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    Clinical Trial Results:
    A Phase II Open-Label Extension Study of Patients Previously Enrolled in Study GA29350 to Evaluate the Long-Term Safety and Efficacy of GDC-0853 in Patients With Moderate to Severe Rheumatoid Arthritis

    Summary
    EudraCT number
    		 2016-000498-19
    Trial protocol
    		 BG  
    Global end of trial date
    17 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2020
    First version publication date
    25 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GA30067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02983227
    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
    17 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long term safety and efficacy of GDC-0853.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 60
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Brazil: 51
    Country: Number of subjects enrolled
    Colombia: 22
    Country: Number of subjects enrolled
    Mexico: 36
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Russian Federation: 74
    Country: Number of subjects enrolled
    Serbia: 36
    Country: Number of subjects enrolled
    Ukraine: 135
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    496
    EEA total number of subjects
    62
    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)
    442
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 138 centers in 19 countries.

    Pre-assignment
    Screening details
    		 496 subjects were enrolled into this OLE study and were included in the ITT and Safety populations.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GDC-0853 (200mg BID) Cohort 1
    Arm description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo.
    Arm type
    		 Experimental

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

    Arm title
    		 GDC-0853 (200mg BID) Cohort 2
    Arm description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo.
    Arm type
    		 Experimental

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

    Number of subjects in period 1
    		GDC-0853 (200mg BID) Cohort 1 GDC-0853 (200mg BID) Cohort 2
    Started
    410
    86
    Completed
    351
    72
    Not completed
    59
    14
         Adverse event, serious fatal
    3
    -
         Physician decision
    3
    1
         Consent withdrawn by subject
    19
    8
         Adverse event, non-fatal
    21
    3
         Multiple Reasons
    2
    1
         Lost to follow-up
    3
    -
         Lack of efficacy
    8
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GDC-0853 (200mg BID) Cohort 1
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo.

    Reporting group title
    GDC-0853 (200mg BID) Cohort 2
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo.

    Reporting group values
    		 GDC-0853 (200mg BID) Cohort 1 GDC-0853 (200mg BID) Cohort 2 Total
    Number of subjects
    		 410 86 496
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 371 71 442
        From 65-84 years
    		 39 15 54
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 49.9 ± 11.7 53.5 ± 12.5 -
    Sex: Female, Male
    Units:
        Female
    		 334 64 398
        Male
    		 76 22 98
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 136 30 166
        Not Hispanic or Latino
    		 267 56 323
        Not Stated
    		 2 0 2
        Unknown
    		 5 0 5
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska native
    		 27 11 38
        Asian
    		 1 0 1
        Black or African American
    		 7 2 9
        Multiple
    		 7 2 9
        Unknown
    		 3 0 3
        White
    		 365 71 436

    End points

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    End points reporting groups
    Reporting group title
    GDC-0853 (200mg BID) Cohort 1
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo.

    Reporting group title
    GDC-0853 (200mg BID) Cohort 2
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo.

    Subject analysis set title
    GDC-0853 (200mg BID) Cohort 1 (PK-Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo. The PK-Evaluable population was defined as all subjects that received any fenebrutinib/GDC-0853 and had sufficient data to enable estimation of key PK parameters. Subjects who received incorrect therapy different from the intended therapy were summarized in the group according to the therapy actually received.

    Subject analysis set title
    GDC-0853 (200mg BID) Cohort 2 (PK-Evaluable Population)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo. The PK-Evaluable population was defined as all participants that received any fenebrutinib/GDC-0853 and had sufficient data to enable estimation of key PK parameters. Participants who received incorrect therapy different from the intended therapy were summarized in the group according to the therapy actually received.

    Subject analysis set title
    GDC-0853 (200mg BID) Cohort 1 (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo. The Intent-To-Treat (ITT) Population was defined as all eligible subjects enrolled in this OLE study.

    Subject analysis set title
    GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo. The Intent-To-Treat (ITT) Population was defined as all eligible subjects enrolled in this OLE study.

    Primary: Percentage of Subjects With Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects With Adverse Events (AEs) [1]
    End point description
    An Adverse Event (AE) was considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events.
    End point type
    Primary
    End point timeframe
    Day 1 up until 8 weeks after the last dose of study drug (up to 1 year, 2 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed, as this study has only 1 arm.
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 GDC-0853 (200mg BID) Cohort 2
    Number of subjects analysed
    410
    86
    Units: Percentage
        number (not applicable)
    60.2
    57.0
    No statistical analyses for this end point

    Primary: Percentage of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 52

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 50% (ACR50) Response at Week 52 [2]
    End point description
    ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
    End point type
    Primary
    End point timeframe
    Week 52
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed, as this study has only 1 arm.
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage
        number (confidence interval 95%)
    57.1 (52.28 to 61.86)
    50.0 (39.43 to 60.57)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving ACR50 Response up to Week 12

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    End point title
    		 Percentage of Subjects Achieving ACR50 Response up to Week 12
    End point description
    ACR50 response is defined as a ≥ 50% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8 and 12
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage
    number (confidence interval 95%)
        Week 4
    37.1 (32.40 to 41.75)
    29.1 (19.47 to 38.67)
        Week 8
    42.4 (37.65 to 47.22)
    34.9 (24.81 to 44.96)
        Week 12
    45.6 (40.79 to 50.43)
    39.5 (29.20 to 49.87)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response
    End point description
    ACR20 response is defined as a ≥ 20% improvement (reduction) compared with baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate]
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage
    number (confidence interval 95%)
        Week 4
    69.0 (64.55 to 73.50)
    58.1 (47.71 to 68.57)
        Week 8
    72.9 (68.63 to 77.23)
    68.6 (58.80 to 78.41)
        Week 12
    74.4 (70.17 to 78.62)
    73.3 (63.90 to 82.61)
        Week 24
    75.4 (71.20 to 79.54)
    72.1 (62.61 to 81.57)
        Week 36
    75.1 (70.94 to 79.31)
    72.1 (62.61 to 81.57)
        Week 52
    75.4 (71.20 to 79.54)
    68.6 (58.80 to 78.41)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving American College of Rheumatology 70% (ACR70) Response

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    End point title
    		 Percentage of Subjects Achieving American College of Rheumatology 70% (ACR70) Response
    End point description
    ACR70 response is defined as a ≥ 70% improvement (reduction) compared with Baseline for both total joint count-68 joints (TJC68) and swollen joint count-66 joints (SJC66), as well as for three of the additional five ACR core set variables: Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain; Patient's Global Assessment of Disease Activity and Physician's Global Assessment of Disease Activity over the previous 24 hours using a VAS where left end of the line 0=no disease activity to right end of the line 100=maximum disease activity; Health Assessment Questionnaire: 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities, 0=without difficulty to 3=unable to do; and acute-phase reactant [either C-reactive protein or Erythrocyte Sedimentation Rate].
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage
    number (confidence interval 95%)
        Week 4
    19.8 (15.90 to 23.61)
    12.8 (5.73 to 19.85)
        Week 8
    21.7 (17.72 to 25.70)
    17.4 (9.42 to 25.46)
        Week 12
    23.9 (19.77 to 28.03)
    19.8 (11.35 to 28.18)
        Week 24
    30.2 (25.80 to 34.69)
    20.9 (12.33 to 29.53)
        Week 36
    32.2 (27.67 to 36.72)
    25.6 (16.36 to 34.80)
        Week 52
    36.3 (31.69 to 41.00)
    27.9 (18.43 to 37.39)
    No statistical analyses for this end point

    Secondary: Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 CRP)

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    End point title
    		 Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (3 Variables) (DAS28-3 CRP)
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    406
    86
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline (C1, n=406; C2, n=86)
    5.49 ± 0.85
    5.59 ± 0.90
        Week 4 (C1, n=398; C2, n=83)
    3.64 ± 1.11
    4.09 ± 1.19
        Week 8 (C1, n=386; C2, n=84)
    3.48 ± 1.06
    3.81 ± 1.15
        Week 12 (C1, n=378; C2, n=83)
    3.37 ± 1.09
    3.73 ± 1.11
        Week 24 (C1, n=372; C2, n=82)
    3.16 ± 1.05
    3.55 ± 1.18
        Week 36 (C1, n=361; C2, n=79)
    3.05 ± 1.05
    3.36 ± 1.06
        Week 52 (C1, n=349; C2, n=71)
    2.90 ± 1.03
    3.17 ± 1.28
    No statistical analyses for this end point

    Secondary: Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (4 Variables) (DAS28-4 CRP)

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    End point title
    		 Disease Activity Score Based on 28-Joints Count and C-Reactive Protein (4 Variables) (DAS28-4 CRP)
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    391
    86
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline (C1, n=387; C2, n=86)
    5.83 ± 0.88
    5.95 ± 0.94
        Week 4 (C1, n=391; C2, n=83)
    3.70 ± 1.19
    4.22 ± 1.34
        Week 8 (C1, n=378; C2, n=84)
    3.53 ± 1.13
    3.92 ± 1.25
        Week 12 (C1, n=373; C2, n=83)
    3.39 ± 1.14
    3.81 ± 1.21
        Week 24 (C1, n=369; C2, n=82)
    3.18 ± 1.13
    3.64 ± 1.27
        Week 36 (C1, n=360; C2, n=79)
    3.06 ± 1.14
    3.44 ± 1.21
        Week 52 (C1, n=348; C2, n=71)
    2.87 ± 1.09
    3.22 ± 1.40
    No statistical analyses for this end point

    Secondary: Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (3 Variables) (DAS28-3 ESR)

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    End point title
    		 Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (3 Variables) (DAS28-3 ESR)
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    404
    86
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Baseline (C1, n=404; C2, n=86)
    6.17 ± 0.79
    6.38 ± 0.88
        Week 4 (C1, n=397; C2, n=85)
    4.25 ± 1.16
    4.80 ± 1.26
        Week 8 (C1, n=389; C2, n=83)
    4.04 ± 1.14
    4.51 ± 1.17
        Week 12 (C1, n=381; C2, n=83)
    3.89 ± 1.16
    4.40 ± 1.11
        Week 24 (C1, n=375; C2, n=83)
    3.65 ± 1.08
    4.15 ± 1.27
        Week 36 (C1, n=361; C2, n=79)
    3.46 ± 1.15
    3.96 ± 1.15
        Week 52 (C1, n=347; C2, n=72)
    3.35 ± 1.14
    3.74 ± 1.31
    No statistical analyses for this end point

    Secondary: Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 ESR)

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    End point title
    		 Disease Activity Score Based on 28-Joints Count and Erythrocyte Sedimentation Rate (4 Variables) (DAS28-4 ESR)
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. DAS28 Remission is defined as a DAS28 score < 2.6. Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    390
    86
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Baseline (C1, n=385; C2, n=86)
    6.48 ± 0.85
    6.71 ± 0.96
        Week 4 (C1, n=390; C2, n=85)
    4.27 ± 1.25
    4.89 ± 1.41
        Week 8 (C1, n=381; C2, n=83)
    4.04 ± 1.23
    4.58 ± 1.29
        Week 12 (C1, n=376; C2, n=83)
    3.87 ± 1.23
    4.44 ± 1.25
        Week 24 (C1, n=373; C2, n=83)
    3.62 ± 1.16
    4.20 ± 1.37
        Week 36 (C1, n=360; C2, n=79)
    3.43 ± 1.24
    3.99 ± 1.30
        Week 52 (C1, n=346; C2, n=72)
    3.27 ± 1.20
    3.74 ± 1.42
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Remission Based on Disease Activity Score Based on 28-Joints Count (DAS28)

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    End point title
    		 Percentage of Subjects With Remission Based on Disease Activity Score Based on 28-Joints Count (DAS28)
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage of Subjects
    number (not applicable)
        Week 4
    8.8
    7.0
        Week 8
    10.7
    8.1
        Week 12
    13.9
    8.1
        Week 24
    17.8
    14.0
        Week 36
    22.4
    11.6
        Week 52
    25.6
    23.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Low Disease Activity (LDA) Based on DAS28

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    End point title
    		 Percentage of Subjects With Low Disease Activity (LDA) Based on DAS28
    End point description
    The DAS28 score is a measure of the patient's disease activity calculated using the tender joint count (TJC) [28 joints], swollen joint count (SJC) [28 joints], patient's global assessment of disease activity [visual analog scale: 0=no disease activity to 100=maximum disease activity] and the erythrocyte sedimentation rate (ESR) for a total possible score of 0 to approximately 10. Scores below 2.6 indicate best disease control and scores above 5.1 indicate worse disease control. LDAS is defined as DAS28 ≤ 3.2.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    410
    86
    Units: Percentage of Subjects
    number (not applicable)
        Week 4
    20.0
    12.8
        Week 8
    21.2
    17.4
        Week 12
    26.6
    12.8
        Week 24
    33.7
    27.9
        Week 36
    38.3
    29.1
        Week 52
    42.2
    29.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With ACR/EULAR Remission

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    End point title
    		 Percentage of Subjects With ACR/EULAR Remission
    End point description
    Assessed according to the Boolean based definition (tender joint count =<1, swollen joint count =<1, C-reactive Protein (CRP) =<1, and patient global assessment =<1). Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    401
    86
    Units: Percentage of Subjects
    number (not applicable)
        Week 4 (C1, n=401; C2, n=86)
    5.0
    5.8
        Week 8 (C1, n=397; C2, n=85)
    7.8
    5.9
        Week 12 (C1, n=390; C2, n=83)
    7.4
    7.2
        Week 24 (C1, n=378; C2, n=83)
    13.0
    6.0
        Week 36 (C1, n=366; C2, n=79)
    15.6
    11.4
        Week 52 (C1, n=353; C2, n=75)
    17.8
    10.7
    No statistical analyses for this end point

    Secondary: Change from Baseline in Simplified Disease Activity Index (SDAI)

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    End point title
    		 Change from Baseline in Simplified Disease Activity Index (SDAI)
    End point description
    Simplified Disease Activity Index (SDAI) is the numerical sum of five outcome parameters: TJC and SJC (based on a 28-joint assessment), PtGA and PhGA (based on 0-10 cm VAS, where 0 = no disease activity and 10 = worst disease activity), and CRP. SDAI total score ranges from 0 (no disease activity) to 86 (maximal disease activity), where higher scores represents higher disease activity. The SDAI =< 3.3 indicates disease remission, > 3.4 to 11 indicates low disease activity, > 11 to 26 indicates moderate disease activity, and > 26 indicates high disease activity. Number of subjects for whom data were actually collected is indicated for each time point. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    373
    84
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=373; C2, n=83)
    -24.36 ± 13.58
    -21.00 ± 13.49
        Week 8 (C1, n=362; C2, n=84)
    -26.17 ± 13.58
    -24.06 ± 13.57
        Week 12 (C1, n=355; C2, n=83)
    -27.91 ± 12.89
    -25.21 ± 13.37
        Week 24 (C1, n=352; C2, n=82)
    -29.61 ± 13.14
    -26.45 ± 14.17
        Week 36 (C1, n=342; C2, n=79)
    -30.47 ± 13.72
    -28.22 ± 14.16
        Week 52 (C1, n=331; C2, n=71)
    -31.69 ± 13.12
    -29.68 ± 13.77
    No statistical analyses for this end point

    Secondary: Change from Baseline in Clinical Disease Activity Index (CDAI)

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    End point title
    		 Change from Baseline in Clinical Disease Activity Index (CDAI)
    End point description
    CDAI was derived as the sum of the following: tender joint count (TJC), swollen joint count (SJC), participant global assessment (PGA) of disease activity, and physician assessment of disease activity. TJC and SJC were taken as the number of tender and swollen joints, respectively, out of 28 assessed joints. PGA and physician assessment of disease activity were scored 0-100 millimeters (mm) and rounded to the nearest centimeter (cm) on a visual analog scale (VAS), where higher scores indicate greater perceived disease activity. The total CDAI score range was 0-76, where higher scores indicate increased disease activity. Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest. Negative values indicate improvement/reduction in RA disease activity. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    374 [3]
    86 [4]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=374; C2, n=86)
    -23.41 ± 13.11
    -19.81 ± 13.15
        Week 8 (C1, n=366; C2, n=84)
    -25.14 ± 13.06
    -22.48 ± 12.59
        Week 12 (C1, n=360; C2, n=83)
    -26.82 ± 12.31
    -23.82 ± 12.37
        Week 24 (C1, n=356; C2, n=83)
    -28.52 ± 12.52
    -25.09 ± 13.18
        Week 36 (C1, n=343; C2, n=79)
    -29.40 ± 12.99
    -26.66 ± 12.98
        Week 52 (C1, n=332; C2, n=72)
    -30.61 ± 12.43
    -27.43 ± 13.43
    Notes
    [3] - Number of subjects for whom data were actually collected is indicated for each time point.
    [4] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Tender/Painful Joint Count Based on 68 Joints

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    End point title
    		 Change from Baseline in Tender/Painful Joint Count Based on 68 Joints
    End point description
    Tender Joint Count: a total of 68 joints will be assessed for tenderness. Each joint is assessed for the presence/absence of tenderness. 68 joints are assessed for tenderness and joints are classified as tender/not tender giving a total possible tender joint count score of 0 to 68. A negative change from Baseline indicated improvement. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    406 [5]
    86 [6]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=400; C2, n=86)
    -15.02 ± 12.38
    -13.23 ± 12.27
        Week 8 (C1, n=404; C2, n=86)
    -16.11 ± 12.45
    -15.19 ± 12.59
        Week 12 (C1, n=406; C2, n=86)
    -16.55 ± 12.39
    -15.99 ± 12.03
        Week 24 (C1, n=406; C2, n=86)
    -17.96 ± 12.24
    -16.65 ± 11.35
        Week 36 (C1, n=406; C2, n=86)
    -18.48 ± 12.77
    -17.51 ± 11.60
        Week 52 (C1, n=406; C2, n=86)
    -18.70 ± 12.99
    -17.73 ± 11.88
    Notes
    [5] - Number of subjects for whom data were actually collected is indicated for each time point.
    [6] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Swollen Joint Count Based on 66 Joints

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    End point title
    		 Change from Baseline in Swollen Joint Count Based on 66 Joints
    End point description
    Swollen Joint Count: a total of 66 joints will be assessed for swelling. Each joint is assessed for the presence/absence of swelling. 66 joints were assessed for swelling and joints are classified as swollen/not swollen giving a total possible swollen joint count score of 0 to 66. A negative change from Baseline indicated improvement. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    406 [7]
    86 [8]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=400; C2, n=86)
    -10.20 ± 8.43
    -7.85 ± 6.71
        Week 8 (C1, n=404; C2, n=86)
    -10.95 ± 8.48
    -9.12 ± 6.65
        Week 12 (C1, n=406; C2, n=86)
    -11.40 ± 8.22
    -9.08 ± 6.84
        Week 24 (C1, n=406; C2, n=86)
    -11.93 ± 8.33
    -9.86 ± 6.61
        Week 36 (C1, n=406; C2, n=86)
    -12.15 ± 8.57
    -9.98 ± 6.96
        Week 52 (C1, n=406; C2, n=86)
    -12.17 ± 8.55
    -9.59 ± 8.78
    Notes
    [7] - Number of subjects for whom data were actually collected is indicated for each time point.
    [8] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient's Assessment of Arthritis Pain, Using Visual Analog Scale (VAS) Score

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    End point title
    		 Change from Baseline in Patient's Assessment of Arthritis Pain, Using Visual Analog Scale (VAS) Score
    End point description
    Patient's Assessment of Pain over the previous 24 hours: using a Visual Analog Scale (VAS) left end of the line 0=no pain to right end of the line 100=unbearable pain. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    371 [9]
    86 [10]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=371; C2, n=86)
    -30.62 ± 26.60
    -26.34 ± 25.98
        Week 8 (C1, n=365; C2, n=84)
    -32.57 ± 26.77
    -27.21 ± 23.36
        Week 12 (C1, n=354; C2, n=83)
    -35.68 ± 26.44
    -29.49 ± 26.70
        Week 24 (C1, n=356; C2, n=83)
    -37.19 ± 26.85
    -30.30 ± 26.42
        Week 36 (C1, n=343; C2, n=79)
    -39.50 ± 27.20
    -33.14 ± 27.22
        Week 52 (C1, n=330; C2, n=72)
    -42.40 ± 26.22
    -38.21 ± 26.37
    Notes
    [9] - Number of subjects for whom data were actually collected is indicated for each time point.
    [10] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Patient's Global Assessment of Arthritis, Using VAS Score

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    End point title
    		 Change from Baseline in Patient's Global Assessment of Arthritis, Using VAS Score
    End point description
    Participant-assessed arthritis pain was scored on a 100-mm VAS, where the distance from 0 mm represented the participant's self evaluation of arthritis pain (0 mm=none; 100 mm=very severe). Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest, where negative change indicated a decrease in participant-assessed arthritis pain. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    375 [11]
    86 [12]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=375; C2, n=86)
    -30.21 ± 27.47
    -26.03 ± 24.50
        Week 8 (C1, n=366; C2, n=84)
    -32.67 ± 26.85
    -28.79 ± 23.07
        Week 12 (C1, n=360; C2, n=83)
    -35.63 ± 26.19
    -31.16 ± 25.32
        Week 24 (C1, n=356; C2, n=83)
    -36.94 ± 27.23
    -31.76 ± 25.09
        Week 36 (C1, n=343; C2, n=79)
    -39.40 ± 26.77
    -33.73 ± 25.82
        Week 52 (C1, n=332; C2, n=72)
    -42.91 ± 25.90
    -36.58 ± 24.74
    Notes
    [11] - Number of subjects for whom data were actually collected is indicated for each time point.
    [12] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Physician's Global Assessment of Arthritis, Using VAS Score

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    End point title
    		 Change from Baseline in Physician's Global Assessment of Arthritis, Using VAS Score
    End point description
    Physician's assessment of participant's disease activity was scored on a 100-mm VAS, where the distance from 0 mm represented the physician's assessment of the participant's disease activity (0 mm=very good; 100 mm=very poor). Change from baseline at a particular time point was calculated among patients with data available at both baseline and the time point of interest, where negative change from baseline indicated an improvement in physician-assessed disease activity. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    399 [13]
    86 [14]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=399; C2, n=86)
    -37.07 ± 20.75
    -30.65 ± 24.09
        Week 8 (C1, n=390; C2, n=84)
    -39.29 ± 20.30
    -35.32 ± 22.36
        Week 12 (C1, n=383; C2, n=83)
    -42.23 ± 20.20
    -37.37 ± 22.14
        Week 24 (C1, n=376; C2, n=83)
    -44.40 ± 20.94
    -41.11 ± 23.86
        Week 36 (C1, n=362; C2, n=79)
    -45.52 ± 20.76
    -43.13 ± 24.14
        Week 52 (C1, n=350; C2, n=72)
    -48.57 ± 19.99
    -44.81 ± 23.85
    Notes
    [13] - Number of subjects for whom data were actually collected is indicated for each time point.
    [14] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in C-Reactive Protein (CRP) Levels

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    End point title
    		 Change from Baseline in C-Reactive Protein (CRP) Levels
    End point description
    C-reactive protein is a biological marker of inflammation and is measured in milligrams per decilitre (mg/dL). (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    398 [15]
    84 [16]
    Units: (mg/dL)
    arithmetic mean (standard deviation)
        Week 4 (C1, n=398; C2, n=83)
    -0.95 ± 2.18
    -1.09 ± 3.10
        Week 8 (C1, n=386; C2, n=84)
    -1.02 ± 2.41
    -1.58 ± 2.60
        Week 12 (C1, n=378; C2, n=83)
    -1.03 ± 2.21
    -1.40 ± 3.38
        Week 24 (C1, n=372; C2, n=82)
    -1.03 ± 2.48
    -1.46 ± 2.99
        Week 36 (C1, n=361; C2, n=79)
    -1.11 ± 2.44
    -1.56 ± 3.04
        Week 52 (C1, n=349; C2, n=71)
    -1.12 ± 2.55
    -1.81 ± 2.75
    Notes
    [15] - Number of subjects for whom data were actually collected is indicated for each time point.
    [16] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score

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    End point title
    		 Change from Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score
    End point description
    The Stanford Health Assessment Questionnaire disability index is a patient-reported outcome used to assess difficulty in performing activities of daily living. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and common daily activities. To respond to each question, a four-level response with higher scores showing larger functional limitations, was chosen. Scoring is as follows with respect to performance of participant’s everyday activities: 0 (equals)=without difficulties; 1= with some difficulties; 2=with great difficulties; and 3=unable to perform these actions at all. The composite HAQ-DI score is the mean of the eight domain scores and the score ranges from 0 (no functional impairment) to 3 (maximum functional impairment). A negative change from baseline indicates improvement. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 8, 12, 24, 36 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    360 [17]
    81 [18]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 4 (C1, n=360; C2, n=81)
    -0.70 ± 0.64
    -0.55 ± 0.56
        Week 8 (C1, n=358; C2, n=80)
    -0.77 ± 0.65
    -0.59 ± 0.62
        Week 12 (C1, n=358; C2, n=78)
    -0.80 ± 0.67
    -0.60 ± 0.59
        Week 24 (C1, n=349; C2, n=78)
    -0.83 ± 0.66
    -0.63 ± 0.58
        Week 36 (C1, n=338; C2, n=74)
    -0.89 ± 0.63
    -0.62 ± 0.66
        Week 52 (C1, n=323; C2, n=70)
    -0.98 ± 0.64
    -0.69 ± 0.62
    Notes
    [17] - Number of subjects for whom data were actually collected is indicated for each time point.
    [18] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in 36-Item Short-Form Health Survey (SF-36) Version 2.0 (V2) Scores for Physical and Mental Components

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    End point title
    		 Change from Baseline in 36-Item Short-Form Health Survey (SF-36) Version 2.0 (V2) Scores for Physical and Mental Components
    End point description
    The 36-Item Short Form Health Survey (SF-36v2) is a questionnaire used to assess functional health and well-being and consists of eight domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional and Mental Health. The SF-36v2 is summarized into Physical Component Summary (PCS) (Phys Comp Sc chnge) and Mental Component Summary (MCS) (Ment Comp Sc chnge) scores. The PCS and MCS scores range from 0 to 100, with 0=worst score (or quality of life) and 100=best score. A positive change from baseline indicates improvement. (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    356 [19]
    83 [20]
    Units: Number on a Scale
    arithmetic mean (standard deviation)
        Week 12 (Phys Comp Sc chnge) (C1, n=356; C2, n=83)
    11.35 ± 9.13
    8.22 ± 8.73
        Week 12 (Ment Comp Sc chnge) (C1, n=356; C2, n=83)
    6.52 ± 12.98
    4.74 ± 11.53
        Week 24 (Phys Comp Sc chnge) (C1, n=350; C2, n=80)
    12.31 ± 9.12
    8.28 ± 8.53
        Week 24 (Ment Comp Sc chnge) (C1, n=350; C2, n=80)
    6.63 ± 13.23
    6.08 ± 11.76
        Week 52 (Phys Comp Sc chnge) (C1, n=330; C2, n=72)
    13.89 ± 9.32
    10.42 ± 8.94
        Week 52 (Ment Comp Sc chnge) (C1, n=330; C2, n=72)
    7.00 ± 13.81
    6.77 ± 11.60
    Notes
    [19] - Number of subjects for whom data were actually collected is indicated for each time point.
    [20] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score

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    End point title
    		 Change from Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score
    End point description
    The FACIT-Fatigue Scale consists of 13 items designed to measure the degree of fatigue experienced by the patient in the previous 7 days. For each question, there are five possible responses: 0 (not at all), 1 (a little bit), 2 (somewhat), 3 (quite a bit), 4 (very much). A total fatigue score is calculated by summing all items, and possible total scores range from 0 (maximum fatigue) to 52 (no fatigue). A positive change from baseline indicates an improvement in the patient’s fatigue (less fatigue). (C1, n=X; C2, n=X) refers to number of subjects analysed in Cohorts 1 and 2 (C1/C2) at each timepoint.
    End point type
    Secondary
    End point timeframe
    Weeks 12, 24 and 52
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (ITT Population) GDC-0853 (200mg BID) Cohort 2 (ITT Population)
    Number of subjects analysed
    350 [21]
    83 [22]
    Units: Score on a Scale
    arithmetic mean (standard deviation)
        Week 12 (C1, n=350; C2, n=83)
    11.44 ± 10.36
    9.28 ± 8.51
        Week 24 (C1, n=347; C2, n=80)
    11.74 ± 10.75
    10.41 ± 8.51
        Week 52 (C1, n=327; C2, n=72)
    12.87 ± 10.58
    10.87 ± 9.25
    Notes
    [21] - Number of subjects for whom data were actually collected is indicated for each time point.
    [22] - Number of subjects for whom data were actually collected is indicated for each time point.
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Time Curve (AUC) of GDC-0853 at Steady State (AUC,ss)

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    End point title
    		 Area Under the Concentration Time Curve (AUC) of GDC-0853 at Steady State (AUC,ss)
    End point description
    Population PK model estimated AUC of GDC-0853 at steady-state. AUC was measured in Nanograms (ng) per millilitre (mL)*hour (hr).
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (PK-Evaluable Population) GDC-0853 (200mg BID) Cohort 2 (PK-Evaluable Population)
    Number of subjects analysed
    388
    81
    Units: Ng/mL*(hr)
        arithmetic mean (standard deviation)
    13400 ± 6930
    15600 ± 7850
    No statistical analyses for this end point

    Secondary: Minimum Observed Plasma Concentration of GDC-0853 at Steady State (Ctrough,ss)

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    End point title
    		 Minimum Observed Plasma Concentration of GDC-0853 at Steady State (Ctrough,ss)
    End point description
    Population PK model estimated minimal plasma concentration (Ctrough) of GDC-0853 at steady-state (ss).
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (PK-Evaluable Population) GDC-0853 (200mg BID) Cohort 2 (PK-Evaluable Population)
    Number of subjects analysed
    388
    81
    Units: ng/mL
        arithmetic mean (standard deviation)
    387 ± 244
    467 ± 285
    No statistical analyses for this end point

    Secondary: Plasma Decay Half-Life of GDC-0853 at Steady State (t1/2,ss)

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    End point title
    		 Plasma Decay Half-Life of GDC-0853 at Steady State (t1/2,ss)
    End point description
    Population PK model estimated plasma decay half life of GDC-0853 at steady-state.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (PK-Evaluable Population) GDC-0853 (200mg BID) Cohort 2 (PK-Evaluable Population)
    Number of subjects analysed
    388
    81
    Units: hr
        arithmetic mean (standard deviation)
    7.94 ± 3.16
    9.01 ± 4.9
    No statistical analyses for this end point

    Secondary: Apparent Oral Clearance of GDC-0853 at Steady State (CL/F,ss)

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    End point title
    		 Apparent Oral Clearance of GDC-0853 at Steady State (CL/F,ss)
    End point description
    Population PK model estimated apparent oral clearance of GDC-0853 at steady-state.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour) on Weeks 0 (Day 1), 4, 12, 24, 36, and 52/early termination
    End point values
    		 GDC-0853 (200mg BID) Cohort 1 (PK-Evaluable Population) GDC-0853 (200mg BID) Cohort 2 (PK-Evaluable Population)
    Number of subjects analysed
    388
    81
    Units: L/hr
        arithmetic mean (standard deviation)
    39.5 ± 12.6
    35.3 ± 10.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up until 8 weeks after the last dose of study drug (up to 1 year, 2 months).
    Adverse event reporting additional description
    The Safety-evaluable population was defined as all subjects who received any study drug and had at least one assessment of safety. AEs that were entered into the database at the time of the database lock were included in the AE analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    GDC-0853 (200mg BID) Cohort 2
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 2 of Study GA29350. Cohort 2 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to one or two tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) therapy, and then randomized to 12 weeks of GDC-0853 (200 mg BID) or placebo.

    Reporting group title
    GDC-0853 (200mg BID) Cohort 1
    Reporting group description
    		 Subjects received GDC-0853 orally twice daily (BID) for 52 weeks, after completing 12 weeks in Cohort 1 of Study GA29350. Cohort 1 subjects in GA29350 were enrolled with moderate to severe active Rheumatoid Arthritis (RA) and an inadequate response to previous methotrexate (MTX) therapy and then randomized to 12 weeks of GDC-0853 (50 mg daily, 150 mg daily, or 200 mg BID), adalimumab, or placebo.

    Serious adverse events
    		 GDC-0853 (200mg BID) Cohort 2 GDC-0853 (200mg BID) Cohort 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 86 (4.65%)
    26 / 410 (6.34%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BASAL CELL CARCINOMA
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG CARCINOMA CELL TYPE UNSPECIFIED STAGE IV
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    VAGINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    HEAD INJURY
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 86 (1.16%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT DISLOCATION
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE INJURIES
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIO-RESPIRATORY ARREST
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    ISCHAEMIC STROKE
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VERTEBROBASILAR INSUFFICIENCY
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    IRON DEFICIENCY ANAEMIA
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLAMMATORY BOWEL DISEASE
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    0 / 86 (0.00%)
    2 / 410 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    CELLULITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NECROTISING SOFT TISSUE INFECTION
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 410 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    HYPONATRAEMIA
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 410 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GDC-0853 (200mg BID) Cohort 2 GDC-0853 (200mg BID) Cohort 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 86 (4.65%)
    22 / 410 (5.37%)
    Infections and infestations
    URINARY TRACT INFECTION
         subjects affected / exposed
    4 / 86 (4.65%)
    22 / 410 (5.37%)
         occurrences all number
    7
    28

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Aug 2016
    Following updates were made: [1] Updating of background and nonclinical experience with GDC-0853; [2] Clarification of secondary efficacy objective to assess Boolean- and SDAI-based remission; [3] Removal of Week 2 assessments; [4] Updating of rationale for GDC-0853 dose and schedule; [5] Clarification of inclusion criterion for completion of Parent Study GA29350; [6] Updating of storage temperature for GDC-0853; [7] Clarification of Dosing for Day 1; [8] Updating of Labeling of dates on the blister wallets and bottles; [9] Removal of male-specific Informed Consent; [10] Clarification of method of patient-reported (via electronic device) and clinician-reported outcomes (paper based); [11] Addition of Updated nonclinical information and [12] Updating of Management guidelines.

    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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