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    Clinical Trial Results:
    An adaptive Phase 2 randomized double-blind, placebo-controlled multi-center study to evaluate the safety and efficacy of multiple LOU064 doses in patients with moderate to severe Sjögren’s Syndrome (LOUiSSe)

    Summary
    EudraCT number
    		 2018-004387-54
    Trial protocol
    		 DE   HU   GB   ES   BE   DK   BG  
    Global end of trial date
    23 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLOU064E12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04035668
    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
    23 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to characterize the dose-response relationship of remibrutinib based on change from baseline in EULAR Sjögren’s syndrome Disease Activity Index (ESSDAI) at Week 24*. *The change from baseline in ESSDAI at Week 24 of Part 1 was analyzed and reported. The dose-response relationship was not evaluated as it was planned as per the statistical analysis plan for Part 2 which was not conducted.
    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
    12 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    China: 7
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    73
    EEA total number of subjects
    33
    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)
    58
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 26 investigative sites in 12 countries.

    Pre-assignment
    Screening details
    		 The screening period of up to 6 weeks began after the subject had provided written informed consent. Eligible subjects were randomized in a 1:1:1 ratio to one of the 3 treatment groups.

    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
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remibrutinib 100 mg bid
    Arm description
    		 Remibrutinib 100 mg twice daily (bid)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Remibrutinib
    Investigational medicinal product code
    LOU064
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Remibrutinib 100 mg was administered orally as two 50 mg hard gelatin capsules. Patients in the remibrutinib 100 mg twice daily (bid) dose group took 2 capsules of active medication in the morning and 2 capsules of active medication in the evening.

    Arm title
    		 Remibrutinib 100 mg qd
    Arm description
    		 Remibrutinib 100 mg once daily (qd)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took 2 capsules of active medication in the morning and 2 capsules of the placebo in the evening.

    Investigational medicinal product name
    Remibrutinib
    Investigational medicinal product code
    LOU064
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Remibrutinib 100 mg was administered orally as two 50 mg hard gelatin capsules. Patients in the remibrutinib 100 mg once daily (qd) dose group took 2 capsules of active medication in the morning and 2 capsules of the placebo in the evening.

    Arm title
    		 Placebo
    Arm description
    		 Placebo group
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered orally as two hard gelatin capsules. Patients in the placebo dose group took 2 capsules of placebo in the morning and 2 capsules of placebo in the evening.

    Number of subjects in period 1
    		Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo
    Started
    24
    25
    24
    Completed
    17
    17
    21
    Not completed
    7
    8
    3
         Physician decision
    2
    1
    1
         Subject Decision
    2
    2
    -
         Adverse event
    3
    4
    2
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Remibrutinib 100 mg bid
    Reporting group description
    		 Remibrutinib 100 mg twice daily (bid)

    Reporting group title
    Remibrutinib 100 mg qd
    Reporting group description
    		 Remibrutinib 100 mg once daily (qd)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Reporting group values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Total
    Number of subjects
    		 24 25 24 73
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 19 21 18 58
        From 65-84 years
    		 5 4 6 15
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.5 ( 15.21 ) 54.8 ( 10.51 ) 51.0 ( 13.94 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 24 24 23 71
        Male
    		 0 1 1 2
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 7 7 7 21
        White
    		 17 17 16 50
        Unknown
    		 0 1 0 1
        Black or African American
    		 0 0 1 1
    Subject analysis sets

    Subject analysis set title
    Any remibrutinib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in any of the two remibrutinib treatment groups

    Subject analysis sets values
    		 Any remibrutinib
    Number of subjects
    49
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    40
        From 65-84 years
    9
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    52.2 ( 13.6 )
    Sex: Female, Male
    Units: participants
        Female
    48
        Male
    1
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    14
        White
    34
        Unknown
    1
        Black or African American
    0

    End points

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    End points reporting groups
    Reporting group title
    Remibrutinib 100 mg bid
    Reporting group description
    		 Remibrutinib 100 mg twice daily (bid)

    Reporting group title
    Remibrutinib 100 mg qd
    Reporting group description
    		 Remibrutinib 100 mg once daily (qd)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Subject analysis set title
    Any remibrutinib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients in any of the two remibrutinib treatment groups

    Primary: Change from baseline in EULAR Sjögren’s syndrome Disease Activity Index (ESSDAI) total score at Week 24

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    End point title
    		 Change from baseline in EULAR Sjögren’s syndrome Disease Activity Index (ESSDAI) total score at Week 24
    End point description
    ESSDAI is a validated disease outcome measure for Sjögren’s Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    24
    24
    24
    48
    Units: score on scale
        least squares mean (standard error)
    -3.70 ( 0.80 )
    -4.70 ( 0.78 )
    -1.34 ( 0.74 )
    -4.20 ( 0.56 )
    Statistical analysis title
    		 Week 24 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [1]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.71
         upper limit
    		 -1.01
    Notes
    [1] - one-sided p-value
    Statistical analysis title
    		 Week 24 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg bid v Remibrutinib 100 mg qd
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 1.25

    Secondary: Change from baseline in ESSDAI total score over time

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    End point title
    		 Change from baseline in ESSDAI total score over time
    End point description
    ESSDAI is a validated disease outcome measure for Sjögren’s Syndrome. The instrument contains 12 organ-specific domains contributing to disease activity: constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, muscular, peripheral nervous system, central nervous system, hematological and biological. For each domain, features of disease activity were scored according to their severity. These scores were summed across the 12 domains in a weighted manner to provide the total score. ESSDAI total score ranges from 0 to 123 with higher values indicating more disease activity. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSDAI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16 and Week 20
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    24
    24
    24
    48
    Units: score on scale
    least squares mean (standard error)
        Week 2
    -1.05 ( 0.52 )
    -1.68 ( 0.52 )
    -0.37 ( 0.55 )
    -1.37 ( 0.37 )
        Week 4
    -2.54 ( 0.62 )
    -2.57 ( 0.60 )
    -0.79 ( 0.61 )
    -2.55 ( 0.43 )
        Week 8
    -2.93 ( 0.71 )
    -2.74 ( 0.72 )
    -2.36 ( 0.69 )
    -2.83 ( 0.51 )
        Week 12
    -2.56 ( 0.75 )
    -3.66 ( 0.74 )
    -1.92 ( 0.73 )
    -3.11 ( 0.53 )
        Week 16
    -2.57 ( 0.74 )
    -4.02 ( 0.71 )
    -2.16 ( 0.69 )
    -3.29 ( 0.51 )
        Week 20
    -3.26 ( 0.75 )
    -4.40 ( 0.73 )
    -1.84 ( 0.69 )
    -3.83 ( 0.52 )
    Statistical analysis title
    		 Week 2 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065 [2]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.29
         upper limit
    		 0.3
    Notes
    [2] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [3]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.24
         upper limit
    		 -0.29
    Notes
    [3] - one-sided p-value
    Statistical analysis title
    		 Week 16 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094 [4]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.84
         upper limit
    		 0.57
    Notes
    [4] - one-sided p-value
    Statistical analysis title
    		 Week 12 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.093 [5]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 0.59
    Notes
    [5] - one-sided p-value
    Statistical analysis title
    		 Week 8 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.289 [6]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 1.22
    Notes
    [6] - one-sided p-value
    Statistical analysis title
    		 Week 20 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [7]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.71
         upper limit
    		 -0.28
    Notes
    [7] - one-sided p-value
    Statistical analysis title
    		 Week 2 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.84
    Statistical analysis title
    		 Week 4 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.75
         upper limit
    		 1.69
    Statistical analysis title
    		 Week 8 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.83
         upper limit
    		 2.21
    Statistical analysis title
    		 Week 12 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 1.01
    Statistical analysis title
    		 Week 16 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 0.6
    Statistical analysis title
    		 Week 20 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.22
         upper limit
    		 0.95

    Secondary: Change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) total score over time

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    End point title
    		 Change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) total score over time
    End point description
    ESSPRI is an established disease outcome measure for Sjögren’s Syndrome. It consists of three domains of dryness, pain, and fatigue. The patient can assess the severity of symptoms they experience on a single 0-10 numerical scale for each of the three domains. The ESSPRI score is defined as the mean of scores from the three scales: (dryness + pain +fatigue) /3. ESSPRI total score ranges from 0 to 10 with higher values indicating more disease symptoms. A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in ESSPRI for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    24
    24
    24
    48
    Units: score on scale
    least squares mean (standard error)
        Week 2
    0.18 ( 0.26 )
    -0.44 ( 0.26 )
    -0.09 ( 0.27 )
    -0.13 ( 0.18 )
        Week 4
    -0.14 ( 0.30 )
    -0.72 ( 0.30 )
    -0.35 ( 0.30 )
    -0.43 ( 0.21 )
        Week 8
    -0.38 ( 0.31 )
    -0.83 ( 0.31 )
    -0.57 ( 0.29 )
    -0.60 ( 0.22 )
        Week 12
    -0.32 ( 0.31 )
    -0.88 ( 0.31 )
    -0.66 ( 0.29 )
    -0.60 ( 0.22 )
        Week 16
    -0.39 ( 0.37 )
    -0.77 ( 0.36 )
    -0.71 ( 0.34 )
    -0.58 ( 0.26 )
        Week 20
    -0.74 ( 0.39 )
    -0.92 ( 0.38 )
    -0.92 ( 0.36 )
    -0.83 ( 0.27 )
        Week 24
    -0.76 ( 0.35 )
    -1.17 ( 0.34 )
    -1.13 ( 0.31 )
    -0.96 ( 0.24 )
    Statistical analysis title
    		 Week 2 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46 [8]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 0.62
    Notes
    [8] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.418 [9]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 0.66
    Notes
    [9] - one-sided p-value
    Statistical analysis title
    		 Week 8 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.466 [10]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 0.7
    Notes
    [10] - one-sided p-value
    Statistical analysis title
    		 Week 12 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56 [11]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 0.79
    Notes
    [11] - one-sided p-value
    Statistical analysis title
    		 Week 16 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.616 [12]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 0.99
    Notes
    [12] - one-sided p-value
    Statistical analysis title
    		 Week 20 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.581 [13]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 0.99
    Notes
    [13] - one-sided p-value
    Statistical analysis title
    		 Week 24 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.663 [14]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.96
    Notes
    [14] - one-sided p-value
    Statistical analysis title
    		 Week 2 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 0.11
    Statistical analysis title
    		 Week 4 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.42
         upper limit
    		 0.26
    Statistical analysis title
    		 Week 8 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 0.42
    Statistical analysis title
    		 Week 12 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 0.31
    Statistical analysis title
    		 Week 16 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 0.65
    Statistical analysis title
    		 Week 20 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.39
         upper limit
    		 0.65
    Statistical analysis title
    		 Week 24 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.37
         upper limit
    		 0.57

    Secondary: Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) total score over time

    		 Close Top of page
    End point title
    		 Change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) total score over time
    End point description
    FACIT-F v4 is a short, 13-item, easy-to-administer tool that measures an individual’s level of fatigue during their usual daily activities over the past week. The level of fatigue was measured on a 5-point Likert scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). FACIT-F total score ranges from 0 to 52 with higher values indicating higher quality of life (less fatigue). A positive change from baseline is a favorable outcome. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in FACIT-F for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    23
    24
    23
    47
    Units: score on scale
    least squares mean (standard error)
        Week 2
    -0.51 ( 1.35 )
    1.80 ( 1.32 )
    3.37 ( 1.43 )
    0.64 ( 0.95 )
        Week 4
    3.97 ( 1.57 )
    4.83 ( 1.50 )
    3.51 ( 1.58 )
    4.40 ( 1.09 )
        Week 8
    3.79 ( 1.66 )
    4.00 ( 1.64 )
    5.26 ( 1.60 )
    3.90 ( 1.17 )
        Week 12
    4.25 ( 1.86 )
    4.88 ( 1.80 )
    7.30 ( 1.77 )
    4.56 ( 1.30 )
        Week 16
    3.29 ( 2.08 )
    4.40 ( 1.97 )
    7.73 ( 1.98 )
    3.84 ( 1.44 )
        Week 20
    4.32 ( 2.30 )
    10.01 ( 2.20 )
    5.77 ( 2.17 )
    7.16 ( 1.60 )
        Week 24
    4.64 ( 2.55 )
    8.17 ( 2.45 )
    7.45 ( 2.32 )
    6.40 ( 1.77 )
    Statistical analysis title
    		 Week 2 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94 [15]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.18
         upper limit
    		 0.73
    Notes
    [15] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.322 [16]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.95
         upper limit
    		 4.74
    Notes
    [16] - one-sided p-value
    Statistical analysis title
    		 Week 8 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.753 [17]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.32
         upper limit
    		 2.59
    Notes
    [17] - one-sided p-value
    Statistical analysis title
    		 Week 12 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.891 [18]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.13
         upper limit
    		 1.66
    Notes
    [18] - one-sided p-value
    Statistical analysis title
    		 Week 16 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.941 [19]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.77
         upper limit
    		 1.01
    Notes
    [19] - one-sided p-value
    Statistical analysis title
    		 Week 20 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.304 [20]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.01
         upper limit
    		 6.79
    Notes
    [20] - one-sided p-value
    Statistical analysis title
    		 Week 24 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64 [21]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.89
         upper limit
    		 4.79
    Notes
    [21] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.46
         upper limit
    		 5.18
    Statistical analysis title
    		 Week 2 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 6.07
    Statistical analysis title
    		 Week 8 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.43
         upper limit
    		 4.83
    Statistical analysis title
    		 Week 12 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.53
         upper limit
    		 5.78
    Statistical analysis title
    		 Week 20 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.66
         upper limit
    		 12.04
    Statistical analysis title
    		 Week 16 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 6.82
    Statistical analysis title
    		 Week 24 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.53
         upper limit
    		 10.59

    Secondary: Change from baseline in EuroQual 5 dimensions (EQ-5D) VAS score over time

    		 Close Top of page
    End point title
    		 Change from baseline in EuroQual 5 dimensions (EQ-5D) VAS score over time
    End point description
    EQ-5D is a standardized instrument that measures the health-related quality of life. The EQ-5D consists of a descriptive system and a visual analog scale (VAS).The EQ-5D VAS records the patient’s self-rated health on a vertical visual analogue scale with 0 representing ‘Worst imaginable Health State’ and 100 ‘Best imaginable Health State’. A positive change from baseline is a favorable outcome. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in EQ-5D VAS score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    23
    24
    23
    47
    Units: score on scale
    least squares mean (standard error)
        Week 2
    -2.86 ( 3.16 )
    -3.05 ( 3.11 )
    -3.02 ( 3.28 )
    -2.95 ( 2.22 )
        Week 4
    -0.03 ( 2.86 )
    -1.74 ( 2.71 )
    2.99 ( 2.87 )
    -0.88 ( 1.97 )
        Week 8
    1.76 ( 3.20 )
    1.46 ( 3.20 )
    3.44 ( 3.04 )
    1.61 ( 2.26 )
        Week 12
    1.58 ( 2.82 )
    -2.36 ( 2.71 )
    4.00 ( 2.64 )
    -0.39 ( 1.95 )
        Week 16
    4.27 ( 3.54 )
    -0.44 ( 3.27 )
    1.79 ( 3.28 )
    1.92 ( 2.41 )
        Week 20
    5.37 ( 3.33 )
    -0.91 ( 3.15 )
    5.29 ( 3.01 )
    2.23 ( 2.29 )
        Week 24
    5.73 ( 3.65 )
    1.81 ( 3.47 )
    2.07 ( 3.22 )
    3.77 ( 2.52 )
    Statistical analysis title
    		 Week 2 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.494 [22]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.84
         upper limit
    		 7.96
    Notes
    [22] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.866 [23]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.81
         upper limit
    		 3.06
    Notes
    [23] - one-sided p-value
    Statistical analysis title
    		 Week 8 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.684 [24]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.37
         upper limit
    		 5.73
    Notes
    [24] - one-sided p-value
    Statistical analysis title
    		 Week 12 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.908 [25]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.93
         upper limit
    		 2.14
    Notes
    [25] - one-sided p-value
    Statistical analysis title
    		 Week 16 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.487 [26]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8
         upper limit
    		 8.26
    Notes
    [26] - one-sided p-value
    Statistical analysis title
    		 Week 20 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79 [27]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.61
         upper limit
    		 4.49
    Notes
    [27] - one-sided p-value
    Statistical analysis title
    		 Week 24 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34 [28]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.48
         upper limit
    		 9.88
    Notes
    [28] - one-sided p-value
    Statistical analysis title
    		 Week 8 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.34
         upper limit
    		 8.74
    Statistical analysis title
    		 Week 4 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.59
         upper limit
    		 6.17
    Statistical analysis title
    		 Week 2 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.06
         upper limit
    		 8.68
    Statistical analysis title
    		 Week 20 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.44
         upper limit
    		 2.87
    Statistical analysis title
    		 Week 16 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.34
         upper limit
    		 4.93
    Statistical analysis title
    		 Week 12 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.74
         upper limit
    		 3.86
    Statistical analysis title
    		 Week 24 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.01
         upper limit
    		 6.16

    Secondary: Change from baseline in Physician Global Assessment Scale (PhGA) score over time

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    End point title
    		 Change from baseline in Physician Global Assessment Scale (PhGA) score over time
    End point description
    The physician’s global assessment scale was used for the Investigator to rate the disease activity of their patient using 100 mm visual analog scale (VAS) ranging from “no disease activity” (0) to “maximal disease activity” (100). A negative change from baseline indicates improvement. The baseline value is defined as the last assessment performed prior to administration of the first dose of study treatment. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in PhGA score for all post-baseline time points up to Week 24. Values estimated from the model are presented in this table.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20 and Week 24
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo Any remibrutinib
    Number of subjects analysed
    24
    24
    24
    48
    Units: score on scale
    least squares mean (standard error)
        Week 2
    -4.02 ( 2.85 )
    -4.21 ( 2.90 )
    -4.82 ( 3.10 )
    -4.12 ( 2.04 )
        Week 4
    -8.93 ( 2.96 )
    -9.58 ( 2.89 )
    -7.28 ( 2.95 )
    -9.26 ( 2.08 )
        Week 8
    -13.78 ( 3.28 )
    -13.68 ( 3.39 )
    -13.23 ( 3.16 )
    -13.73 ( 2.37 )
        Week 12
    -9.45 ( 3.68 )
    -13.85 ( 3.63 )
    -17.67 ( 3.52 )
    -11.65 ( 2.60 )
        Week 16
    -7.25 ( 3.74 )
    -19.37 ( 3.61 )
    -15.90 ( 3.51 )
    -13.31 ( 2.61 )
        Week 20
    -17.31 ( 3.48 )
    -23.56 ( 3.43 )
    -17.57 ( 3.20 )
    -20.43 ( 2.45 )
        Week 24
    -13.15 ( 3.95 )
    -21.25 ( 3.88 )
    -20.15 ( 3.54 )
    -17.20 ( 2.78 )
    Statistical analysis title
    		 Week 8 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45 [29]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.4
         upper limit
    		 7.41
    Notes
    [29] - one-sided p-value
    Statistical analysis title
    		 Week 4 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.294 [30]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.22
         upper limit
    		 5.27
    Notes
    [30] - one-sided p-value
    Statistical analysis title
    		 Week 2 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.575 [31]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.75
         upper limit
    		 8.16
    Notes
    [31] - one-sided p-value
    Statistical analysis title
    		 Week 20 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.241 [32]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.96
         upper limit
    		 5.24
    Notes
    [32] - one-sided p-value
    Statistical analysis title
    		 Week 16 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.722 [33]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.16
         upper limit
    		 11.34
    Notes
    [33] - one-sided p-value
    Statistical analysis title
    		 Week 12 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.913 [34]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 14.78
    Notes
    [34] - one-sided p-value
    Statistical analysis title
    		 Week 24 Remibrutinib vs Placebo
    Comparison groups
    Placebo v Any remibrutinib
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.742 [35]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.09
         upper limit
    		 11.99
    Notes
    [35] - one-sided p-value
    Statistical analysis title
    		 Week 2 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.28
         upper limit
    		 7.91
    Statistical analysis title
    		 Week 4 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.87
         upper limit
    		 7.58
    Statistical analysis title
    		 Week 8 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.28
         upper limit
    		 9.48
    Statistical analysis title
    		 Week 12 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.71
         upper limit
    		 5.9
    Statistical analysis title
    		 Week 16 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.47
         upper limit
    		 -1.77
    Statistical analysis title
    		 Week 20 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16
         upper limit
    		 3.5
    Statistical analysis title
    		 Week 24 Remibrutinib qd vs bid
    Comparison groups
    Remibrutinib 100 mg qd v Remibrutinib 100 mg bid
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.16
         upper limit
    		 2.96

    Secondary: Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
    End point description
    Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as TEAEs. TEAEs are defined as adverse events that started after the first dose of study medications or adverse events present prior to start of double-blind treatment but increased in severity. The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up 30 days after last dose (Week 29)
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Placebo
    Number of subjects analysed
    24
    25
    24
    Units: participants
        TEAE
    22
    21
    20
        Study drug-related TEAE
    10
    8
    9
        Serious TEAE
    1
    1
    1
    No statistical analyses for this end point

    Secondary: Maximum observed blood concentration (Cmax) of remibrutinib at Week 4

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    End point title
    		 Maximum observed blood concentration (Cmax) of remibrutinib at Week 4 [36]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
    Notes
    [36] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    16
    13
    Units: ng/mL
        arithmetic mean (standard deviation)
    183 ( 82.5 )
    225 ( 154 )
    No statistical analyses for this end point

    Secondary: Maximum observed blood concentration (Cmax) of remibrutinib at Week 24

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    End point title
    		 Maximum observed blood concentration (Cmax) of remibrutinib at Week 24 [37]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Cmax is defined as the maximum (peak) observed blood concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
    Notes
    [37] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    14
    10
    Units: ng/mL
        arithmetic mean (standard deviation)
    224 ( 202 )
    169 ( 77.9 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum observed blood concentration (Tmax) of remibrutinib at Week 4

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    End point title
    		 Time to reach maximum observed blood concentration (Tmax) of remibrutinib at Week 4 [38]
    End point description
    Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
    Notes
    [38] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    16
    13
    Units: hours
        median (full range (min-max))
    1.00 (0.500 to 3.00)
    1.00 (0.500 to 4.00)
    No statistical analyses for this end point

    Secondary: Time to reach maximum observed blood concentration (Tmax) of remibrutinib at Week 24

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    End point title
    		 Time to reach maximum observed blood concentration (Tmax) of remibrutinib at Week 24 [39]
    End point description
    Remibrutinib was determined in whole blood by a validated LC-MS/MS method with a LLOQ of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. Tmax is defined as the time to reach maximum (peak) blood concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
    Notes
    [39] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    14
    10
    Units: hours
        median (full range (min-max))
    1.00 (0.500 to 3.00)
    1.00 (0.500 to 3.08)
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve within a dosing interval (tau) at steady-state (AUCtau) of remibrutinib at Week 4

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    End point title
    		 Area under the blood concentration-time curve within a dosing interval (tau) at steady-state (AUCtau) of remibrutinib at Week 4 [40]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
    Notes
    [40] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    16
    8
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    569 ( 311 )
    1020 ( 700 )
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve within a dosing interval (tau) at steady-state (AUCtau) of remibrutinib at Week 24

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    End point title
    		 Area under the blood concentration-time curve within a dosing interval (tau) at steady-state (AUCtau) of remibrutinib at Week 24 [41]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUCtau is defined as the area under the blood concentration-time curve calculated/extrapolated to the end of a dosing interval (tau) at steady-state. Tau was 24 hours for the qd dosing group and 12 hours for the bid dosing group. For the calculation of AUCtau, the pre-dose concentrations at Week 4 and Week 24 were duplicated as 24 hours and 12 hours concentrations for the qd and bid groups, respectively. The linear trapezoidal method was used for AUCtau calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
    Notes
    [41] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    14
    6
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    670 ( 380 )
    636 ( 306 )
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve from time zero to 4 hours post-dose (AUC0-4h) of remibrutinib at Week 4

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    End point title
    		 Area under the blood concentration-time curve from time zero to 4 hours post-dose (AUC0-4h) of remibrutinib at Week 4 [42]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
    Notes
    [42] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    16
    13
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    351 ( 169 )
    393 ( 207 )
    No statistical analyses for this end point

    Secondary: Area under the blood concentration-time curve from time zero to 4 hours post-dose (AUC0-4h) of remibrutinib at Week 24

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    End point title
    		 Area under the blood concentration-time curve from time zero to 4 hours post-dose (AUC0-4h) of remibrutinib at Week 24 [43]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. AUC0-4h is defined as the area under the blood concentration-time curve from time zero to 4 hours post-dose, which was the last sampling time. The linear trapezoidal method was used for AUC0-4h calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
    Notes
    [43] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    14
    10
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    420 ( 259 )
    317 ( 144 )
    No statistical analyses for this end point

    Secondary: Elimination half-life (T1/2) of remibrutinib at Week 4

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    End point title
    		 Elimination half-life (T1/2) of remibrutinib at Week 4 [44]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 4
    Notes
    [44] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    11
    9
    Units: hours
        arithmetic mean (standard deviation)
    3.08 ( 0.998 )
    3.86 ( 2.28 )
    No statistical analyses for this end point

    Secondary: Elimination half-life (T1/2) of remibrutinib at Week 24

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    End point title
    		 Elimination half-life (T1/2) of remibrutinib at Week 24 [45]
    End point description
    Remibrutinib was determined in whole blood by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.0 ng/mL. Pharmacokinetic (PK) parameters were calculated based on remibrutinib blood concentrations by using the actual recorded sampling times and non-compartmental methods with Phoenix WinNonlin (version 8 or higher). Concentrations below the LLOQ were treated as zero. T1/2 is defined as the time taken for the blood concentration, as well as the amount of the drug in the body, to fall by one-half.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.5, 1, 2, 3 and 4 hours post-dose at Week 24
    Notes
    [45] - 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: PK parameters were only applicable to remibrutinib groups.
    End point values
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd
    Number of subjects analysed
    11
    8
    Units: hours
        arithmetic mean (standard deviation)
    3.15 ( 0.907 )
    3.88 ( 1.95 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment up 30 days after last dose (Week 29)
    Adverse event reporting additional description
    Any sign or symptom that occurs from first dose of study treatment up to 30 days after last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Remibrutinib 100 mg bid
    Reporting group description
    		 Remibrutinib 100 mg twice daily (bid)

    Reporting group title
    Remibrutinib 100 mg qd
    Reporting group description
    		 Remibrutinib 100 mg once daily (qd)

    Reporting group title
    Total
    Reporting group description
    		 All participants

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Reporting group title
    Any remibrutinib
    Reporting group description
    		 Patients in any of the two remibrutinib treatment groups

    Serious adverse events
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Total Placebo Any remibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 25 (4.00%)
    3 / 73 (4.11%)
    1 / 24 (4.17%)
    2 / 49 (4.08%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
    0 / 24 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    1 / 73 (1.37%)
    0 / 24 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    1 / 73 (1.37%)
    1 / 24 (4.17%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Remibrutinib 100 mg bid Remibrutinib 100 mg qd Total Placebo Any remibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 24 (62.50%)
    12 / 25 (48.00%)
    44 / 73 (60.27%)
    17 / 24 (70.83%)
    27 / 49 (55.10%)
    Investigations
    Blood immunoglobulin G increased
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    2 / 24 (8.33%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 25 (4.00%)
    3 / 73 (4.11%)
    0 / 24 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    2
    1
    3
    0
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    0
    2
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 25 (12.00%)
    9 / 73 (12.33%)
    5 / 24 (20.83%)
    4 / 49 (8.16%)
         occurrences all number
    1
    3
    10
    6
    4
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
    3 / 24 (12.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    Lymphopenia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
    3 / 24 (12.50%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    Neutropenia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
    2 / 24 (8.33%)
    2 / 49 (4.08%)
         occurrences all number
    1
    3
    6
    2
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 25 (8.00%)
    3 / 73 (4.11%)
    1 / 24 (4.17%)
    2 / 49 (4.08%)
         occurrences all number
    0
    2
    3
    1
    2
    Fatigue
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 25 (0.00%)
    5 / 73 (6.85%)
    2 / 24 (8.33%)
    3 / 49 (6.12%)
         occurrences all number
    3
    0
    6
    3
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    2 / 24 (8.33%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    Abdominal pain
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
    1 / 24 (4.17%)
    3 / 49 (6.12%)
         occurrences all number
    1
    2
    4
    1
    3
    Diarrhoea
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 25 (0.00%)
    3 / 73 (4.11%)
    1 / 24 (4.17%)
    2 / 49 (4.08%)
         occurrences all number
    2
    0
    3
    1
    2
    Nausea
         subjects affected / exposed
    4 / 24 (16.67%)
    1 / 25 (4.00%)
    7 / 73 (9.59%)
    2 / 24 (8.33%)
    5 / 49 (10.20%)
         occurrences all number
    4
    1
    7
    2
    5
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    0
    2
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
    2 / 24 (8.33%)
    2 / 49 (4.08%)
         occurrences all number
    0
    2
    4
    2
    2
    Arthralgia
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 25 (8.00%)
    4 / 73 (5.48%)
    1 / 24 (4.17%)
    3 / 49 (6.12%)
         occurrences all number
    1
    4
    7
    2
    5
    Myalgia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    3 / 73 (4.11%)
    2 / 24 (8.33%)
    1 / 49 (2.04%)
         occurrences all number
    0
    1
    3
    2
    1
    Sjogren's syndrome
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    0
    2
    0
    2
    Muscle spasms
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 25 (8.00%)
    2 / 73 (2.74%)
    0 / 24 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    0
    2
    2
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 25 (4.00%)
    6 / 73 (8.22%)
    3 / 24 (12.50%)
    3 / 49 (6.12%)
         occurrences all number
    3
    1
    8
    4
    4
    Sinusitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    2 / 24 (8.33%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 24 (12.50%)
    0 / 25 (0.00%)
    5 / 73 (6.85%)
    2 / 24 (8.33%)
    3 / 49 (6.12%)
         occurrences all number
    3
    0
    6
    3
    3
    Urinary tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 25 (4.00%)
    4 / 73 (5.48%)
    2 / 24 (8.33%)
    2 / 49 (4.08%)
         occurrences all number
    1
    1
    4
    2
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    2 / 73 (2.74%)
    2 / 24 (8.33%)
    0 / 49 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2019
    The reason for this amendment was to respond and comply with change requests received from a regulatory authority following the first submission of the original protocol. It included a clarification of exclusion criterion number 20 on male sterilization, the deletion of the term “guardian” and a clarification of the study stopping rules.
    08 Jun 2020
    This amendment primarily aimed to align the eligibility criterion for resting heart rate (exclusion criterion #11) with a normal resting heart rate of Sjögren’s Syndrome (SjS) patients and with that of the parallel LOU064 protocols. Lowering the minimum required resting heart rate to 50 bpm (from 60 bpm) does not impact patient safety as LOU064 does not have a negative chronotropic effect. The reference point for stop of previous treatments (exclusion criterion #2) and dose adjustments for concomitant treatments (exclusion criterion #4) was changed from screening to baseline, to reflect the starting point of the additional experimental study treatment. Chloroquine in a dose up to 250 mg/day was added as an alternative allowed concomitant therapy to hydroxychloroquine (exclusion criterion #6). These treatments cover the same pharmacological principles but have different availability in different countries. Other changes were made to clarify inconsistencies and to make minor corrections. The introduced changes did not significantly impact patient safety, study population, trial conduct, or scientific value of the trial.
    05 Nov 2020
    The main purpose of this protocol amendment was to extend unblinding of interim analysis 1 and 2 (Part 1 data) to other sponsor staff. This did allow the clinical team to share unblinded results with sponsor decision boards as required for appropriate decision making on the study and on the project. Investigators and study patients will remain blinded throughout the study. Part 2 of the study will remain blinded until the final analysis for the sponsor too. Consequently, to ensure that the unblinding of Part 1 did not bias the assessment of the primary objective of the study, only Part 2 data will be used for the primary analysis of the entire study. The replacement policy was updated to allow for over recruitment of Part 1 patients in case of a higher than expected early discontinuation rate. Regarding the coronavirus disease 2019 (COVID-19) pandemic, the situation and benefit-risk assessment was carefully considered for this study. Based on these considerations, it was not considered that the COVID-19 pandemic changes the overall risk-benefit assessment for this study and therefore no changes regarding this topic were included in this amendment. However, in order to reduce study patients from potential viral exposure, some study procedures including hospital visits may need to be modified which could lead to protocol deviations. Other changes were made to clarify inconsistencies and to make minor corrections.
    12 Feb 2021
    The main purpose of this protocol amendment was a formulation switch from hard gelatin capsules to film-coated tablets to be effective only for Part 2 of the study. The patients in Part 2 were to be provided film-coated tablets, however, patients in Part 1 did continue receiving hard gelatin capsules. Film-coated tablets were to be introduced in Part 2 of the study as this formulation is the proposed market formulation. A relative bioavailability study (CLOU064X2105) has been conducted to compare the exposure of both formulations. Initial results indicated that Cmax and AUC values were in line with results from the first in human study (CLOU064X2101) given the high variability in the PK of LOU064 seen in all clinical trials. Despite the fact that Cmax and AUC were slightly lower for the film-coated tablets when compared to the hard gelatin capsules there is no change in the benefit-risk, the safety or drug-drug interaction profile and no requirement to adapt the dose. The inclusion of the film-coated tablets in Part 2 was to support the seamless switch to the final market image to be used in all Phase III trials. The patient replacement policy was updated to allow for patients over recruitment in Part 2 in case of higher than expected early discontinuation rate not due to adverse drug reactions or adverse events.

    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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