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    Clinical Trial Results:
    A randomized, double-blind, parallel group phase III multi-center trial to compare twice daily topical application of M518101, Daivonex® and vehicle in patients with plaque psoriasis

    Summary
    EudraCT number
    		 2013-001632-21
    Trial protocol
    		 LT   HU   PL   BG   AT  
    Global end of trial date
    07 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Nov 2021
    First version publication date
    18 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M518101-EU04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Maruho Co.,Ltd.
    Sponsor organisation address
    Kyoto R&D Center, 93, Awata-cho, Chudoji, Shimogyo-ku, Kyoto, Japan, 600-8815
    Public contact
    Clinical Trials Information, Maruho Co.,Ltd. Kyoto R&D Center, +81 (0)75-325-3279, ctinfo@mii.maruho.co.jp
    Scientific contact
    Clinical Trials Information, Maruho Co.,Ltd. Kyoto R&D Center, +81 (0)75-325-3279, ctinfo@mii.maruho.co.jp
    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
    27 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial was designed with two sequentially assessed primary objectives as described in the EMA guideline (Points to consider on switching between superiority and non-inferiority. EMA, July 2000). For the first stage, the primary objective was to demonstrate that M518101 was non-inferior to Daivonex® in % reduction in mPASI and success rate based on IGA. If non-inferiority was demonstrated, the analysis was to proceed to the second stage, which was to demonstrate that M518101 was more effective than Daivonex® in the same endpoints. In addition, superiority to Vehicle for both M518101 and Daivonex® were tested for the same endpoints.
    Protection of trial subjects
    The study was completed in accordance with ICH guidelines. Compliance with this standard provides public assurance that the rights, safety and well-being of the study subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki
    Background therapy
    		 During the screening period subjects should have had adhered to their standard skin care regimen and may have used their standard emollients/moisturizers as symptoms required.
    Evidence for comparator
    		 This study was designed consistent with European guidelines for psoriasis that allow for demonstration of non-inferiority to an active control as long as the treatment is also superior to vehicle. Scientifically, efficacy is most convincingly established by demonstrating superiority to a comparator (vehicle or active control). Furthermore, the comparisons serve to establish that there are no clinically unacceptable differences in safety and tolerability compared with either a comparator drug or vehicle. The comparator identified for this study on psoriasis (Daivonex® ointment, calcipotriol) or calcipotriene) is an established vitamin D3 ointment. A vehicle arm was included to show the possible influence on psoriasis due to skin care effects of the vehicle formulation.
    Actual start date of recruitment
    31 Oct 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
    Poland: 322
    Country: Number of subjects enrolled
    Austria: 21
    Country: Number of subjects enrolled
    Bulgaria: 75
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Hungary: 91
    Country: Number of subjects enrolled
    Lithuania: 72
    Country: Number of subjects enrolled
    Romania: 62
    Country: Number of subjects enrolled
    Ukraine: 93
    Worldwide total number of subjects
    788
    EEA total number of subjects
    695
    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)
    737
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 53 centers in 8 countries (Poland, Germany, Hungary, Bulgaria, Romania, Lithuania, Ukraine, Austria) between 31 October 2013 (first subject first visit) to 07 January 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 1068 potential subjects were screened after signing an informed consent form, of whom 788 subjects were randomized to receive study treatment.

    Period 1
    Period 1 title
    Comparative Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Period1:M518101
    Arm description
    		 Subjects were blindly randomized in M518101 BID, 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    M518101
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    M518101 BID application was performed during 8 weeks in Period 1. Based on application guidance and depending on affected BSA (maximum 20%) it was calculated that each application required up to 5 g ointment. (up to 10 g ointment per day).

    Arm title
    		 Period1:Daivonex® ointment
    Arm description
    		 Subjects were blindly randomized in Daivonex® ointment BID, 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Daivonex® ointment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Daivonex® ointment BID application was performed during 8 weeks in Period 1. Based on application guidance and depending on affected BSA (maximum 20%) it was calculated that each application required up to 5 g ointment. (up to 10 g ointment per day).

    Arm title
    		 Period1:Vehicle
    Arm description
    		 Subjects were blindly randomized in Vehicle BID, 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle BID application was performed during 8 weeks in Period 1. Based on application guidance and depending on affected BSA (maximum 20%) it was calculated that each application required up to 5 g ointment. (up to 10 g ointment per day).

    Number of subjects in period 1
    		Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Started
    318
    313
    157
    Completed
    267
    284
    127
    Not completed
    51
    29
    30
         Consent withdrawn by subject
    20
    12
    17
         Physician decision
    1
    -
    -
         QTcF measurements increased 60 msec from Baseline
    1
    1
    -
         Non-compliant use of the study drug
    -
    -
    1
         Adverse event, non-fatal
    19
    3
    -
         Other
    1
    2
    1
         Worsening of psoriasis
    2
    4
    3
         Lost to follow-up
    5
    3
    4
         Protocol deviation
    2
    4
    4
    Period 2
    Period 2 title
    Follow-Up Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Period2:M518101
    Arm description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the period2 up to a maximum duration of 8 weeks, and were supplied with vehicle and instructed to apply BID.

    Arm title
    		 Period2:Daivonex® ointment
    Arm description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the period2 up to a maximum duration of 8 weeks, and were supplied with vehicle and instructed to apply BID.

    Arm title
    		 Period2:Vehicle
    Arm description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the period2 up to a maximum duration of 8 weeks, and were supplied with vehicle and instructed to apply BID.

    Number of subjects in period 2 [1]
    		Period2:M518101 Period2:Daivonex® ointment Period2:Vehicle
    Started
    205
    242
    65
    Completed
    195
    217
    65
    Not completed
    10
    25
    0
         Consent withdrawn by subject
    5
    15
    -
         Physician decision
    1
    3
    -
         Non-compliant use of the study drug
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
         Other
    2
    1
    -
         Pregnancy
    1
    -
    -
         Worsening of psoriasis
    -
    1
    -
         Lost to follow-up
    1
    1
    -
         Protocol deviation
    -
    2
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who achieved ≥ mPASI50 (at least a 50% improvement in mPASI score) at WEEK 8 were eligible to participate in the follow-up phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Period1:M518101
    Reporting group description
    		 Subjects were blindly randomized in M518101 BID, 8 weeks.

    Reporting group title
    Period1:Daivonex® ointment
    Reporting group description
    		 Subjects were blindly randomized in Daivonex® ointment BID, 8 weeks.

    Reporting group title
    Period1:Vehicle
    Reporting group description
    		 Subjects were blindly randomized in Vehicle BID, 8 weeks.

    Reporting group values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle Total
    Number of subjects
    		 318 313 157 788
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 295 297 145 737
        From 65-84 years
    		 23 16 12 51
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.8 ± 14.10 43.9 ± 13.11 43.4 ± 14.67 -
    Gender categorical
    Units: Subjects
        Female
    		 109 135 60 304
        Male
    		 209 178 97 484
    Race
    Units: Subjects
        White/Caucasian
    		 318 312 157 787
        Other
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Period1:M518101
    Reporting group description
    		 Subjects were blindly randomized in M518101 BID, 8 weeks.

    Reporting group title
    Period1:Daivonex® ointment
    Reporting group description
    		 Subjects were blindly randomized in Daivonex® ointment BID, 8 weeks.

    Reporting group title
    Period1:Vehicle
    Reporting group description
    		 Subjects were blindly randomized in Vehicle BID, 8 weeks.
    Reporting group title
    Period2:M518101
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Reporting group title
    Period2:Daivonex® ointment
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Reporting group title
    Period2:Vehicle
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Primary: The success rate based on IGA score at WEEK 8

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    End point title
    		 The success rate based on IGA score at WEEK 8
    End point description
    The success rate was defined as the subject having ''absence'' of disease or ''very mild'' disease with at least a 2-grade improvement in the IGA at WEEK 8 when compared to Baseline.
    End point type
    Primary
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    318
    313
    157
    Units: percentage of subjects
        number (not applicable)
    46.5
    57.2
    21.7
    Statistical analysis title
    		 M518101 vs Vehicle
    Comparison groups
    Period1:M518101 v Period1:Vehicle
    Number of subjects included in analysis
    475
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.279
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.091
         upper limit
    		 5.143
    Statistical analysis title
    		 M518101 vs Daivonex® ointment
    Comparison groups
    Period1:M518101 v Period1:Daivonex® ointment
    Number of subjects included in analysis
    631
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.007
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.474
         upper limit
    		 0.891

    Primary: % reduction in mPASI at WEEK 8 compared to Baseline

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    End point title
    		 % reduction in mPASI at WEEK 8 compared to Baseline
    End point description
    End point type
    Primary
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    270
    286
    128
    Units: percentage of units on a scale
        least squares mean (confidence interval 95%)
    62.265 (58.242 to 66.287)
    70.959 (66.969 to 74.948)
    39.340 (33.580 to 45.100)
    Statistical analysis title
    		 M518101 vs Vehicle
    Comparison groups
    Period1:M518101 v Period1:Vehicle
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM/ANCOVA Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    22.925
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.966
         upper limit
    		 29.884
    Statistical analysis title
    		 M518101 vs Daivonex® ointment
    Comparison groups
    Period1:M518101 v Period1:Daivonex® ointment
    Number of subjects included in analysis
    556
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.002 [1]
    Method
    		 MMRM/ANCOVA Model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -8.694
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.276
         upper limit
    		 -3.112
    Notes
    [1] - The hypothesis testing non-inferiority of M518101 vs Daivonex® ointment could not be rejected since the lower bound of the 95% CI of the LS mean difference in % reduction in mPASI (-14.276) was lower than the non- inferiority margin(-Δ1= -11%).

    Secondary: mPASI50 rate at WEEK 8

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    End point title
    		 mPASI50 rate at WEEK 8
    End point description
    End point type
    Secondary
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    318
    313
    157
    Units: percentage of subjects
        number (not applicable)
    69.8
    82.7
    43.9
    No statistical analyses for this end point

    Secondary: mPASI75 rate at WEEK 8

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    End point title
    		 mPASI75 rate at WEEK 8
    End point description
    End point type
    Secondary
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    318
    313
    157
    Units: percentage of subjects
        number (not applicable)
    39.9
    56.2
    21.7
    No statistical analyses for this end point

    Secondary: Change in PSI total score at WEEK 8 compared to Baseline

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    End point title
    		 Change in PSI total score at WEEK 8 compared to Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    270
    286
    128
    Units: units on a scale
        arithmetic mean (standard deviation)
    -9.9 ± 4.27
    -11.3 ± 3.64
    -7.2 ± 4.52
    No statistical analyses for this end point

    Secondary: % reduction in mPASI at WEEK 1 compared to Baseline

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    End point title
    		 % reduction in mPASI at WEEK 1 compared to Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    week 1
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    313
    311
    154
    Units: percentage of units on a scale
        least squares mean (confidence interval 95%)
    23.522 (21.361 to 25.683)
    24.504 (22.327 to 26.682)
    15.877 (12.875 to 18.879)
    No statistical analyses for this end point

    Other pre-specified: Duration of response (time to relapse)

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    End point title
    		 Duration of response (time to relapse)
    End point description
    According to the EMA guideline relapse was defined when the maximal improvement from Baseline is reduced by > 50%.
    End point type
    Other pre-specified
    End point timeframe
    The date at which the relapse occurred
    End point values
    		 Period2:M518101 Period2:Daivonex® ointment Period2:Vehicle
    Number of subjects analysed
    204
    242
    65
    Units: days
        median (inter-quartile range (Q1-Q3))
    57.0 (56.0 to 57.0)
    57.0 (55.0 to 57.0)
    57.0 (55.0 to 57.0)
    No statistical analyses for this end point

    Other pre-specified: Change in QOL-DLQI score from Baseline to WEEK 8

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    End point title
    		 Change in QOL-DLQI score from Baseline to WEEK 8
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    269
    284
    128
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -4.3 (-4.86 to -3.71)
    -5.9 (-6.43 to -5.29)
    -3.2 (-3.98 to -2.35)
    No statistical analyses for this end point

    Other pre-specified: Time course change in mean % reduction in mPASI score

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    End point title
    		 Time course change in mean % reduction in mPASI score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 1,2,4,6,8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    313 [2]
    311 [3]
    154 [4]
    Units: percentage of units on a scale
    least squares mean (confidence interval 95%)
        week1
    23.522 (21.361 to 25.683)
    24.504 (22.327 to 26.682)
    15.877 (12.875 to 18.879)
        week2
    39.667 (37.008 to 42.325)
    41.925 (39.249 to 44.600)
    27.221 (23.499 to 30.943)
        week4
    50.366 (47.227 to 53.505)
    55.685 (52.529 to 58.840)
    31.302 (26.881 to 35.723)
        week6
    58.289 (55.098 to 61.480)
    65.916 (62.713 to 69.118)
    37.518 (32.988 to 42.048)
        week8
    62.265 (58.242 to 66.287)
    70.959 (66.969 to 74.948)
    39.340 (33.580 to 45.100)
    Notes
    [2] - week1:N=313, week2:N=306, week4:N=300, week6:N=289, week8:N=270
    [3] - week1:N=311, week2:N=304, week4:N=299, week6:N=290, week8:N=286
    [4] - week1:N=154, week2:N=151, week4:N=148, week6:N=136, week8:N=128
    No statistical analyses for this end point

    Other pre-specified: Time course change in PSI total score

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    End point title
    		 Time course change in PSI total score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 1,2,4,6,8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    270
    286
    128
    Units: units on a scale
    least squares mean (confidence interval 95%)
        week1
    -4.3 (-4.62 to -3.97)
    -4.2 (-4.51 to -3.85)
    -2.5 (-2.99 to -2.07)
        week2
    -6.6 (-7.00 to -6.29)
    -6.9 (-7.29 to -6.57)
    -4.6 (-5.09 to -4.09)
        week4
    -7.9 (-8.31 to -7.55)
    -8.9 (-9.26 to -8.50)
    -5.6 (-6.12 to -5.06)
        week6
    -9.0 (-9.42 to -8.66)
    -10.1 (-10.53 to -9.76)
    -6.3 (-6.82 to -5.75)
        week8
    -9.5 (-9.99 to -9.10)
    -11.0 (-11.40 to -10.52)
    -6.8 (-7.42 to -6.15)
    No statistical analyses for this end point

    Other pre-specified: Change in BSA at WEEK 8 compared to the Baseline

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    End point title
    		 Change in BSA at WEEK 8 compared to the Baseline
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    269
    283
    127
    Units: percentage
        least squares mean (confidence interval 95%)
    -2.9 (-3.28 to -2.43)
    -3.3 (-3.73 to -2.90)
    -1.9 (-2.45 to -1.26)
    No statistical analyses for this end point

    Other pre-specified: Time course change in mPASI rates (50% and 75%)

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    End point title
    		 Time course change in mPASI rates (50% and 75%)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 1,2,4,6,8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    313 [5]
    311 [6]
    154 [7]
    Units: percentage of units on a scale
    number (not applicable)
        mPASI50 response WEEK 1
    10.1
    8.9
    5.1
        mPASI50 response WEEK 2
    36.2
    37.4
    16.6
        mPASI50 response WEEK 4
    55.7
    65.5
    26.1
        mPASI50 response WEEK 6
    67.3
    81.5
    37.6
        mPASI50 response WEEK 8
    69.8
    82.7
    43.9
        mPASI75 response WEEK 1
    1.3
    0.3
    0.0
        mPASI75 response WEEK 2
    5.7
    5.4
    0.6
        mPASI75 response WEEK 4
    17.3
    21.1
    3.8
        mPASI75 response WEEK 6
    28.9
    38.7
    11.5
        mPASI75 response WEEK 8
    39.9
    56.2
    21.7
    Notes
    [5] - Week 1:N=313, Week 2:N=306, Week 4:N=300, Week 6:N=289, Week 8:N=270
    [6] - Week 1:N=311, Week 2:N=304, Week 4:N=299, Week 6:N=290, Week 8:N=286
    [7] - Week 1:N=154, Week 2:N=151, Week 4:N=148, Week 6:N=136, Week 8:N=128
    No statistical analyses for this end point

    Other pre-specified: Time course change in IGA success rate

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    End point title
    		 Time course change in IGA success rate
    End point description
    End point type
    Other pre-specified
    End point timeframe
    week 1,2,4,6,8
    End point values
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle
    Number of subjects analysed
    318
    313
    157
    Units: percentage of units on a score
    number (not applicable)
        week1
    3.8
    1.9
    0
        week2
    10.4
    9.3
    4.5
        week4
    20.1
    25.6
    4.5
        week6
    33.0
    41.2
    14.0
        week8
    46.5
    57.2
    21.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Period1:M518101
    Reporting group description
    		 Subjects were blindly randomized in M518101 BID, 8 weeks.

    Reporting group title
    Period1:Daivonex® ointment
    Reporting group description
    		 Subjects were blindly randomized in Daivonex® ointment BID, 8 weeks.

    Reporting group title
    Period1:Vehicle
    Reporting group description
    		 Subjects were blindly randomized in Vehicle BID, 8 weeks.

    Reporting group title
    Period2:M518101
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Reporting group title
    Period2:Daivonex® ointment
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Reporting group title
    Period2:Vehicle
    Reporting group description
    		 Subjects who achieved >= mPASI50 improvement at WEEK 8 were eligible to enter the Vehicle BID of period2 up to maximum duration of 8 weeks.

    Serious adverse events
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle Period2:M518101 Period2:Daivonex® ointment Period2:Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 315 (0.63%)
    1 / 312 (0.32%)
    2 / 158 (1.27%)
    0 / 204 (0.00%)
    1 / 242 (0.41%)
    0 / 66 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fracture displacement
         subjects affected / exposed
    0 / 315 (0.00%)
    1 / 312 (0.32%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 315 (0.00%)
    0 / 312 (0.00%)
    1 / 158 (0.63%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    0 / 315 (0.00%)
    0 / 312 (0.00%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    1 / 242 (0.41%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    alternative dictionary used: MedDRA 17.1
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 312 (0.00%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 315 (0.00%)
    0 / 312 (0.00%)
    1 / 158 (0.63%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Peritionsillar abscess
         subjects affected / exposed
    1 / 315 (0.32%)
    0 / 312 (0.00%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Period1:M518101 Period1:Daivonex® ointment Period1:Vehicle Period2:M518101 Period2:Daivonex® ointment Period2:Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 315 (12.38%)
    17 / 312 (5.45%)
    6 / 158 (3.80%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
    General disorders and administration site conditions
    Application site pain
    Additional description: No data available to report for period2.
         subjects affected / exposed
    7 / 315 (2.22%)
    3 / 312 (0.96%)
    1 / 158 (0.63%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    9
    6
    1
    0
    0
    0
    Application site pruritus
    Additional description: No data available to report for period2.
         subjects affected / exposed
    7 / 315 (2.22%)
    2 / 312 (0.64%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    8
    4
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Contact dermatitis
    Additional description: No data available to report for period2.
         subjects affected / exposed
    16 / 315 (5.08%)
    3 / 312 (0.96%)
    0 / 158 (0.00%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    19
    3
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
    Additional description: No data available to report for period2.
         subjects affected / exposed
    9 / 315 (2.86%)
    9 / 312 (2.88%)
    5 / 158 (3.16%)
    0 / 204 (0.00%)
    0 / 242 (0.00%)
    0 / 66 (0.00%)
         occurrences all number
    9
    10
    6
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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