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    Clinical Trial Results:
    A Phase 2a, 15-Day, Randomized, Parallel Group, Double-Blind, Multi-Centre, Vehicle Controlled Trial to Assess the Efficacy and Local Safety of a Cream Containing 0.5% Roflumilast - a Phosphodiesterase Type 4 Inhibitor (PDE4i) Dermal Formulation – on Atopic Dermatitis Patients with Skin Lesions of Moderate Severity

    Summary
    EudraCT number
    		 2012-003000-12
    Trial protocol
    		 DE  
    Global end of trial date
    18 Mar 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ROF-DERM_203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01856764
    WHO universal trial number (UTN)
    		 U1111-1133-6455
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, Illinois, United States, 60015
    Public contact
    Medical Director, Takeda, +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, 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
    24 Jun 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of dermal 0.5% roflumilast cream formulation compared with vehicle on the reduction of atopic dermatitis (AD) lesions during 15 days of treatment in AD subjects with skin lesions of moderate severity, using the modified local SCORing Atopic Dermatitis (SCORAD) tool.
    Protection of trial subjects
    This study was conducted with respect for the study subjects in accordance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP) guidance, and all applicable local regulations. All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 3 centers in Germany from 10 June 2013 to 18 March 2014.

    Pre-assignment
    Screening details
    		 Participants with an historical diagnosis of Atopic Dermatitis were enrolled in 1 of 2 twice daily (BID) treatment groups.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.5% Roflumilast Cream
    Arm description
    		 Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    0.5% Roflumilast Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.

    Arm title
    		 Vehicle Cream
    Arm description
    		 Roflumilast formulation vehicle, cream, topically, twice daily for up to 15 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.5% Roflumilast Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.

    Investigational medicinal product name
    Vehicle Cream
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Roflumilast formulation vehicle, cream, topically, twice daily for up to 15 days.

    Number of subjects in period 1
    		0.5% Roflumilast Cream Vehicle Cream
    Started
    20
    20
    Completed
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    0.5% Roflumilast Cream
    Reporting group description
    		 Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.

    Reporting group title
    Vehicle Cream
    Reporting group description
    		 Roflumilast formulation vehicle, cream, topically, twice daily for up to 15 days.

    Reporting group values
    		 0.5% Roflumilast Cream Vehicle Cream Total
    Number of subjects
    		 20 20 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 20 20 40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.7 ± 11.5 36.5 ± 9.65 -
    Gender categorical
    Units: Subjects
        Female
    		 9 11 20
        Male
    		 11 9 20
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Black or African American
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 20 20 40
        Multiracial
    		 0 0 0
    Smoking classfication
    Units: Subjects
        Subject has never smoked
    		 5 8 13
        Subject is a current smoker
    		 10 9 19
        Subject is an ex-smoker
    		 5 3 8
    Female Reproductive Status
    Units: Subjects
        Postmenopausal
    		 0 0 0
        Surgically Sterile
    		 0 0 0
        Female of Childbearing Potential
    		 9 11 20
        N/A (Subject is Male)
    		 11 9 20
    Height
    Units: Centimeter
        arithmetic mean (standard deviation)
    		 177.3 ± 9.27 174.9 ± 10.13 -
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 81.72 ± 21.757 78.31 ± 12.965 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.65 ± 5.007 25.59 ± 3.477 -
    Baseline Modified Local SCORing Atopic Dermatitis (SCORAD)
    Units: Scores on a scale
        arithmetic mean (full range (min-max))
    		 5.6 (4 to 8) 5.85 (4 to 8) -
    Baseline Transepidermal Water Loss (TEWL)
    Units: g/m^2/hr
        arithmetic mean (full range (min-max))
    		 41.47 (17.8 to 69.8) 41.57 (17.8 to 63.3) -
    Baseline Participant Assessment of Pruritis
    Units: Scores on a scale
        arithmetic mean (full range (min-max))
    		 5.05 (0 to 9) 5 (2 to 10) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who received at least one application of any double-blind study medication.

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    40
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34.6 ± 10.66
    Gender categorical
    Units: Subjects
        Female
    20
        Male
    20
    Race
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Black or African American
        Native Hawaiian or Other Pacific Islander
        White
    40
        Multiracial
    Smoking classfication
    Units: Subjects
        Subject has never smoked
    13
        Subject is a current smoker
    19
        Subject is an ex-smoker
    8
    Female Reproductive Status
    Units: Subjects
        Postmenopausal
    0
        Surgically Sterile
    0
        Female of Childbearing Potential
    20
        N/A (Subject is Male)
    20
    Height
    Units: Centimeter
        arithmetic mean (standard deviation)
    176.1 ± 9.66
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    80.02 ± 17.762
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    25.62 ± 4.255
    Baseline Modified Local SCORing Atopic Dermatitis (SCORAD)
    Units: Scores on a scale
        arithmetic mean (full range (min-max))
    5.725 (4 to 8)
    Baseline Transepidermal Water Loss (TEWL)
    Units: g/m^2/hr
        arithmetic mean (full range (min-max))
    41.52 (17.8 to 69.8)
    Baseline Participant Assessment of Pruritis
    Units: Scores on a scale
        arithmetic mean (full range (min-max))
    5.025 (0 to 10)

    End points

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    End points reporting groups
    Reporting group title
    0.5% Roflumilast Cream
    Reporting group description
    		 Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.

    Reporting group title
    Vehicle Cream
    Reporting group description
    		 Roflumilast formulation vehicle, cream, topically, twice daily for up to 15 days.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who received at least one application of any double-blind study medication.

    Primary: Change From Baseline to Day 15 in Modified Local SCORing Atopic Dermatitis (SCORAD)

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    End point title
    		 Change From Baseline to Day 15 in Modified Local SCORing Atopic Dermatitis (SCORAD)
    End point description
    Modified Local SCORAD is the sum of 5 individual indexes; erythema, edema/papulation, oozing/crusts, excoriations and lichenification scored on a 4 point scale, where 0=absent and 3=severe, with a total possible score of 15. Higher scores indicate greater severity.
    End point type
    Primary
    End point timeframe
    Baseline and Day 15
    End point values
    		 0.5% Roflumilast Cream Vehicle Cream
    Number of subjects analysed
    19 [1]
    20
    Units: Scores on a scale
        least squares mean (standard error)
    -2.3 ± 0.354
    -1.75 ± 0.347
    Notes
    [1] - One subject in the 0.5% Roflumilast group was missing Day 15 data.
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    0.5% Roflumilast Cream v Vehicle Cream
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.276 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5542
         upper limit
    		 0.4574
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.496
    Notes
    [2] - This was an exploratory study designed to obtain preliminary information on the efficacy and safety of topical roflumilast for the treatment of AD.
    [3] - Mixed Model Repeated Measures (MMRM) Model: SCORAD change from baseline = treatment + visit + treatment by visit interaction + baseline SCORAD score.

    Secondary: Change From Baseline to Day 15 in Transepidermal Water Loss (TEWL) Values

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    End point title
    		 Change From Baseline to Day 15 in Transepidermal Water Loss (TEWL) Values
    End point description
    Diffusion of water through the skin is measured using a Tewameter. At each visit, 3 measurements are taken per treatment area (at 3 different areas of the target lesion). The TEWL value at each visit is the average of these measurements.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 0.5% Roflumilast Cream Vehicle Cream
    Number of subjects analysed
    19
    20
    Units: g/m^2/hr
        least squares mean (standard error)
    -18.6 ± 2.467
    -12.69 ± 2.417
    Statistical analysis title
    		 Statiscal Analysis
    Comparison groups
    0.5% Roflumilast Cream v Vehicle Cream
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.095 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -5.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.9134
         upper limit
    		 1.0835
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.454
    Notes
    [4] - MMRM model: TEWL change from baseline = treatment + visit + treatment by visit interaction + baseline TEWL score.

    Secondary: Change From Baseline to Day 15 in Participants’ Assessment of Pruritus

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    End point title
    		 Change From Baseline to Day 15 in Participants’ Assessment of Pruritus
    End point description
    Severity of pruritus is assessed by the participants and recorded on a numeric scale ranging from 0 to 10, where 0 indicates the absence of the symptoms and 10 indicates the most severe symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 15
    End point values
    		 0.5% Roflumilast Cream Vehicle Cream
    Number of subjects analysed
    19 [5]
    20
    Units: Scores on a Scale
        least squares mean (standard error)
    -3.05 ± 0.426
    -1.5 ± 0.417
    Notes
    [5] - One subject in the 0.5% Roflumilast group was missing Day 15 data.
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    0.5% Roflumilast Cream v Vehicle Cream
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.013 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7656
         upper limit
    		 -0.3492
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.596
    Notes
    [6] - MMRM model: Assessment of Pruritus change from baseline = treatment + visit + treatment by visit interaction + baseline Assessment of Pruritus score.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time informed consent is signed through 7 days after the last dose of study drug (up to Day 22)
    Adverse event reporting additional description
    The population consisted of all randomized participants. At each visit, 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
    0.5% Roflumilast Cream
    Reporting group description
    		 Roflumilast 0.5%, cream, topically, twice daily for up to 15 days.

    Reporting group title
    Vehicle Cream
    Reporting group description
    		 Roflumilast formulation vehicle, cream, topically, twice daily for up to 15 days.

    Serious adverse events
    		 0.5% Roflumilast Cream Vehicle Cream
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.5% Roflumilast Cream Vehicle Cream
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 20 (25.00%)
    3 / 20 (15.00%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Red blood cells urine positive
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application Site Pain
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2012
    Protocol Amendment 1 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. • Clarified contraception duration. • Clarified that subjects not capable of giving informed consent were not allowed to participate in the study. • Clarified that subjects with a history of regulator antidepressant administration would not be included. • Added language to exclude institutionalized subjects. • Added text to clarify that antidepressant use was excluded during the study. • Lowered the threshold value for withdrawing subjects due to LFT abnormalities. • Increased total volume of blood drawn due to extra clinical laboratory tests at Day 8. • Clarified laboratory analysis and the use of a central laboratory. • Clarified pregnancy and SAE reporting process. • Corrected typographical errors.
    15 Mar 2013
    Protocol Amendment 2 The following changes were implemented in Protocol Amendment 2: • Changed the sponsor name.

    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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