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    Clinical Trial Results:
    A Randomized, Single-Center, Observer-Blind, Vehicle- and Active Comparator-Controlled Phase 1b Study to Assess the Effect and Local Safety and Tolerability of Roflumilast and BYK321084 – Phosphodiesterase Type 4 Inhibitors (PDE4i) Dermal Formulations in Patients with Chronic Plaque Psoriasis using a Psoriasis Plaque Test

    Summary
    EudraCT number
    		 2012-002998-62
    Trial protocol
    		 DE  
    Global end of trial date
    30 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ROF-PSOR_104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1168-0955
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A single-center 3-week proof of mechanism/exploratory study to assess the effect and safety of topical roflumilast (0.5% dermal cream) and BYK321084 (5% and 0.5% dermal creams) compared to a vehicle (to roflumilast) formulation and 2 active comparators (betamethasone valerate 0.1% cream and calcipotriol 0.005% cream).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2013
    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
    Germany: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    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)
    0
    Adults (18-64 years)
    14
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants took part in the study at 1 investigative site in Germany from 13 June 2013 to 30 October 2013.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of Chronic Plaque Psoriasis were randomized to determine the placement order of six treatments: roflumilast 0.5%, TAK-084 5%, TAK-084 0.5%, vehicle to roflumilast, betamethasone valerate 0.1%, cream and calcipotriol 0.005% creams.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    The study was conducted observer-blind, ie, only the investigator performing the measurements and assessments was blinded to treatment.

    Arms
    Arm title
    		 All Randomized Participants
    Arm description
    		 Roflumilast 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 5%, dermal cream, 100 µL applied topically under Finn skin chambers, Vehicle to roflumilast, dermal cream, 100 µL applied topically under Finn skin chambers, betamethasone valerate 0.1%, dermal cream, 100 µL applied topically under Finn skin chambers, and calcipotriol 0.005%, dermal cream, 100 µL applied under Finn skin chambers, once daily for 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roflumilast 0.5% Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Roflumilast 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Investigational medicinal product name
    TAK-084 0.5% Cream
    Investigational medicinal product code
    Other name
    BYK321084
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    TAK-084 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Investigational medicinal product name
    TAK-084 5% Cream
    Investigational medicinal product code
    Other name
    BYK321084
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    TAK-084 5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Investigational medicinal product name
    Vehicle to Roflumilast Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle to roflumilast, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Investigational medicinal product name
    Betamethasone Valerate 0.1% Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Betamethasone valerate 0.1%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Investigational medicinal product name
    Calcipotriol 0.005% Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Calcipotriol 0.005%, dermal cream, 100 µL applied under Finn skin chambers, once daily for 21 days.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: The study was conducted observer-blind, ie, only the investigator performing the measurements and assessments was blinded to treatment.
    Number of subjects in period 1
    		All Randomized Participants
    Started
    15
    Completed
    15

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 14 14
        From 65-84 years
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.1 ± 12.41 -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 12 12
    Race
    Units: Subjects
        White
    		 15 15
    Smoking Classification
    Units: Subjects
        Never Smoked
    		 3 3
        Current Smoker
    		 6 6
        Ex-smoker
    		 6 6
    Female Reproductive Status
    Units: Subjects
        Postmenopausal
    		 0 0
        Surgically Sterile
    		 1 1
        Female of Childbearing Potential
    		 2 2
        N/A (Subject is Male)
    		 12 12
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 178.2 ± 7.84 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 88.07 ± 14.28 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.61 ± 3.316 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    All Randomized Participants
    Reporting group description
    		 Roflumilast 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 5%, dermal cream, 100 µL applied topically under Finn skin chambers, Vehicle to roflumilast, dermal cream, 100 µL applied topically under Finn skin chambers, betamethasone valerate 0.1%, dermal cream, 100 µL applied topically under Finn skin chambers, and calcipotriol 0.005%, dermal cream, 100 µL applied under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    Vehicle to Roflumilast Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Vehicle to roflumilast, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    Roflumilast 0.5% Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Roflumilast 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    TAK-084 0.5% Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    TAK-084 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    TAK-084 5% Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    TAK-084 5%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    Betamethasone Valerate 0.1% Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Betamethasone valerate 0.1%, dermal cream, 100 µL applied topically under Finn skin chambers, once daily for 21 days.

    Subject analysis set title
    Calcipotriol 0.005% Cream
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Calcipotriol 0.005%, dermal cream, 100 µL applied under Finn skin chambers, once daily for 21 days.

    Primary: Change from Baseline in Thickness of the Psoriatic Skin Infiltrate on Day 22

    		 Close Top of page
    End point title
    		 Change from Baseline in Thickness of the Psoriatic Skin Infiltrate on Day 22
    End point description
    Thickness of psoriatic skin infiltrate was assessed using 20 MHz sonographic measurement. A negative change from Baseline indicated improved skin condition. Full Analysis Set included all randomized participants who received at least 1 application of study medication analyzed according to randomized treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Day 22
    End point values
    		 Vehicle to Roflumilast Cream Roflumilast 0.5% Cream TAK-084 0.5% Cream TAK-084 5% Cream Betamethasone Valerate 0.1% Cream Calcipotriol 0.005% Cream
    Number of subjects analysed
    15
    15
    15
    15
    15
    15
    Units: µm
        arithmetic mean (standard deviation)
    -70.3 ± 96.84
    -307.4 ± 150.17
    -223.9 ± 88.96
    -287.1 ± 157.37
    -357.3 ± 130.64
    -258 ± 107.65
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Roflumilast 0.5% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Roflumilast 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -237.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -320
         upper limit
    		 -154.1
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    TAK-084 0.5% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -153.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -224.1
         upper limit
    		 -83.1
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    TAK-084 5% cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -216.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -298.7
         upper limit
    		 -134.7
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Betamethasone Valerate 0.1% Cream versus Vehicle Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -286.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -362
         upper limit
    		 -211.9
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Calcipotriol 0.005% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -187.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -256.8
         upper limit
    		 -118.5
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Roflumilast 0.5% Cream versus Betamethasone Valerate 0.1% Cream.
    Comparison groups
    Roflumilast 0.5% Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    49.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.6
         upper limit
    		 96.2
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    TAK-084 0.5% Cream versus Betamethasone Valerate 0.1% Cream.
    Comparison groups
    TAK-084 0.5% Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    133.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.2
         upper limit
    		 196.5
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    TAK-084 5% Cream versus Betamethasone Valerate 0.1% Cream.
    Comparison groups
    Betamethasone Valerate 0.1% Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    70.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.2
         upper limit
    		 118.2
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Calcipotriol 0.005% Cream versus Betamethasone Valerate 0.1% Cream.
    Comparison groups
    Betamethasone Valerate 0.1% Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    99.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 63.3
         upper limit
    		 135.3
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Roflumilast 0.5% Cream versus Calcipotriol 0.005% Cream.
    Comparison groups
    Roflumilast 0.5% Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -49.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -111.6
         upper limit
    		 12.8
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    TAK-084 0.5% Cream versus Calcipotriol 0.005% Cream.
    Comparison groups
    TAK-084 0.5% Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    34.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.6
         upper limit
    		 85.7
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    TAK-084 5% Cream versus Calcipotriol 0.005% Cream.
    Comparison groups
    Calcipotriol 0.005% Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.339
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -92
         upper limit
    		 33.9

    Secondary: Change from Baseline in Thickness of the Psoriatic Skin Infiltrate on Days 8 and 15

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    End point title
    		 Change from Baseline in Thickness of the Psoriatic Skin Infiltrate on Days 8 and 15
    End point description
    Thickness of psoriatic skin infiltrate was assessed using 20 MHz sonographic measurement. A negative change from Baseline indicated improved skin condition. Full Analysis Set included all randomized participants who received at least 1 application of study medication analyzed according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 8 and 15
    End point values
    		 Vehicle to Roflumilast Cream Roflumilast 0.5% Cream TAK-084 0.5% Cream TAK-084 5% Cream Betamethasone Valerate 0.1% Cream Calcipotriol 0.005% Cream
    Number of subjects analysed
    15
    15
    15
    15
    15
    15
    Units: µm
    arithmetic mean (standard deviation)
        Day 8
    3.3 ± 44.88
    -222.9 ± 136.2
    -90.6 ± 76.72
    -204.1 ± 144.53
    -253.6 ± 104.6
    -184.1 ± 104.52
        Day 15
    -45.3 ± 89.01
    -277.7 ± 153.38
    -154.5 ± 88.85
    -239.1 ± 146.55
    -311.8 ± 113.41
    -182.3 ± 153.02
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    0.5% Roflumilast Cream versus Vehicle to Roflumilast Cream at Day 8.
    Comparison groups
    Vehicle to Roflumilast Cream v Roflumilast 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -226.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -302.7
         upper limit
    		 -149.6
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    TAK-084 0.5% Cream versus Vehicle to Roflumilast Cream at Day 8.
    Comparison groups
    TAK-084 0.5% Cream v Vehicle to Roflumilast Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -93.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -138.9
         upper limit
    		 -48.8
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    TAK-084 5% Cream versus Vehicle to Roflumilast Cream at Day 8.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -207.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -291.3
         upper limit
    		 -123.5
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Betamethasone Valerate Cream 0.1% versus Vehicle to Roflumilast Cream at Day 8.
    Comparison groups
    Vehicle to Roflumilast Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -256.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -327
         upper limit
    		 -186.7
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Calcipotriol 0.005% Cream versus Vehicle to Roflumilast at Day 8.
    Comparison groups
    Vehicle to Roflumilast Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -187.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -252.6
         upper limit
    		 -122.1
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Roflumilast 0.5% Cream versus Vehicle to Roflumilast Cream at Day 15.
    Comparison groups
    Vehicle to Roflumilast Cream v Roflumilast 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -232.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -311.6
         upper limit
    		 -153.2
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Tak-084 0.5% Cream versus Vehicle to Roflumilast Cream on Day 15.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -109.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -171.2
         upper limit
    		 -47.3
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Tak-084 5% Cream versus Vehicle to Roflumilast Cream on Day 15.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -193.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -268.4
         upper limit
    		 -119.3
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Betamethasone Valerate 0.1% Cream versus Vehicle to Roflumilast Cream on Day 15.
    Comparison groups
    Vehicle to Roflumilast Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -266.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -334.8
         upper limit
    		 -198.2
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Calcipotriol 0.005% Cream versus Vehicle to Roflumilast at Day 15.
    Comparison groups
    Vehicle to Roflumilast Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -137
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -258.3
         upper limit
    		 -15.7

    Secondary: Area Under the Curve (AUC) of the Baseline-Corrected Thickness of the Psoriatic Skin Infiltrate

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    End point title
    		 Area Under the Curve (AUC) of the Baseline-Corrected Thickness of the Psoriatic Skin Infiltrate
    End point description
    Thickness of psoriatic skin infiltrate was assessed using 20 MHz sonographic measurement at Baseline and Days 8, 15 and 22. Baseline corrected AUC values were calculated using the linear trapezoidal rule. Full Analysis Set included all randomized participants who received at least 1 application of study medication analyzed according to randomized treatment. If Baseline measurement was missing AUC was set to missing. If 1 Post-Baseline measurement was missing Last Observation Carried Forward was used. If 2 or more post-Baseline measurements were missing AUC was set to missing.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 1, 8, 15 and 22
    End point values
    		 Vehicle to Roflumilast Cream Roflumilast 0.5% Cream TAK-084 0.5% Cream TAK-084 5% Cream Betamethasone Valerate 0.1% Cream Calcipotriol 0.005% Cream
    Number of subjects analysed
    15
    15
    15
    15
    15
    15
    Units: µm·day
        arithmetic mean (standard deviation)
    -540.17 ± 1162.715
    -4579.63 ± 2495.896
    -2499.7 ± 1300.153
    -4107.6 ± 2564.958
    -5208.23 ± 1950.179
    -3467.33 ± 1455.8
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Roflumilast 0.5% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Roflumilast 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4039.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5351.01
         upper limit
    		 -2727.93
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    TAK-084 0.5% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 0.5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1959.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2779.91
         upper limit
    		 -1139.15
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    TAK-084 5% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v TAK-084 5% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3567.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4900.71
         upper limit
    		 -2234.15
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Betamethasone Valerate 0.1% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Betamethasone Valerate 0.1% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4668.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5858.76
         upper limit
    		 -3477.37
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Calcipotriol 0.005% Cream versus Vehicle to Roflumilast Cream.
    Comparison groups
    Vehicle to Roflumilast Cream v Calcipotriol 0.005% Cream
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Paired t-test
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2927.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4082.44
         upper limit
    		 -1771.89

    Secondary: Change from Baseline in Clinical Severity of the Psoriatic Lesions

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    End point title
    		 Change from Baseline in Clinical Severity of the Psoriatic Lesions
    End point description
    The investigator assessed the clinical severity of the treated psoriatic lesions compared to Baseline as part of the skin examination procedure, including photography, using a 5-Point Scale: -1=worsened to 3=completely healed. A higher number change from Baseline is the best. Full Analysis Set included all randomized participants who received at least 1 application of study medication analyzed according to randomized treatment.
    End point type
    Secondary
    End point timeframe
    Baseline and Days, 8, 15 and 22
    End point values
    		 Vehicle to Roflumilast Cream Roflumilast 0.5% Cream TAK-084 0.5% Cream TAK-084 5% Cream Betamethasone Valerate 0.1% Cream Calcipotriol 0.005% Cream
    Number of subjects analysed
    15
    15
    15
    15
    15
    15
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Day 8
    0 ± 0
    1.5 ± 0.52
    0.1 ± 0.26
    0.9 ± 0.46
    2 ± 0.53
    1.1 ± 0.46
        Day 15
    0.1 ± 0.35
    1.9 ± 0.59
    0.3 ± 0.46
    1 ± 0.53
    2.2 ± 0.41
    1.1 ± 0.7
        Day 22
    0.1 ± 0.26
    1.9 ± 0.7
    0.5 ± 0.64
    1.3 ± 0.8
    2.3 ± 0.49
    1.1 ± 0.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First treatment to 30 days past last treatment (Up to 36 days)
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    All Participants
    Reporting group description
    		 Roflumilast 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 0.5%, dermal cream, 100 µL applied topically under Finn skin chambers, TAK-084 5%, dermal cream, 100 µL applied topically under Finn skin chambers, vehicle to roflumilast, dermal cream, 100 µL applied topically under Finn skin chambers, betamethasone valerate 0.1%, dermal cream, 100 µL applied topically under Finn skin chambers, and calcipotriol 0.005%, dermal cream, 100 µL applied under Finn skin chambers, once daily for 21 days.

    Serious adverse events
    		 All Participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Skin erosion
         subjects affected / exposed
    1 / 15 (6.67%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
         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
    15 Oct 2012
    The following changes were implemented in Protocol Amendment 1: • Changed department name for SAE and pregnancy reporting. • Changed the signatory responsibility for pharmacovigilance and clinical trial management. • Corrected the manufacturer of the hydrocolloid dressing. • Clarified that subjects not capable of giving informed consent would not be allowed to participate in the study. • Added language to exclude subjects with extensive ultraviolet light exposure in the 4 weeks prior to study medication application and institutionalized subjects. • Added specific section for exclusion of known inhibitors of CYP2D6 and CYP1A2 per regulatory request. • Revised laboratory analysis of white blood cell count. • Clarified pregnancy and SAE reporting process. • Corrected storage and shipment conditions of genotyping sample. • Added pharmacogenomic sample to schedule of study procedures. • Corrected typographical errors.

    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.
    Note: Due to a EudraCT system error, the number of participants analzyed for the Statistical Analyses is appearing as 30. The actual number of participants analyzed is 15. When the issue is corrected the record will be updated with the proper data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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