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    Clinical Trial Results:
    A multi-center, randomized, double-blind, three-arm, 16 week, adaptive phase III clinical study to investigate the efficacy and safety of LAS41008 vs LASW1835 and vs placebo in patients with moderate to severe plaque psoriasis

    Summary
    EudraCT number
    2012-000055-13
    Trial protocol
    DE   AT   NL   PL  
    Global end of trial date
    19 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Dec 2016
    First version publication date
    11 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M41008-1102
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    ALMIRALL S.A.
    Sponsor organisation address
    Laureà Miró 408-410, Sant Feliu de Llobregat (Barcelona), Spain, 08980
    Public contact
    Disclosure Central Team, ALMIRALL S.A., R&D@almirall.com
    Scientific contact
    Disclosure Central Team, ALMIRALL S.A., R&D@almirall.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 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are: Superiority of LAS41008 versus placebo based on the proportion of subjects achieving PASI 75 (a reduction of at least 75% in the Psoriasis Area and Severity Index) at Week 16 Superiority of LAS41008 versus placebo based on the proportion of subjects achieving a score of 'clear' or 'almost clear' in the Physician’s Global Assessment (PGA) at Week 16 Non-inferiority of LAS41008 compared to LASW1835 (internal code for Fumaderm®) regarding PASI 75 at Week 16
    Protection of trial subjects
    This study was conducted in accordance with the protocol, Good Clinical Practice (GCP), ICH (International Conference on Harmonization) guidelines, and the ethical principles set forth in the Declaration of Helsinki and its amendments (October 2008) A favourable opinion of the relevant independent ethics committees was obtained prior to the start of the study and written informed consent was obtained from all patients prior to entry into the study. The investigator explained to each patient, orally and in writing (patient information sheet), the nature, significance, risks and implications of the trial
    Background therapy
    -
    Evidence for comparator
    Fumaderm® is a prescription only medicine currently approved only in Germany, where it is the most commonly prescribed oral therapy for the treatment of psoriasis Several publications and other prescribing evidence indicate that Fumaderm® is used by specialist dermatology centers under local legal arrangements in a number of other countries throughout Europe
    Actual start date of recruitment
    07 Jan 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Poland: 321
    Country: Number of subjects enrolled
    Austria: 65
    Country: Number of subjects enrolled
    Germany: 302
    Worldwide total number of subjects
    699
    EEA total number of subjects
    699
    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)
    637
    From 65 to 84 years
    61
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in a total of 57 sites, 7 in Austria, 36 in Germany, 12 in Poland, and 2 in the Netherlands The first patient visit was in January 2013 and the last patient visit was October 2015

    Pre-assignment
    Screening details
    A total of 839 patients were screened and 704 patients were randomised Wash-out periods were 2 weeks (corticosteroids, vitamin A or D analogues, anthracene derivatives, tar and salicylic acid preparations), 1 month (conventional systemic antipsoriatic drugs and phototherapy), 3 months (antipsoriatic biologics) or 6 months (cytostatics)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    LAS41008
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    LAS41008
    Investigational medicinal product code
    Other name
    Dimethyl fumarate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the first three weeks of the treatment period, patients received up to 3 x 1 tablet containing 30 mg LAS41008 (30 mg/day in Week 1, 60 mg/day in Week 2 and 90 mg/day in Week 3) During the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 tablets each containing 120 mg LAS41008 leading to a maximum of 720 mg/day (120 mg/day in Week 4, 240 mg/day in Week 5, 360 mg/day in Week 6, 480 mg/day in Week 7, 600 mg/day in Week 8, 720 mg/day in Week 9 onwards) In case of individual intolerability of the increased dosage, the patient was to receive the last tolerated dose, which was then to be maintained until the end of the treatment period If treatment success (patient achieved a score of 'clear' or 'almost clear' in the PGA or >90% improvement in PASI from baseline) was reached before administration of the maximum dose of 720 mg/day, no further dose increase was necessary and the dosage was to be steadily reduced to an individual maintenance dose

    Arm title
    Fumaderm®
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Fumaderm®
    Investigational medicinal product code
    Other name
    Dimethyl fumarate
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the first three weeks of the treatment period, patients received up to 3 x 1 tablet containing 30 mg Fumaderm® (30 mg/day in Week 1, 60 mg/day in Week 2 and 90 mg/day in Week 3) During the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 tablets each containing 120 mg Fumaderm® leading to a maximum of 720 mg/day (120 mg/day in Week 4, 240 mg/day in Week 5, 360 mg/day in Week 6, 480 mg/day in Week 7, 600 mg/day in Week 8, 720 mg/day in Week 9 onwards) In case of individual intolerability of the increased dosage, the patient was to receive the last tolerated dose, which was then to be maintained until the end of the treatment period If treatment success (patient achieved a score of 'clear' or 'almost clear' in the PGA or >90% improvement in PASI from baseline) was reached before administration of the maximum dose of 720 mg/day, no further dose increase was necessary and the dosage was to be steadily reduced to an individual maintenance dose

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    During the first three weeks of the treatment period, patients received up to 3 x 1 placebo and during the subsequent 13 weeks (Week 4 until Week 16), patients received up to 3 x 2 placebo tablets

    Number of subjects in period 1
    LAS41008 Fumaderm® Placebo
    Started
    279
    283
    137
    Completed treatment period
    176
    176
    98
    Completed
    42
    51
    17
    Not completed
    237
    232
    120
         Protocol deviation
    6
    8
    1
         Lack of efficacy
    46
    49
    48
         Adverse event, serious fatal
    -
    1
    -
         Not specified
    56
    38
    19
         Adverse event, non-fatal
    66
    70
    6
         Consent withdrawn by subject
    40
    40
    29
         Lost to follow-up
    23
    26
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LAS41008
    Reporting group description
    -

    Reporting group title
    Fumaderm®
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group values
    LAS41008 Fumaderm® Placebo Total
    Number of subjects
    279 283 137 699
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44 ± 15.24 45 ± 13.84 44 ± 14.26 -
    Gender categorical
    Units: Subjects
        Female
    105 98 44 247
        Male
    174 185 93 452

    End points

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    End points reporting groups
    Reporting group title
    LAS41008
    Reporting group description
    -

    Reporting group title
    Fumaderm®
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Primary: Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16

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    End point title
    Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16
    End point description
    PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Primary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
        number (not applicable)
    37.5
    40.3
    15.3
    Statistical analysis title
    LAS41008 vs Placebo
    Statistical analysis description
    P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of the p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure Co-primary endpoints were non-adjusted The last observation carried forward (LOCF) method was used for missing data
    Comparison groups
    Placebo v LAS41008
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Wald test
    Parameter type
    Mean difference (net)
    Point estimate
    0.222
    Confidence interval
         level
    99.24%
         sides
    2-sided
         lower limit
    0.107
         upper limit
    0.337
    Notes
    [1] - p value is significant if <0.0038
    Statistical analysis title
    LAS-41008 vs Fumaderm®
    Statistical analysis description
    P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of the p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure Co-primary endpoints were non-adjusted The last observation carried forward (LOCF) method was used for missing data
    Comparison groups
    Fumaderm® v LAS41008
    Number of subjects included in analysis
    540
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0003 [2]
    Method
    Wald test
    Parameter type
    Mean difference (net)
    Point estimate
    -0.028
    Confidence interval
         level
    99.24%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.084
    Notes
    [2] - p value is significant if <0.0038

    Primary: Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16

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    End point title
    Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Primary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
        number (not applicable)
    33
    37.4
    13
    Statistical analysis title
    LAS41008 vs Placebo
    Statistical analysis description
    P values are derived from the Wald test for risk differences and a combination (p value Stage 1 x p value Stage 2) of p-values from Stage 1 (from study start to the time of the interim analysis) and Stage 2 (period comprising the remaining treatment period and the first 2 months of follow up for all subjects continuing in the study) according to the Bauer & Köhne procedure Co-primary endpoints were non-adjusted The last observation carried forward (LOCF) method was used for missing data
    Comparison groups
    Placebo v LAS41008
    Number of subjects included in analysis
    398
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [3]
    Method
    Wald test
    Parameter type
    Median difference (net)
    Point estimate
    0.2
    Confidence interval
         level
    99.24%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    0.31
    Notes
    [3] - p value is significant if <0.0038

    Secondary: Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 3 and 8

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    End point title
    Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 3 and 8
    End point description
    PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    Week 3 and 8 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        Week 3
    1.1
    0.4
    0
        Week 8
    7.5
    8.4
    5.3
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 50 and PASI 90 at Week 3, 8, and 16

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    End point title
    Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 50 and PASI 90 at Week 3, 8, and 16
    End point description
    PASI 50 is a reduction of at least 50% in the Psoriasis Area and Severity Index (PASI); PASI 90 is a reduction of at least 90% in the PASI The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    Week 3, 8, and 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        PASI 50 Week 3
    5.6
    5.9
    2.3
        PASI 50 Week 8
    26.6
    31.9
    17.6
        PASI 50 Week 16
    53.6
    61.9
    29
        PASI 90 Week 3
    0
    0
    0
        PASI 90 Week 8
    1.5
    1.5
    0
        PASI 90 Week 16
    18.4
    22.3
    0
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 3 and 8

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    End point title
    Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 3 and 8
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 3 and 8 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        Week 3
    0.4
    0
    0
        Week 8
    5.6
    7
    2.3
    No statistical analyses for this end point

    Secondary: Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at Week 3, 8, 16, and 2 months treatment-free

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    End point title
    Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at Week 3, 8, 16, and 2 months treatment-free
    End point description
    The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    Week 3, 8 and 16 of treatment and 2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Score
    arithmetic mean (standard deviation)
        Week 3 (absolute values)
    14.4 ± 6.42
    14.5 ± 7.38
    14.8 ± 5.53
        Week 8 (absolute values)
    11 ± 5.78
    11.2 ± 8.04
    12.9 ± 6.57
        Week 16 (absolute values)
    7.8 ± 6.8
    7.8 ± 8.73
    11.9 ± 7.25
        2 months treatment-free (absolute values)
    8.1 ± 6.74
    8.3 ± 8.78
    11.8 ± 7.55
        Week 3 (percent change)
    -11.8 ± 24.19
    -12.3 ± 22.14
    -8.2 ± 18.11
        Week 8 (percent change)
    -30.9 ± 33.36
    -33.1 ± 31.77
    -20 ± 31.2
        Week 16 (percent change)
    -50.8 ± 41.78
    -54.1 ± 39.94
    -27 ± 37.62
        2 months treatment-free (percent change)
    -48.5 ± 41.72
    -51.6 ± 39.87
    -27.5 ± 39.28
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score at Week 3

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    End point title
    Physician's Global Assessment score at Week 3
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 3 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    0
    0
    0
        PGA Score 1
    0.4
    0
    0
        PGA Score 2
    10.1
    11.7
    10.7
        PGA Score 3
    62.5
    60.8
    55.7
        PGA Score 4
    22.1
    24.2
    32.1
        PGA Score 5
    4.9
    3.3
    1.5
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score at Week 8

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    End point title
    Physician's Global Assessment score at Week 8
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 8 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    0.4
    0
    0
        PGA Score 1
    5.2
    7
    2.3
        PGA Score 2
    31.1
    35.2
    27.5
        PGA Score 3
    48.7
    43.6
    45
        PGA Score 4
    12.4
    12.1
    23.7
        PGA Score 5
    2.2
    2.2
    1.5
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score at Week 16

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    End point title
    Physician's Global Assessment score at Week 16
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    6.4
    7.7
    0.8
        PGA Score 1
    26.6
    29.7
    12.2
        PGA Score 2
    23.2
    25.6
    20.6
        PGA Score 3
    33.7
    26.7
    42.7
        PGA Score 4
    8.6
    8.1
    20.6
        PGA Score 5
    1.5
    2.2
    3.1
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score 2 months treatment-free

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    End point title
    Physician's Global Assessment score 2 months treatment-free
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    6
    7
    0
        PGA Score 1
    21
    23.4
    15.3
        PGA Score 2
    28.8
    28.6
    18.3
        PGA Score 3
    33
    28.6
    44.3
        PGA Score 4
    9.4
    9.9
    20.6
        PGA Score 5
    1.9
    2.6
    1.5
    No statistical analyses for this end point

    Secondary: Mean % change from baseline in % body surface area (BSA) affected

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    End point title
    Mean % change from baseline in % body surface area (BSA) affected
    End point description
    End point type
    Secondary
    End point timeframe
    Week 3, 8, 16 of treatment and 2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of BSA
    arithmetic mean (standard deviation)
        Week 3
    -0.5 ± 5.02
    -0.5 ± 3.63
    -0.7 ± 4.73
        Week 8
    -4.1 ± 7.56
    -3.5 ± 6.2
    -2.3 ± 7.59
        Week 16
    -13.2 ± 12.07
    -11.3 ± 10.25
    -4.9 ± 10.76
        2 months treatment-free
    -13.5 ± 11.52
    -12.7 ± 10.67
    -7.2 ± 13.22
    No statistical analyses for this end point

    Secondary: Treatment success rate

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    End point title
    Treatment success rate
    End point description
    Treatment success was defined as patients achieving either a 'clear' or 'almost clear score in the Physician's Global Assessment (PGA) score and/or Psoriasis Area and Severity Index (PASI) 90
    End point type
    Secondary
    End point timeframe
    Week 3, 8, 16 of treatment and 2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        Week 3
    0.4
    0
    0
        Week 8
    5.6
    7
    2.3
        Week 16
    33.3
    38.1
    13
        2 months treatment-free
    27.5
    32.6
    15.3
    No statistical analyses for this end point

    Secondary: Remission rate

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    End point title
    Remission rate
    End point description
    The remission rate was defined as a score of 'clear' in the Physician's Global Assessment (PGA) score
    End point type
    Secondary
    End point timeframe
    Week 3, Week 8, Week 16 of treatment and 2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent
    number (not applicable)
        Week 3
    0
    0
    0
        Week 8
    0.4
    0
    0
        Week 16
    6.4
    7.7
    0.8
        2 months treatment-free
    6
    7
    0
    No statistical analyses for this end point

    Secondary: Mean time to relapse within 2 months of stopping therapy

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    End point title
    Mean time to relapse within 2 months of stopping therapy
    End point description
    Relapse was defined as the event when the achieved maximal improvement from baseline was subsequently reduced by ≥50% based on the Psoriasis Area and Severity Index (PASI)
    End point type
    Secondary
    End point timeframe
    Up to 2 months after stopping therapy
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    16 [4]
    17 [5]
    16 [6]
    Units: Days
        arithmetic mean (standard error)
    66.8 ± 0.74
    65 ± 0.72
    59.6 ± 1.65
    Notes
    [4] - 16/175 patients in the LAS41008 group had a relapse
    [5] - 17/179 patients in the Fumaderm® group had a relapse
    [6] - 16/68 patients in the placebo group had a relapse
    No statistical analyses for this end point

    Secondary: Time to rebound within 2 months of stopping therapy

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    End point title
    Time to rebound within 2 months of stopping therapy
    End point description
    Rebound was defined as worsening of psoriasis over baseline value (Psoriasis Area and Severity Index [PASI]≥125%) or new pustular, erythrodermic or more inflammatory psoriasis occurring within 2 months of stopping therapy
    End point type
    Secondary
    End point timeframe
    Up to 2 months after stopping therapy
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    2 [7]
    4 [8]
    7 [9]
    Units: Days
        arithmetic mean (standard error)
    63.7 ± 0.4
    64.6 ± 0.36
    62.3 ± 1.12
    Notes
    [7] - 2/177 patients in the LAS41008 group had a rebound
    [8] - 4/183 patients in the Fumaderm® group had a rebound
    [9] - 7/75 patients in the placebo group had a rebound
    No statistical analyses for this end point

    Secondary: Patient Benefit Index (PBI) at Week 16 and 2 months treatment-free

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    End point title
    Patient Benefit Index (PBI) at Week 16 and 2 months treatment-free
    End point description
    The Patient Benefit Index (PBI) was calculated based on the Patient Need Questionnaire (PNQ) assessed at the start of treatment and on the Patient Benefit Questionnaire (PBQ) assessed after 16 weeks of treatment and during the follow-up period In the PNQ, patients were asked to indicate how important they considered 25 different treatment goals on a five-point scale from 'not at all' to 'very' In the PBQ, patients were asked if the study treatment had helped them to achieve these goals The PBI was calculated by averaging the preference-weighed results of all items
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment and 2 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    254
    260
    119
    Units: Score
    arithmetic mean (standard deviation)
        Week 16
    2.1 ± 1.25
    2.1 ± 1.24
    1.3 ± 1.1
        2 months treatment-free
    2.4 ± 1.05
    2.4 ± 1.02
    1.5 ± 1.17
    No statistical analyses for this end point

    Secondary: Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at 6 and 12 months treatment-free

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    End point title
    Absolute values and percent change from baseline in Psoriasis Area and Severity Index (PASI) at 6 and 12 months treatment-free
    End point description
    The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    6 and 12 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Score
    arithmetic mean (standard deviation)
        6 months treatment-free (absolute values)
    9 ± 6.61
    9.4 ± 8.65
    12 ± 7.36
        12 months treatment-free (absolute values)
    9.4 ± 6.68
    9.5 ± 8.57
    11.8 ± 7.47
        6 months treatment-free (percent change)
    -42.7 ± 41.38
    -44.2 ± 40.6
    -25.2 ± 39.46
        12 months treatment-free (percent change)
    -40.6 ± 41.93
    -43.6 ± 39.19
    -27.5 ± 39.91
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score 6 months treatment-free

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    End point title
    Physician's Global Assessment score 6 months treatment-free
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    6 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    3.4
    2.9
    0
        PGA Score 1
    16.9
    17.2
    10.7
        PGA Score 2
    27.3
    32.6
    22.9
        PGA Score 3
    40.1
    33.3
    43.5
        PGA Score 4
    10.1
    11.4
    21.4
        PGA Score 5
    2.2
    2.6
    1.5
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment score 12 months treatment-free

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    End point title
    Physician's Global Assessment score 12 months treatment-free
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    12 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of patients
    number (not applicable)
        PGA Score 0
    2.6
    3.7
    0
        PGA Score 1
    15.4
    16.8
    9.2
        PGA Score 2
    27.3
    29.7
    26.7
        PGA Score 3
    40.8
    35.5
    41.2
        PGA Score 4
    11.6
    11.7
    21.4
        PGA Score 5
    2.2
    2.6
    1.5
    No statistical analyses for this end point

    Secondary: Mean % change from baseline in % body surface area (BSA) affected at 6 and 12 months treatment-free

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    End point title
    Mean % change from baseline in % body surface area (BSA) affected at 6 and 12 months treatment-free
    End point description
    End point type
    Secondary
    End point timeframe
    6 and 12 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percent of BSA
    arithmetic mean (standard deviation)
        6 months treatment-free
    -11.4 ± 11.57
    -9 ± 11.75
    -9.2 ± 13.58
        12 months treatment-free
    -10.2 ± 15.44
    -11 ± 8.65
    -9.2 ± 7.59
    No statistical analyses for this end point

    Secondary: Mean time to relapse including data up to 12 months treatment-free

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    End point title
    Mean time to relapse including data up to 12 months treatment-free
    End point description
    Relapse was defined as the event when the achieved maximal improvement from baseline was subsequently reduced by ≥50% based on PASI
    End point type
    Secondary
    End point timeframe
    Up to 12 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    54 [10]
    66 [11]
    40 [12]
    Units: Days
        arithmetic mean (standard error)
    377.3 ± 13.04
    354.9 ± 11.99
    226.4 ± 9.54
    Notes
    [10] - 54/267 patients in the LAS41008 group had a relapse
    [11] - 66/273 patients in the Fumaderm® group had a relapse
    [12] - 40/131 patients in the placebo group had a relapse
    No statistical analyses for this end point

    Secondary: Dermatology Life Quality Index (DLQI) score

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    End point title
    Dermatology Life Quality Index (DLQI) score
    End point description
    The Dermatology Life Quality Index (DLQI) is a patient-reported outcome that also includes assessment of improvement in symptoms such as pruritus The questionnaire comprises 10 questions (eg, over the last week, how itchy, sore, painful or stinging has your skin been?) relating to symptoms and feelings, daily activities, leisure, work and school, personal relationships and treatment The scoring of each question was as follows: 0 = not at all 1 = a little 2 = a lot 3 = very much The DLQI was calculated by summing the score for each question, resulting in a maximum of 30 and a minimum of 0
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment and 2, 6 and 12 months treatment-free
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Score
    arithmetic mean (standard deviation)
        Week 16
    5.4 ± 6.07
    6.1 ± 7.18
    8.5 ± 6.88
        2 months treatment-free
    4.8 ± 5.57
    5.4 ± 6.12
    7.8 ± 5.98
        6 months treatment-free
    5.8 ± 6.66
    6.6 ± 5.77
    7.6 ± 6.33
        12 months treatment-free
    7.8 ± 6.63
    8 ± 6.55
    7 ± 5.96
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by intake of potentially nephrotoxic medicines

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    End point title
    Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by intake of potentially nephrotoxic medicines
    End point description
    PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        Patients using potentially nephrotoxic medicine
    39
    28
    11.8
        Not using potentially nephrotoxic medicine
    37.2
    43
    15.8
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by age group

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    End point title
    Proportion of patients achieving Psoriasis Area and Severity Index (PASI) 75 at Week 16 by age group
    End point description
    PASI 75 is a reduction of at least 75% in the Psoriasis Area and Severity Index (PASI) The PASI requires the assessment of erythema (E), infiltration (I), desquamation (D), and body surface area involvement (A) over 4 body regions: head (h), trunk (t), upper (u) and lower (l) extremities Degree of severity (per body region) for each variable: 0 = no symptom 1 = slight 2 = moderate 3 = marked 4 = very marked Surface area involved (per body region): 1 = <10% 2 = 10-29% 3 = 30-49% 4 = 50-69% 5 = 70-89% 6 = 90-100%
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        ≤35 years
    34.4
    48.6
    20.6
        35 to ≤55 years
    36.8
    37.3
    13.2
        >55 years
    42.6
    37.7
    13.8
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by intake of potentially nephrotoxic medicines

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    End point title
    Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by intake of potentially nephrotoxic medicines
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        Patients using potentially nephrotoxic medicine
    34.1
    22
    5.9
        Not using potentially nephrotoxic medicine
    32.7
    40.8
    14
    No statistical analyses for this end point

    Secondary: Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by age group

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    End point title
    Proportion of patients achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment at Week 16 by age group
    End point description
    The Physician's Global Assessment (PGA) is scored as: 0 = clear (no signs of psoriasis (post-inflammatory hyperpigmentation may be present)) 1 = almost clear (intermediate between mild and clear) 2 = mild (slight plaque elevation, scaling and/or erythema) 3 = moderate (moderate plaque elevation, scaling and/or erythema) 4 = moderate to severe (marked plaque elevation, scaling and/or erythema) 5 = severe (very marked plaque elevation, scaling and/or erythema)
    End point type
    Secondary
    End point timeframe
    Week 16 of treatment
    End point values
    LAS41008 Fumaderm® Placebo
    Number of subjects analysed
    267
    273
    131
    Units: Percentage
    number (not applicable)
        Aged ≤35 years
    29
    48.6
    20.6
        Aged >35 to ≤55 years
    34
    34.5
    10.3
        Aged >55 years
    36.8
    31.1
    10.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the 16 week (± 3 days) treatment period and 12 months (± 10 days) follow-up period
    Adverse event reporting additional description
    Serious adverse events with onset >30 days after end of treatment were not classified as serious treatment-emergent adverse events
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    LAS41008
    Reporting group description
    Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product

    Reporting group title
    Fumaderm®
    Reporting group description
    Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product

    Reporting group title
    Placebo
    Reporting group description
    Safety analysis set (SAS) defined as all patients who were randomised and received at least one dose of the investigational medicinal product

    Serious adverse events
    LAS41008 Fumaderm® Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 279 (3.23%)
    8 / 283 (2.83%)
    5 / 137 (3.65%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Spinal fusion surgery
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 279 (0.72%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subendocardial ischaemia
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 279 (0.00%)
    1 / 283 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    1 / 279 (0.36%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 279 (0.00%)
    0 / 283 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    LAS41008 Fumaderm® Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    201 / 279 (72.04%)
    203 / 283 (71.73%)
    60 / 137 (43.80%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    51 / 279 (18.28%)
    44 / 283 (15.55%)
    2 / 137 (1.46%)
         occurrences all number
    124
    90
    2
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    25 / 279 (8.96%)
    28 / 283 (9.89%)
    0 / 137 (0.00%)
         occurrences all number
    26
    31
    0
    Eosinophilia
         subjects affected / exposed
    25 / 279 (8.96%)
    15 / 283 (5.30%)
    0 / 137 (0.00%)
         occurrences all number
    26
    15
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    103 / 279 (36.92%)
    109 / 283 (38.52%)
    20 / 137 (14.60%)
         occurrences all number
    151
    175
    25
    Abdominal pain upper
         subjects affected / exposed
    56 / 279 (20.07%)
    59 / 283 (20.85%)
    10 / 137 (7.30%)
         occurrences all number
    72
    83
    10
    Abdominal pain
         subjects affected / exposed
    54 / 279 (19.35%)
    43 / 283 (15.19%)
    6 / 137 (4.38%)
         occurrences all number
    103
    70
    8
    Nausea
         subjects affected / exposed
    30 / 279 (10.75%)
    24 / 283 (8.48%)
    5 / 137 (3.65%)
         occurrences all number
    42
    37
    5
    Flatulence
         subjects affected / exposed
    15 / 279 (5.38%)
    16 / 283 (5.65%)
    7 / 137 (5.11%)
         occurrences all number
    18
    16
    7
    Vomiting
         subjects affected / exposed
    12 / 279 (4.30%)
    17 / 283 (6.01%)
    2 / 137 (1.46%)
         occurrences all number
    14
    18
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    24 / 279 (8.60%)
    28 / 283 (9.89%)
    15 / 137 (10.95%)
         occurrences all number
    42
    37
    16
    Erythema
         subjects affected / exposed
    26 / 279 (9.32%)
    22 / 283 (7.77%)
    3 / 137 (2.19%)
         occurrences all number
    68
    32
    3
    Skin burning sensation
         subjects affected / exposed
    21 / 279 (7.53%)
    18 / 283 (6.36%)
    3 / 137 (2.19%)
         occurrences all number
    49
    32
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2012
    Concomitant therapy with cytostatics and medications with known harmful influences on the kidneys was prohibited A severe decline in the leukocyte (WBC) count – particularly with parameters below 3000/μL, or other pathological blood count changes or a creatinine increase above normal, were added as examples of adverse events that would constitute possible reasons for premature withdrawal of subjects It was added that during the first three weeks of treatment no dose reductions were possible
    07 Feb 2013
    It was clarified that patients could be included with prior therapy with systemic drugs for psoriasis that was discontinued due to an adverse event or insufficient effect It was clarified that male patients except vasectomized males (instead of previously including vasectomized males) had to use contraceptive measures BSA assessments at each follow-up visit were added PGA assessment at screening was added It was clarified that during the first week of treatment with the maintenance dose (week 4) no dose reduction was possible It was clarified that the sponsor reserved the right to modify or terminate the study at any time in agreement with the involved Ethics Committees and Competent Authorities
    15 May 2013
    Patients taking medications with known harmful influence on the kidneys were now to be included (and not, as previously described, excluded from the study) and a new secondary objective was added to assess safety and efficacy of LAS41008 and Fumaderm® in this subgroup of patients An analysis of the safety and efficacy of LAS41008 and Fumaderm® when administered concomitantly with medicines known to have potential nephrotoxic effects, e.g. angiotensin-converting enzyme, angiotensin II inhibitors and statins was added A more detailed definition of severe renal impairment was added and a more detailed definition of abnormal liver enzymes was added The risk benefit assessment was updated
    03 Nov 2014
    Clarification that a full integrated clinical study report was to be written after all patients had completed the 2 month follow up examination and that the 6 month and 12 month follow-up data was to be included in an updated study report after all patients had completed the 12 month follow-up

    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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