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    Clinical Trial Results:
    A phase 4 trial comparing the efficacy of subcutaneous injections of brodalumab to oral administrations of fumaric acid esters in adults with moderate to severe plaque psoriasis

    Summary
    EudraCT number
    		 2016-003867-21
    Trial protocol
    		 DE  
    Global end of trial date
    21 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Feb 2020
    First version publication date
    13 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0160-1327
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03331835
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical Disclosure, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Disclosure, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of subcutaneous injections of brodalumab to oral administration of fumaric acid esters in subjects with moderate to severe plaque psoriasis who are naive to systemic treatment.
    Protection of trial subjects
    This clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18th World Medical Association General Assembly, 1964, and subsequent amendments. All subjects or their legally acceptable representative received written and verbal information concerning the clinical trial. Subjects or their legally acceptable representative were asked to consent that their personal data were recorded, collected, processed and could be transferred to EU and non-EU countries in accordance with any national legislation regulating privacy and data protection.
    Background therapy
    		 -
    Evidence for comparator
    		 An oral preparation containing fumaric acid esters (dimethyl fumarate and monoethyl fumarate salts; Fumaderm®) was selected as comparator, because it is a well-established and widely used systemic treatment in Germany for patients with moderate to severe plaque psoriasis in whom topical therapy is not effective (Nast et al. J Dtsch Dermatol Ges. 2018;165]:645-669). Fumaric acid esters were recommended in 2017 as appropriate comparator for this patient population by the Federal Joint Committee (G-BA), a German decision-making body (Scientific Advice [2016-B-165] of the Gemeinsamer Bundesausschuss (G-BA) according to § 8 Abs.1 AM-NutzenV. 2017).
    Actual start date of recruitment
    01 Oct 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 210
    Worldwide total number of subjects
    210
    EEA total number of subjects
    210
    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)
    193
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Number of subjects screened: 325 Screening failures: 101 Withdrawn before randomisation: 14

    Period 1
    Period 1 title
    Open-label treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The risk of bias related to open-label treatment was mitigated by blinded investigator assessments and detailed precautions were taken to avoid unblinding assessors. Due to potential dose adjustments needed for subjects randomised to fumaric acid esters, the investigator and subject needed to know the treatment allocated. The sponsor was also blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Brodalumab
    Arm description
    		 Brodalumab 210 mg s.c. injection Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brodalumab
    Investigational medicinal product code
    Other name
    Kyntheum (R)
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage: 210 mg in 1.5 mL solution for subcutaneous injection (140 mg/mL). Weekly administration for the first 3 weeks (Weeks 0, 1, and 2) followed by administration every 2 weeks (Q2W) up to Week 24.

    Arm title
    		 Fumaric acid esters
    Arm description
    		 Oral fumaric acid esters up to 240 mg 3 times daily (TID)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    fumaric acid esters
    Investigational medicinal product code
    Other name
    Fumaderm (R), Fumaderm (R) initial
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administration by participant 3 times daily in doses ranging from 30 to 240 mg dimethyl fumarate per oral administration.

    Number of subjects in period 1
    		Brodalumab Fumaric acid esters
    Started
    105
    105
    Completed
    91
    58
    Not completed
    14
    47
         Consent withdrawn by subject
    1
    8
         Adverse event, non-fatal
    7
    28
         Other reason
    5
    5
         Lost to follow-up
    -
    2
         Lack of efficacy
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brodalumab
    Reporting group description
    		 Brodalumab 210 mg s.c. injection Q2W

    Reporting group title
    Fumaric acid esters
    Reporting group description
    		 Oral fumaric acid esters up to 240 mg 3 times daily (TID)

    Reporting group values
    		 Brodalumab Fumaric acid esters Total
    Number of subjects
    		 105 105 210
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 96 97 193
        From 65-84 years
    		 9 8 17
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ( 14.3 ) 43.9 ( 13.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 32 33 65
        Male
    		 73 72 145
    Race
    Units: Subjects
        Asian
    		 1 0 1
        White
    		 104 105 209
    Ethnicity
    Units: Subjects
        Not Hispanic Or Latino
    		 100 103 203
        Not reported
    		 1 1 2
        Unknown
    		 4 1 5
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 175 ( 9.6 ) 176 ( 9.8 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 87.8 ( 20.4 ) 86.6 ( 21.1 ) -
    Weight in weight group <100 kg
    Units: kg
        arithmetic mean (standard deviation)
    		 78.4 ( 11.9 ) 77.2 ( 12.8 ) -
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.5 ( 5.7 ) 28.0 ( 6.0 ) -
    Duration of psoriasis
    Units: years
        arithmetic mean (standard deviation)
    		 14.3 ( 11.5 ) 13.2 ( 11.7 ) -
    PASI score
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 17.2 ( 5.9 ) 17.8 ( 6.7 ) -
    sPGA score
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 3.5 ( 0.6 ) 3.5 ( 0.7 ) -
    BSA score
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 24.8 ( 15.2 ) 25.5 ( 14.9 ) -
    NAPSI score
    NAPSI score was only collected for subjects with nail involvement at baseline. The number of subjects with a NAPSI score at baseline were n=43 in the brodalumab arm and 38 in the fumaric acid esters arm.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 6.4 ( 4.4 ) 7.7 ( 4.9 ) -
    DLQI score
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 18.8 ( 5.2 ) 18.5 ( 4.9 ) -
    PSI score
    Due to operational difficulties with the ePRO diaries handed our to subjects, baseline PSI data is missing for some subjects. PSI data at baseline was collected from n=83 in the brodalumab arm and n=78 in the fumaric acid esters arm.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 14.8 ( 5.4 ) 17.9 ( 5.3 ) -

    End points

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    End points reporting groups
    Reporting group title
    Brodalumab
    Reporting group description
    		 Brodalumab 210 mg s.c. injection Q2W

    Reporting group title
    Fumaric acid esters
    Reporting group description
    		 Oral fumaric acid esters up to 240 mg 3 times daily (TID)

    Primary: Having Least 75% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 75 Response) From Baseline at Week 24

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    End point title
    		 Having Least 75% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 75 Response) From Baseline at Week 24
    End point description
    Co-primary endpoint
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: percent
        number (not applicable)
    81.0
    38.10
    Statistical analysis title
    		 Analysis of co-primary endpoint PASI75
    Statistical analysis description
    The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    42.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.93
         upper limit
    		 54.79

    Primary: Static Physician’s Global Assessment (sPGA) scale score of 0 or 1 at Week 24

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    End point title
    		 Static Physician’s Global Assessment (sPGA) scale score of 0 or 1 at Week 24
    End point description
    Co-primary endpoint
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: percent
        number (not applicable)
    64.8
    20.0
    Statistical analysis title
    		 Analysis of co-primary endpoint sPGA 0 or 1
    Statistical analysis description
    The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    44.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 32.81
         upper limit
    		 56.71

    Secondary: Having Least 90% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 90 Response) From Baseline at Week 24

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    End point title
    		 Having Least 90% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 90 Response) From Baseline at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: percent
        number (not applicable)
    65.7
    21.9
    Statistical analysis title
    		 Analysis of secondary endpoint PASI90
    Statistical analysis description
    The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    43.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.78
         upper limit
    		 55.84

    Secondary: Having 100% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 100 Response) From Baseline at Week 24

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    End point title
    		 Having 100% Lower Psoriasis Area and Severity Index (PASI) Score Relative to Baseline (PASI 100 Response) From Baseline at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: percent
        number (not applicable)
    40.0
    8.6
    Statistical analysis title
    		 Analysis of secondary endpoint PASI100
    Statistical analysis description
    The difference in response rate between treatment groups was analysed using the Cochran-Mantel-Haenszel test with stratification by weight group (≥100 kg or <100 kg). The null hypotheses of no difference in response rates between brodalumab and fumaric acid esters was tested against the two-sided alternative that there was a difference on a 5% level. Subjects who drop-out of the trial before Week 24 (end of treatment visit) were regarded as non-responders.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    31.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.76
         upper limit
    		 42.1

    Secondary: Change from baseline at Week 24 in PASI score

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    End point title
    		 Change from baseline at Week 24 in PASI score
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    100
    96
    Units: score on a scale
        arithmetic mean (standard error)
    -15.69 ( 0.59 )
    -12.62 ( 0.67 )
    Statistical analysis title
    		 Mean change from baseline in PASI score
    Statistical analysis description
    The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.83
         upper limit
    		 -1.33

    Secondary: PASI improvement (%) from baseline at Week 24

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    End point title
    		 PASI improvement (%) from baseline at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    100
    96
    Units: percentage
        arithmetic mean (standard error)
    -90.03 ( 2.25 )
    -73.67 ( 2.63 )
    Statistical analysis title
    		 PASI improvement (%) from baseline to Week 24
    Statistical analysis description
    The endpoint was analysed using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment. Number of randomised and analysed paticipants differs, as those with missing data in all visits for a given endpoint are not included in the analysis.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (net)
    Point estimate
    -16.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.03
         upper limit
    		 -9.68

    Secondary: Change from baseline at Week 24 in affected BSA

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    End point title
    		 Change from baseline at Week 24 in affected BSA
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: percent
        number (not applicable)
    -20.82
    -11.91
    Statistical analysis title
    		 Change from baseline at Week 24 in affected BSA
    Statistical analysis description
    The endpoint was analysed using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -8.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 -4.81

    Secondary: Psoriasis Symptom Inventory (PSI) responder at Week 24

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    End point title
    		 Psoriasis Symptom Inventory (PSI) responder at Week 24
    End point description
    A PSI responder is defined as having a total score ≤8 and no item score >1. No statistical analysis of this data was performed due to missing data at both baseline and Week 24. This was due to operational challenges with the eDiaries handed out to subjects.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    23 [1]
    15 [2]
    Units: subjects
    15
    13
    Notes
    [1] - Less than 105 subjects had data at Week 24.
    [2] - Less than 105 subjects had data at Week 24.
    No statistical analyses for this end point

    Secondary: PSI total score of 0 at Week 24

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    End point title
    		 PSI total score of 0 at Week 24
    End point description
    No statistical analysis of this data was performed due to missing data at baseline and Week 24. This was due to operational challenges with the eDiary devices handed out to subjects.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    23 [3]
    15 [4]
    Units: subjects
    5
    3
    Notes
    [3] - Less than 105 subjects had data at Week 24.
    [4] - Less than 105 subjects had data at Week 24.
    No statistical analyses for this end point

    Secondary: Number of symptom-free days from randomisation to Week 24

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    End point title
    		 Number of symptom-free days from randomisation to Week 24
    End point description
    A symptom-free day was defined as a total PSI of 0 on that day. No statistical analysis of this data was performed due to missing data at baseline and Week 24. This was due to operational challenges with the eDiary devices handed out to subjects.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    64 [5]
    33 [6]
    Units: days
        arithmetic mean (standard deviation)
    0.44 ( 0.8 )
    0.42 ( 1.3 )
    Notes
    [5] - Less than 105 subjects had data at Week 24
    [6] - Less than 105 subjects had data at Week 24
    No statistical analyses for this end point

    Secondary: Burden of symptoms shown as area under curve (AUC) of PSI total score

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    End point title
    		 Burden of symptoms shown as area under curve (AUC) of PSI total score
    End point description
    Burden of symptoms was assessed as the normalised AUC of PSI total score from baseline to the last available assessment. The AUC for the PSI total score was calculated for each subject using the standard trapezoidal rule. The AUC was then normalised by dividing it with the time from baseline to the last available assessment of the PSI total score.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    83 [7]
    78 [8]
    Units: area under curve
        arithmetic mean (standard error)
    6.00 ( 0.54 )
    10.92 ( 0.55 )
    Notes
    [7] - Not all 105 subjects had data available for analysis for this endpoint
    [8] - Not all 105 subjects had data available for analysis for this endpoint
    Statistical analysis title
    		 AUC of PSI total score
    Statistical analysis description
    The AUC was analysed using an analysis of covariance (ANCOVA) with treatment group, baseline weight group, and the baseline PSI total score as explanatory variables. Treatment groups are defined as randomised treatment.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.31
         upper limit
    		 -3.53

    Secondary: Change from baseline at Week 24 DLQI total score

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    End point title
    		 Change from baseline at Week 24 DLQI total score
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    99
    86
    Units: score on a scale
        arithmetic mean (standard error)
    -16.67 ( 0.61 )
    -14.10 ( 0.70 )
    Statistical analysis title
    		 Change from baseline in DLQI total score at Week24
    Statistical analysis description
    The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    185
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.32
         upper limit
    		 -0.82

    Secondary: DLQI total score of 0 or 1 at Week 24

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    End point title
    		 DLQI total score of 0 or 1 at Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    105
    105
    Units: subjects
    70
    27
    Statistical analysis title
    		 DLQI total score of 0 or 1 at Week 24
    Statistical analysis description
    Estimated risk difference, 95% CI and p-value were derived from CMH analysis stratified by weight group at baseline (≤100 kg, > 100 kg). Non-responder imputation (NRI) was used to impute missing data. Treatment groups were defined as randomised treatment.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    210
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    40.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 28.75
         upper limit
    		 53.16

    Other pre-specified: Change from baseline at Week 24 in NAPSI total score

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    End point title
    		 Change from baseline at Week 24 in NAPSI total score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    24 weeks
    End point values
    		 Brodalumab Fumaric acid esters
    Number of subjects analysed
    43 [9]
    38 [10]
    Units: score on a scale
        arithmetic mean (standard error)
    2.97 ( 0.54 )
    -1.26 ( 0.57 )
    Notes
    [9] - Only subjects with nail psoriasis at baseline were included in this end point.
    [10] - Only subjects with nail psoriasis at baseline were included in this end point.
    Statistical analysis title
    		 Change from baseline in NAPSI score at Week 24
    Statistical analysis description
    The endpoint was analysed by using mixed model for repeated measures (MMRM) model including treatment group, week, interaction between treatment and time, baseline value, and baseline weight group as fixed factors. Within subject covariance was estimated by an unstructured covariance matrix. Treatment groups were defined as randomised treatment.
    Comparison groups
    Brodalumab v Fumaric acid esters
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 -0.19

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Fumaric Acid Ester
    Reporting group description
    		 -

    Reporting group title
    Brodalumab 210 mg Q2W
    Reporting group description
    		 -

    Serious adverse events
    		 Fumaric Acid Ester Brodalumab 210 mg Q2W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 104 (2.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma metastatic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Crohn's disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reactive gastropathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stasis dermatitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fumaric Acid Ester Brodalumab 210 mg Q2W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 102 (94.12%)
    91 / 104 (87.50%)
    Injury, poisoning and procedural complications
    Overdose
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 102 (0.00%)
    8 / 104 (7.69%)
         occurrences all number
    0
    8
    Vascular disorders
    Flushing
    alternative assessment type: Non-systematic
         subjects affected / exposed
    29 / 102 (28.43%)
    0 / 104 (0.00%)
         occurrences all number
    40
    0
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 102 (11.76%)
    13 / 104 (12.50%)
         occurrences all number
    19
    27
    Blood and lymphatic system disorders
    Lymphopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 102 (13.73%)
    2 / 104 (1.92%)
         occurrences all number
    14
    3
    General disorders and administration site conditions
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 104 (4.81%)
         occurrences all number
    8
    6
    Gastrointestinal disorders
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 102 (10.78%)
    2 / 104 (1.92%)
         occurrences all number
    13
    2
    Abdominal pain upper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    28 / 102 (27.45%)
    2 / 104 (1.92%)
         occurrences all number
    43
    2
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    59 / 102 (57.84%)
    4 / 104 (3.85%)
         occurrences all number
    77
    4
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 102 (8.82%)
    6 / 104 (5.77%)
         occurrences all number
    13
    7
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 102 (0.98%)
    6 / 104 (5.77%)
         occurrences all number
    1
    6
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 102 (1.96%)
    6 / 104 (5.77%)
         occurrences all number
    2
    6
    Psychiatric disorders
    Depressive symptom
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 102 (6.86%)
    5 / 104 (4.81%)
         occurrences all number
    7
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 102 (3.92%)
    9 / 104 (8.65%)
         occurrences all number
    4
    10
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 102 (0.98%)
    6 / 104 (5.77%)
         occurrences all number
    1
    6
    Infections and infestations
    Viral upper respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 102 (20.59%)
    35 / 104 (33.65%)
         occurrences all number
    24
    41

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2017
    The reason for the amendment is to implement requirements from the health authorities in Germany.
    17 Aug 2018
    The reason for Amendment 2 is to clarify that exclusion criteria related to the PROs eC-SSRS and PHQ-8 pertain to both the screening and the baseline visit. Also, the wording for the eC-SSRS criteria, and the described assessment hereof, has been updated to reflect the report from the eC-SSRS. The wording in version 3.0 of the protocol was based on the paper version of the C-SSRS.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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