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    Clinical Trial Results:
    A Randomized, Double - Blind, Placebo-Controlled Study to Investigate the Efficacy of Fenebrutinib in Relapsing Multiple Sclerosis

    Summary
    EudraCT number
    		 2021-003772-14
    Trial protocol
    		 CZ   SK   HR  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    12 Apr 2024
    First version publication date
    12 Apr 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GN43271
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05119569
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse, 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    29 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Mar 2023
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The study aims to evaluate the efficacy of fenebrutinib compared with placebo on the total number of new gadolinium (Gd) - enhancing T1 magnetic resonance imaging (MRI) lesions in participants with relapsing multiple sclerosis (RMS).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 12
    Country: Number of subjects enrolled
    Czechia: 46
    Country: Number of subjects enrolled
    Croatia: 19
    Country: Number of subjects enrolled
    Serbia: 26
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    109
    EEA total number of subjects
    67
    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)
    109
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled across 18 sites in 6 countries (Bosnia and Herzegovina, Croatia, Czech Republic, Serbia, Slovakia and the United States). This study is still ongoing.

    Pre-assignment
    Screening details
    		 This study consists of two parts: Double-blind treatment (DBT) phase and an optional Open-label extension (OLE) phase. A total of 129 participants were screened, of which 109 were randomized into the fenebrutinib arm and placebo arm in a 2:1 ratio.

    Period 1
    Period 1 title
    Double Blind Treatment Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBT Phase: Fenebrutinib
    Arm description
    		 Participants received fenebrutinib, 200 milligrams (mg), orally, twice daily (BID) for 12 weeks during the DBT phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenebrutinib
    Investigational medicinal product code
    RO7010939
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered two 100 mg tablets, orally, BID for a total dose of 400 mg of fenebrutinib every day.

    Arm title
    		 DBT Phase: Placebo
    Arm description
    		 Participants received fenebrutinib matching placebo, orally, BID, for 12 weeks during the DBT phase.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered two tablets of placebo orally, BID.

    Number of subjects in period 1
    		DBT Phase: Fenebrutinib DBT Phase: Placebo
    Started
    73
    36
    Completed
    65
    34
    Not completed
    8
    2
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    6
    -
    Period 2
    Period 2 title
    Open Label Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OLE Phase: Fenebrutinib from Fenebrutinib
    Arm description
    		 Participants who received fenebrutinib in the DBT phase were given an option to receive fenebrutinib, 200 mg, orally, BID up to a maximum of 192 weeks in the OLE phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenebrutinib
    Investigational medicinal product code
    RO7010939
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered two 100 mg tablets orally BID for a total dose of 400 mg of fenebrutinib every day.

    Arm title
    		 OLE Phase: Fenebrutinib from Placebo
    Arm description
    		 Participants who received fenebrutinib matching placebo in the DBT phase were given an option to receive fenebrutinib, 200 mg, orally, BID up to a maximum of 192 weeks in the OLE phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fenebrutinib
    Investigational medicinal product code
    RO7010939
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were administered two 100 mg tablets, orally, BID for a total dose of 400 mg of fenbrutinib everyday.

    Number of subjects in period 2
    		OLE Phase: Fenebrutinib from Fenebrutinib OLE Phase: Fenebrutinib from Placebo
    Started
    65
    34
    Completed
    0
    0
    Not completed
    65
    34
         Ongoing in the study
    65
    34

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DBT Phase: Fenebrutinib
    Reporting group description
    		 Participants received fenebrutinib, 200 milligrams (mg), orally, twice daily (BID) for 12 weeks during the DBT phase.

    Reporting group title
    DBT Phase: Placebo
    Reporting group description
    		 Participants received fenebrutinib matching placebo, orally, BID, for 12 weeks during the DBT phase.

    Reporting group values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo Total
    Number of subjects
    		 73 36 109
    Age categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.6 ( 8.5 ) 39.8 ( 7.7 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 52 26 78
        Male
    		 21 10 31
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 72 36 108
        Unknown or Not Reported
    		 1 0 1
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 73 36 109
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    DBT Phase: Fenebrutinib
    Reporting group description
    		 Participants received fenebrutinib, 200 milligrams (mg), orally, twice daily (BID) for 12 weeks during the DBT phase.

    Reporting group title
    DBT Phase: Placebo
    Reporting group description
    		 Participants received fenebrutinib matching placebo, orally, BID, for 12 weeks during the DBT phase.
    Reporting group title
    OLE Phase: Fenebrutinib from Fenebrutinib
    Reporting group description
    		 Participants who received fenebrutinib in the DBT phase were given an option to receive fenebrutinib, 200 mg, orally, BID up to a maximum of 192 weeks in the OLE phase.

    Reporting group title
    OLE Phase: Fenebrutinib from Placebo
    Reporting group description
    		 Participants who received fenebrutinib matching placebo in the DBT phase were given an option to receive fenebrutinib, 200 mg, orally, BID up to a maximum of 192 weeks in the OLE phase.

    Primary: DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scans of the Brain Over 12 Weeks

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    End point title
    		 DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scans of the Brain Over 12 Weeks
    End point description
    Radiologic evaluation for Gd enhancing T1 lesion rate was performed using a standardized MRI protocol at screening, and at Weeks 4, 8, and 12. All MRI scans were read by a centralized reading center for efficacy endpoints. The total number of new Gd-enhancing T1 lesions were calculated as the sum of the individual number of new lesions observed at Weeks 4, 8 and 12. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Primary
    End point timeframe
    MRI scans performed at Weeks 4, 8 and 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    70
    36
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.077 (0.043 to 0.135)
    0.245 (0.144 to 0.418)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0022
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.313
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.149
         upper limit
    		 0.658

    Secondary: DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scans of the Brain Over 12 Weeks

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    End point title
    		 DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scans of the Brain Over 12 Weeks
    End point description
    Radiologic evaluation for new or enlarging T2-weighted lesion rate was performed using a standardized MRI protocol at screening, and at Weeks 4, 8, and 12. All MRI scans were read by a centralized reading center for efficacy endpoints. Total number of new or enlarging T2-weighted lesions were calculated as the sum of the individual number of new or enlarging lesions at Weeks 4, 8, 12. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Secondary
    End point timeframe
    MRI scans performed at Weeks 4, 8 and 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    70
    36
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.168 (0.102 to 0.277)
    0.634 (0.375 to 1.071)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0004
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.265
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.128
         upper limit
    		 0.55

    Secondary: DBT Phase: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 DBT Phase: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, is a congenital anomaly or birth defect. Safety population included all participants who received any study drug.
    End point type
    Secondary
    End point timeframe
    Up to Week 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    73
    36
    Units: participants
        AEs
    28
    12
        SAEs
    0
    0
    No statistical analyses for this end point

    Secondary: DBT Phase: Proportion of Participants Free From any New Gd - Enhancing T1 Lesions and New or Enlarging T2 - Weighted Lesions Observed on MRI Scans of the Brain Over 12 Weeks

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    End point title
    		 DBT Phase: Proportion of Participants Free From any New Gd - Enhancing T1 Lesions and New or Enlarging T2 - Weighted Lesions Observed on MRI Scans of the Brain Over 12 Weeks
    End point description
    Radiologic evaluation for new Gd - enhancing T1 lesions and new or enlarging T2 - weighted lesions were performed using a standardized MRI protocol at screening, and at Weeks 4, 8, and 12. All MRI scans were read by a centralized reading center for efficacy endpoints. Analysis was performed using a logistic regression model performed on the status of both new T1 Gd+ lesion and new or enlarging T2-weighted lesions post-baseline (present or not) adjusted for the stratification factor(s) presence or absence of T1 Gd+ lesions on the screening MRI. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Secondary
    End point timeframe
    MRI scans performed at Weeks 4, 8 and 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    70
    36
    Units: proportion of participants
        number (not applicable)
    72.9
    50.0
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0117
    Method
    		 Logistic Regression Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.317
         upper limit
    		 13.078

    Secondary: OLE Phase: Number of Participants with AEs and SAEs

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    End point title
    		 OLE Phase: Number of Participants with AEs and SAEs
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability or incapacity, is a congenital anomaly or birth defect. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    OLE Baseline (DBT Week 12) up to Week 192
    End point values
    		 OLE Phase: Fenebrutinib from Fenebrutinib OLE Phase: Fenebrutinib from Placebo
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: participants
    Notes
    [1] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [2] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Fenebrutinib

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    End point title
    		 Plasma Concentrations of Fenebrutinib
    End point description
    Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to Week 192
    End point values
    		 OLE Phase: Fenebrutinib from Fenebrutinib OLE Phase: Fenebrutinib from Placebo
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: nanograms per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [3] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [4] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Secondary: Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Number of Participants With Post-baseline Suicidal Ideation or Suicidal Behavior as Measured Using Columbia-Suicide Severity Rating Scale (C-SSRS)
    End point description
    C-SSRS=assessment tool used to assess lifetime suicidality of a participant (at baseline) as well as any new instances of suicidality (C-SSRS since last visit). Structured interview prompts recollection of suicidal ideation, including intensity of ideation, behavior, & attempts with actual/potential lethality. Categories have binary responses (yes/no) & include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Score of 0 is assigned if no suicide risk is present. Score of 1 or higher= suicidal ideation or behavior. Data collection is still ongoing and the results will be disclosed within 1 year from the Study Completion Date.
    End point type
    Secondary
    End point timeframe
    Up to Week 192
    End point values
    		 OLE Phase: Fenebrutinib from Fenebrutinib OLE Phase: Fenebrutinib from Placebo
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: participants
        number (not applicable)
    Notes
    [5] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    [6] - Data collection is ongoing and results will be disclosed within 1 year from Study Completion Date.
    No statistical analyses for this end point

    Other pre-specified: DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 4

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    End point title
    		 DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 4
    End point description
    Radiologic evaluation for Gd enhancing T1 lesion rate was performed using a standardized MRI protocol at screening, and at Week 4. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 4
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    70
    36
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.210 (0.115 to 0.382)
    0.269 (0.128 to 0.565)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5889
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.316
         upper limit
    		 1.922

    Other pre-specified: DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 8

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    End point title
    		 DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 8
    End point description
    Radiologic evaluation for Gd enhancing T1 lesion rate was performed using a standardized MRI protocol at screening, and at Week 8. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 8
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    67
    34
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.025 (0.006 to 0.101)
    0.325 (0.150 to 0.702)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0011
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.076
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.355

    Other pre-specified: DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 12

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    End point title
    		 DBT Phase: New Gd - Enhancing T1 Lesion Rate Observed on MRI Scan of the Brain at Week 12
    End point description
    Radiologic evaluation for Gd enhancing T1 lesion rate was performed using a standardized MRI protocol at screening, and at Week 12. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    63
    33
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.007 (0.001 to 0.052)
    0.066 (0.013 to 0.324)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0038
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.104
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.022
         upper limit
    		 0.481

    Other pre-specified: DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scans of the Brain at Week 4

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    End point title
    		 DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scans of the Brain at Week 4
    End point description
    Radiologic evaluation for new or enlarging T2-weighted lesion rate was performed using a standardized MRI protocol at screening, and at Week 4. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 4
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    70
    36
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.456 (0.274 to 0.757)
    0.891 (0.490 to 1.620)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0958
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.512
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.233
         upper limit
    		 1.126

    Other pre-specified: DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scan of the Brain at Week 8

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    End point title
    		 DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scan of the Brain at Week 8
    End point description
    Radiologic evaluation for new or enlarging T2-weighted lesion rate was performed using a standardized MRI protocol at screening, and at Week 8. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 8
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    67
    34
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.058 (0.023 to 0.144)
    0.549 (0.314 to 0.958)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.039
         upper limit
    		 0.283

    Other pre-specified: DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scan of the Brain at Week 12

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    End point title
    		 DBT Phase: New or Enlarging T2-Weighted Lesion Rate Observed on MRI Scan of the Brain at Week 12
    End point description
    Radiologic evaluation for new or enlarging T2-weighted lesion rate was performed using a standardized MRI protocol at screening, and at Week 12. All MRI scans were read by a centralized reading center for efficacy endpoints. The lesion rate was calculated using a negative binomial regression model adjusted using stratification factor(s) i.e., presence or absence of T1 Gd+ lesions on the screening MRI. Log-transformed number of scans were included in the negative binomial model as an “offset” variable to account for different number of scans. All Randomized Participants set included all randomized participants grouped by treatment as assigned by randomization. Overall number analyzed is the number of participants with evaluable post-baseline MRI scans.
    End point type
    Other pre-specified
    End point timeframe
    MRI scan performed at Week 12
    End point values
    		 DBT Phase: Fenebrutinib DBT Phase: Placebo
    Number of subjects analysed
    63
    33
    Units: adjusted number of new lesions per scan
        number (confidence interval 95%)
    0.015 (0.003 to 0.068)
    0.282 (0.135 to 0.586)
    Statistical analysis title
    		 Fenebrutinib vs Placebo
    Comparison groups
    DBT Phase: Fenebrutinib v DBT Phase: Placebo
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate Ratio
    Point estimate
    0.053
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.012
         upper limit
    		 0.233

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 12
    Adverse event reporting additional description
    Safety population included all participants who received any study drug. Data collected up to the primary completion date is reported here. Adverse events section will be updated one year after the study completion date.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    DBT Phase: Placebo
    Reporting group description
    		 Participants received fenebrutinib matching placebo, orally, BID, for 12 weeks during the DBT phase.

    Reporting group title
    DBT Phase: Fenebrutinib
    Reporting group description
    		 Participants received fenebrutinib, 200 mg, orally, BID for 12 weeks during the DBT phase.

    Serious adverse events
    		 DBT Phase: Placebo DBT Phase: Fenebrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 73 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DBT Phase: Placebo DBT Phase: Fenebrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 36 (11.11%)
    8 / 73 (10.96%)
    Investigations
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 73 (5.48%)
         occurrences all number
    0
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 73 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 73 (5.48%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2021
    1. Changes were made to clarify reporting procedures for increase in transaminase. 2. The pharmacokinetic and biomarker samples and collection timepoints were updated. 3. COVID-19 vaccines administration details were added. 4. The exclusion criterion regarding white blood cell count was updated. 5. The eligibility requirement on disease modifying therapy washout periods prior to study entry was amended to unify across different drug labels/countries. 6. Platelet count ranges for adverse event management of thrombocytopenia were updated.
    15 Dec 2022
    1. Per recommendations from the independent Data Monitoring Committee (iDMC), additional monitoring visits for liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], total and direct bilirubin) were added to the Schedule of Activities. 2. Guidance was provided for management of participants with abnormal liver function tests. 3. The duration of the optional OLE phase was extended from 96 weeks up to a maximum of 192 weeks. 4. Language was updated for the Week 12 lumbar puncture, addition of primary and secondary efficacy estimands, inclusion of biotin as a prohibited concomitant medication, clarifications to exclusion criteria, and updates to discontinuation criteria in relation to thrombocytopenia.

    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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