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

    Summary
    EudraCT number
    		 2021-000424-35
    Trial protocol
    		 SK   DE   DK   AT  
    Global end of trial date
    05 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Oct 2024
    First version publication date
    31 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLOU064A2302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05032157
    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)
    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
    05 Jan 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 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
    01 Dec 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
    Germany: 62
    Country: Number of subjects enrolled
    United States: 86
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Brazil: 4
    Country: Number of subjects enrolled
    Canada: 35
    Country: Number of subjects enrolled
    China: 65
    Country: Number of subjects enrolled
    Denmark: 5
    Country: Number of subjects enrolled
    India: 54
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Slovakia: 10
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Thailand: 25
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Viet Nam: 12
    Worldwide total number of subjects
    455
    EEA total number of subjects
    107
    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)
    420
    From 65 to 84 years
    35
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted globally across 18 countries.

    Pre-assignment
    Screening details
    		 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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LOU064 25 mg 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
    Film-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
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		LOU064 25 mg b.i.d. Placebo
    Started
    300
    155
    Full Analysis Set (FAS)
    297
    153
    Safety Set (SAF)
    297
    153
    Completed
    230
    111
    Not completed
    70
    44
         Physician decision
    7
    2
         Adverse event, non-fatal
    12
    7
         Protocol Deviation
    8
    4
         Patient Decision
    38
    19
         Unsatisfactory therapeutic effect
    4
    7
         Pregnancy
    -
    2
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LOU064 25 mg 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 25 mg b.i.d. Placebo Total
    Number of subjects
    		 300 155 455
    Age Categorical
    Units: Participants
        >= 18 and < 65 years
    		 276 144 420
        >= 65 and < 85 years
    		 24 11 35
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 41.9 ( 14.52 ) 41.3 ( 14.58 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 197 100 297
        Male
    		 103 55 158
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 130 72 202
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 7 3 10
        White
    		 159 79 238
        More than one race
    		 3 1 4
        Unknown or Not Reported
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    LOU064 25 mg 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
    		 Full analysis
    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
    		 Full analysis
    Subject analysis set description
    Patients initially randomized to Placebo (Up to Week 24)

    Subject analysis set title
    Transitioned to LOU064 25 mg b.i.d.
    Subject analysis set type
    		 Sub-group analysis
    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)

    Primary: Mean change from Baseline in Weekly Urticaria Activity Score (UAS7) at Week 12 (Scenario 1 with UAS7 as primary efficacy endpoint)

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    End point title
    		 Mean change from Baseline in Weekly Urticaria Activity 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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Unit on a scale
        least squares mean (standard error)
    -19.41 ( 0.702 )
    -11.73 ( 0.948 )
    Statistical analysis title
    		 UAS7 at Week 12 (Scenario 1)
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.91
         upper limit
    		 -5.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.136

    Primary: Mean 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
    		 Mean 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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Unit on a scale
        least squares mean (standard error)
    -8.95 ( 0.335 )
    -5.72 ( 0.454 )
    Statistical analysis title
    		 ISS7 at Week 12 (Scenario 2)
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.29
         upper limit
    		 -2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.545

    Primary: Mean 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
    		 Mean 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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Unit on a scale
        least squares mean (standard error)
    -10.47 ( 0.394 )
    -6.00 ( 0.531 )
    Statistical analysis title
    		 HSS7 at Week 12 (Scenario 2)
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.71
         upper limit
    		 -3.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.634

    Secondary: Number of Participants who achieved disease activity control (UAS7 =< 6) at Week 12

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    End point title
    		 Number of Participants who achieved disease activity control (UAS7 =< 6) at Week 12
    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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Participants
    139
    30
    Statistical analysis title
    		 Disease activity control (UAS7 =< 6) at Week 12
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.39
         upper limit
    		 6.18

    Secondary: Number of Participants who achieved complete absence of hives and itch (UAS7 = 0) at Week 12

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    End point title
    		 Number of Participants who achieved complete absence of hives and itch (UAS7 = 0) at Week 12
    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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Participants
    83
    10
    Statistical analysis title
    		 UAS7 = 0 at Week 12
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.83
         upper limit
    		 11.78

    Secondary: Number of Participants who achieved early onset of disease activity control (UAS7 =< 6) at Week 2

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    End point title
    		 Number of Participants who achieved early onset of disease activity 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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Participants
    89
    9
    Statistical analysis title
    		 UAS7 =< 6 at Week 2
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.72
         upper limit
    		 16.85

    Secondary: Number of Participants who achieved Dermatology Life Quality Index (DLQI) = 0-1 at Week 12

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    End point title
    		 Number of Participants who achieved Dermatology Life Quality Index (DLQI) = 0-1 at Week 12
    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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Participants
    106
    28
    Statistical analysis title
    		 DLQI= 0-1 at Week 12
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 4.58

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

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    End point title
    		 Mean 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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Weeks
        least squares mean (standard error)
    4.50 ( 0.464 )
    1.38 ( 0.216 )
    Statistical analysis title
    		 Disease activity control (UAS7 =< 6) up to Week 12
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Rate ratio
    Point estimate
    3.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.26
         upper limit
    		 4.71

    Secondary: Number of Participants with Treatment Emergent Adverse Events

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events [1]
    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. Treatment emergent Adverse Event (TEAEs) in this study are events that started after the first dose of study treatment and until 28 days after the last dose of study treatment, or events present prior to the first dose of treatment which increased in severity based on preferred term within 28 days after the last study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to 28 days after last dose of study medication, assessed up to approximately 56 weeks
    Notes
    [1] - 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: Only descriptive statistics performed
    End point values
    		 LOU064 25 mg b.i.d. Double-blind treatment period: LOU064 25 mg b.i.d. Double-blind treatment period: Placebo Transitioned to LOU064 25 mg b.i.d.
    Number of subjects analysed
    297
    297
    153
    129
    Units: Participants
        Patients with at least one Adverse Event (AE)
    228
    205
    112
    71
        Death
    0
    0
    0
    0
        Non-fatal SAE(s)
    12
    10
    6
    2
        Discontinued study treatment due to any AE(s)
    13
    6
    6
    2
        Discontinued study treatment due to any SAE(s)
    1
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Mean cumulative number of angioedema occurrence-free weeks (AAS7 = 0 response) up to Week 12

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    End point title
    		 Mean cumulative number of angioedema occurrence-free weeks (AAS7 = 0 response) up to Week 12
    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 25 mg b.i.d. Placebo
    Number of subjects analysed
    297
    153
    Units: Weeks
        least squares mean (standard error)
    8.81 ( 0.308 )
    6.68 ( 0.343 )
    Statistical analysis title
    		 AAS7= 0 response up to Week 12
    Comparison groups
    LOU064 25 mg b.i.d. v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Parameter type
    		 Rate ratio
    Point estimate
    1.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 1.49

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment adverse events and deaths were reported from first dose of study medication up to 28 days after last dose of study medication, assessed 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
    12 / 297 (4.04%)
    2 / 129 (1.55%)
    6 / 153 (3.92%)
         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)
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Breast cancer
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 129 (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
    Leiomyoma
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Contusion
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Head injury
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 129 (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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 129 (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
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 129 (0.78%)
    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
    Food poisoning
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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 acute
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 129 (0.78%)
    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
    Respiratory, thoracic and mediastinal disorders
    Nasal polyps
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Angioedema
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Chronic spontaneous urticaria
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 129 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Spinal stenosis
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Wound abscess
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    Pneumonia
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 129 (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
    Gastrointestinal infection
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (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
    0 / 297 (0.00%)
    0 / 129 (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
    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
    157 / 297 (52.86%)
    40 / 129 (31.01%)
    66 / 153 (43.14%)
    Investigations
    Lipase increased
         subjects affected / exposed
    9 / 297 (3.03%)
    0 / 129 (0.00%)
    3 / 153 (1.96%)
         occurrences all number
    10
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 297 (7.41%)
    1 / 129 (0.78%)
    8 / 153 (5.23%)
         occurrences all number
    26
    1
    8
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 129 (0.00%)
    5 / 153 (3.27%)
         occurrences all number
    1
    0
    5
    Petechiae
         subjects affected / exposed
    13 / 297 (4.38%)
    5 / 129 (3.88%)
    0 / 153 (0.00%)
         occurrences all number
    28
    5
    0
    Urticaria
         subjects affected / exposed
    9 / 297 (3.03%)
    5 / 129 (3.88%)
    7 / 153 (4.58%)
         occurrences all number
    10
    6
    9
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 297 (3.03%)
    0 / 129 (0.00%)
    2 / 153 (1.31%)
         occurrences all number
    11
    0
    2
    Infections and infestations
    Influenza
         subjects affected / exposed
    8 / 297 (2.69%)
    4 / 129 (3.10%)
    2 / 153 (1.31%)
         occurrences all number
    8
    4
    2
    COVID-19
         subjects affected / exposed
    62 / 297 (20.88%)
    13 / 129 (10.08%)
    21 / 153 (13.73%)
         occurrences all number
    62
    13
    21
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 297 (7.41%)
    8 / 129 (6.20%)
    4 / 153 (2.61%)
         occurrences all number
    25
    9
    5
    Suspected COVID-19
         subjects affected / exposed
    16 / 297 (5.39%)
    4 / 129 (3.10%)
    5 / 153 (3.27%)
         occurrences all number
    16
    4
    5
    Sinusitis
         subjects affected / exposed
    5 / 297 (1.68%)
    1 / 129 (0.78%)
    6 / 153 (3.92%)
         occurrences all number
    5
    1
    6
    Nasopharyngitis
         subjects affected / exposed
    33 / 297 (11.11%)
    3 / 129 (2.33%)
    9 / 153 (5.88%)
         occurrences all number
    42
    3
    14
    Urinary tract infection
         subjects affected / exposed
    11 / 297 (3.70%)
    3 / 129 (2.33%)
    4 / 153 (2.61%)
         occurrences all number
    13
    3
    6
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    10 / 297 (3.37%)
    2 / 129 (1.55%)
    1 / 153 (0.65%)
         occurrences all number
    16
    2
    1
    Hyperlipidaemia
         subjects affected / exposed
    6 / 297 (2.02%)
    6 / 129 (4.65%)
    4 / 153 (2.61%)
         occurrences all number
    8
    6
    4

    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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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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