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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Obinutuzumab in Patients with ISN/RPS 2003 Class III or IV Lupus Nephritis

    Summary
    EudraCT number
    2015-002022-39
    Trial protocol
    ES   FR  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jan 2020
    First version publication date
    31 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA29748
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02550652
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    15 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jan 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This Phase II study will compare the efficacy and safety of obinutuzumab plus mycophenolate mofetil (MMF)/mycophenolic acid (MPA) with placebo plus MMF/MPA in participants with proliferative LN.
    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
    13 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 27
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Colombia: 19
    Country: Number of subjects enrolled
    Costa Rica: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Peru: 13
    Country: Number of subjects enrolled
    United States: 15
    Worldwide total number of subjects
    125
    EEA total number of subjects
    21
    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
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at approximately 60 centers in North America, South America, Europe, and Asia.

    Pre-assignment
    Screening details
    A total of 126 patients were enrolled in the study however one patient randomized to obinutuzumab did not receive study treatment due to a positive pregnancy test, but prior to the first study drug infusion; therefore a total of 125 patients are included in the analysis.

    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
    OBINUTUZUMAB 1000MG and MMF
    Arm description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.
    Arm type
    Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyva, GA101, RO5072759
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Obinutuzumab will be administered as per schedule specified in the respective arm.

    Investigational medicinal product name
    Mycophenolate Mofetil/Mycophenolic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MMF/MPA will be administered as per schedule specified in the respective arm.

    Arm title
    PLACEBO and MMF
    Arm description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.
    Arm type
    Placebo

    Investigational medicinal product name
    Mycophenolate Mofetil/Mycophenolic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MMF/MPA will be administered as per schedule specified in the respective arm.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo matching to obinutuzumab will be administered as per schedule specified in the respective arm.

    Number of subjects in period 1
    OBINUTUZUMAB 1000MG and MMF PLACEBO and MMF
    Started
    63
    62
    Completed
    0
    0
    Not completed
    63
    62
         Lack of efficacy
    1
    -
         Adverse event, serious fatal
    -
    2
         Ongoing in study
    59
    56
         Consent withdrawn by subject
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OBINUTUZUMAB 1000MG and MMF
    Reporting group description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Reporting group title
    PLACEBO and MMF
    Reporting group description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Reporting group values
    OBINUTUZUMAB 1000MG and MMF PLACEBO and MMF Total
    Number of subjects
    63 62 125
    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)
    63 62 125
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    33.1 ± 9.8 31.9 ± 10.1 -
    Sex: Female, Male
    Units:
        Female
    55 51 106
        Male
    8 11 19
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic Or Latino
    42 49 91
        Not Hispanic Or Latino
    20 12 32
        Not Stated
    1 0 1
        Unknown
    0 1 1
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    11 17 28
        Asian
    3 2 5
        Black or African American
    6 5 11
        Multiple
    1 0 1
        Native Hawaiian or other Pacific Islande
    1 0 1
        Unknown
    13 12 25
        White
    28 26 54
    Subject analysis sets

    Subject analysis set title
    Obinutuzumab
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Obinutuzumab
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis sets values
    Obinutuzumab Placebo Obinutuzumab Placebo
    Number of subjects
    63
    62
    64
    61
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    63
    62
    64
    61
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    33.1 ± 9.8
    31.9 ± 10.1
    33.0 ± 9.8
    32.0 ± 10.1
    Sex: Female, Male
    Units:
        Female
    55
    51
    56
    50
        Male
    8
    11
    8
    11
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic Or Latino
    42
    49
    43
    48
        Not Hispanic Or Latino
    20
    12
    20
    12
        Not Stated
    1
    0
    1
    0
        Unknown
    0
    1
    0
    1
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    11
    17
    11
    17
        Asian
    3
    2
    3
    2
        Black or African American
    6
    5
    6
    5
        Multiple
    1
    0
    1
    0
        Native Hawaiian or other Pacific Islande
    1
    0
    1
    0
        Unknown
    13
    12
    1
    0
        White
    28
    26
    13
    12

    End points

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    End points reporting groups
    Reporting group title
    OBINUTUZUMAB 1000MG and MMF
    Reporting group description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Reporting group title
    PLACEBO and MMF
    Reporting group description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Obinutuzumab
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Obinutuzumab
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Subject analysis set title
    Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Primary: Proportion of Participants who Achieve Protocol Defined Complete Renal Response (CRR)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Complete Renal Response (CRR)
    End point description
    Percentage of participants with normalization of serum creatinine, inactive urinary sediment (as evidenced by < 10 red blood cells (RBCs)/high-power field (HPF) and the absence of red cell casts) and urinary protein to creatinine ratio < 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the upper limit of normal (ULN) range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values.
    End point type
    Primary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    34.9
    22.6
    Statistical analysis title
    Protocol Defined CRR
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1145
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    12.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    28.1

    Secondary: Proportion of Participants who Achieve Protocol Defined Overall Response (OR)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Overall Response (OR)
    End point description
    OR includes both CRR and partial renal response (PRR). CRR as defined in primary outcome measure. PRR defined as 50% improvement in urine protein:creatinine ratio, with one of following conditions met: 1. If baseline urine protein:creatinine ratio is ≤ 3.0, then urine protein:creatinine ratio of <1.0. 2. If baseline protein:creatinine ratio is > 3.0, then urine protein:creatinine ratio of <3.0, serum creatinine ≤15% above baseline value, and no urinary red cell casts and either RBCs/HPF ≤50% above baseline or <10 RBCs/HPF.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    55.6
    35.5
    Statistical analysis title
    Protocol defined Overall Response
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0246
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    20.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3
         upper limit
    37.2

    Secondary: Time to First Protocol Defined Overall Response Over the Course of 52 Weeks

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    End point title
    Time to First Protocol Defined Overall Response Over the Course of 52 Weeks
    End point description
    OR includes both CRR and partial renal response (PRR). CRR as defined in the primary outcome measure above. PRR defined as 50% improvement in urine protein:creatinine ratio, with one of following conditions met: 1. If baseline urine protein:creatinine ratio is ≤ 3.0, then urine protein:creatinine ratio of <1.0. 2. If baseline protein:creatinine ratio is > 3.0, then urine protein:creatinine ratio of <3.0, serum creatinine ≤15% above baseline value, and no urinary red cell casts and either RBCs/HPF ≤50% above baseline or <10 RBCs/HPF. Percentage of Participants with response at various time points were measured using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12 (n=56, 60)
    26 (15 to 37)
    19 (10 to 29)
        Week 24 (n=33, 39)
    57 (45 to 70)
    41 (28 to 53)
        Week 36 (n=23, 30)
    63 (50 to 75)
    51 (38 to 64)
        Week 52 (n=13, 20)
    75 (64 to 86)
    58 (45 to 71)
    Statistical analysis title
    Time to First Protocol Defined OR
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0537
    Method
    Logrank
    Confidence interval

    Secondary: Proportion of Participants who Achieve Protocol Defined Partial Renal Response (PRR)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Partial Renal Response (PRR)
    End point description
    PRR defined as serum creatinine ≤15% above baseline value, no urinary red cell casts and either RBCs/HPF ≤ 50% above baseline or < 10 RBCs/HPF, 50% improvement in urine protein:creatinine ratio, with one of following conditions met: 1. If baseline urine protein:creatinine ratio is ≤ 3.0, then a urine protein:creatinine ratio of < 1.0. 2. If baseline protein:creatinine ratio is > 3.0, then a urine protein:creatinine ratio of < 3.0.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    55.6
    33.9
    Statistical analysis title
    Protocol Defined PRR
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.015
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    21.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.7
         upper limit
    38.7

    Secondary: Proportion of Participants who Achieve Protocol Defined CRR at Week 24

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    End point title
    Proportion of Participants who Achieve Protocol Defined CRR at Week 24
    End point description
    CRR defined as normalization of serum creatinine, inactive urinary sediment (as evidenced by < 10 red blood cells (RBCs)/high-power field (HPF) and the absence of red cell casts) and urinary protein to creatinine ratio < 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the upper limit of normal (ULN) range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    36.5
    25.0
    Statistical analysis title
    Protocol Defined CRR
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2145
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    11.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.8
         upper limit
    28.9

    Secondary: Time to Protocol Defined CRR Over the Course of 52 Weeks

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    End point title
    Time to Protocol Defined CRR Over the Course of 52 Weeks
    End point description
    CRR included normalization of serum creatinine, inactive urinary sediment (as evidenced by < 10 RBCs/HPF and the absence of red cell casts) and urinary protein to creatinine ratio < 0.5. Normalization of serum creatinine is defined as serum creatinine ≤ the ULN range of central laboratory values if baseline serum creatinine is above the ULN or serum creatinine ≤ 15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values. Percentage of participants with response at various time points were measured using Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
    number (confidence interval 95%)
        Week 12 (n=61, 61)
    10 (2 to 17)
    10 (2 to 17)
        Week 24 (n=48, 50)
    26 (15 to 37)
    28 (16 to 39)
        Week 36 (n=39, 39)
    36 (24 to 48)
    35 (23 to 47)
        Week 52 (n=26, 32)
    50 (37 to 63)
    40 (28 to 53)
    Statistical analysis title
    Time to Protocol Defined CRR
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2516
    Method
    Logrank
    Confidence interval

    Secondary: Percent Change From Baseline in Anti-Double Stranded Deoxyribonucleic Acid (Anti-dsDNA) Levels

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    End point title
    Percent Change From Baseline in Anti-Double Stranded Deoxyribonucleic Acid (Anti-dsDNA) Levels
    End point description
    Anti-dsDNA antibodies are a group of anti-nuclear antibodies targeting double stranded DNA.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: log anti-dsDNA levels
        arithmetic mean (standard deviation)
    -0.863 ± 1.157
    -0.140 ± 1.125
    Statistical analysis title
    Anti-Ds DNA
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.811
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.142
         upper limit
    -0.48

    Secondary: Change From Baseline in Complement component 3 (C3) Levels

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    End point title
    Change From Baseline in Complement component 3 (C3) Levels
    End point description
    Complement C3 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: g/L
        arithmetic mean (standard deviation)
    0.318 ± 0.295
    0.111 ± 0.265
    Statistical analysis title
    C3
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0002
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.178
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.086
         upper limit
    0.27

    Secondary: Change From Baseline in C4 Levels

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    End point title
    Change From Baseline in C4 Levels
    End point description
    Complement C4 is a blood test that reflects activation of complement pathway associated with immune deposition in certain autoimmune diseases.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: g/L
        arithmetic mean (standard deviation)
    0.099 ± 0.098
    0.004 ± 0.164
    Statistical analysis title
    C4
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.053
         upper limit
    0.117

    Secondary: Proportion of Participants who Achieve Protocol Defined Modified CRR (mCRR1)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Modified CRR (mCRR1)
    End point description
    mCRR1 has got two components only, i.e. serum Creatinine and urinary protein to creatinine ratio. mCRR1 is defined by attainment of normalization of serum creatinine as evidenced by 1.) serum creatinine ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is above the ULN or serum creatinine ≤15% above baseline and ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine ≤ the ULN range of central laboratory values and 2.) Urinary protein to creatinine ratio <0.5.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    39.7
    25.8
    Statistical analysis title
    mCRR1
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.09
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    13.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.4
         upper limit
    30.1

    Secondary: Proportion of Participants who Achieve Protocol Defined Second mCRR (mCRR2)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Second mCRR (mCRR2)
    End point description
    mCRR2 is defined by normalization of serum creatinine, inactive urinary sediment (as evidenced by < 10 RBCs/HPF and the absence of red cell casts), and urinary protein to creatinine ratio <0.5. Normalization of serum creatinine as evidenced by the following: Serum creatinine ≤15% above baseline if baseline (Day 1) serum creatinine is above the normal range of the central laboratory values or ≤ the ULN range of central laboratory values if baseline (Day 1) serum creatinine is ≤ the ULN range of central laboratory values.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    44.4
    33.9
    Statistical analysis title
    mCRR2
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1838
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    10.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    27.6

    Secondary: Proportion of Participants who Achieve Protocol Defined Third mCRR (mCRR3)

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    End point title
    Proportion of Participants who Achieve Protocol Defined Third mCRR (mCRR3)
    End point description
    mCRR3 is defined by normalization of serum creatine as evidenced by serum creatinine ≤ the ULN range of central laboratory values and urinary protein to creatinine ratio < 0.5.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: percentage of participants
        number (not applicable)
    46.0
    38.7
    Statistical analysis title
    mCRR3
    Comparison groups
    Obinutuzumab v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3726
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Proportion Difference
    Point estimate
    7.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    24.6

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    Percentage of Participants With Adverse Events
    End point description
    An adverse event 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 an abnormal laboratory finding, for example), 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. AEs, including AEs of Special Interest and AEs of Particular Interest, were reported based on the national cancer institute common terminology criteria for AEs, Version 4.0 (NCI-CTCAE, v4.0). Reported are the number of subjects with AEs, Grade 3-5 AEs, and Serious Adverse Events (SAEs).
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    64
    61
    Units: percentage of participants
    number (not applicable)
        Adverse Events
    85.9
    85.2
        Serious Adverse Events
    14.1
    21.3
        Grade 3-5 Infections
    1.6
    18.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events of Special Interest: Infusion Related Reactions, Infections, Thrombocytopenia and Neutropenia

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    End point title
    Percentage of Participants with Adverse Events of Special Interest: Infusion Related Reactions, Infections, Thrombocytopenia and Neutropenia
    End point description
    Neutropenia is defined as low neutrophil count (ANC <1.0 x 109/L). Infusion related reaction is defined as a type of hypersensitivity reaction (pruritus, chills, diaphoresis, fever) that develops during or shortly after administration of a drug. Thrombocytopenia is defined as deficiency of platelets (<150 x 10^9/L) in the blood. Infections include all events of infections under the SOC of infections and infestations in this study.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    64
    61
    Units: percentage of participants
    number (not applicable)
        Infusion Related Reactions
    15.6
    9.8
        Infections
    64.1
    59.0
        Thrombocytopenia
    0
    0
        Neutropenia
    4.7
    1.6
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Circulating CD19-Positive B-Cell Levels

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    End point title
    Percent Change From Baseline in Circulating CD19-Positive B-Cell Levels
    End point description
    CD19+ B cell is a transmembrane protein that is encoded by the gene CD19.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 12, Week 24, Week 52
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: cells/uL
    arithmetic mean (standard deviation)
        Baseline (n=63, 62)
    327.902 ± 330.562
    353.499 ± 454.165
        Week 2 (n=39, 42)
    -97.469 ± 12.899
    39.293 ± 145.247
        Week 4 (n=45, 36)
    -98.777 ± 5.235
    -5.186 ± 78.469
        Week 12 (n=41, 45)
    -97.045 ± 15.506
    0.661 ± 134.421
        Week 24 (n=42, 37)
    -96.628 ± 10.207
    -11.446 ± 86.793
        Week 52 (n=39, 42)
    -98.620 ± 5.677
    37.695 ± 220.857
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab

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    End point title
    Percentage of Participants With Anti-Drug Antibody (ADA) to Obinutuzumab
    End point description
    Antibodies are a blood protein produced in response to and counteracting a specific antigen.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52 (up to approximately 38 months)
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: percentage of participants
        number (not applicable)
    9.38
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Obinutuzumab

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    End point title
    Maximum Observed Plasma Concentration (Cmax) of Obinutuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0, Week 24, Week 52
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: ug/mL
    arithmetic mean (standard deviation)
        Week 0-24
    559 ± 112
        Week 24-52
    605 ± 115
        Week 0-52
    605 ± 115
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration Versus Time Curve (AUC) of Obinutuzumab

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    End point title
    Area Under the Plasma Concentration Versus Time Curve (AUC) of Obinutuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Week 0, Week 24, Week 52
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: ug/mL*day
    arithmetic mean (standard deviation)
        Week 0-24
    10595 ± 4016
        Week 24-52
    15811 ± 5543
        Week 0-52
    26406 ± 9027
    No statistical analyses for this end point

    Secondary: Systemic Clearance of Obinutuzumab

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    End point title
    Systemic Clearance of Obinutuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, Week 24, Week 52
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: L/day
    arithmetic mean (standard deviation)
        Day 0
    0.255 ± 0.136
        Week 24
    0.147 ± 0.0564
        Week 52
    0.137 ± 0.0535
    No statistical analyses for this end point

    Secondary: Volume of Distribution Under Steady State (Vss) of Obinutuzumab

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    End point title
    Volume of Distribution Under Steady State (Vss) of Obinutuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, Week 24, Week 52
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: Litre
    arithmetic mean (standard deviation)
        Day 0
    3.67 ± 0.591
        Week 24
    3.67 ± 0.591
        Week 52
    3.67 ± 0.591
    No statistical analyses for this end point

    Secondary: Terminal Plasma Half-Life (t1/2) of Obinutuzumab

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    End point title
    Terminal Plasma Half-Life (t1/2) of Obinutuzumab
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0, Week 24, Week 52
    End point values
    Obinutuzumab
    Number of subjects analysed
    64
    Units: day
    arithmetic mean (standard deviation)
        Day 0
    13.1 ± 3.7
        Week 24
    20.5 ± 5.6
        Week 52
    22.1 ± 6.7
    No statistical analyses for this end point

    Secondary: Change from Baseline of Participant's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score

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    End point title
    Change from Baseline of Participant's Global Assessment of Disease Activity Visual Analog Scale (VAS) Score
    End point description
    Each VAS had a range from 0-100 with higher scores indicating greater symptom impact on global health status.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Weeks 4, 12, 24, 36, 52/early termination
    End point values
    Obinutuzumab Placebo
    Number of subjects analysed
    63
    62
    Units: score on scale
    arithmetic mean (standard deviation)
        Baseline
    41.3 ± 25.59
    39.4 ± 24.76
        Week 4
    -14.4 ± 18.28
    -8.7 ± 22.69
        Week 12
    -19.9 ± 25.07
    -11.6 ± 25.22
        Week 24
    -25.1 ± 25.26
    -20.8 ± 24.74
        Week 36
    -24.8 ± 25.71
    -19.6 ± 25.04
        Week 52
    -25.4 ± 26.49
    -23.3 ± 25.76
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to Week 52 (approximately 38 months)
    Adverse event reporting additional description
    The safety population was defined as all participants who have received at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    PLACEBO and MMF
    Reporting group description
    Participants will receive placebo matching to obinutuzumab IV infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated based on tolerability to a target dose of 2.0 - 2.5 g/day (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Reporting group title
    OBINUTUZUMAB 1000MG and MMF
    Reporting group description
    Participants will receive obinutuzumab 1000 milligrams (mg) intravenous (IV) infusion on Days 1, 15, 168, and 182 along with MMF/MPA at a starting dose of 1500 mg/day (or equivalent) administered orally in 2 or 3 divided doses. MMF/MPA dose will be up titrated based on tolerability to a target dose of 2.0 - 2.5 grams per day (g/day) (or equivalent). Investigators, at their discretion, may use MPA as a substitute for MMF, with a 360 mg dose being equivalent to a 500 mg dose of MMF. During screening or at randomization, if clinically indicated, participants may receive 750-1000 mg methylprednisolone IV once daily for up to 3 days to treat underlying LN clinical activity. Participants will receive 0.5 mg/kg oral prednisone, tapering this prednisone dose, per protocol, starting on Day 16 and reducing the prednisone dosage to 7.5 mg/day by Week 12.

    Serious adverse events
    PLACEBO and MMF OBINUTUZUMAB 1000MG and MMF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 61 (21.31%)
    9 / 64 (14.06%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    PSYCHOTIC DISORDER
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    INFLUENZA A VIRUS TEST POSITIVE
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT INCREASED
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    NEUTROPENIA
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ASTHMA
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    EPILEPSY
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IDIOPATHIC INTRACRANIAL HYPERTENSION
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC ENCEPHALOPATHY
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    LUPUS NEPHRITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC LUPUS ERYTHEMATOSUS
         subjects affected / exposed
    1 / 61 (1.64%)
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHIOLITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS CHORIORETINITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS MYOCARDITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISSEMINATED CYTOMEGALOVIRAL INFECTION
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOMETRITIS BACTERIAL
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    3 / 61 (4.92%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA BACTERAEMIA
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS CRYPTOCOCCAL
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORAL CANDIDIASIS
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         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 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    PLACEBO and MMF OBINUTUZUMAB 1000MG and MMF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 61 (50.82%)
    45 / 64 (70.31%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 61 (1.64%)
    6 / 64 (9.38%)
         occurrences all number
    1
    6
    Injury, poisoning and procedural complications
    INFUSION RELATED REACTION
         subjects affected / exposed
    6 / 61 (9.84%)
    7 / 64 (10.94%)
         occurrences all number
    7
    7
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 64 (6.25%)
         occurrences all number
    2
    4
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 64 (7.81%)
         occurrences all number
    3
    5
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 64 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 61 (4.92%)
    4 / 64 (6.25%)
         occurrences all number
    3
    5
    DIARRHOEA
         subjects affected / exposed
    5 / 61 (8.20%)
    2 / 64 (3.13%)
         occurrences all number
    5
    2
    NAUSEA
         subjects affected / exposed
    3 / 61 (4.92%)
    5 / 64 (7.81%)
         occurrences all number
    3
    5
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    4 / 61 (6.56%)
    12 / 64 (18.75%)
         occurrences all number
    6
    14
    CONJUNCTIVITIS
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 64 (6.25%)
         occurrences all number
    1
    6
    GASTROENTERITIS
         subjects affected / exposed
    6 / 61 (9.84%)
    3 / 64 (4.69%)
         occurrences all number
    7
    4
    HERPES ZOSTER
         subjects affected / exposed
    5 / 61 (8.20%)
    5 / 64 (7.81%)
         occurrences all number
    6
    6
    INFLUENZA
         subjects affected / exposed
    1 / 61 (1.64%)
    4 / 64 (6.25%)
         occurrences all number
    1
    4
    NASOPHARYNGITIS
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 64 (4.69%)
         occurrences all number
    4
    3
    PHARYNGITIS
         subjects affected / exposed
    2 / 61 (3.28%)
    5 / 64 (7.81%)
         occurrences all number
    2
    6
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    5 / 61 (8.20%)
    5 / 64 (7.81%)
         occurrences all number
    6
    6
    URINARY TRACT INFECTION
         subjects affected / exposed
    8 / 61 (13.11%)
    9 / 64 (14.06%)
         occurrences all number
    11
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2015
    Additional text has been provided on ACE inhibitors and angiotensin-receptor blockers with regards to their known teratogenic effects.
    02 Feb 2016
    The assessment of damage throught the Glucocorticoid Toxicity Change Index (GTCI) was added as an exploratory objective. Clarifications were made that all B cells and not just CD19+ B cells will be evaluated in renal biopsies. Clarifications were made that eligible renal biopsies can be taken during screening as well as within 6 months prior to screening. The requirement for active urinary sediment to qualify patients for the study was removed. Exclusion criteria was updated. The dosing regimen for the study treatments and the follow up period were updated. Secondary objectives were updated. Procedures and process for various data collections and the time period of collection were updated.

    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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