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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebocontrolled Phase 3 study of remibrutinib (LOU064) to investigate the efficacy, safety, and tolerability for 52 weeks in adult chronic spontaneous urticaria patients inadequately controlled by H1-antihistamines

    Summary
    EudraCT number
    		 2021-000471-37
    Trial protocol
    		 HU   CZ   IT   ES   BG  
    Global end of trial date
    19 Jan 2024

    Results information
    Results version number
    		 v1
    This version publication date
    27 Nov 2024
    First version publication date
    27 Nov 2024
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLOU064A2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05030311
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to establish the efficacy, safety, and tolerability of remibrutinib 25 mg b.i.d. in adult patients suffering from chronic spontaneous urticaria (CSU) inadequately controlled by second generation H1-antihistamines (H1-AHs) in comparison to placebo.
    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
    30 Nov 2021
    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
    Argentina: 47
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Czechia: 16
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    India: 58
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    Korea, Republic of: 37
    Country: Number of subjects enrolled
    Mexico: 17
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    Türkiye: 35
    Country: Number of subjects enrolled
    United States: 121
    Worldwide total number of subjects
    470
    EEA total number of subjects
    94
    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)
    425
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted globally across 18 countries. Participants underwent a screening period of up to 4 weeks.

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LOU064 25mg b.i.d.
    Arm description
    		 Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib
    Investigational medicinal product code
    LOU064
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Remibrutinib 25 mg b.i.d.

    Arm title
    		 Placebo
    Arm description
    		 Patients initially randomized to Placebo (Up to Week 24)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		LOU064 25mg b.i.d. Placebo
    Started
    313
    157
    Safety Set
    309
    153
    Full Analysis Set (FAS)
    309
    153
    Completed
    251
    124
    Not completed
    62
    33
         Consent withdrawn by subject
    31
    17
         Physician decision
    5
    2
         Adverse event, non-fatal
    13
    5
         Technical problems
    -
    1
         Unsatisfactory therapeutic effect
    4
    3
         Lost to follow-up
    5
    1
         Protocol deviation
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LOU064 25mg b.i.d.
    Reporting group description
    		 Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients initially randomized to Placebo (Up to Week 24)

    Reporting group values
    		 LOU064 25mg b.i.d. Placebo Total
    Number of subjects
    		 313 157 470
    Age Categorical
    Units: Participants
        >= 18 - < 65 years
    		 282 143 425
        >= 65 - < 85 years
    		 31 14 45
        >= 85 years
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 44.6 ( 14.27 ) 45.9 ( 13.44 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 212 109 321
        Male
    		 101 48 149
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 12 14 26
        Asian
    		 94 46 140
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 12 3 15
        White
    		 188 89 277
        More than one race
    		 6 2 8
        Unknown or Not Reported
    		 1 2 3
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 76 44 120
        Not Hispanic or Latino
    		 237 113 350
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    LOU064 25mg b.i.d.
    Reporting group description
    		 Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients initially randomized to Placebo (Up to Week 24)

    Subject analysis set title
    Double-blind treatment period: LOU064 25 mg b.i.d.
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients initially randomized to Remibrutinib (Up to Week 24)

    Subject analysis set title
    Double-blind treatment period: Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients initially randomized to Placebo (Up to Week 24)

    Subject analysis set title
    Entire Study period: LOU064 25mg b.i.d.
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients initially randomized to Remibrutinib during the Double-blind treatment period and continued Remibrutinib during the Open-label treatment period (Up to Week 52)

    Subject analysis set title
    Open-label period: Transitioned to LOU064 25 mg b.i.d.
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients initially randomized to placebo during the Double-blind treatment period and switched to Remibrutinib during the Open-label treatment period (Weeks 25-52)

    Subject analysis set title
    LOU064 25mg b.i.d.
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    LOU064 25mg b.i.d.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Placebo

    Primary: Change from baseline in Weekly Urticaria Score (UAS7) at Week 12 (Scenario 1 with UAS7 as primary efficacy endpoint)

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    End point title
    		 Change from baseline in Weekly Urticaria Score (UAS7) at Week 12 (Scenario 1 with UAS7 as primary efficacy endpoint)
    End point description
    The Weekly Urticaria Activity Score (UAS7) is a simple scoring system to evaluate urticaria signs and symptoms. It is based on scoring wheals (hive severity score) and itch (itch severity score) separately on a scale of 0 (no signs/symptoms) to 3 (intense signs/symptoms) over 7 days. The final score is calculated by adding together the daily scores, which can range from 0 to 6, for 7 days. This results in a maximum total score of 42 (highest urticaria severity), and a minimum possible score of 0. This endpoint is a secondary endpoint for testing strategy Scenario 2 with Weekly Itch Severity Score (ISS7) and Weekly Hives Severity Score (HSS7) as co-primary efficacy endpoints).
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Scores on a scale
        least squares mean (standard error)
    -20.02 ( 0.716 )
    -13.79 ( 0.980 )
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.45
         upper limit
    		 -4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.136

    Primary: Change from Baseline in Weekly Itch Severity Score (ISS7) at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)

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    End point title
    		 Change from Baseline in Weekly Itch Severity Score (ISS7) at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)
    End point description
    The severity of the itch was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (severe). A weekly score (ISS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest itch severity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint).
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Scores on a scale
        least squares mean (standard error)
    -9.52 ( 0.343 )
    -6.89 ( 0.470 )
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Statistical analysis description
    ISS7 at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.7
         upper limit
    		 -1.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.544

    Primary: Change from baseline in Weekly Hives Severity Score (HSS7) at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)

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    End point title
    		 Change from baseline in Weekly Hives Severity Score (HSS7) at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)
    End point description
    The hives (wheals) severity score, defined by number of hives, was recorded by the participant twice daily in their electronic Diary, on a scale of 0 (none) to 3 (> 12 hives/12 hours). A weekly score (HSS7) was derived by adding up the average daily scores of the 7 days preceding the visit. The possible range of the weekly score was therefore 0 - 21 (highest hives activity). This endpoint is a secondary endpoint for testing strategy Scenario 1 with Weekly Urticaria Activity Score (UAS7) as the primary efficacy endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Scores on a scale
        least squares mean (standard error)
    -10.47 ( 0.401 )
    -6.86 ( 0.548 )
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Statistical analysis description
    HSS7 at Week 12 (Scenario 2 with ISS7 and HSS7 as co-primary efficacy endpoints)
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.85
         upper limit
    		 -2.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.635

    Secondary: Number of patients who achieved disease activity control (UAS7 ≤6)

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    End point title
    		 Number of patients who achieved disease activity control (UAS7 ≤6)
    End point description
    The percentage of patients achieving disease activity control (UAS7 =< 6) at Week 12 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 – 42 (highest hives and itch severity).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Participants
    154
    38
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Statistical analysis description
    Disease activity control (UAS7 =< 6) at Week 12
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 4.84

    Secondary: Number of patients who achieved complete absence of hives and itch (UAS7 = 0

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    End point title
    		 Number of patients who achieved complete absence of hives and itch (UAS7 = 0
    End point description
    The proportion of patients achieving complete absence of hives and itch (UAS7 = 0) at Week 12 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 – 42 (highest hives and itch severity).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Participants
    96
    16
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Statistical analysis description
    Complete absence of hives and itch (UAS7 = 0) at Week 12
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.16
         upper limit
    		 6.82

    Secondary: Number of patients who achieved DLQI = 0 - 1

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    End point title
    		 Number of patients who achieved DLQI = 0 - 1
    End point description
    The Dermatology Life Quality Index (DLQI) is a 10-item (grouped in 6 domains) dermatology-specific quality of life (QoL) measure. Participants are rating 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). Domain scores are calculated for: Symptoms and Feelings (0-6), Daily Activities (0-6), Leisure (0-6), Work and School (0-3), Personal Relationships (0-6), Treatment (0-3). The overall DLQI score range was split into score bands and validated in terms of their meaning/relevance to patients overall. DLQI = 0-1 means no effect on patient's life.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    308
    153
    Units: Participants
    120
    34
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    461
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.53
         upper limit
    		 3.9

    Secondary: Cumulative number of weeks with disease activity control (UAS7 <= 6) up to Week 12

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    End point title
    		 Cumulative number of weeks with disease activity control (UAS7 <= 6) up to Week 12
    End point description
    Maintaining disease activity control was assessed as cumulative number of weeks with an UAS7 =< 6 response between baseline and Week 12. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 – 42 (highest hives and itch severity).
    End point type
    Secondary
    End point timeframe
    up to Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: weeks
        least squares mean (standard error)
    5.17 ( 0.414 )
    1.92 ( 0.241 )
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Rate ratio
    Point estimate
    2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.01
         upper limit
    		 3.61

    Secondary: Number of patients with early onset of disease control (UAS7 ≤ 6 at week 2)

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    End point title
    		 Number of patients with early onset of disease control (UAS7 ≤ 6 at week 2)
    End point description
    The percentage of patients achieving disease activity control (UAS7 =< 6) at Week 2 was assessed to evaluate the efficacy of Remibrutinib in Chronic Spontaneous Urticaria (CSU) patients. The UAS7 is the sum of the Weekly Hives Severity Score (HSS7) and the Weekly Itch Severity Score (ISS7). The possible range of the UAS7 score is 0 – 42 (highest hives and itch severity).
    End point type
    Secondary
    End point timeframe
    Week 2
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Participants
    104
    5
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    15.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.18
         upper limit
    		 39.77

    Secondary: Number of participants with Adverse Events

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    End point title
    		 Number of participants with Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product. Pts = patients w/ = with sign. = significant
    End point type
    Secondary
    End point timeframe
    On-treatment adverse events are reported from first dose of study medication up to 28 days after last dose of study medication, for a timeframe up to approximately 56 weeks
    End point values
    		 Double-blind treatment period: LOU064 25 mg b.i.d. Double-blind treatment period: Placebo Entire Study period: LOU064 25mg b.i.d. Open-label period: Transitioned to LOU064 25 mg b.i.d.
    Number of subjects analysed
    309
    153
    309
    133
    Units: Participants
        Patients with at least one AE
    188
    86
    218
    62
        Pts w/ serious or other sign. events - Death
    0
    0
    0
    0
        Pts w/ serious or other significant events - SAEs
    10
    1
    13
    1
        Discontinued study treatment due to any AEs
    11
    3
    15
    2
        Discontinued study treatment due to any SAEs
    2
    0
    3
    1
        Treatment interruption due to AEs
    17
    9
    18
    3
        Treatment interruption due to SAEs
    5
    1
    5
    0
    No statistical analyses for this end point

    Secondary: Cumulative number of weeks without angioedema (AAS7 = 0)

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    End point title
    		 Cumulative number of weeks without angioedema (AAS7 = 0)
    End point description
    Angioedema occurrence was recorded once daily in the evening in the electronic Diary by the participant. Reporting the occurrence of angioedema was used as opening question for the assessment of the Angioedema Activity Score (AAS). The AAS consists of 5 questions with 4 answer options (scored 0-3) for each item, with a minimum score of 0 and a maximum score of 15 per day. The AAS score over 7 days (AAS7) ranges from 0 (no angioedema episodes) to 105 (highest angioedema severity).
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 LOU064 25mg b.i.d. Placebo
    Number of subjects analysed
    309
    153
    Units: Weeks
        least squares mean (standard error)
    8.43 ( 0.274 )
    6.72 ( 0.330 )
    Statistical analysis title
    		 LOU064 25mg b.i.d. v Placebo
    Statistical analysis description
    Angioedema occurrence-free weeks (AAS7 = 0 response) up to Week 12
    Comparison groups
    LOU064 25mg b.i.d. v Placebo
    Number of subjects included in analysis
    462
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Rate ratio
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.12
         upper limit
    		 1.41

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment adverse events are reported from first dose of study medication up to 28 days after last dose of study medication, for a timeframe up to approximately 56 weeks
    Adverse event reporting additional description
    Any sign or symptom that occurred during the conduct of the trial and safety follow-up. The safety analysis were done on the safety population, which included all randomized subjects who received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    LOU064 25mg b.i.d.
    Reporting group description
    		 LOU064 25mg b.i.d.

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

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 LOU064 25mg b.i.d. Transitioned to LOU064 25mg b.i.d. Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 309 (4.21%)
    1 / 133 (0.75%)
    1 / 153 (0.65%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mucinous adenocarcinoma of appendix
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Small intestine adenocarcinoma
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Benign renal neoplasm
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Angina pectoris
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Abortion spontaneous
         subjects affected / exposed
    0 / 309 (0.00%)
    1 / 133 (0.75%)
    0 / 153 (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
    Gastrointestinal disorders
    Gastrointestinal wall thickening
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 309 (0.00%)
    0 / 133 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Skin and subcutaneous tissue disorders
    Chronic spontaneous urticaria
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Musculoskeletal and connective tissue disorders
    Spondylolisthesis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Back pain
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Appendicitis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Hypokalaemia
         subjects affected / exposed
    1 / 309 (0.32%)
    0 / 133 (0.00%)
    0 / 153 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 LOU064 25mg b.i.d. Transitioned to LOU064 25mg b.i.d. Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 309 (44.98%)
    26 / 133 (19.55%)
    53 / 153 (34.64%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 309 (8.09%)
    3 / 133 (2.26%)
    11 / 153 (7.19%)
         occurrences all number
    30
    3
    11
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 309 (3.24%)
    1 / 133 (0.75%)
    3 / 153 (1.96%)
         occurrences all number
    15
    2
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    11 / 309 (3.56%)
    0 / 133 (0.00%)
    3 / 153 (1.96%)
         occurrences all number
    11
    0
    4
    Diarrhoea
         subjects affected / exposed
    11 / 309 (3.56%)
    2 / 133 (1.50%)
    7 / 153 (4.58%)
         occurrences all number
    11
    2
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 309 (3.88%)
    0 / 133 (0.00%)
    2 / 153 (1.31%)
         occurrences all number
    14
    0
    2
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    11 / 309 (3.56%)
    2 / 133 (1.50%)
    1 / 153 (0.65%)
         occurrences all number
    13
    2
    1
    Urticaria
         subjects affected / exposed
    11 / 309 (3.56%)
    2 / 133 (1.50%)
    8 / 153 (5.23%)
         occurrences all number
    26
    2
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 309 (2.91%)
    2 / 133 (1.50%)
    5 / 153 (3.27%)
         occurrences all number
    10
    2
    5
    Infections and infestations
    COVID-19
         subjects affected / exposed
    31 / 309 (10.03%)
    6 / 133 (4.51%)
    14 / 153 (9.15%)
         occurrences all number
    31
    6
    14
    Urinary tract infection
         subjects affected / exposed
    17 / 309 (5.50%)
    1 / 133 (0.75%)
    4 / 153 (2.61%)
         occurrences all number
    20
    1
    4
    Nasopharyngitis
         subjects affected / exposed
    22 / 309 (7.12%)
    6 / 133 (4.51%)
    5 / 153 (3.27%)
         occurrences all number
    27
    6
    7
    Influenza
         subjects affected / exposed
    10 / 309 (3.24%)
    4 / 133 (3.01%)
    2 / 153 (1.31%)
         occurrences all number
    13
    4
    2
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 309 (3.88%)
    3 / 133 (2.26%)
    2 / 153 (1.31%)
         occurrences all number
    18
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2022
    The key rationale for this amendment was to implement recommendations from the US FDA regarding statistical analysis covering intercurrent event handling for COVID-19 related reasons for treatment discontinuation and the use of the same covariates in both primary and secondary endpoints. The other key aspect was to ensure consistency across the program involving both pivotal studies (CLOU064A2301 and CLOU064A2302).

    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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