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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2013-001538-16
    Trial protocol
    		 GB   DE   FR   RO  
    Global end of trial date
    13 Feb 2018

    Results information
    Results version number
    		 v1
    This version publication date
    26 Aug 2018
    First version publication date
    26 Aug 2018
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0076-1017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02038569
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical Disclosure Specialist, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Disclosure Specialist, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was 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.
    Protection of trial subjects
    This clinical trial was conducted in accordance with the revision current at the start of the trial of the World Medical Association’s Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the clinical trial was voluntary and that the subject could withdraw from the clinical trial at any time and for any reason. All subjects and their legally acceptable representatives were given an opportunity to ask questions and were given sufficient time to consider before consenting. Subjects who were not of legal age gave assent to their participation in the trial. The subject’s and legally acceptable representatives' signed and dated informed consent and assent to participate in the clinical trial were obtained prior to any trial related activities being carried out in accordance with ICH Good Clinical Practice (GCP) Section 4.8 and all applicable laws and regulations. Overdosage with calcipotriol may be associated with hypercalcaemia, and clinically important hypercalcaemia could be managed at the investigator’s discretion with rehydration, biphosphonate administration or according to local instructions. Overdosage with betamethasone dipropionate may result in suppression of the pituitary adrenal function, and could be treated symptomatically at the investigator's discretion. There is a risk of allergic hypersensitivity reactions with administration of Cortrosyn®/Synacthen®. Prior to the injection, the physician administering the injection was prepared to treat any possible hypersensitivity reactions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 45
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Poland: 14
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    125
    EEA total number of subjects
    98
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    125
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male or female, 12 to 16 years 11 months, psoriasis on body and scalp. •10-35% BSA; ≥20% scalp; at least moderate severity for subjects performing HPA assessment. •≥3% BSA; ≥10% scalp; at least mild severity for subjects not performing HPA assessment. 125 screened. 107 assigned to treatment, 1 lost to follow up and, 17 didn't meet entry criteria

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LEO 80185
    Arm description
    		 This arm contains all 107 subjects that were assigned to treatment and constitutes the full analysis set and the safety analysis set. 31 subjects in this arm performed additional hypothalamic-pituitary axis assessments and constitute the per protocol analysis set.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LEO 80185
    Investigational medicinal product code
    Other name
    Daivobet® gel , Xamiol® gel, Dovobet gel ®, and Taclonex® Topical Suspension
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    LEO 80185 gel is formulated as a gel containing Calcipotriol 50 mcg/g (as hydrate) and Betamethasone 0.5 mg/g (as dipropionate).LEO 80185 gel was applied once daily to all affected areas of the scalp and body. For subjects aged 12 to less than 15 years with a body surface area below 1.3 m2, the maximum weekly dosage of LEO 80185 gel was 55 g gel per week. For subjects aged 12 to less than 15 years with a body surface area above 1.3 m2 and subjects older than 15 years with a body surface area below 1.3 m2, the maximum weekly dosage of LEO 80185 gel was 75 g gel per week. For subjects aged older than 15 years with a body surface area above 1.3 m2, the maximum weekly dosage of LEO 80185 gel was 100 g gel per week. No maximum weekly dosage of LEO 80185 gel was defined for subjects performing HPA assessments.

    Number of subjects in period 1 [1]
    		LEO 80185
    Started
    107
    Completed
    102
    Not completed
    5
         Consent withdrawn by subject
    3
         Adverse event, non-fatal
    1
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 125 subjects were screened in the trial. Out of the 125 screened subjects, 17 were screening failures, and 1 subject screening but was immediately lost to follow-up. The remaining 107 subjects were assigned tothe treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 107 107
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 107 107
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    All subjects included were between 12 years and 16 years 11 months.
    Units: years
        arithmetic mean (standard deviation)
    		 14.2 ± 1.4 -
    Gender categorical
    Units: Subjects
        Female
    		 62 62
        Male
    		 45 45
    Subject analysis sets

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    For the analysis of the results from the ACTH-challenge test, the per protocol analysis set was defined by including the subjects performing HPA axis assessments from the full analysis set, but was to exclude the subjects who did not apply any LEO 80185 gel, met the inclusion criterion concerning evidence of adrenal function suppression at baseline, or provide any results for the ACTH-challenge test after receiving IMP.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    107 subjects who applied LEO 80185 gel at least once and were included in the analysis of efficacy.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    107 subjects who applied LEO 80185 gel at least once and for whom either the presence or confirmed absence of adverse events was available.

    Subject analysis sets values
    		 Per protocol analysis set Full analysis set Safety analysis set
    Number of subjects
    31
    107
    107
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    31
    107
    107
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    All subjects included were between 12 years and 16 years 11 months.
    Units: years
        arithmetic mean (standard deviation)
    14.2 ± 1.2
    14.2 ± 1.4
    14.2 ± 1.4
    Gender categorical
    Units: Subjects
        Female
    17
    62
    62
        Male
    14
    45
    45

    End points

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    End points reporting groups
    Reporting group title
    LEO 80185
    Reporting group description
    		 This arm contains all 107 subjects that were assigned to treatment and constitutes the full analysis set and the safety analysis set. 31 subjects in this arm performed additional hypothalamic-pituitary axis assessments and constitute the per protocol analysis set.

    Subject analysis set title
    Per protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    For the analysis of the results from the ACTH-challenge test, the per protocol analysis set was defined by including the subjects performing HPA axis assessments from the full analysis set, but was to exclude the subjects who did not apply any LEO 80185 gel, met the inclusion criterion concerning evidence of adrenal function suppression at baseline, or provide any results for the ACTH-challenge test after receiving IMP.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    107 subjects who applied LEO 80185 gel at least once and were included in the analysis of efficacy.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    107 subjects who applied LEO 80185 gel at least once and for whom either the presence or confirmed absence of adverse events was available.

    Primary: Adverse Drug Reactions (ADRs)

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    End point title
    		 Adverse Drug Reactions (ADRs) [1]
    End point description
    Number of Adverse Drug Reactions (ADRs) defined as adverse events for which the investigator has not described the causal relationship to LEO 80185 gel as “not related”.
    End point type
    Primary
    End point timeframe
    8 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107
    Units: Number of adverse drug reactions
        Blood cortisol decreased
    2
        Blood parathyroid hormone increased
    1
        Acne
    1
        Erythema
    1
        Hyperparathyroidism
    1
        Folliculitis
    1
        Headache
    1
    No statistical analyses for this end point

    Primary: Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 4

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    End point title
    		 Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 4 [2]
    End point description
    Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 4
    End point type
    Primary
    End point timeframe
    Week 4
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Per protocol analysis set
    Number of subjects analysed
    31
    Units: Number of subjects
        Serum cortisol equal to or below 18 mcg/dL
    4
        Serum cortisol above 18 mcg/dL
    27
    No statistical analyses for this end point

    Primary: Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 8

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    End point title
    		 Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 8 [3]
    End point description
    Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at 30 Minutes After ACTH-challenge, Week 8
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Per protocol analysis set
    Number of subjects analysed
    31
    Units: Number of subjects
        Serum cortisol equal to or below 18 mcg/dL
    2
        Serum cortisol above 18 mcg/dL
    27
        No assessment performed, withdrawn before Week 8
    2
    No statistical analyses for this end point

    Primary: Change in Albumin-corrected Serum Calcium From Baseline to Week 4

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    End point title
    		 Change in Albumin-corrected Serum Calcium From Baseline to Week 4 [4]
    End point description
    Change in Albumin-corrected Serum Calcium From Baseline to Week 4
    End point type
    Primary
    End point timeframe
    Week 4
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [5]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.012 ± 0.131
    Notes
    [5] - Data available for 100 subjects
    No statistical analyses for this end point

    Primary: Change in Albumin-corrected Serum Calcium From Baseline to Week 8

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    End point title
    		 Change in Albumin-corrected Serum Calcium From Baseline to Week 8 [6]
    End point description
    Change in Albumin-corrected Serum Calcium From Baseline to Week 8
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [7]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.008 ± 0.125
    Notes
    [7] - Data available for 87 subjects
    No statistical analyses for this end point

    Primary: Change in Albumin-corrected Serum Calcium From Baseline to End of Treatment

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    End point title
    		 Change in Albumin-corrected Serum Calcium From Baseline to End of Treatment [8]
    End point description
    Change in Albumin-corrected Serum Calcium From Baseline to End of Treatment, Defined as the Last Value Recorded after Baseline Up to and Including Week 8.
    End point type
    Primary
    End point timeframe
    End of treatment
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [9]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.003 ± 0.121
    Notes
    [9] - Data available for 102 subjects
    No statistical analyses for this end point

    Primary: Change in 24-hour Urinary Calcium Excretion From Baseline to Week 4

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    End point title
    		 Change in 24-hour Urinary Calcium Excretion From Baseline to Week 4 [10]
    End point description
    Change in 24-hour Urinary Calcium Excretion From Baseline to Week 4
    End point type
    Primary
    End point timeframe
    Week 4
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [11]
    Units: mmol/24hr
        arithmetic mean (standard deviation)
    -0.493 ± 1.669
    Notes
    [11] - Data available for 85 subjects
    No statistical analyses for this end point

    Primary: Change in 24-hour Urinary Calcium Excretion From Baseline to Week 8

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    End point title
    		 Change in 24-hour Urinary Calcium Excretion From Baseline to Week 8 [12]
    End point description
    Change in 24-hour Urinary Calcium Excretion From Baseline to Week 8
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [13]
    Units: mmol/24hr
        arithmetic mean (standard deviation)
    0.040 ± 1.638
    Notes
    [13] - Data available for 72 subjects
    No statistical analyses for this end point

    Primary: Change in 24-hour Urinary Calcium Excretion From Baseline to End of Treatment

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    End point title
    		 Change in 24-hour Urinary Calcium Excretion From Baseline to End of Treatment [14]
    End point description
    Change in 24-hour Urinary Calcium Excretion From Baseline to End of Treatment, Defined as the Last Value Recorded after Baseline Up to and Including Week 8.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis is required for this end point.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [15]
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.069 ± 1.593
    Notes
    [15] - Data available for 85 subjects
    No statistical analyses for this end point

    Secondary: Adverse Events (AEs)

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    End point title
    		 Adverse Events (AEs)
    End point description
    Number of Adverse Events (AEs)
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107
    Units: Adverse events
        Nasopharyngitis
    6
        Rhinitis
    2
        Folliculitis
    1
        Hordeolum
    1
        Impetigo
    1
        Peritonsillar abscess
    1
        Upper respiratory tract infection
    1
        Viral infection
    1
        Blood parathyroid hormone increased
    5
        Blood cortisol decreased
    2
        Eosinophil count increased
    1
        Headache
    8
        Balance disorder
    1
        Dizziness
    1
        Syncope
    1
        Cough
    2
        Oropharyngeal pain
    2
        Dyspnoea
    1
        Epistaxis
    1
        Respiratory disorder
    1
        Acne
    1
        Erythema
    1
        Pruritus
    1
        Sunburn
    1
        Abdominal pain upper
    1
        Constipation
    1
        Diarrhoea
    1
        Back pain
    1
        Muscle spasms
    1
        Musculoskeletal chest pain
    1
        Neck pain
    1
        Dysmenorrhoea
    3
        Arthropod sting
    1
        Concussion
    1
        Sleep disorder
    1
        Suicide attempt
    1
        Cardiovascular disorder
    1
        Hyperparathyroidism
    1
        Iron deficiency
    1
        Wisdom teeth removal
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 4

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    End point title
    		 Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 4
    End point description
    Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 4
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Per protocol analysis set
    Number of subjects analysed
    31
    Units: Number of subjects
        Serum cortisol equal to or below 18 mcg/dL
    0
        Serum cortisol above 18 mcg/dL
    31
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 8

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    End point title
    		 Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 8
    End point description
    Number of Subjects With Serum Cortisol Concentration of ≤18 mcg/dl at Both 30 and 60 Minutes After ACTH-challenge at Week 8
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Safety analysis set
    Number of subjects analysed
    31
    Units: Number of subjects
        Serum cortisol equal to or below 18 mcg/dL
    0
        Serum cortisol above 18 mcg/dL
    29
        No assessment performed, withdrawn before Week 8
    2
    No statistical analyses for this end point

    Secondary: Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 4

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    End point title
    		 Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 4
    End point description
    Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 4
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [16]
    Units: mmol/g
        arithmetic mean (standard deviation)
    -0.098 ± 1.642
    Notes
    [16] - Data available for 85 subjects
    No statistical analyses for this end point

    Secondary: Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 8

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    End point title
    		 Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 8
    End point description
    Change in Urinary Calcium:Creatinine Ratio From Baseline to Week 8
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [17]
    Units: mmol/g
        arithmetic mean (standard deviation)
    0.219 ± 1.700
    Notes
    [17] - Data available for 72 subjects
    No statistical analyses for this end point

    Secondary: Change in Serum Alkaline Phosphatase From Baseline to Week 4

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    End point title
    		 Change in Serum Alkaline Phosphatase From Baseline to Week 4
    End point description
    Change in Serum Alkaline Phosphatase From Baseline to Week 4
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [18]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.4 ± 31.4
    Notes
    [18] - Data available for 100 subjects
    No statistical analyses for this end point

    Secondary: Change in Serum Alkaline Phosphatase From Baseline to Week 8

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    End point title
    		 Change in Serum Alkaline Phosphatase From Baseline to Week 8
    End point description
    Change in Serum Alkaline Phosphatase From Baseline to Week 8
    End point type
    Secondary
    End point timeframe
    Week 8
    End point values
    		 Safety analysis set
    Number of subjects analysed
    107 [19]
    Units: mmol/L
        arithmetic mean (standard deviation)
    -6.8 ± 42.6
    Notes
    [19] - Data available for 87 subjects
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Evaluation AUC(0-t)

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    End point title
    		 Pharmacokinetic Evaluation AUC(0-t)
    End point description
    AUC(0-t) values for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, and MC1080. Betamethasone diproprionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-proprionate was only detected in 12 samples from 5 subjects. Calcipotriol and MC1080 were never detected above lower limit of quantification. Therefore it was not possible to calculate AUC(0-t) for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, or MC1080. Non-calculated values have been entered as "0".
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 LEO 80185
    Number of subjects analysed
    33 [20]
    Units: pg*h/mL
    number (not applicable)
        Betamethasone dipropionate (n=4)
    0
        Betamethasone 17-proprionate (n=5)
    0
        Calcipotriol (n=0)
    0
        MC1080 (n=0)
    0
    Notes
    [20] - PK evaluation was performed in 33 subjects. Analysis set not defined in clinical trial protocol.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Evaluation AUC(0-infinity)

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    End point title
    		 Pharmacokinetic Evaluation AUC(0-infinity)
    End point description
    AUC(0-infinity) values for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, and MC1080. Betamethasone diproprionate was only detected above lower limit of quantification in 5 samples from 4 subjects. Calcipotriol and MC1080 were never detected above lower limit of quantification. Therefore it was not possible to calculate AUC(0-infinity) for betamethasone dipropionate, calcipotriol, or MC1080. Non-calculated values have been entered as "0".
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 LEO 80185
    Number of subjects analysed
    33 [21]
    Units: pg*h/mL
    number (not applicable)
        Betamethasone dipropionate (n=4)
    0
        Betamethasone 17-proprionate (n=5)
    325
        Calcipotriol (n=0)
    0
        MC1080 (n=0)
    0
    Notes
    [21] - PK evaluation was performed in 33 subjects. Analysis set not defined in clinical trial protocol.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Evaluation C(max)

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    End point title
    		 Pharmacokinetic Evaluation C(max)
    End point description
    C(max) values for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, and MC1080. Betamethasone diproprionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-proprionate was only detected in 12 samples from 5 subjects, therefore pharmakokinetic profiles could not be calculated. Presented C(max) values for betamethasone dipropionate and betamethasone 17-proprionate are the highest value observed at any time point. Calcipotriol and MC1080 were never detected above lower limit of quantification, therefore no C(max) values are available for calcipotriol and MC1080. Non-calculated values have been entered as "0".
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 LEO 80185
    Number of subjects analysed
    33 [22]
    Units: pg/mL
    number (not applicable)
        Betamethasone dipropionate (n=4)
    104
        Betamethasone 17-proprionate (n=5)
    126
        Calcipotriol (n=0)
    0
        MC1080 (n=0)
    0
    Notes
    [22] - PK evaluation was performed in 33 subjects. Analysis set not defined in clinical trial protocol.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Evaluation T(max)

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    End point title
    		 Pharmacokinetic Evaluation T(max)
    End point description
    T(max) values for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, and MC1080. Betamethasone diproprionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-proprionate was only detected in 12 samples from 5 subjects. Calcipotriol and MC1080 were never detected above lower limit of quantification. Therefore it was not possible to calculate T(max) for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, or MC1080. Non-calculated values have been entered as "0".
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 LEO 80185
    Number of subjects analysed
    33 [23]
    Units: hours
    number (not applicable)
        Betamethasone dipropionate (n=4)
    0
        Betamethasone 17-proprionate (n=5)
    0
        Calcipotriol (n=0)
    0
        MC1080 (n=0)
    0
    Notes
    [23] - PK evaluation was performed in 33 subjects. Analysis set not defined in clinical trial protocol.
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Evaluation T(½)

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    End point title
    		 Pharmacokinetic Evaluation T(½)
    End point description
    T(½) values for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, and MC1080. Betamethasone diproprionate was only detected above lower limit of quantification in 5 samples from 4 subjects and betamethasone 17-proprionate was only detected in 12 samples from 5 subjects. Calcipotriol and MC1080 were never detected above lower limit of quantification. Therefore it was not possible to calculate T(½) for betamethasone dipropionate, betamethasone 17-proprionate, calcipotriol, or MC1080. Non-calculated values have been entered as "0".
    End point type
    Secondary
    End point timeframe
    Week4
    End point values
    		 LEO 80185
    Number of subjects analysed
    33 [24]
    Units: hours
    number (not applicable)
        Betamethasone dipropionate (n=4)
    0
        Betamethasone 17-proprionate (n=5)
    0
        Calcipotriol (n=0)
    0
        MC1080 (n=0)
    0
    Notes
    [24] - PK evaluation was performed in 33 subjects. Analysis set not defined in clinical trial protocol.
    No statistical analyses for this end point

    Secondary: Subjects With “Controlled Disease” According to the Investigator’s Global Assessment of Disease Severity on the Body at End of Treatment

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    End point title
    		 Subjects With “Controlled Disease” According to the Investigator’s Global Assessment of Disease Severity on the Body at End of Treatment
    End point description
    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, defined as the last value recorded up to and including Week 8.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Full analysis set
    Number of subjects analysed
    107
    Units: Number of subjects
        Controlled
    62
        Non-controlled
    45
    No statistical analyses for this end point

    Secondary: Percentage Change in PASI From Baseline to End of Treatment

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    End point title
    		 Percentage Change in PASI From Baseline to End of Treatment
    End point description
    Percentage Change in PASI From Baseline to End of Treatment, Defined as the Last Value Recorded Up to and Including Week 8.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Full analysis set
    Number of subjects analysed
    107
    Units: Percentage change in PASI
        arithmetic mean (standard deviation)
    -78.7 ± 32.4
    No statistical analyses for this end point

    Secondary: 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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    End point title
    		 Subjects With “Controlled Disease” According to the Patient’s Global Assessment of Disease Severity on the Body at End of Treatment
    End point description
    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 patient’s global assessment of disease severity on the body at end of treatment, defined as the last value recorded up to and including Week 8.
    End point type
    Secondary
    End point timeframe
    End of treatment
    End point values
    		 Full analysis set
    Number of subjects analysed
    107
    Units: Number of subjects
        Controlled
    67
        Non-controlled
    40
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs/SAEs were followed up until final outcome was determined. After a subject left the trial, investigator followed up all SAEs and AEs deemed possibly/probably related to IMP for 14± 2 days or until final outcome was determined, whichever came first.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 This arm contains all 107 subjects that were assigned to treatment and constitutes the safety analysis set.

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 107 (0.93%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 107 (35.51%)
    Surgical and medical procedures
    Wisdom teeth removal
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    3 / 107 (2.80%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Respiratory disorder
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Investigations
    Blood parathyroid hormone increased
         subjects affected / exposed
    4 / 107 (3.74%)
         occurrences all number
    5
    Blood cortisol decreased
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences all number
    2
    Eosinophil count increased
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Concussion
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Cardiac disorders
    Cardiovascular disorder
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    8
    Balance disorder
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Sunburn
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 107 (5.61%)
         occurrences all number
    6
    Rhinitis
         subjects affected / exposed
    2 / 107 (1.87%)
         occurrences all number
    2
    Folliculitis
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Hordeolum
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Impetigo
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Peritonsillar abscess
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 107 (0.93%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2013
    Clarifications concerning efficacy, pharmacokinetic, and laboratory assessments; calculation of body surface area concomitant medications, vitamin D supplementation; details concerning discontinuation and end of treatment.
    12 Jun 2014
    Specification of US sites assigned to perform HPA axis and PK assessments; clarification of the main inclusion criteria for all subjects; additional inclusion criteria for subjects not performing HPA axis and PK assessments; dose for HPA axis subgroup; limit of vitamin D analogues; Australia & New Zealand removed as participating countries; sites updated; simplification to SAE reporting.
    16 Feb 2015
    Extent of BSA; definitions of controlled disease based on baseline disease severity, inclusion of subjects with mild disease severity; update of LSLV; specifications of data handling; additional inclusion criteria for HPA/ non-HPA subjects.
    14 Aug 2015
    Inclusion of Central and Eastern European sites; allowing German sites to perform HPA axis and PK assessments.
    24 Nov 2015
    Inclusion of Romanian sites for HPA axis and PK assessments; update of LSLV; inclusion of Synacthen® information.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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