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    Clinical Trial Results:
    A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot and Dose-Ranging Study of GDC-0853 in Patients with Refractory Chronic Spontaneous Urticaria (CSU).

    Summary
    EudraCT number
    		 2016-004624-35
    Trial protocol
    		 DE   PL  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Sep 2020
    First version publication date
    18 Sep 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS39684
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03137069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    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
    Final
    Date of interim/final analysis
    25 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety and pharmacokinetics of GDC-0853.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 All Subjects were already treated with anti-histamines.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2017
    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
    Canada: 64
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United States: 41
    Worldwide total number of subjects
    134
    EEA total number of subjects
    29
    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)
    125
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 21 centers in 3 countries.

    Pre-assignment
    Screening details
    		 A total of 134 subjects were enrolled at 21 centers.

    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, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Placebo
    Arm description
    		 Subjects received matching placebo twice daily from Day 1 to 56.
    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
    Placebo matching GDC-0853 was administered.

    Arm title
    		 Cohort 1: GDC-0853 200mg BID
    Arm description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0853
    Investigational medicinal product code
    Other name
    fenebrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0853 was administered orally twice daily (BID) at a dose of 200mg.

    Arm title
    		 Cohort 2: Placebo
    Arm description
    		 Subjects received matching placebo up to twice daily from Day 1 to 56.
    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
    Placebo matching GDC-0853 was administered.

    Arm title
    		 Cohort 2: GDC-0853 50mg QD
    Arm description
    		 Subjects received GDC-0853 50mg once daily from Day 1 to 56.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0853
    Investigational medicinal product code
    Other name
    fenebrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0853 was administered orally once daily (QD) at a dose of 50mg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching GDC-0853 was administered.

    Arm title
    		 Cohort 2: GDC-0853 150mg QD
    Arm description
    		 Subjects received GDC-0853 150mg once daily from Day 1 to 56.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0853
    Investigational medicinal product code
    Other name
    fenebrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0853 was administered orally once daily (QD) at a dose of 150mg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching GDC-0853 was administered.

    Arm title
    		 Cohort 2: GDC-0853 200mg BID
    Arm description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GDC-0853
    Investigational medicinal product code
    Other name
    fenebrutinib
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GDC-0853 was administered orally twice daily (BID) at a dose of 200mg.

    Number of subjects in period 1
    		Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: Placebo Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID
    Started
    13
    28
    23
    23
    24
    23
    Completed
    12
    22
    20
    17
    22
    21
    Not completed
    1
    6
    3
    6
    2
    2
         Consent withdrawn by subject
    1
    2
    2
    2
    -
    -
         Physician decision
    -
    -
    -
    1
    -
    -
         Data Entry Error
    -
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    3
    1
    1
    -
    1
         Study Terminated by Sponsor
    -
    -
    -
    -
    1
    -
         Protocol deviation
    -
    1
    -
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    		 Subjects received matching placebo twice daily from Day 1 to 56.

    Reporting group title
    Cohort 1: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    		 Subjects received matching placebo up to twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 50mg QD
    Reporting group description
    		 Subjects received GDC-0853 50mg once daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 150mg QD
    Reporting group description
    		 Subjects received GDC-0853 150mg once daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Reporting group values
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: Placebo Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID Total
    Number of subjects
    		 13 28 23 23 24 23 134
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 13 28 21 22 20 21 125
        From 65-84 years
    		 0 0 2 1 4 2 9
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 43.6 ( 11.0 ) 41.3 ( 15.9 ) 40.2 ( 14.7 ) 45.0 ( 13.1 ) 43.3 ( 16.7 ) 44.3 ( 13.0 ) -
    Sex: Female, Male
    Units:
        Female
    		 11 22 17 18 20 16 104
        Male
    		 2 6 6 5 4 7 30
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 0 1 5 2 5 2 15
        Not Hispanic or Latino
    		 13 27 16 21 19 20 116
        Not Stated
    		 0 0 1 0 0 1 2
        Unknown
    		 0 0 1 0 0 0 1
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 3 4 3 1 4 15
        Black or African American
    		 1 1 1 1 0 2 6
        White
    		 10 24 18 19 23 16 110
        Multiple
    		 2 0 0 0 0 1 3

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    		 Subjects received matching placebo twice daily from Day 1 to 56.

    Reporting group title
    Cohort 1: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    		 Subjects received matching placebo up to twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 50mg QD
    Reporting group description
    		 Subjects received GDC-0853 50mg once daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 150mg QD
    Reporting group description
    		 Subjects received GDC-0853 150mg once daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Subject analysis set title
    Cohort 1: Placebo (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received matching placebo twice daily from Day 1 to 56.

    Subject analysis set title
    Cohort 1: GDC-0853 200mg BID (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Subject analysis set title
    Cohort 2: Placebo (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received matching placebo up to twice daily from Day 1 to 56. One subject in Cohort 2 was randomized into the Placebo arm (Cohort 2: Placebo) and received the Placebo treatment in the study. However due to a data entry error, this subject was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm in the Safety-evaluable population.

    Subject analysis set title
    Cohort 2: GDC-0853 50mg QD (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received GDC-0853 50mg once daily from Day 1 to 56.

    Subject analysis set title
    Cohort 2: GDC-0853 150mg QD (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received GDC-0853 150mg once daily from Day 1 to 56.

    Subject analysis set title
    Cohort 2: GDC-0853 200mg BID (Safety-Evaluable Population)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received GDC-0853 200mg twice daily from Day 1 to 56. One subject in Cohort 2 was randomized into the Placebo arm (Cohort 2: Placebo) and received the Placebo treatment in the study. However due to a data entry error, this subject was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm in the Safety-evaluable population.

    Primary: Change from Baseline in the Urticaria Activity Score over 7 days (UAS7) at Day 57

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    End point title
    		 Change from Baseline in the Urticaria Activity Score over 7 days (UAS7) at Day 57
    End point description
    The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (Day 57 score minus Baseline score) indicates improvement. This was assessed in the Modified Intent-To-Treat (mITT) Population defined as all subjects who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized.
    End point type
    Primary
    End point timeframe
    Baseline and Day 57
    End point values
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: Placebo Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID
    Number of subjects analysed
    12
    22
    20
    19
    22
    21
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -19.16 ( 13.49 )
    -24.05 ( 9.74 )
    -11.25 ( 10.81 )
    -15.69 ( 14.25 )
    -17.05 ( 10.19 )
    -21.80 ( 14.80 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Cohort 1: Placebo v Cohort 1: GDC-0853 200mg BID
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 > 0.0559
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -7.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -13.01
         upper limit
    		 -1.03
    Notes
    [1] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 50mg QD
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 > 0.8892
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 5.58
    Notes
    [2] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 150mg QD
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 > 0.0717
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -6.43
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -12.29
         upper limit
    		 -0.57
    Notes
    [3] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 200mg BID
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 > 0.0097
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -9.53
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -15.5
         upper limit
    		 -3.55
    Notes
    [4] - Covariates included were region, treatment group, visit, and visit by treatment group interaction

    Secondary: Percentage of Subjects who are Well-Controlled (UAS7 ≤ 6)

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    End point title
    		 Percentage of Subjects who are Well-Controlled (UAS7 ≤ 6)
    End point description
    The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. Subjects with UAS7 score ≤6 are considered well controlled. This was assessed in the Modified Intent-To-Treat (mITT) Population defined as all subjects who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Day 57
    End point values
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: Placebo Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID
    Number of subjects analysed
    13
    28
    23
    23
    24
    23
    Units: Percentage of Participants
        number (not applicable)
    30.8
    57.1
    21.7
    34.8
    45.8
    56.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Cohort 1: Placebo v Cohort 1: GDC-0853 200mg BID
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 > 0.1087
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Stratified by region
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 50mg QD
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 > 0.3418
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - Stratified by region
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 150mg QD
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 > 0.0459
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [7] - Stratified by region
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 200mg BID
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 > 0.019
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [8] - Stratified by region

    Secondary: Change from Baseline in the UAS7 at Day 29

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    End point title
    		 Change from Baseline in the UAS7 at Day 29
    End point description
    The Urticaria Activity Score (UAS) is a composite, diary-recorded score with numeric severity intensity ratings (0=none to 3=intense/severe) for the number of wheals (hives) and the intensity of the pruritus (itch) over the past 12 hours (twice daily). The daily UAS is calculated as the average of the morning and evening scores. The UAS7 is the weekly sum of the daily UAS, which is the composite score of the intensity of pruritus and the number of wheals. The maximum UAS7 value is 42. A higher score indicates worse disease. A negative change score (Day 29 score minus Baseline score) indicates improvement. This was assessed in the Modified Intent-To-Treat (mITT) Population defined as all subjects who received at least one dose of study treatment grouped for analysis according to the treatment arm to which they were randomized.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 29
    End point values
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: Placebo Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID
    Number of subjects analysed
    13
    24
    21
    19
    23
    21
    Units: Score on a Scale
        arithmetic mean (standard deviation)
    -9.69 ( 10.70 )
    -22.15 ( 10.33 )
    -9.05 ( 9.82 )
    -16.97 ( 14.31 )
    -13.75 ( 12.93 )
    -21.69 ( 16.22 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Cohort 1: Placebo v Cohort 1: GDC-0853 200mg BID
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 > 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -12.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -18.94
         upper limit
    		 -6.82
    Notes
    [9] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 50mg QD
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 > 0.4565
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -2.83
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -9.11
         upper limit
    		 3.46
    Notes
    [10] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 150mg QD
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 > 0.1711
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -5.03
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -11.1
         upper limit
    		 1.03
    Notes
    [11] - Covariates included were region, treatment group, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Cohort 2: Placebo v Cohort 2: GDC-0853 200mg BID
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 > 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -10.76
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -16.97
         upper limit
    		 -4.56
    Notes
    [12] - Covariates included were region, treatment group, visit, and visit by treatment group interaction

    Secondary: Percentage of Subjects with Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects with Adverse Events (AEs)
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. This was assessed in the Safety-evaluable population defined as all subjects who received at least one dose of study drug with subjects grouped according to their actual treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).
    End point values
    		 Cohort 1: Placebo (Safety-Evaluable Population) Cohort 1: GDC-0853 200mg BID (Safety-Evaluable Population) Cohort 2: Placebo (Safety-Evaluable Population) Cohort 2: GDC-0853 50mg QD (Safety-Evaluable Population) Cohort 2: GDC-0853 150mg QD (Safety-Evaluable Population) Cohort 2: GDC-0853 200mg BID (Safety-Evaluable Population)
    Number of subjects analysed
    13
    28
    22
    23
    24
    24
    Units: Percentage of Subjects
        number (not applicable)
    61.5
    71.4
    54.5
    60.9
    66.7
    58.3
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of fenebrutinib (GDC-0853) at specified timepoints

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    End point title
    		 Plasma Concentrations of fenebrutinib (GDC-0853) at specified timepoints [13]
    End point description
    Plasma Concentration Data for fenebrutinib (GDC-0853) will be tabulated and summarised by visits. Descriptive summary statistics for Arithmetic Mean and Standard Deviation will be presented. This was assessed in the PK-evaluable population defined as all subjects who received at least one dose of fenebrutinib (GDC-0853) and had at least 1 evaluable post-dose PK sample. Subjects who received incorrect therapy different from the intended therapy were summarized in the group according to the therapy actually received. Please note that the Placebo Cohorts were not evaluated for this Outcome Measure. 999 = Not Estimable.
    End point type
    Secondary
    End point timeframe
    Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Placebo Cohorts were not evaluated for PK Analysis.
    End point values
    		 Cohort 1: GDC-0853 200mg BID Cohort 2: GDC-0853 50mg QD Cohort 2: GDC-0853 150mg QD Cohort 2: GDC-0853 200mg BID
    Number of subjects analysed
    28
    23
    24
    23
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Day 8
    378 ( 389 )
    38.5 ( 36.9 )
    178 ( 237 )
    424 ( 385 )
        Day 57
    283 ( 315 )
    19.6 ( 26.3 )
    24.7 ( 17.7 )
    219 ( 293 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up until 4 weeks after the last dose of study drug (up to 2 years, 5 months).
    Adverse event reporting additional description
    One subject in Cohort 2 was randomized into the Placebo arm (Cohort 2: Placebo) and received the Placebo treatment in the study. However due to a data entry error, this subject was inadvertently analysed in the (Cohort 2: GDC-0853 200 mg BID) arm in the Safety-evaluable population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Cohort 1: Placebo
    Reporting group description
    		 Subjects received matching placebo twice daily from Day 1 to 56.

    Reporting group title
    Cohort 1: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 50mg QD
    Reporting group description
    		 Subjects received GDC-0853 50mg once daily from Day 1 to 56.

    Reporting group title
    Cohort 2: Placebo
    Reporting group description
    		 Subjects received matching placebo up to twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 200mg BID
    Reporting group description
    		 Subjects received GDC-0853 200mg twice daily from Day 1 to 56.

    Reporting group title
    Cohort 2: GDC-0853 150mg QD
    Reporting group description
    		 Subjects received GDC-0853 150mg once daily from Day 1 to 56.

    Serious adverse events
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: GDC-0853 50mg QD Cohort 2: Placebo Cohort 2: GDC-0853 200mg BID Cohort 2: GDC-0853 150mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    3 / 28 (10.71%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    PERIORBITAL CELLULITIS
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Placebo Cohort 1: GDC-0853 200mg BID Cohort 2: GDC-0853 50mg QD Cohort 2: Placebo Cohort 2: GDC-0853 200mg BID Cohort 2: GDC-0853 150mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 13 (61.54%)
    16 / 28 (57.14%)
    7 / 23 (30.43%)
    7 / 22 (31.82%)
    12 / 24 (50.00%)
    13 / 24 (54.17%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 28 (7.14%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    3 / 24 (12.50%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    0
    0
    3
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 28 (7.14%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    0
    0
    2
    1
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    BONE CONTUSION
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    CONTUSION
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 28 (7.14%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    INJURY
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 28 (7.14%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    0
    0
    1
    0
    HEADACHE
         subjects affected / exposed
    3 / 13 (23.08%)
    4 / 28 (14.29%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    3 / 24 (12.50%)
    1 / 24 (4.17%)
         occurrences all number
    3
    5
    0
    2
    3
    1
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    FATIGUE
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    FEELING ABNORMAL
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Eye disorders
    VISION BLURRED
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    2 / 22 (9.09%)
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    NAUSEA
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 28 (7.14%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    2 / 24 (8.33%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    1
    0
    2
    2
    Skin and subcutaneous tissue disorders
    CHRONIC SPONTANEOUS URTICARIA
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 28 (7.14%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    3
    2
    1
    0
    3
    URTICARIA
         subjects affected / exposed
    0 / 13 (0.00%)
    5 / 28 (17.86%)
    3 / 23 (13.04%)
    2 / 22 (9.09%)
    5 / 24 (20.83%)
    4 / 24 (16.67%)
         occurrences all number
    0
    5
    3
    2
    5
    4
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    1 / 23 (4.35%)
    1 / 22 (4.55%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    Infections and infestations
    EYE INFECTION
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    3 / 13 (23.08%)
    7 / 28 (25.00%)
    3 / 23 (13.04%)
    1 / 22 (4.55%)
    3 / 24 (12.50%)
    3 / 24 (12.50%)
         occurrences all number
    3
    9
    3
    1
    4
    4
    TOOTH INFECTION
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 28 (0.00%)
    0 / 23 (0.00%)
    0 / 22 (0.00%)
    0 / 24 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 28 (3.57%)
    0 / 23 (0.00%)
    1 / 22 (4.55%)
    2 / 24 (8.33%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    1
    2
    0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 28 (0.00%)
    1 / 23 (4.35%)
    0 / 22 (0.00%)
    1 / 24 (4.17%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    1
    0
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2017
    Following updates were made: [1] Addition of a dose-ranging cohort (Cohort 2) gated on the basis of results from an interim analysis of Cohort 1 and language updated throughout the protocol to include the additional cohort accordingly; [2] Updates to background information on GDC-0853; [3] Clarification to exploratory biomarker objectives and endpoints; [4] Addition of the collection and storage of a blood sample for possible future DNA analyses; [5] Clarification to method of randomization; [6] Updating of reporting of the term “sudden death” to also require the presumed cause of death; [7] Clarification to event reporting for hospitalization; [8] Addition of content from previous protocol clarification letters and [9] Updating of Informed Consent Forms to reflect changes in the Protocol.
    09 Aug 2018
    Following updates were made: [1] Updating of name of study drug from GDC-0853 to fenebrutinib throughout the document; [2] Update to Medical Monitor contact; [3] General enrolment update; [4] Clarification regarding use of rescue medication and contradictory language regarding tubal ligation; [5] Update to Inclusion Criteria; [6] Clarification of fasting before morning clinic visits; [7] Update to Bilastine dose range; [8] Clarification regarding effect of ethinyl estradiol with fenebrutinib, use of prohibited therapies, corticosteroids for exacerbations and eligibility criteria for re-screening; [9] Clarification of the UAS7 definition and [10] Additional information regarding Whole Genome Sequencing (WGS), Infections, Bleeding and Gastrointestinal effects.

    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.
    Recruitment was stopped after an interim analysis of Cohort 2 based on pre-specified internal criteria.
    For support, Contact us.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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