notice. 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 102 of 123
 
 
 
1. The relevant data may be disclosed to national and international health and medicines 
authorities in connection with an application for marketing authorization; to national 
and international health and medicines authorities according to national and interna-
tional law on reporting of adverse events in clinical trials. 
2. Only data required in the specific situation concerned may be disclosed. 
3. The data may be disclosed to the recipient only in a form that does not identify indi-
vidual persons. It must thus not be possible for the recipient on the basis of the received 
data alone to identify the persons related to the data. 
4. The Company shall at any time be able to verify to the Data Protection Agency which 
transfers of data have been made. 
 
AUTHORISATION to transfer personal data to third countries 
In connection with its notification the Company has applied for authorisation to transfer 
personal data to third countries. The company wishes to transfer data for the purpose of data 
processing to be carried out by named data processors in third countries. 
Furthermore, the Company wishes to transfer data to health and medicines authorities in third 
countries to comply with these countries’ law on reporting of adverse events in clinical trials 
and in connection with applications for a marketing authorization. 
According to Section 50(2) of Act on Processing of Personal Data, transfer of sensitive data to 
third countries can take place with the authorisation of the Data Protection Agency. According 
to section 50 (5), the Data Protection Agency may lay down more detailed conditions for the 
carrying out of the processing operations for reasons of protection of the privacy of the data 
subject in question. 
The Data Protection Agency hereby grants authorisation to transfer data to third 
countries, cf. Section 50(2) of Act on Processing of Personal Data. 
The authorisation is granted on the following terms: 
Period of validity: The grant is valid until further notice. 
 


English translation of the Danish Data Protection Agency’s terms and 
conditions for the processing of clinical trial data by medical companies 
Appendix I, Page 103 of 123
 
 
 
1. Data may be transferred for processing by data processors with whom the Company 
has an agreement on data processing, and to health and medicines authorities in third 
countries in order to comply with the law of these countries on reporting of adverse 
events in clinical trials and in connection with an application for marketing authoriza-
tion. 
2. When data are transferred to and from third countries the necessary safety measure-
ments must be taken to ensure that the data are not abused and to prevent unauthorized 
access. The data shall be delivered personally or sent by courier or registered post. 
Electronic transmission of data may take place only if the data are securely encrypted 
during the entire transmission. Transfer of sensitive personal data requires strong en-
cryption. 
3. Transfer of data to third countries takes place at the responsibility of the Company. The 
Company must therefore in each individual case assess whether the relevant transfer 
can take place, especially in consideration of the recipient's data safety. If it is assessed 
that the level of protection at the recipient's place is not adequate, transfer is not al-
lowed. 
4. The Company shall be able at any time to verify to the Data Protection Agency to 
which third countries data have been transferred and the purpose of this. 
The following terms furthermore apply to transfer to data processors in third countries. 
5. Processing of the data must take place only at the instance of the Company and at the 
Company's responsibility. 
6. The Company shall always be in a position to notify the Data Protection Agency of the 
data processor’s name and address. 
7. Prior to any transfer of data a written agreement shall be made with the recipient to the 
effect that the Data Protection Agency’s conditions for processing of the data in Den-
mark shall be complied with when the data processor processes the data. 
8. As responsible for the processing, the Company shall obtain information sufficient to 
ensure that the terms of the Data Protection Agency are complied with.  
9. When the data are no longer to be processed by the data processor they must be erased 
or returned to the Company. 
The terms of the Data Protection Agency are valid until further notice. The Data Protection 
Agency reserves the right to take up the terms for revisions at a later date, if required. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 104 of 123
 
 
 
Appendix II 
Declaration of Helsinki last amended Seoul 2008 
 
 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 105 of 123
 
 
 
Policy 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these princi-
ples. 
3. It is the duty of the physician to promote and safeguard the health of patients, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfilment of this duty. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 106 of 123
 
 
 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The 
health of my patient will be my first consideration," and the International Code of 
Medical Ethics declares that, "A physician shall act in the patient's best interest when 
providing medical care." 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, effective-
ness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and bur-
dens. 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influ-
ence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable interna-
tional norms and standards. No national or international ethical, legal or regulatory re-
quirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of per-
sonal information of research subjects. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 107 of 123
 
 
 
12. Medical research involving human subjects must conform to generally accepted scien-
tific principles, be based on a thorough knowledge of the scientific literature, other rel-
evant sources of information, and adequate laboratory and, as appropriate, animal ex-
perimentation. The welfare of animals used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that may 
harm the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declara-
tion have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe ar-
rangements for post-study access by study subjects to interventions identified as bene-
ficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must 
be independent of the researcher, the sponsor and any other undue influence. It must 
take into consideration the laws and regulations of the country or countries in which 
the research is to be performed as well as applicable international norms and standards 
but these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor on-
going studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol 
may be made without consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals 
with the appropriate scientific training and qualifications. Research on patients or 
healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professional 
and never the research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this pop-
ulation or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 108 of 123
 
 
 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities in-
volved in the research in comparison with foreseeable benefits to them and to other in-
dividuals or communities affected by the condition under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before recruit-
ment of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless 
they are confident that the risks involved have been adequately assessed and can be sat-
isfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive 
and beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be volun-
tary. Although it may be appropriate to consult family members or community leaders, 
no competent individual may be enrolled in a research study unless he or she freely 
agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must 
be adequately informed of the aims, methods, sources of funding, any possible 
conflicts of interest, institutional affiliations of the researcher, the anticipated benefits 
and potential risks of the study and the discomfort it may entail, and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to 
participate in the study or to withdraw consent to participate at any time without 
reprisal. Special attention should be given to the specific information needs of 
individual potential subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician 
or another ap-propriately qualified individual must then seek the potential subject's 
freely-given in-formed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 109 of 123
 
 
 
25. For medical research using identifiable human material or data, physicians must nor-
mally seek consent for the collection, analysis, storage and/or reuse. There may be situ-
ations where consent would be impossible or impractical to obtain for such research or 
would pose a threat to the validity of the research. In such situations the research may 
be done only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician 
should be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed con-
sent should be sought by an appropriately qualified individual who is completely inde-
pendent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be in-
cluded in a research study that has no likelihood of benefit for them unless it is intend-
ed to promote the health of the population represented by the potential subject, the re-
search cannot instead be performed with competent persons, and the research entails 
only minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in 
addition to the consent of the legally authorized representative. The potential subject's 
dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research population. In such circumstances the physician should seek informed consent 
from the legally authorized representative. If no such representative is available and if 
the research cannot be delayed, the study may proceed without informed consent 
provided that the specific reasons for involving subjects with a condition that renders 
them unable to give informed consent have been stated in the research protocol and the 
study has been approved by a research ethics committee. Consent to remain in the 
research should be obtained as soon as possible from the subject or a legally authorized 
repre-sentative. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 110 of 123
 
 
 
30. Authors, editors and publishers all have ethical obligations with regard to the publica-
tion of the results of research. Authors have a duty to make publicly available the re-
sults of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. They should adhere to accepted guidelines for ethical report-
ing. Negative and inconclusive as well as positive results should be published or oth-
erwise made publicly available. Sources of funding, institutional affiliations and con-
flicts of interest should be declared in the publication. Reports of research not in ac-
cordance with the principles of this Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and 
if the physician has good reason to believe that participation in the research study will 
not adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following circum-
stances: 
33. The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or  
34. Where for compelling and scientifically sound methodological reasons the use of pla-
cebo is necessary to determine the efficacy or safety of an intervention and the patients 
who receive placebo or no treatment will not be subject to any risk of serious or irre-
versible harm. Extreme care must be taken to avoid abuse of this option. 
35. At the conclusion of the study, patients entered into the study are entitled to be in-
formed about the outcome of the study and to share any benefits that result from it, for 
example, access to interventions identified as beneficial in the study or to other appro-
priate care or benefits. 
36. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient's decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
 


Declaration of Helsinki last amended Seoul 2008 
Appendix II, Page 111 of 123
 
 
 
37. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in 
the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, this intervention should be made the object of 
research, designed to evaluate its safety and efficacy. In all cases, new information 
should be recorded and, where appropriate, made publicly available. 
 
22.10.2008 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 112 of 123
 
 
 
Appendix III 
U.S. Prescribing Information for CORTROSYN® (cosyntronin) for injection 
 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 113 of 123
 
 
 
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 
effect. These are considered to be without physiological or clinical significance.  
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 114 of 123
 
 
 
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.  
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 115 of 123
 
 
 
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.  
 
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.  
 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 116 of 123
 
 
 
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, re-
act 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.  
 
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.)  
 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 117 of 123
 
 
 
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 
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 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 118 of 123
 
 
 
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 test-
ing. 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.  
 
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 
 


US Prescribing Information for CORTROSYN® (cosyntronin) for 
injection 
 
Appendix III, Page 119 of 123
 
 
 
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.  
 
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  
 
 


WHO Classification of Corticosteroids 
 
Appendix IV, Page 120 of 123
 
 
 
Appendix IV 
WHO Classification of Corticosteroids 
 
 
 
 


WHO Classification of Corticosteroids 
 
Appendix IV, Page 121 of 123
 
 
 
WHO CLASSIFICATION OF TOPICAL CORTICOSTEROIDS 
Based on the Anatomical Therapeutic Chemical (ATC) classification system 
 
Group I: weak 
Hydrocortisone 
 
Methylprednisolone 
 
Prednisolone 
  
Group II: moderately potent 
Alclometasone 
 
Clobetasone 
 
Desonide 
 
Flumetasone 
 
Fluocortin butyl 
 
Fluprednidene 
 
Hydrocortisone butyrate 
 
Triamcinolone 
 
Group III: potent 
Amcinonide 
 
Beclometasone 
 
Betamethasone 
 
Betamethasone dipropionate 
 
Budesonide 
 
Desoximetasone 
 
Diflorasone 
 
Diflucortolone 
 
Fluclorolone acetonide 
 
Fludroxycortide 
 
Fluocinolone acetonide 
 
Fluocinonide 
 
Fluocortolone 
 
Fluticasone 
 
Halometasone 
 
Mometasone 
 
Prednicarbate 
 
Ulobetasol 
 
Group IV: very potent 
Clobetasol 
 
Halcinonide 
 
 


Itch and Sleep Questionnaire 
 
Appendix V, Page 122 of 123
 
 
 
 
Appendix V 
Itch and Sleep Questionnaire 
 
 
 
 


Itch and Sleep Questionnaire 
 
Appendix V, Page 123 of 123
 
 
 
Itch and Sleep Questionnaire 
Subject CRF Number _________ 
Visit ______ 
Date ______ 
 
Please rate the intensity of your maximal itching on your scalp during the last 24 hours 
No itch___________________________________________________Worst possible 
 
 
Please rate the intensity of your maximal itching on your body (upper limbs, trunk and lower 
limbs) during the last 24 hours 
No itch___________________________________________________Worst possible 
 
 
  
Please rate your sleep loss during the last 24 hours 
No sleep loss______________________________________________Worst possible 
 
 
 


 
 
 
 
 
 
E L E C T R O NI C S I G N A T U R E S 
 
Electr o nic si g n at ure m a de wit hi n e D oc L E O by L E O P h ar m a A/ S e m pl oyees or e m pl oyees of a ny 
L E O P h ar m a A/ S affili ate l oc ate d a ny w here i n t he w orl d, are t o be c o nsi dere d t o be le g ally bi n di n g 
e q uiv ale nt of tr a diti o n al h a n d writte n si g n at ures. 
 
 
 
Si g ne d b y 
Me a ni n g of Si g n at ure 
Ser ver D ate 
(d d- M M M- y y y y  H H: m m ‘ G M T’ Z)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
L P 0 0 7 6- 1 0 1 7 2 0 1 3- 0 0 1 5 3 8- 1 6 Cli nic al St u d y Pr ot oc ol
1 7- A pr- 2 0 1 3 - E n glis h
Hea d of De part me nt, Me dical
A p pr o val
1 7- A pr- 2 0 1 3 1 7: 2 1 G M T + 0 2
Hea d of Bi ostatistics A p pr o val 
1 7- A pr- 2 0 1 3 1 7: 2 9 G M T + 0 2
 
P P D
P P D

SAP_000.pdf: 
 
 
 
 
Statistical Analysis Plan  
 
 
Effect of Calcipotriol plus Betamethasone Dipropionate Gel on the HPA 
Axis and Calcium Metabolism in Adolescent Subjects (Aged 12 to 16 
Years, 11 months) with Scalp and Body Psoriasis 
 
A phase 2 trial evaluating the safety and efficacy of once daily use of LEO 80185 gel 
containing calcipotriol 50 mcg/g plus betamethasone 0.5 mg/g (as dipropionate) in 
adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis 
 
An international, multi-centre, prospective, non-controlled, open, single-group, 8-week trial 
in adolescent subjects (aged 12 to 16 years, 11 months) with scalp and body psoriasis 
 
 
 
 
 
 
 
 
 
 
 
LEO Pharma A/S 
Trial ID: 
LP0076-1017 
 
Date: 
 
16-Mar-2018 
 
Version: 
1.0 
 
TMF-000048500 - Version 1.0


Trial ID: LP0076-1017 
Date: 16-Mar-2018 
Version: 1.0 
Page 2 of 27 
 
 
 
 
 
 
1 Statistical Analysis Plan Approval 
1.1 Approval Statement 
On behalf of LEO, the Biostatistics Lead and the Medical Lead, are authorised to approve the 
Statistical Analysis Plan. 
The QC statistician has by approving this document confirmed that the statistical information 
has been subject to statistical quality control. 
The following persons have approved this Statistical Analysis Plan using electronic signatures 
as presented on the last page of this document. 
 
 
Biostatistics Lead, Global Clinical Operations 
 
 
 
 
 
 
 
Medical Lead, Medical Sciences and Safety 
 
 
 
 
 
 
 
QC Statistician, Biostata Aps 
 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD


Trial ID: LP0076-1017 
Date: 16-Mar-2018 
Version: 1.0 
Page 3 of 27 
 
 
 
 
 
 
2 Statistical Analysis Plan Statements 
2.1 Compliance with Good Clinical Practice 
This Statistical Analysis Plan is designed to comply with the standards issued by the 
International Conference on Harmonisation (ICH) (E3: Structure and Content of Clinical 
Study Reports, E6: Good Clinical Practice, and E9: Statistical Principles for Clinical Trials). 
 


Trial ID: LP0076-1017 
Date: 16-Mar-2018 
Version: 1.0 
Page 4 of 27 
 
 
 
 
 
 
Table of Contents 
1 Statistical Analysis Plan Approval ......................................................................................... 2 
1.1 Approval Statement ........................................................................................................... 2 
2 Statistical Analysis Plan Statements ...................................................................................... 3 
2.1 Compliance with Good Clinical Practice .......................................................................... 3 
Table of Contents ....................................................................................................................... 4 
3 List of Abbreviations ............................................................................................................. 5 
3.1 List of Abbreviations ......................................................................................................... 5 
4 Statistical Analysis Plan Authors ........................................................................................... 5 
5 Introduction ........................................................................................................................... 5 
6 Statistical Analysis ................................................................................................................. 7 
6.1 Baseline Considerations .................................................................................................... 7 
6.1.1 
Compliance .................................................................................................................... 8 
6.2 Analysis of Efficacy .......................................................................................................... 9 
6.3 Analysis of Safety ............................................................................................................. 9 
6.4 ACTH-Challenge ............................................................................................................... 9 
6.4.1 
Exposure ...................................................................................................................... 10 
6.4.2 
Drug Accountability .................................................................................................... 10 
6.4.3 
Adverse Events ............................................................................................................ 11 
6.4.4 
Laboratory Data ........................................................................................................... 12 
6.4.5 
Other observations ....................................................................................................... 12 
6.5 General Principles ........................................................................................................... 13 
6.5.1 
Pooling of Trial Sites ................................................................................................... 13 
6.5.2 
Handling of Drop-outs and Missing Values ................................................................ 13 
6.5.4 
Treatment Labels ......................................................................................................... 15 
Appendix I ................................................................................................................................ 16 


Trial ID: LP0076-1017 
Date: 16-Mar-2018 
Version: 1.0 
Page 5 of 27 
 
 
 
 
 
 
3 List of Abbreviations 
3.1 List of Abbreviations 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
CRF 
Case Report Form 
CTR 
Clinical Trial Report 
ICH 
International Conference on Harmonisation 
IGA 
Investigator’s global assessment 
LOCF 
Last Observation Carried Forward 
LLOQ 
Lower Limit of Quantification 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PASI 
Psoriasis Area and Severity Index 
PK 
Pharmacokinetics 
SAP 
Statistical Analysis Plan 
4 Statistical Analysis Plan Authors 
, MSc, Senior Statistician, Biostatistics, LEO Pharma A/S, DK-2750, Ballerup, 
Denmark, tel: +45 
, e-mail: 
@leo-pharma.com 
, MSc, Senior Statistician, Biostatistics, LEO Pharma A/S, DK-2750, Ballerup, 
Denmark, tel: +45 
, e-mail: 
@leo-pharma.com 
, PhD, Clincal Project Manager, Trial Management, LEO Pharma A/S, DK-2750, 
Ballerup, Denmark, tel: +45 
, e-mail: 
@leo-pharma.com 
, MSc, Principal Medical Writer, Medical Communication, LEO Pharma 
A/S, DK-2750, Ballerup, Denmark, tel: +45 
, e-mail: 
@leo-pharma.com 
, MD PhD, Principal Medical Expert, Medical Department, LEO Pharma 
A/S, DK-2750, Ballerup, Denmark, tel: +45 
, e-mail: 
@leo-pharma.com 
5 Introduction 
The statistical analysis will be performed as outlined in the Consolidated Clinical Study 
Protocol. This Statistical Analysis Plan, prepared after review of the data, contains a more 
technical and detailed elaboration of some points in the statistical analysis described in the 
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protocol. Minor deviations from the planned data presentation and analysis are accounted for. 
The analysis sets which are to be used for the statistical analysis are presented in Analysis Set 
Definition Document.  
Table 1 includes protocol amendments that are relevant to the statistical reporting. The 
inclusion criteria for subjects not performed HPA and PK assessments has been updated in 
Consolidated Clinical Study Protocol, version 4.0, dated 16-Feb-2015. The extent of psoriasis 
required on the body and the severity of psoriasis required on the body and the scalp has been 
revised to better reflect psoriasis commonly seen in the adolescent population. The definition 
of ‘controlled disease’ under the secondary response criteria was updated accordingly. More 
details can be found in LP0076-1017 Summary of Amendment(s) to a Clinical Trial 
Authorisation, 02-Mar-2015 (v1.0).  
Table 1: Protocol amendments that are relevant to the statistical reporting.  
Section no in Consolidated 
Clinical Study Protocol 
version 4.0 and 6.0 
To 
From :  
10.4.1.3 (a and b, BODY)  
The inclusion criteria for subjects 
not performing HPA and PK 
assessments was updated. 
At SV2 and Visit 1, a clinical 
diagnosis of body (trunk and/or 
limbs) psoriasis which is: 
a. more than or equal to 3% of the 
body surface area (excluding 
psoriatic lesions of the face and 
sensitive areas), and 
b. of at least mild severity 
according to the investigator’s 
global assessment of disease 
severity on the body. 
At SV2 and Visit 1, a clinical 
diagnosis of scalp psoriasis which 
is: 
a. more than or equal to 10% of the 
scalp area, and 
b. of at least mild severity 
according to the investigator’s 
global assessment of disease 
severity on the scalp 
At SV2 and Visit 1, a clinical 
diagnosis of scalp and body (trunk 
and/or limbs) psoriasis which is: 
a. of an extent of 10 to 35% of the 
body surface area (excluding 
psoriatic lesions of the face and 
sensitive areas.  Sensitive areas 
include armpits, groin, under the 
breasts and in other skin folds 
around the genitals and buttocks), 
and 
b. of at least moderate severity 
according to the investigator’s 
global assessment of disease 
severity on the body. 
 


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10.4.1.3 (a and b, SCALP) 
The inclusion criteria for subjects 
not performing HPA and PK 
assessments was updated. 
At SV2 and Visit 1, a clinical 
diagnosis of scalp psoriasis which 
is: 
a. more than or equal to 10% of the 
scalp area, and 
b. of at least mild severity 
according to the investigator’s 
global assessment of disease 
severity on the scalp 
At SV2 and Visit 1, a clinical 
diagnosis of scalp psoriasis which 
is:  
a. more than or equal to 10% of 
the scalp area, and 
b. of at least moderate severity 
according to the investigator’s 
global assessment of disease 
severity on the scalp. 
10.10.1 
Revised secondary response 
criteria.  
Subjects with “Controlled disease” 
(i.e., “Clear” or “Almost clear” for 
subjects with at 
least “Moderate” disease at 
baseline, “Clear” for subjects with 
“Mild” disease at baseline) 
according to the investigator’s 
global assessment of disease 
severity on the body at 
end of treatment. 
Subjects with “Controlled disease” 
(i.e., “Clear” or “Almost clear”) 
according to the investigator’s 
global assessment of disease 
severity on the body at end of 
treatment. 
 
 
 
6 Statistical Analysis 
The statistical analysis will be carried out as described in the Consolidated Clinical Study 
Protocol with a few exceptions as described below. 
Lists of planned tables, figures and individual subject data listings for the Clinical Trial 
Report are provided in Appendix 1. 
6.1 Baseline Considerations 
According to the protocol descriptive statistics of demographics and other baseline 
characteristics will be presented for all subjects in the safety analysis set and per protocol 
analysis set as these are the datasets used for primary response criteria.  
Age and sex will be presented by country and not by centre as described in the protocol, due 
to too few number of subjects at most centres.    
The age will be presented in three categories: 


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 Overall  
 12 to 14 years 
 15 to <17 years.  
A table of serum cortisol concentrations at time 0, and at 30 and 60 min after ACTH challenge 
at baseline, although not planned in the protocol, will be produced for the per protocol 
analysis set. 
Any abnormalities recorded during physical examination will be included in concurrent 
diagnoses table.  
The baseline is defined as last assessment performed prior the first application of IMP.  
6.1.1 Compliance 
As described in the protocol, compliance with treatment instructions will be tabulated for all 
subjects who applied any IMP. Compliance with treatment instructions will be presented for 
all subjects in the safety analysis set and per protocol analysis set. Compliance is defined by 
number of missed days due to other reasons than cleared psoriasis in relation to treatment 
period. Treatment period is defined as the number of days from the treatment assignment at 
Visit 1 to either trial completion or early withdrawal.  
The number and percentage of subjects who either did or did not comply with the trial 
treatment regimen will be summarized. The extent of non-compliance as categories of the 
percentage of applications missed will also be presented: 
 No 
 Yes: <=10% applications missed    
 Yes: >10% to <=20% applications missed 
 Yes: >20% to <=30% applications missed 
 Yes: >30% to <=40% applications missed 
 Yes: >40% to <=50% applications missed 
 Yes: >50% applications missed 
 Total 


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6.2 Analysis of Efficacy 
The statistical analysis of efficacy will be based on the full analysis set according to the 
defined response criteria in the protocol.  
‘Controlled disease’ will be presented in a table by age group, the categories to be used are the 
same as defined in section 6.1. 
Additional tables, not planned in the protocol, will be produced: 
 Controlled disease (IGA on the body) at end of treatment by race 
 Controlled disease (IGA on the body) at end of treatment by baseline total extent of 
psoriasis 
Baseline for the efficacy is defined as last observation collected prior the first application of 
IMP, and is defined as Visit 1 for all assessments.  
6.3 Analysis of Safety 
The analysis of safety will be based on the safety analysis set according to the defined 
response criteria in the protocol, with the exception of the ACTH-challenge test which will be 
based on the per protocol analysis set. 
Baseline for the safety analysis is defined as last observation collected prior the first 
application of IMP, which is Screening Visit 2.  
6.4 ACTH-Challenge 
The results from the ACTH-challenge will be presented as described in the protocol for the 
per protocol analysis set. 
According to the ACTH-challenge procedure described in the protocol, samples of venous 
blood were to drawn exactly 30 min and 60 min after the CORTROSYN®/SYNACTHIEN® 
injection, however a time deviation of +/- 10 minutes is considered acceptable as the overall 
value of the test is to observe substantial increases in cortisol levels and identify adrenal 
insufficiency up to 1 hour after the initial injection, therefore the exact timing of the 
incremental  time points (30 and 60 minutes) is of less importance. Samples outside the 
acceptable deviation will not be included in the analysis. No measurements outside the 
acceptable deviation were observed.  


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6.4.1 Exposure 
As described in the protocol, the duration of exposure (weeks) and extent of exposure 
(subject-treatment-weeks) to LEO 80185 will be summarized for the safety analysis set. 
6.4.2 Drug Accountability 
The amount of IMP used in grams and the average weekly amount used in grams will be 
tabulated for the safety analysis set, and separately for three different treatment periods (first 
four weeks, second four weeks, and the total treatment period).  
The average weekly amount of IMP used, during the total treatment period, in defined usage 
categories, will be tabulated; this table was not planned in the protocol: 
 <20 g/week 
 20 to <40 g/week 
 >=60 g/week 
 Total 
The mean weight of full bottles, including label of IMP, is presented in Table 1 for each batch 
and kit number. Also the label type is given.  
Table 2: Mean weight of full bottles of IMP by batch number and kit number 
Batch number 
Kit number 
Weight of a full bottle + 
label (g) 
Label Type 
131537101 
0001 - 3200 
86.8 g 
Booklet 
P14090 
3201 - 4757 
86.9 g 
Booklet 
P14090 
4758 - 5600 
86.6 g 
Single panel 
P14090  
5797-5955 
87.0 g 
Single panel 
 
For each treatment period the following rules for calculating amount of IMP used will apply. 
For each subject the weight of IMP used for a particular treatment period will be determined 
by calculating the difference between the weight of a set of full bottles dispensed and the 
weight of the returned bottles. 
If any subjects received bottles for a particular treatment period but did not return them all, 
then the amount of IMP used for that treatment period will not be calculated. If any bottles are 


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not dispensed, they will not contribute to the weight of IMP used for that treatment period. If 
any bottles are returned with their seal unbroken, the weight of IMP used from that bottle will 
be assigned a value of zero. If a returned bottle weighs more than the estimated mean weight 
of a full bottle, it will be assumed that zero grams were used. 
The average weekly amount of IMP used will be calculated for each subject as the amount of 
IMP used for a particular treatment period, divided by the duration (days) of the treatment 
period and then multiplied by 7. 
6.4.3 Adverse Events 
The AEs will be presented for the safety analysis set as described in the protocol. 
The AEs are coded in accordance with the MedDRA dictionary version 15.1. 
The number of events will be presented in all adverse events tables where number of subjects 
is presented.  
One subject had a serious adverse event and one subject was withdrawn early from the trial 
due to an adverse event, therefore serious adverse events and adverse events leading to 
withdrawal will not be tabulated, but will be evaluated separately in the report.   
Additional tables, not planned in the protocol will be produced: 
 Adverse events by age group, MedDRA, primary system organ class and preferred 
term 
 Adverse events by sex, MedDRA primary system organ class and preferred term 
 Adverse events by race, MedDRA primary system organ class and preferred term 
 Adverse events by baseline IGA on the body, MedDRA primary system organ class 
and preferred term 
 Adverse events by baseline total extent of psoriasis,  MedDRA primary system organ 
class and preferred term 
 Adverse events by IMP usage (<40 g/week, ≥40 g/week), MedDRA primary system 
organ class and preferred term.  
Adverse events will be presented separately for subjects using at least 40 g per week of IMP 
during the total treatment period and for those using less than 40 g per week of IMP during 
the total treatment period. 
 


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6.4.4 Laboratory Data 
The laboratory data will be presented for the safety analysis set as described in the protocol.  
However, 25-hydroxy vitamin D baseline values will not be summarized since no abnormal 
values have been observed. 
The following approach will be used in case of repeated or missed laboratory measurements: 
 if an initial measurement was normal but the measurement was still repeated then the 
initial measurement will be presented in the tables and both measurements will be 
included in the listing. 
 if an initial measurement was repeated by mistake then the initial measurement will be 
presented in the tables and both measurements will be included in the listing.  
 if an initial measurement was abnormal and the measurement was repeated due to a 
technical problem then the repeated measurement will be presented in the tables and  both 
measurements will be included in the listing. 
 if an initial measurement was missing but a measurement from an unscheduled visit is 
available and the unscheduled visit was performed within 5 days after the actual visit then 
the measurement from the unscheduled visit will be used, for example one measurement 
from an unscheduled visit after Visit 3 will be included in the analysis of albumin 
corrected serum calcium (gives a total of 100 measurements).  
 
The number of measurements outside the reference range will be presented in relevant 
laboratory tables. The number of measurements for other than primary and secondary 
endpoints that fall outside the limit for quantification will be presented in relevant laboratory 
tables.  
 
6.4.5 Other observations 
PK evaluation 
As most plasma concentrations were below LLOQ the PK parameters will not be calculated at 
Week 4 for each assayed compound.  
Plasma concentrations will be presented in the listing.  
Vital signs 


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For systolic and diastolic blood pressure and heart rate, the absolute value by visit and change 
from baseline (SV2) to Week 4 (Visit 3) and Week 8 (Visit 5) will be summarized 
Clinically significant abnormalities in the vital signs at baseline (SV2), Week 4 and/or Week 8 
will not be presented since no clinically significant abnormalities were observed. Any 
abnormalities at Week 4 and/or Week 8 that were not present at baseline will be presented in 
the listing. 
The following approach will be used in case of repeated vital signs measurements: 
 if an initial measurement was normal but the measurement was still repeated then the 
initial measurement will be presented in the tables 
 if an initial measurement was abnormal and the measurement was repeated then the 
average of both measurements will be presented in the tables. 
 
All measurements will be included in the listings (initial measurement and repeated 
measurements). 
6.5 General Principles 
6.5.1 Pooling of Trial Sites 
There will be no pooling of centres.  
6.5.2 Handling of Drop-outs and Missing Values 
The efficacy and laboratory data will be tabulated by visit using an observed cases approach 
except for the tabulation of end of treatment values for which the LOCF approach will be 
used. 
The extent of missing values are described in 


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Table 3 for the primary endpoints and secondary endpoints involving laboratory 
measurements: 


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Table 3: Number of missing values and number of observations/Total.1  
 
Number of Missing Values  
(Number of observations/Total) 
Endpoint  
Test 
Screening Visit 2 
Week 4 
Week 8 
Primary 
Albumin corrected 
serum calcium 
0 
(107/107) 
5 
(99/104) 
3 
(87/90) 
Primary 
24-hours urinary 
calcium excretion 
9 
(98/107) 
12 
(92/104) 
11 
(79/90) 
Primary 
Serum Cortisol at 
time 0 
0 
(33/33) 
1 
(31/32) 
1 
(29/30) 
Primary 
Serum Cortisol at 
time 30 min2 
0 
(33/33) 
1 
(31/32) 
1 
(29/30) 
Primary 
Serum Cortisol at 
time 60 min2 
0 
(33/33) 
1 
(31/32) 
1 
(29/30) 
Secondary 
Urinary 
calcium:creatinine 
ratio 
9 
(98/107) 
12 
(92/104) 
11 
(79/90) 
Secondary 
Serum alkaline 
phosphatase  
0 
(107/107) 
5 
(99/104) 
3 
(87/90) 
1: Duplicates by subject, visit and numerical results are excluded. The table includes only subjects assigned to treatment 
2: Serum Cortiosol 30 min and 60 min after ACTH challenge 
 
 
 
 
 
 


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6.5.4 Treatment Labels 
The treatment label to be used in text and tables in the CTR and in the individual subject data 
listings is ‘LEO 80185’. 


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Appendix I 
Tables, Figures and Listings 
 
 


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Tables and Figures, Baseline Characteristics and Investigational Product Data (Module 
2) 
Tables 
Table 1-1 Subject enrolment and treatment assignment  by country and by centre: enrolled 
subjects and subjects assigned treatment 
Table 1-2 Reasons for withdrawal during the screening phase: enrolled subjects. 
Table 1-3 Reasons for withdrawal during the treatment phase: safety analysis set and per 
protocol analysis set 
Table 1-4 Sex, ethnicity, race and skin type: safety analysis set and per protocol analysis set 
Table 1-5 Age, BMI, height, weight and duration of psoriasis: safety analysis set and per 
protocol analysis set 
Table 1-6 Investigator’s global assessment of disease severity on the body at baseline: safety 
analysis set and per protocol analysis set 
Table 1-7 Patient’s global assessment of disease severity on the body at baseline: safety 
analysis set and per protocol analysis set 
Table 1-8 Investigator’s assessment of extent of psoriasis at baseline: safety analysis set and 
per protocol analysis set 
Table 1-9 PASI at baseline: safety analysis set and per protocol analysis set 
Table 1-10 Concomitant medication at baseline: safety analysis set and per protocol analysis 
set 
Table 1-11 Concurrent diagnoses at baseline: safety analysis set and per protocol analysis set 
Table 1-12 Age by country: safety analysis set and per protocol analysis set 
Table 1-13 Sex by country: safety analysis set and per protocol analysis set 
Table 1-14 Serum cortisol concentration at time 0, and at 30 and 60 min after ACTH 
challenge at baseline:  per protocol analysis set 


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Table 1-15 Compliance with treatment instructions: safety analysis set and per protocol 
analysis set 
Figures 
Figure 1-1 Visit attendance: enrolled subjects 
Figure 1-2 Trial analysis sets: enrolled subjects 
 
Tables and Figures, Efficacy Data (Module 3) 
Tables 
Table 2-1 Investigator’s global assessment of disease severity on the body by visit and at end 
of treatment: full analysis set 
Table 2-2 Controlled disease (IGA on the body) by visit and at end of treatment: full analysis 
set 
Table 2-3 Controlled disease (IGA on the body) at end of treatment by age group: full analysis 
set 
Table 2-4 Controlled disease (IGA on the body) at end of treatment by sex: full analysis set 
Table2-5 Controlled disease (IGA on the body) at end of treatment by race: full analysis set 
Table 2-6 Controlled disease (IGA on the body) at end of treatment by baseline IGA on the 
body: full analysis set 
Table 2-7 Controlled disease (IGA on the body) at end of treatment by baseline total extent of 
psoriasis: full analysis set 
Table 2-8 Controlled disease (IGA on the body) at end of treatment by country: full analysis 
set 
Table 2-9 PASI by visit and at end of treatment: full analysis set 
Table 2-10 Percentage change in PASI from baseline to each visit and end of treatment: full 
analysis set 


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Table 2-11 Investigator’s global assessment of disease severity on the scalp by visit and at end 
of treatment: full analysis set 
Table 2-12 Controlled disease (IGA on the scalp) by visit and at end of treatment: full analysis 
set 
Table 2-13 Investigator’s assessment of extent of psoriasis (total involvement as % of BSA) at 
baseline, Week 4 and Week 8: full analysis set and per protocol analysis set 
Table 2-14 Investigator’s assessment of extent of psoriasis (on body as % of BSA) at baseline, 
Week 4 and Week 8: full analysis set and per protocol analysis set 
Table 2-15 Investigator’s assessment of extent of psoriasis (on scalp as % of scalp area) at 
baseline, Week 4 and Week 8: full analysis set and per protocol analysis set 
Table 2-16 Patient’s global assessment of disease severity on the body by visit and at end of 
treatment: full analysis set 
Table 2-17 Controlled disease (patient’s global assessment on the body) by visit and at end of 
treatment: full analysis set 
Table 2-18 Patient’s global assessment of disease severity on the scalp by visit and at end of 
treatment: full analysis set 
Table 2-19 Controlled disease (patient’s global assessment on the scalp) by visit and at end of 
treatment: full analysis set 
Table 2-20 Patient’s assessment of itching on the body by visit and at end of treatment: full 
analysis set 
Table 2-21 Change in itching on the body from baseline to each visit and at end of treatment: 
full analysis set 
Table 2-22 Patient’s assessment of itching on the scalp by visit and at end of treatment: full 
analysis set 
Table 2-23 Change in itching on the scalp from baseline to each visit and at end of treatment: 
full analysis set 
Table 2-24 Patient’s assessment of sleep loss by visit and at end of treatment: full analysis set 


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Table 2-25 Change in sleep loss from baseline to each visit and end of treatment: full analysis 
set 
Tables and Figures, Safety Data (Module 4) 
Tables 
Table 3-1 Subjects with serum cortisol concentration <=18 mcg/dL at 30 minutes after ACTH 
challenge at Week 4 and Week 8: per protocol analysis set 
Table 3-2 Subjects with serum cortisol concentration <=18 mcg/dL at both 30 and 60 minutes 
after ACTH challenge at Week 4 and Week 8: per protocol analysis set 
Table 3-3 Serum cortisol concentration at time 0 and at 30 and 60 minutes after ACTH 
challenge at baseline, Week 4 and Week 8: per protocol analysis set 
Table 3-4 Individual data for subjects with serum cortisol concentration <=18 mcg/dL at 
either 30 minutes or 60 minutes after ACTH challenge: per protocol analysis set 
Table 3-5 Change in albumin-corrected serum calcium from baseline to Week 4, Week 8 and 
end of treatment: safety analysis set 
Table 3-6 Albumin-corrected serum calcium at baseline, Week 4, Week 8 and end of 
treatment: safety analysis set 
Table 3-7 Albumin-corrected serum calcium categorised as low, normal or high at Week 4, 
Week 8 and end of treatment shown against baseline category: safety analysis set 
Table 3-8 Change in 24-hour urinary calcium excretion from baseline to Week 4, Week 8 and 
end of treatment: safety analysis set 
Table 3-9 24-hour urinary calcium excretion at baseline, Week 4, Week 8 and end of 
treatment: safety analysis set 
Table 3-10 24-hour urinary calcium excretion categorised as low, normal or high at Week 4, 
Week 8 and end of treatment shown against baseline category: safety analysis set 
Table 3-11 Change in 24-hour urinary calcium excretion from baseline to Week 4, Week 8 and 
end of treatment in subjects with complete urinary collection: safety analysis set 


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Table 3-12 24-hour urinary calcium excretion at baseline, Week 4, Week 8 and end of 
treatment in subjects with complete urinary collection: safety analysis set 
Table 3-13 24-hour urinary calcium excretion categorised as low, normal or high at Week 4, 
Week 8 and end of treatment shown against baseline category in subjects with complete 
urinary collection: safety analysis set 
Table 3-14 Change in urinary calcium:creatinine ratio from baseline to Week 4 and Week 8: 
safety analysis set 
Table 3-15 Urinary calcium:creatinine ratio categorised as low, normal or high at Week 4 and 
Week 8 shown against baseline category: safety analysis set 
Table 3-16 Change in serum alkaline phosphatase from baseline to Week 4 and Week 8: safety 
analysis set 
Table 3-17 Serum alkaline phosphatase categorised as low, normal or high at Week 4 and 
Week 8 shown against baseline category: safety analysis set 
Table 3-18 Change in haematology parameters from baseline to Week 4 and Week 8: safety 
analysis set 
Table 3-19 Change in other biochemistry parameters from baseline to Week 4 and Week 8: 
safety analysis set 
Table 3-20 Change in other urinalysis parameters from baseline to Week 4 and Week 8: safety 
analysis set 
Table 3-21 Haematology parameters at baseline, Week 4 and Week 8: safety analysis set 
Table 3-22 Haematology parameters categorised as low, normal or high at Week 4 and Week 8 
shown against baseline category: safety analysis set 
Table 3-23 Biochemistry parameters at baseline, Week 4 and Week 8: safety analysis set 
Table 3-24 Other biochemistry parameters categorised as low, normal or high at Week 4 and 
Week 8 shown against baseline category: safety analysis set 
Table 3-25 Urinalysis parameters at baseline, Week 4 and Week 8: safety analysis set 


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Table 3-26 Other urinalysis parameters categorised as low, normal or high at Week 4 and 
Week 8 shown against baseline category: safety analysis set 
Table 3-27 Presence of urinary glucose and ketones at Week 4 and Week 8 against presence at 
baseline: safety analysis set 
Table 3-28 Duration and extent of exposure to treatment: safety analysis set 
Table 3-29 Amount of IMP used: safety analysis set 
Table 3-30 Average weekly amount of IMP used: safety analysis set 
Table 3-31 Average weekly amount of IMP used in defined usage categories: safety analysis 
set 
Table 3-32 Overall summary of adverse events: safety analysis set 
Table 3-33 Adverse events by MedDRA primary system organ class: safety analysis set 
Table 3-34 Adverse events by MedDRA primary system organ class and preferred term: safety 
analysis set 
Table 3-35 Intensity of adverse events by MedDRA primary system organ class and preferred 
term: safety analysis set 
Table 3-36 Causal relationship of adverse events to IMP by MedDRA primary system organ 
class and preferred term: safety analysis set 
Table 3-37 Adverse drug reactions by MedDRA primary system organ class and preferred 
term: safety analysis set 
Table 3-38 Intensity of adverse drug reactions by MedDRA primary system organ class and 
preferred term: safety analysis set 
Table 3-39 Lesional/perilesional adverse events by MedDRA primary system organ class and 
preferred term: safety analysis set 
Table 3-40 Lesional/perilesional adverse events on the body by MedDRA primary system 
organ class and preferred term: safety analysis set 


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Table 3-41 Lesional/perilesional adverse events on the scalp by MedDRA primary system 
organ class and preferred term: safety analysis set 
Table 3-42 Adverse events by age group, MedDRA primary system organ class and preferred 
term: safety analysis set 
Table 3-43 Adverse events by sex,  MedDRA primary system organ class and preferred term: 
safety analysis set 
Table 3-44 Adverse events by race, MedDRA primary system organ class and preferred term: 
safety analysis set 
Table 3-45 Adverse events by baseline IGA on the body, MedDRA primary system organ 
class and preferred term: safety analysis set 
Table 3-46 Adverse events by baseline total extent of psoriasis, MedDRA primary system 
organ class and preferred term: safety analysis set 
Table 3-47 Adverse events by IMP usage (<40 g/week, ≥40 g/week), MedDRA primary 
system organ class and preferred term: safety analysis set 
Table 3-48 Systolic blood pressure by visit: safety analysis set 
Table 3-49 Change in systolic blood pressure from baseline to Week 4 and Week 8: safety 
analysis set 
Table 3-50 Diastolic blood pressure by visit: safety analysis set 
Table 3-51 Change in diastolic blood pressure from baseline to Week 4 and Week 8: safety 
analysis set 
Table 3-52 Heart rate by visit: safety analysis set 
Table 3-53 Change in heart rate from baseline to Week 4 and Week 8: safety analysis set 
 
 


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Patient Data Listings (Appendix 1) 
1-7 Subjects Receiving Investigational Product from Specific Batches 
 Patient Data Listings (Appendix 2) 
Appendix 2.1: Discontinued Subjects 
Listing 1-1 Screening Failures 
Listing 1-2 Reason(s) for Withdrawal from Trial 
 
Appendix 2.2: Protocol Deviations  
Listing 2-1 Protocol Deviations  
Listing 2-2 Comments from CRF 
 
Appendix 2.3: Trial Analysis Sets 
Listing 3-1 Trial Analysis Set 
Listing 3-2 Reasons for Exclusion from Analysis Set 
 
Appendix 2.4: Demographic Data 
Listing 4-1 Demographics 
Listing 4-2 Duration of Psoriasis Vulgaris.  
Listing 4-3 Actual Trial Period 
Listing 4-4 Medical History 


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Listing 4-5 Concomitant Diagnoses at Baseline 
Listing 4-6 Concomitant Medication 
 
Appendix 2.5: Compliance and/or Investigational Product Concentration Data  
Listing 5-1 Compliance 
Listing 5-2 Drug Accountability 
Listing 5-3 Exposure Dates 
 
Appendix 2.6: Efficacy  Data 
Listing 6-1: Investigator’s Global Assessment of Disease Severity  
Listing 6-2: Investigator’s Assessment of Extent of Psoriasis 
Listing 6-3: Investigator’s Assessment of Extent and Severity of Clinical Signs and PASI 
Score 
Listing 6-4: Patient’s Global Assessment of Disease Severity 
Listing 6-5: Patient’s Assessment of Itch and Sleep Loss 
 
Appendix 2.7: Safety Data 
Listing 7-1 Deaths  
Listing 7-2 Serious Adverse Events  
Listing 7-3 Subjects withdrawn due to AE 
Listing 7-4 Severe Adverse Events 
Listing 7-5 Adverse Events 


Trial ID: LP0076-1017 
Date: 16-Mar-2018 
Version: 1.0 
Page 27 of 27 
 
 
 
 
 
 
Listing 7-6 Dietary Calcium Intake 
Appendix 2.8: Listing of Laboratory Values by Subject 
Listing 8-1 Physical Examination, Abnormal Findings 
Listing 8-2 Laboratory Measurements 
Listing 8-3 Abnormal Laboratory Measurements 
Listing 8-4 Vital Signs 
Listing 8-5 ACTH Challenge Test 
Listing 8-6 Plasma Concentrations. 
 
Additional Tables for Results Reporting in Clinical Trial Data Registries 
Table 4-1 Age group: subjects assigned to treatment 
Table 4-2 Non-serious AEs occurring in ≥[X]% subjects by MedDRA primary SOC and 
preferred term: safety analysis set 
[Note: X% is 5% or smaller percentage] 


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