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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo- controlled Phase 2b dose-finding study to investigate the efficacy, safety and tolerability of LOU064 in adult chronic spontaneous urticaria (CSU) patients inadequately controlled by H1-antihistamines

    Summary
    EudraCT number
    		 2018-000993-31
    Trial protocol
    		 DE   CZ   GB   FR   SK   HU   BE   ES   DK   NL  
    Global end of trial date
    15 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Feb 2022
    First version publication date
    06 Feb 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLOU064A2201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03926611
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Study Director, Novartis Pharma AG, 1 (862) 778-8300, novartis.email@novartis.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
    22 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to characterize the dose-response relationship of LOU064 administered once or twice daily in subjects with CSU with respect to change from baseline in UAS7 at Week 4. UAS7 is the sum of the HSS7 score (weekly Hives Severity Sore) and the ISS7 score (weekly Itch Severity Score). The possible range of the weekly UAS7 score is 0 – 42 (highest activity).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 44
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Slovakia: 8
    Country: Number of subjects enrolled
    Canada: 26
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Turkey: 7
    Worldwide total number of subjects
    311
    EEA total number of subjects
    154
    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)
    279
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 311 participants enrolled at 82 investigative sites in 17 countries. This Randomized Set included all randomized subjects, regardless of whether or not they actually received study medication. Subjects were analyzed according to the treatment assigned at randomization.

    Pre-assignment
    Screening details
    		 Informed consent was obtained from each subject in writing at screening before any procedure was performed. The study was explained to each subject by investigator, who answered any questions, and written information was also provided.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LOU064 Arm 1
    Arm description
    		 10 mg LOU064 qd capsule once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 10 mg q.d.
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg capsule q.d. once daily

    Arm title
    		 LOU064 Arm 2
    Arm description
    		 35 mg capsule qd LOU064 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 35 mg q.d.
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    35 mg capsule q.d. once daily

    Arm title
    		 LOU064 Arm 3
    Arm description
    		 100 mg capsule qd LOU064 once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 100 mg q.d.
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg capsule q.d. once daily

    Arm title
    		 LOU064 Arm 4
    Arm description
    		 10 mg capsule LOU064 bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 10 mg bid
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg capsule bid

    Arm title
    		 LOU064 Arm 5
    Arm description
    		 25 mg capsule LOU064 bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 25 mg bid
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg capsule bid

    Arm title
    		 LOU064 Arm 6
    Arm description
    		 100 mg capsule LOU064 bid
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib 100 mg bid
    Investigational medicinal product code
    LOU064
    Other name
    LOU064
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg capsule bid

    Arm title
    		 Placebo Arm
    Arm description
    		 Participants took matching placebo twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo capsule twice daily

    Number of subjects in period 1
    		LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Started
    44
    44
    47
    44
    44
    45
    43
    Randomized set (RAN)
    44
    44
    47
    44
    44
    45
    43
    Full analysis set (FAS)
    44
    43
    47
    44
    43
    45
    42
    Safety set (SAF)
    44
    44
    47
    44
    43
    45
    42
    Completed
    41
    41
    45
    40
    40
    36
    38
    Not completed
    3
    3
    2
    4
    4
    9
    5
         Consent withdrawn by subject
    1
    1
    1
    -
    -
    1
    3
         Physician decision
    -
    -
    -
    -
    -
    1
    -
         Covid-19 pandemic
    -
    -
    1
    -
    1
    2
    -
         Adverse event, non-fatal
    -
    -
    -
    3
    1
    3
    -
         Technical problems
    -
    -
    -
    -
    -
    1
    -
         Protocol deviation
    1
    -
    -
    1
    1
    1
    1
         Lack of efficacy
    1
    2
    -
    -
    1
    -
    1

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    LOU064 Arm 1
    Reporting group description
    		 10 mg LOU064 qd capsule once daily

    Reporting group title
    LOU064 Arm 2
    Reporting group description
    		 35 mg capsule qd LOU064 once daily

    Reporting group title
    LOU064 Arm 3
    Reporting group description
    		 100 mg capsule qd LOU064 once daily

    Reporting group title
    LOU064 Arm 4
    Reporting group description
    		 10 mg capsule LOU064 bid

    Reporting group title
    LOU064 Arm 5
    Reporting group description
    		 25 mg capsule LOU064 bid

    Reporting group title
    LOU064 Arm 6
    Reporting group description
    		 100 mg capsule LOU064 bid

    Reporting group title
    Placebo Arm
    Reporting group description
    		 Participants took matching placebo twice daily

    Reporting group values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm Total
    Number of subjects
    		 44 44 47 44 44 45 43 311
    Age Categorical
    Units: Participants
        <=18 years
    		 0 0 0 0 0 0 0 0
        Between 18 and 65 years
    		 41 39 44 39 39 41 36 279
        >=65 years
    		 3 5 3 5 5 4 7 32
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 42.5 ± 16.04 44.0 ± 16.47 45.2 ± 13.40 46.1 ± 15.21 47.4 ± 14.62 44.9 ± 13.76 45.1 ± 15.24 -
    Sex: Female, Male
    Units: Participants
        Female
    		 35 30 39 32 32 29 25 222
        Male
    		 9 14 8 12 12 16 18 89
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 36 37 40 36 36 36 35 256
        Black or African American
    		 1 0 0 0 0 0 1 2
        Asian
    		 7 6 7 7 7 9 7 50
        Native Hawaiian or Other Pacific
    		 0 0 0 1 0 0 0 1
        American Indian or Alaska Native
    		 0 0 0 0 1 0 0 1
        Multiple
    		 0 1 0 0 0 0 0 1
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The FAS included all randomized subjects. Following the intent-to-treat principle, subjects were analyzed according to the treatment and strata assigned to at randomization. The mis-randomized subjects (mis-randomized in IRT) were excluded.

    Subject analysis sets values
    		 Full Analysis Set (FAS)
    Number of subjects
    309
    Age Categorical
    Units: Participants
        <=18 years
    0
        Between 18 and 65 years
    279
        >=65 years
    30
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    ±
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        White
        Black or African American
        Asian
        Native Hawaiian or Other Pacific
        American Indian or Alaska Native
        Multiple

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    LOU064 Arm 1
    Reporting group description
    		 10 mg LOU064 qd capsule once daily

    Reporting group title
    LOU064 Arm 2
    Reporting group description
    		 35 mg capsule qd LOU064 once daily

    Reporting group title
    LOU064 Arm 3
    Reporting group description
    		 100 mg capsule qd LOU064 once daily

    Reporting group title
    LOU064 Arm 4
    Reporting group description
    		 10 mg capsule LOU064 bid

    Reporting group title
    LOU064 Arm 5
    Reporting group description
    		 25 mg capsule LOU064 bid

    Reporting group title
    LOU064 Arm 6
    Reporting group description
    		 100 mg capsule LOU064 bid

    Reporting group title
    Placebo Arm
    Reporting group description
    		 Participants took matching placebo twice daily

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The FAS included all randomized subjects. Following the intent-to-treat principle, subjects were analyzed according to the treatment and strata assigned to at randomization. The mis-randomized subjects (mis-randomized in IRT) were excluded.

    Primary: Change from baseline in weekly Urticaria Activity Score (UAS7) at Week 4

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    End point title
    		 Change from baseline in weekly Urticaria Activity Score (UAS7) at Week 4
    End point description
    UAS7 score change (LS mean Change) from baseline at Week 4 estimated with a mixed-effect repeated measurement analysis of UAS7 score change from baseline (FAS) The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (week 4 score minus Baseline score) indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline, Week 4
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    42
    Units: Scores on a scale
        least squares mean (standard error)
    -19.10 ± 1.686
    -19.08 ± 1.690
    -14.65 ± 1.624
    -15.99 ± 1.686
    -20.02 ± 1.708
    -18.06 ± 1.691
    -5.44 ± 1.739
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    Placebo Arm v LOU064 Arm 1
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -13.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -17.51
         upper limit
    		 -9.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.334
    Notes
    [1] - LOU064 10 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 2 v Placebo Arm
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -13.64
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -17.49
         upper limit
    		 -9.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.336
    Notes
    [2] - LOU064 35 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 3 v Placebo Arm
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -9.21
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -12.97
         upper limit
    		 -5.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.277
    Notes
    [3] - LOU064 100 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 4 v Placebo Arm
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -10.55
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.38
         upper limit
    		 -6.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.319
    Notes
    [4] - LOU064 10 mg b.i.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 5 v Placebo Arm
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -14.58
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -18.43
         upper limit
    		 -10.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.334
    Notes
    [5] - LOU064 25 mg b.i.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 6 v Placebo Arm
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -12.62
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -16.45
         upper limit
    		 -8.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.327
    Notes
    [6] - LOU064 100 mg b.i.d.

    Secondary: Change from baseline in weekly Urticaria Activity Score (UAS7) at week 12

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    End point title
    		 Change from baseline in weekly Urticaria Activity Score (UAS7) at week 12
    End point description
    UAS7 score change (LS mean Change) from baseline at Week 12 estimated with a mixed-effect repeated measurement analysis of UAS7 score change from baseline (FAS)
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    41
    41
    45
    40
    39
    35
    39
    Units: Score
        least squares mean (standard error)
    -18.11 ± 1.934
    -17.97 ± 1.934
    -15.27 ± 1.850
    -17.67 ± 1.939
    -20.21 ± 1.964
    -17.38 ± 1.985
    -7.87 ± 2.001
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 1 v Placebo Arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -10.24
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.72
         upper limit
    		 -5.77
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.71
    Notes
    [7] - LOU064 10 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 2 v Placebo Arm
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -10.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.58
         upper limit
    		 -5.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.711
    Notes
    [8] - LOU064 35 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 3 v Placebo Arm
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.0027
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -7.4
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -11.75
         upper limit
    		 -3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.635
    Notes
    [9] - LOU064 100 mg q.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 4 v Placebo Arm
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.0002
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -9.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.25
         upper limit
    		 -5.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.696
    Notes
    [10] - LOU064 10 mg b.i.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 5 v Placebo Arm
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -12.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -16.82
         upper limit
    		 -7.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.714
    Notes
    [11] - LOU064 25 mg b.i.d.
    Statistical analysis title
    		 UAS7 score change (LS mean Change)
    Comparison groups
    LOU064 Arm 6 v Placebo Arm
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.0003
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean
    Point estimate
    -9.52
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -14.03
         upper limit
    		 -5.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.733
    Notes
    [12] - LOU064 100 mg b.i.d.

    Secondary: Percentage of participants with either complete absence of hives and itch (UAS7=0) or well-controlled disease (UAS7<=6)

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    End point title
    		 Percentage of participants with either complete absence of hives and itch (UAS7=0) or well-controlled disease (UAS7<=6)
    End point description
    UAS7=0 and UAS7<=6 response rate over time by treatment group (non-responder imputation) The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates more severe disease. A negative change score (week 4 score minus Baseline score) indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    42
    Units: Percent of participants
    number (confidence interval 90%)
        UAS7=0
    29.5 (18.7 to 43.0)
    29.5 (18.7 to 43.0)
    29.8 (19.3 to 42.7)
    31.8 (20.6 to 45.3)
    41.9 (29.3 to 55.5)
    26.7 (16.5 to 39.8)
    14.3 (6.7 to 26.7)
        UAS<=6
    47.7 (34.8 to 61.0)
    52.3 (39.0 to 65.2)
    38.3 (26.6 to 51.4)
    47.7 (34.8 to 61.0)
    55.8 (42.3 to 68.6)
    42.2 (29.9 to 55.5)
    28.6 (17.7 to 42.3)
    No statistical analyses for this end point

    Secondary: Cumulative number of weeks with an AAS7=0 response

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    End point title
    		 Cumulative number of weeks with an AAS7=0 response
    End point description
    The Weekly angioedema activity score (AAS) is a validated tool to assess occurrence of episodes of angioedema. If the subject reports the occurrence of angioedema ("opening question") with “no”, AAS score for this day is 0. If “yes” is the answer to the opening question, the subject will continue to answer questions about the duration, severity and impact on daily functioning and appearance of the angioedema. The AAS7 is a weekly AAS score (AAS7). Minimum and maximum possible AAS7 scores are 0−105. Higher score means more severe disease.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    42
    Units: Weeks
        arithmetic mean (standard deviation)
    10.2 ± 2.33
    10.5 ± 2.59
    10.0 ± 3.06
    9.8 ± 3.05
    10.3 ± 2.45
    9.2 ± 3.38
    8.2 ± 3.50
    No statistical analyses for this end point

    Secondary: Percentage of participants with DLQI score of 0 or 1

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    End point title
    		 Percentage of participants with DLQI score of 0 or 1
    End point description
    Percentage of subjects with DLQI 0/1 response by treatment group and visit (non-responder imputation) The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific quality of life (QoL) measure. Subjects rate their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-related QoL). A DLQI score of 0 or 1 means that there is no impact of a skin disease on the patient's life.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    42
    Units: Percentage of participants
    number (confidence interval 90%)
        Week 4
    38.6 (26.5 to 52.2)
    29.5 (18.7 to 43.0)
    29.8 (19.3 to 42.7)
    29.5 (18.7 to 43.0)
    51.2 (37.8 to 64.3)
    33.3 (22.1 to 46.7)
    16.7 (8.4 to 29.4)
        Week 12
    34.1 (22.6 to 47.6)
    40.9 (28.6 to 54.4)
    38.3 (26.6 to 51.4)
    40.9 (28.6 to 54.4)
    53.5 (40.0 to 66.5)
    35.6 (24.0 to 48.9)
    28.6 (17.7 to 42.3)
    No statistical analyses for this end point

    Secondary: Mean change from baseline in DLQI score

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    End point title
    		 Mean change from baseline in DLQI score
    End point description
    Summary of DLQI score and change from baseline The Dermatology Life Quality Index (DLQI) is a 10-item dermatology-specific quality of life (QoL) measure. Subjects rate their dermatology symptoms as well as the impact of their skin condition on various aspects of their lives thinking about the previous 7 days. An overall score is calculated and ranges from 0 to 30 (higher score meaning worse disease-related QoL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 12
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6 Placebo Arm
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    42
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 4
    -9.60 ± 7.214
    -8.38 ± 7.241
    -7.18 ± 7.534
    -6.20 ± 6.416
    -9.21 ± 7.994
    -6.15 ± 5.149
    -3.33 ± 8.090
        Week 12
    -9.03 ± 6.216
    -7.31 ± 9.392
    -6.60 ± 7.798
    -8.25 ± 6.551
    -8.97 ± 8.891
    -6.27 ± 5.513
    -4.38 ± 6.780
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve (AUC) of LOU064

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    End point title
    		 Area under the blood concentration-time curve (AUC) of LOU064 [13]
    End point description
    Assessment of the area under the blood concentration-time curve (AUC) up to four hours following oral administration at Week 4 and Week 12 .
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not planned
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Week 4
    45.2 ± 18.4
    131 ± 65.4
    427 ± 314
    55.9 ± 32.3
    107 ± 56.8
    418 ± 246
        Week 12
    41.8 ± 19.5
    159 ± 151
    441 ± 313
    54.4 ± 29.4
    118 ± 66.6
    469 ± 240
    No statistical analyses for this end point

    Secondary: Observed maximum blood concentration (Cmax) of LOU064

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    End point title
    		 Observed maximum blood concentration (Cmax) of LOU064 [14]
    End point description
    Assessment of the observed maximum blood concentration (Cmax) of LOU064 following drug administration at Week 4 and Week 12 .
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not planned
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4
    27.6 ± 13.7
    67.2 ± 32.7
    194 ± 142
    32.2 ± 18.7
    55.5 ± 34.7
    196 ± 144
        Week 12
    26.1 ± 14.5
    80.3 ± 53.9
    199 ± 137
    31.2 ± 16.0
    64.9 ± 42.3
    219 ± 125
    No statistical analyses for this end point

    Secondary: Time to reach the maximum concentration (Tmax) of LOU064

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    End point title
    		 Time to reach the maximum concentration (Tmax) of LOU064 [15]
    End point description
    Assessment of the time to reach the maximum concentration (Tmax) of LOU064 following drug administration at Weeks 4 and  12
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analysis was not planned
    End point values
    		 LOU064 Arm 1 LOU064 Arm 2 LOU064 Arm 3 LOU064 Arm 4 LOU064 Arm 5 LOU064 Arm 6
    Number of subjects analysed
    44
    44
    47
    44
    43
    45
    Units: hours
    median (full range (min-max))
        Week 4
    1.33 (0.00 to 4.00)
    1.54 (0.00 to 4.00)
    1.52 (0.500 to 3.00)
    0.900 (0.00 to 2.00)
    1.15 (0.00 to 3.02)
    1.52 (0.00 to 3.08)
        Week 12
    1.17 (0.00 to 4.08)
    1.48 (0.500 to 4.00)
    1.61 (0.00 to 4.00)
    1.17 (0.500 to 4.00)
    1.32 (0.00 to 4.00)
    1.39 (0.5000 to 4.00)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) and Serious Adverse Events were collected after signature of the informed consent form until 30 days after last dose of study treatment, and up to 16 weeks
    Adverse event reporting additional description
    AEs and SAEs are any untoward sign or symptom that occurs during the study treatment and up to 16 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    LOU064 10mg q.d.
    Reporting group description
    		 LOU064 10mg q.d.

    Reporting group title
    LOU064 35mg q.d.
    Reporting group description
    		 LOU064 35mg q.d.

    Reporting group title
    LOU064 100mg q.d.
    Reporting group description
    		 LOU064 100mg q.d.

    Reporting group title
    LOU064 10mg b.i.d.
    Reporting group description
    		 LOU064 10mg b.i.d.

    Reporting group title
    LOU064 25mg b.i.d.
    Reporting group description
    		 LOU064 25mg b.i.d.

    Reporting group title
    LOU064 100mg b.i.d.
    Reporting group description
    		 LOU064 100mg b.i.d.

    Reporting group title
    Any LOU064
    Reporting group description
    		 Any LOU064

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 LOU064 10mg q.d. LOU064 35mg q.d. LOU064 100mg q.d. LOU064 10mg b.i.d. LOU064 25mg b.i.d. LOU064 100mg b.i.d. Any LOU064 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    2 / 44 (4.55%)
    2 / 43 (4.65%)
    0 / 45 (0.00%)
    5 / 267 (1.87%)
    0 / 42 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 45 (0.00%)
    1 / 267 (0.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Chronic spontaneous urticaria
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    0 / 45 (0.00%)
    2 / 267 (0.75%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
    0 / 45 (0.00%)
    1 / 267 (0.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Renal abscess
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    0 / 44 (0.00%)
    1 / 43 (2.33%)
    0 / 45 (0.00%)
    1 / 267 (0.37%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LOU064 10mg q.d. LOU064 35mg q.d. LOU064 100mg q.d. LOU064 10mg b.i.d. LOU064 25mg b.i.d. LOU064 100mg b.i.d. Any LOU064 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 44 (34.09%)
    13 / 44 (29.55%)
    10 / 47 (21.28%)
    12 / 44 (27.27%)
    11 / 43 (25.58%)
    13 / 45 (28.89%)
    74 / 267 (27.72%)
    11 / 42 (26.19%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 44 (2.27%)
    7 / 44 (15.91%)
    4 / 47 (8.51%)
    3 / 44 (6.82%)
    6 / 43 (13.95%)
    5 / 45 (11.11%)
    26 / 267 (9.74%)
    6 / 42 (14.29%)
         occurrences all number
    1
    8
    4
    11
    6
    6
    36
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    2 / 44 (4.55%)
    1 / 43 (2.33%)
    0 / 45 (0.00%)
    6 / 267 (2.25%)
    0 / 42 (0.00%)
         occurrences all number
    3
    0
    0
    2
    1
    0
    6
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 44 (0.00%)
    0 / 47 (0.00%)
    4 / 44 (9.09%)
    0 / 43 (0.00%)
    1 / 45 (2.22%)
    7 / 267 (2.62%)
    2 / 42 (4.76%)
         occurrences all number
    3
    0
    0
    4
    0
    1
    8
    2
    Nausea
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 44 (6.82%)
    1 / 47 (2.13%)
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    2 / 45 (4.44%)
    10 / 267 (3.75%)
    0 / 42 (0.00%)
         occurrences all number
    2
    3
    1
    1
    1
    2
    10
    0
    Skin and subcutaneous tissue disorders
    Chronic spontaneous urticaria
         subjects affected / exposed
    3 / 44 (6.82%)
    2 / 44 (4.55%)
    3 / 47 (6.38%)
    3 / 44 (6.82%)
    1 / 43 (2.33%)
    2 / 45 (4.44%)
    14 / 267 (5.24%)
    1 / 42 (2.38%)
         occurrences all number
    3
    2
    3
    3
    1
    2
    14
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 44 (15.91%)
    2 / 44 (4.55%)
    2 / 47 (4.26%)
    4 / 44 (9.09%)
    4 / 43 (9.30%)
    4 / 45 (8.89%)
    23 / 267 (8.61%)
    3 / 42 (7.14%)
         occurrences all number
    8
    3
    2
    5
    4
    4
    26
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 44 (4.55%)
    2 / 47 (4.26%)
    0 / 44 (0.00%)
    3 / 43 (6.98%)
    0 / 45 (0.00%)
    8 / 267 (3.00%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    2
    0
    4
    0
    9
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2019
    The primary rationale for this amendment was to align the eligibility criteria for resting heart rate (exclusion criterion 6) with a normal resting heart rate of CSU subjects. Additionally, the following clarifications were introduced: - Compliance requirements before Day 1 was clarified. - Eligibility criteria regarding INR was aligned with liver events - Fasting requirements before and during PK visits were clarified
    11 May 2020
    The purpose of this amendment was to address the impact of the COVID-19 pandemic on this study by: - Clarifying implications of the use of local laboratory assessments as per investigator letters “Handling of Protocol Deviations for Trials CLOU064A2201 and CLOU064A2201E1 resulting from the Coronavirus (COVID-19) outbreak” and “Coronavirus (COVID-19) outbreak: Novartis Clinical Trial Continuity for Trials CLOU064A2201 and CLOU064A2201E1” dated 02-Apr-2020. - Introducing an additional IA with a data cut-off date of 07-Apr-2020, the day recruitment for this study was temporarily paused because of the COVID-19 pandemic. The aim of this IA was to assess the benefit-risk ratio of LOU064 based on data collected prior to the recruitment pause due to the COVID-19 pandemic.

    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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