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    Clinical Trial Results:
    A Multicentric, Open-Label, Single Arm Study of Obinutuzumab Short Duration Infusion (SDI) in Patients with Previously Untreated Advanced Follicular Lymphoma

    Summary
    EudraCT number
    		 2018-003255-38
    Trial protocol
    		 NL   DE  
    Global end of trial date
    25 Jan 2023

    Results information
    Results version number
    		 v4(current)
    This version publication date
    23 Mar 2024
    First version publication date
    04 Aug 2021
    Other versions
    		 v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MO40597
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03817853
    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
    Final
    Date of interim/final analysis
    25 Jan 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This open-label, single arm study evaluated the safety of obinutuzumab administered as a short duration infusion (SDI; target 90-minute infusion) during cycle 2 and from cycle 2 onwards in combination with chemotherapy in participants with previously untreated advanced follicular lymphoma (FL).
    Protection of trial subjects
    All study subjects were required to read and sign and Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Feb 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 19
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    113
    EEA total number of subjects
    45
    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)
    69
    From 65 to 84 years
    43
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 35 sites across 7 countries.

    Pre-assignment
    Screening details
    		 Of the all participants population (114 participants), one participant did not receive the study treatment, thus the safety-evaluable population included 113 participants.

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

    Arms
    Arm title
    		 All Participants
    Arm description
    		 Participants were enrolled in an induction phase and received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator was free to choose the chemotherapy for each participant.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Obinutuzumab
    Investigational medicinal product code
    Other name
    Gazyva
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During induction, obinutuzumab was administered as a 1000 mg IV infusion on Day 1, 8 and 15 during Cycle 1, and on Day 1 of subsequent cycles, for 6-8 cycles. Each cycle is 21 or 28 days long depending on the chemotherapy regimen allocated. During maintenance, 1000 mg of obinutuzumab as single agent was administered as an SDI every 8 weeks (+ or - 10 days) for 2 years or until disease progression).

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bendamustine was administered on Days 1 and 2 for Cycles 1–6 at a dose of 90 mg/m2/day, for six 28-day cycles.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine 1.4 mg/m^2 (maximum 2 mg) IV, administered on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin 50 mg/m^2 IV, administered on Day 1 of each 21-day cycle, for six cycles.

    Investigational medicinal product name
    Prednisone/Prednisolone/Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 100 mg (or equivalent prednisolone or methylprednisolone), administered orally on Days 1-5 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 750 milligrams per square metre (mg/m^2), administered intravenously (IV) on Day 1 of each 21-day cycle, for six cycles for CHOP treatment or eight cycles for CVP treatment.

    Number of subjects in period 1
    		All Participants
    Started
    113
    Started Maintenance
    95
    Completed Maintenance
    67 [1]
    Started Follow-up
    99
    Completed Follow-up
    92 [2]
    Completed
    93
    Not completed
    20
         Physician decision
    2
         Consent withdrawn by subject
    4
         Adverse Event
    5
         Progressive Disease
    6
         Various reasons
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: As this is a single arm study, we are displaying the numbers of those who continued on in the study through maintenance and follow-up.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: As this is a single arm study, we are displaying the numbers of those who continued on in the study through maintenance and follow-up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Participants
    Reporting group description
    		 Participants were enrolled in an induction phase and received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator was free to choose the chemotherapy for each participant.

    Reporting group values
    		 All Participants Total
    Number of subjects
    		 113 113
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 69 69
        From 65-84 years
    		 43 43
        85 years and over
    		 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.9 ± 12.7 -
    Sex: Female, Male
    Units: Subjects
        Male
    		 57 57
        Female
    		 56 56
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 33 33
        Not Hispanic or Latino
    		 80 80
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 27 27
        White
    		 82 82
        Other
    		 2 2
        Multiple
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    All Participants
    Reporting group description
    		 Participants were enrolled in an induction phase and received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator was free to choose the chemotherapy for each participant.

    Subject analysis set title
    Short duration infusion population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This population included all enrolled participants who did not experience a Grade 3 or 4 IRR during Cycle 1 (i.e. at any of the 3 Cycle 1 infusions) and received obinutuzumab as an SDI at Cycle 2.

    Subject analysis set title
    Maintenance: Obinutuzumab
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator was free to choose the chemotherapy for each participant. Participants who achieved a partial response (PR) or complete response (CR) following the induction phase received obinutuzumab maintenance therapy. 1000 mg of obinutuzumab as single agent was administered as an SDI every 8 weeks (+ or - 10 days) for 2 years or until disease progression).

    Subject analysis set title
    Follow-up
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants with stable disease (SD) or progressive disease (PD) as best response after induction therapy discontinued study treatment and underwent a safety follow-up visit at 3 months (90 days (+ or - 10 days)). All participants were followed up at 3 months (90 days (+ or - 10 days)) from the time of the last dose of study treatment.

    Primary: Percentage of Grade >=3 Infusion-Related Reactions (IRRs) During Cycle 2 in Patients Who Had Previously Received Obinutuzumab at the Standard Infusion Rate During Cycle 1 Without Experiencing a Grade 3 or 4 IRR

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    End point title
    		 Percentage of Grade >=3 Infusion-Related Reactions (IRRs) During Cycle 2 in Patients Who Had Previously Received Obinutuzumab at the Standard Infusion Rate During Cycle 1 Without Experiencing a Grade 3 or 4 IRR [1]
    End point description
    IRRs were defined as all adverse events (AEs) that occurred during or within 24 hours from the end of study treatment infusion and were judged as related to infusion of study treatment components by the investigator. The Short Duration Infusion (SDI) population included all enrolled particpants who did not experience a Grade 3 or 4 IRR during cycle 1 (i.e. at any of the three Cycle 1 infusions), received obinutuzumab given at the standard rate only during Cycle 1, and received obinutuzumab as an SDI at cycle 2.
    End point type
    Primary
    End point timeframe
    Within 24 hours from the end of study treatment infusion of Day 1 in Cycle 2 (1 cycle: 21 or 28 days depending on the chemotherapy selected)
    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: This endpoint is presented with a point estimate and a 95% confidence interval according to Clopper&Pearson
    End point values
    		 Short duration infusion population
    Number of subjects analysed
    99
    Units: Percentage of Participants
        number (confidence interval 95%)
    0 (0.00 to 3.66)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs)
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant who was administered a pharmaceutical product, regardless of causal attribution. An AE was therefore any unfavourable 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. Pre-existing conditions which worsened during the study, recurrence of an intermittent medical condition, deterioration in a laboratory value or other clinical test or were related to a protocol-mandated intervention were also considered AEs. Grading was completed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. The safety population included all participants who received at least one dose of obinutuzumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (approximately 4 years)
    End point values
    		 All Participants Maintenance: Obinutuzumab Follow-up
    Number of subjects analysed
    113
    95
    99
    Units: Percentage of Participants
        number (not applicable)
    99.1
    90.5
    27.3
    No statistical analyses for this end point

    Secondary: Percentage of IRRs Regardless of Grade by Cycle

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    End point title
    		 Percentage of IRRs Regardless of Grade by Cycle
    End point description
    IRRs were defined as all adverse events (AEs) that occurred during or within 24 hours from the end of study treatment infusion and were judged as related to infusion of study treatment components by the investigator. The safety population included all participants who received at least one dose of obinutuzumab.
    End point type
    Secondary
    End point timeframe
    Within 24 hours from the end of study treatment infusion in all cycles, including maintenance ((1 cycle: 21 or 28 days depending on the chemotherapy selected); up to approximately 2.5 years)
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Percentage of Participants
    number (not applicable)
        Cycle 1 Day 1 (n=113)
    50.4
        Cycle 1 Day 2 (n=51)
    7.8
        Cycle 1 Day 8 (n=112)
    5.4
        Cycle 1 Day 15 (n=111)
    4.5
        Cycle 2 (n=110)
    11.8
        Cycle 3 (n=108)
    8.3
        Cycle 4 (n=108)
    6.5
        Cycle 5 (n=107)
    5.6
        Cycle 6 (n=105)
    4.8
        Cycle 7 (n=55)
    3.6
    No statistical analyses for this end point

    Secondary: Time to IRR From Infusion to Onset of the IRR During Cycle 2

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    End point title
    		 Time to IRR From Infusion to Onset of the IRR During Cycle 2
    End point description
    Time to IRR (of any grade) in Cycle 2 was defined as the time from the start of infusion (i.e., start date/time of infusion of the first component of study treatment) in Cycle 2 to the onset of the IRR (of any grade) during Cycle 2. The SDI population included all enrolled particpants who did not experience a Grade 3 or 4 IRR during cycle 1 (i.e. at any of the three Cycle 1 infusions), received obinutuzumab given at the standard rate only during Cycle 1, and received obinutuzumab as an SDI at cycle 2. For this outcome measure, only one participant was analyzed. 9999999 = Standard deviation (SD) is not available because only 1 participant had the time to IRR recorded and the SD for one value is not defined.
    End point type
    Secondary
    End point timeframe
    From infusion to onset of IRR during Cycle 2 (1 cycle: 21 or 28 days depending on the chemotherapy selected)
    End point values
    		 Short duration infusion population
    Number of subjects analysed
    1
    Units: Hours
        arithmetic mean (standard deviation)
    11.800 ± 9999999
    No statistical analyses for this end point

    Secondary: Duration (In Minutes) of Obinutuzumab Administration by Cycle

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    End point title
    		 Duration (In Minutes) of Obinutuzumab Administration by Cycle
    End point description
    The duration of obinutuzumab administration (in minutes) by cycle was defined as the difference between the end time and the start time of obinutuzumab administration. The safety population included all participants who received at least one dose of obinutuzumab.
    End point type
    Secondary
    End point timeframe
    All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years)
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Minutes
    arithmetic mean (standard deviation)
        Cycle(C) 1 Day(D) 1 (n=100)
    295.96 ± 147.87
        C1D8 (n=107)
    215.97 ± 46.99
        C1D15 (n=102)
    208.91 ± 33.13
        C2 (n=103)
    101.48 ± 20.56
        C3 (n=101)
    103.29 ± 65.45
        C4 (n=101)
    99.26 ± 13.90
        C5 (n=100)
    98.46 ± 16.48
        C6 (n=102)
    99.10 ± 12.18
        C7 (n=51)
    98.84 ± 13.61
        C8 (n=50)
    95.68 ± 4.12
        Maintenance Week 1 (n=83)
    97.64 ± 10.08
        Maintenance Week 9 (n=63)
    96.78 ± 8.49
        Maintenance Week 17 (n=48)
    97.77 ± 7.66
        Maintenance Week 25 (n=31)
    97.16 ± 7.23
        Maintenance Week 33 (n=24)
    95.08 ± 4.27
        Maintenance Week 41 (n=13)
    95.77 ± 5.26
        Maintenance Week 49 (n=9)
    93.56 ± 4.48
        Maintenance Week 57 (n=2)
    93.50 ± 4.95
    No statistical analyses for this end point

    Secondary: Duration of Grade >=3 IRRs Associated with the obinutuzumab Administered as an SDI by Cycle

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    End point title
    		 Duration of Grade >=3 IRRs Associated with the obinutuzumab Administered as an SDI by Cycle
    End point description
    The duration, in minutes, of IRRs during all cycles, where obinutuzumab was administered as an SDI. The safety population included all participants who received at least one dose of obinutuzumab. For this outcome measure, only one participant was analyzed. 9999999=SD is not available because only 1 participant had the duration of IRR recorded and the SD for one value is not defined.
    End point type
    Secondary
    End point timeframe
    All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years)
    End point values
    		 All Participants
    Number of subjects analysed
    1 [2]
    Units: Minutes
    arithmetic mean (standard deviation)
        Cycle 5
    165.0 ± 9999999
    Notes
    [2] - No data reported
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) at the End of Induction (EOI) Therapy

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    End point title
    		 Objective Response Rate (ORR) at the End of Induction (EOI) Therapy
    End point description
    ORR at EOI therapy was defined as the percentage of particpants with either a CR, CR unconfirmed or PR at the EOI visit, as determined by the investigator and according to the guidelines used at the site. The safety population included all participants who received at least one dose of obinutuzumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of induction therapy (up to approximately 6 months)
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Percentage of Participants
    number (not applicable)
        Complete Response (n=77)
    68.1
        Complete Response unconfirmed (n=0)
    0
        Partial Response (n=22)
    19.5
    No statistical analyses for this end point

    Secondary: Type of Grade >=3 IRRs Associated with the obinutuzumab Administered as an SDI by Cycle

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    End point title
    		 Type of Grade >=3 IRRs Associated with the obinutuzumab Administered as an SDI by Cycle
    End point description
    The safety population included all participants who received at least one dose of obinutuzumab. Only 1 participant had a Grade >=3 IRR, with 3 symptoms in Cycle 5. Weight increased was a grade 1 symptom belonging to the grade 3 IRRs.
    End point type
    Secondary
    End point timeframe
    All cycles including maintenance (1 cycle: 21 or 28 days depending on the chemotherapy selected; up to approximately 2.5 years)
    End point values
    		 All Participants
    Number of subjects analysed
    1
    Units: Percentage of Participants
    number (not applicable)
        Cycle (C) 5- Hypertension (n=1)
    33.3
        C5 - Renal failure (n=1)
    33.3
        C5 - Weight increased (n=1)
    33.3
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at the End of the Study

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    End point title
    		 Overall Survival (OS) at the End of the Study
    End point description
    OS was defined as the time from start of treatment (date of first intake of any study treatment component) to death from any cause. The safety population included all participants who received at least one dose of obinutuzumab. 9999999 = Due to low number of events, the median and upper CI limit was not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to approximately 4 years)
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Months
        median (confidence interval 95%)
    9999999 (33.97 to 9999999)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS) Rate at the End of the Study

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    End point title
    		 Progression-Free Survival (PFS) Rate at the End of the Study
    End point description
    PFS was defined as the time from start of treatment to the first occurrence of disease progression as assessed by the investigator according to the guidelines used at the site or death from any cause. The safety population included all participants who received at least one dose of obinutuzumab. 9999999 = Due to the low number of events, the upper CI limit was not evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of study (up to approximately 4 years)
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Months
        median (confidence interval 95%)
    33.97 (32.13 to 9999999)
    No statistical analyses for this end point

    Secondary: Complete Response (CR) Rate at 30 Months (CR30), as Assessed by the Investigator and According to the Guidelines Used at the Site

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    End point title
    		 Complete Response (CR) Rate at 30 Months (CR30), as Assessed by the Investigator and According to the Guidelines Used at the Site
    End point description
    The CR30 rate was defined as the percentage of participants with a CR at 30 months from study treatment initiation (date of first intake of any study treatment component), as determined by the investigator according to the guidelines used at the site. The safety population included all participants who received at least one dose of obinutuzumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 months
    End point values
    		 All Participants
    Number of subjects analysed
    113
    Units: Percentage of Participants
        number (confidence interval 95%)
    55.6 (45.68 to 65.12)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to end of study (approximately 4 years)
    Adverse event reporting additional description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant who was administered a pharmaceutical product, regardless of causal attribution. Grading was completed according to the CTCAE, version 5.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    All Participants
    Reporting group description
    		 Participants were enrolled in an induction phase and received 6-8 cycles of obinutuzumab, combined with 6 or 8 cycles of standard chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone/prednisolone/methylprednisolone [CHOP - 21-day cycle) or bendamustine (28-day cycle), or cyclophosphamide, vincristine, and prednisone/prednisolone/methylprednisolone [CVP - 21-day cycle]). Participants received an additional two doses of obinutuzumab on Days 8 and 15 of Cycle 1. The investigator was free to choose the chemotherapy for each participant.

    Reporting group title
    Maintenance
    Reporting group description
    		 Participants who achieved a partial response (PR) or complete response (CR) following the induction phase received obinutuzumab maintenance therapy. 1000 mg of obinutuzumab as single agent was administered as an SDI every 8 weeks (+ or - 10 days) for 2 years or until disease progression).

    Reporting group title
    Follow-up
    Reporting group description
    		 Participants with stable disease (SD) or progressive disease (PD) as best response after induction therapy discontinued study treatment and underwent a safety follow-up visit at 3 months (90 days (+ or - 10 days)). All participants were followed up at 3 months (90 days (+ or - 10 days)) from the time of the last dose of study treatment.

    Serious adverse events
    		 All Participants Maintenance Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 113 (18.58%)
    17 / 95 (17.89%)
    11 / 99 (11.11%)
         number of deaths (all causes)
    9
    8
    4
         number of deaths resulting from adverse events
    0
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic bronchial carcinoma
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obliterative bronchiolitis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiorenal syndrome
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    5 / 113 (4.42%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 113 (1.77%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroiditis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 113 (0.88%)
    1 / 95 (1.05%)
    4 / 99 (4.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 113 (2.65%)
    2 / 95 (2.11%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Severe acute respiratory syndrome
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 113 (0.88%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 113 (0.00%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 113 (0.00%)
    4 / 95 (4.21%)
    3 / 99 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    0 / 95 (0.00%)
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 113 (0.00%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Participants Maintenance Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 113 (98.23%)
    76 / 95 (80.00%)
    13 / 99 (13.13%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    7 / 113 (6.19%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    8
    0
    0
    Hypertension
         subjects affected / exposed
    5 / 113 (4.42%)
    7 / 95 (7.37%)
    0 / 99 (0.00%)
         occurrences all number
    5
    8
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 113 (9.73%)
    6 / 95 (6.32%)
    1 / 99 (1.01%)
         occurrences all number
    13
    6
    1
    Fatigue
         subjects affected / exposed
    18 / 113 (15.93%)
    3 / 95 (3.16%)
    1 / 99 (1.01%)
         occurrences all number
    19
    3
    1
    Malaise
         subjects affected / exposed
    12 / 113 (10.62%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences all number
    15
    2
    0
    Mucosal inflammation
         subjects affected / exposed
    9 / 113 (7.96%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    9
    0
    0
    Pyrexia
         subjects affected / exposed
    15 / 113 (13.27%)
    11 / 95 (11.58%)
    0 / 99 (0.00%)
         occurrences all number
    18
    14
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 113 (3.54%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    4
    4
    0
    Respiratory, thoracic and mediastinal disorders
    Hiccups
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    8
    0
    0
    Cough
         subjects affected / exposed
    10 / 113 (8.85%)
    12 / 95 (12.63%)
    0 / 99 (0.00%)
         occurrences all number
    10
    13
    0
    Oropharyngeal pain
         subjects affected / exposed
    5 / 113 (4.42%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    5
    4
    0
    Dyspnoea
         subjects affected / exposed
    3 / 113 (2.65%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    3
    5
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    19 / 113 (16.81%)
    5 / 95 (5.26%)
    1 / 99 (1.01%)
         occurrences all number
    19
    5
    1
    Anxiety
         subjects affected / exposed
    6 / 113 (5.31%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences all number
    6
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 95 (3.16%)
    1 / 99 (1.01%)
         occurrences all number
    10
    3
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 113 (8.85%)
    4 / 95 (4.21%)
    1 / 99 (1.01%)
         occurrences all number
    14
    4
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 113 (2.65%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    3
    4
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    69 / 113 (61.06%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    128
    3
    0
    Fall
         subjects affected / exposed
    4 / 113 (3.54%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    4
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    7
    3
    0
    Headache
         subjects affected / exposed
    18 / 113 (15.93%)
    7 / 95 (7.37%)
    0 / 99 (0.00%)
         occurrences all number
    19
    7
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    9 / 113 (7.96%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences all number
    13
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    19 / 113 (16.81%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    19
    3
    0
    Paraesthesia
         subjects affected / exposed
    5 / 113 (4.42%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences all number
    5
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    20 / 113 (17.70%)
    4 / 95 (4.21%)
    1 / 99 (1.01%)
         occurrences all number
    28
    8
    1
    Neutropenia
         subjects affected / exposed
    68 / 113 (60.18%)
    16 / 95 (16.84%)
    2 / 99 (2.02%)
         occurrences all number
    116
    27
    2
    Lymphopenia
         subjects affected / exposed
    22 / 113 (19.47%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    36
    5
    0
    Leukopenia
         subjects affected / exposed
    20 / 113 (17.70%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    34
    6
    0
    Anaemia
         subjects affected / exposed
    20 / 113 (17.70%)
    3 / 95 (3.16%)
    1 / 99 (1.01%)
         occurrences all number
    25
    3
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    39 / 113 (34.51%)
    6 / 95 (6.32%)
    0 / 99 (0.00%)
         occurrences all number
    42
    6
    0
    Abdominal pain
         subjects affected / exposed
    11 / 113 (9.73%)
    3 / 95 (3.16%)
    1 / 99 (1.01%)
         occurrences all number
    13
    3
    1
    Diarrhoea
         subjects affected / exposed
    15 / 113 (13.27%)
    5 / 95 (5.26%)
    1 / 99 (1.01%)
         occurrences all number
    18
    6
    1
    Dyspepsia
         subjects affected / exposed
    8 / 113 (7.08%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    8
    4
    0
    Nausea
         subjects affected / exposed
    48 / 113 (42.48%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    67
    6
    0
    Vomiting
         subjects affected / exposed
    15 / 113 (13.27%)
    1 / 95 (1.05%)
    0 / 99 (0.00%)
         occurrences all number
    17
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    9 / 113 (7.96%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    10
    4
    0
    Stomatitis
         subjects affected / exposed
    5 / 113 (4.42%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    5
    3
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    5 / 113 (4.42%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences all number
    5
    2
    0
    Dry skin
         subjects affected / exposed
    3 / 113 (2.65%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    3
    5
    0
    Night sweats
         subjects affected / exposed
    0 / 113 (0.00%)
    5 / 95 (5.26%)
    0 / 99 (0.00%)
         occurrences all number
    0
    5
    0
    Rash maculo-papular
         subjects affected / exposed
    6 / 113 (5.31%)
    0 / 95 (0.00%)
    0 / 99 (0.00%)
         occurrences all number
    7
    0
    0
    Alopecia
         subjects affected / exposed
    17 / 113 (15.04%)
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences all number
    18
    1
    1
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    11 / 113 (9.73%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences all number
    14
    2
    0
    Back pain
         subjects affected / exposed
    14 / 113 (12.39%)
    8 / 95 (8.42%)
    0 / 99 (0.00%)
         occurrences all number
    16
    9
    0
    Pain in extremity
         subjects affected / exposed
    3 / 113 (2.65%)
    4 / 95 (4.21%)
    0 / 99 (0.00%)
         occurrences all number
    3
    4
    0
    Arthralgia
         subjects affected / exposed
    7 / 113 (6.19%)
    13 / 95 (13.68%)
    0 / 99 (0.00%)
         occurrences all number
    7
    14
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 113 (2.65%)
    6 / 95 (6.32%)
    1 / 99 (1.01%)
         occurrences all number
    3
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 113 (6.19%)
    2 / 95 (2.11%)
    1 / 99 (1.01%)
         occurrences all number
    7
    3
    1
    COVID-19
         subjects affected / exposed
    0 / 113 (0.00%)
    11 / 95 (11.58%)
    5 / 99 (5.05%)
         occurrences all number
    0
    12
    5
    Herpes zoster
         subjects affected / exposed
    4 / 113 (3.54%)
    2 / 95 (2.11%)
    0 / 99 (0.00%)
         occurrences all number
    4
    2
    0
    Sinusitis
         subjects affected / exposed
    1 / 113 (0.88%)
    6 / 95 (6.32%)
    0 / 99 (0.00%)
         occurrences all number
    1
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 113 (3.54%)
    6 / 95 (6.32%)
    0 / 99 (0.00%)
         occurrences all number
    4
    6
    0
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    7 / 113 (6.19%)
    5 / 95 (5.26%)
    0 / 99 (0.00%)
         occurrences all number
    7
    6
    0
    Decreased appetite
         subjects affected / exposed
    7 / 113 (6.19%)
    3 / 95 (3.16%)
    0 / 99 (0.00%)
         occurrences all number
    7
    3
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 113 (4.42%)
    1 / 95 (1.05%)
    1 / 99 (1.01%)
         occurrences all number
    5
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 113 (1.77%)
    8 / 95 (8.42%)
    0 / 99 (0.00%)
         occurrences all number
    2
    8
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Oct 2018
    This amendment was created to clarify that participants with prior radiotherapy for FL were excluded from the study; clarification that rescreening of participants was possible at any time; the guidance on the use of premedication before obinutuzumab infusion to reduce the risk of IRRs in participants was updated; additional guidance was provided on hepatitis B reactiviation management; clarification was added that the assessment of LVEF was only required for participants who received obinutuzumab with CHOP chemotherapy; assessments of B symptoms at the end-of-infusion, during maintenance, and at the end-of maintenance was not required and that it was only mandatory at screening; clarifications were added to state the assessments of weight at follow-up and response assessments at screening were not required; clarification that hepatitis B virus DNA PCR testing would be performed every 3-4 weeks for participants with prior HBV infection of who are carriers of HBV; the study title was updated to change “Gazyva” to “obinutuzumab” since the trade name differs depending on the country.
    06 Dec 2018
    This protocol was amended to state that the addition to the steroid premedication, participants would also receive premedication with an anti-histamine and antipyretic before the first cycle of obinutuzumab given as an SDI.
    12 Sep 2019
    The protocol was amended to allow participants who experienced a first Grade 3 IRR during SDI dosing to continue to receive SDI dosing during their current and next infusion. The statistical analysis plan was updated to include earlier reporting of the efficacy data at the EOI therapy. Clarification that the SDI population was used for the analysis of the secondary safety endpoint and the primary endpoint analysis. Exclusion criteria was updated to exclude participants with known HTLV-1 infection. Updates to the inclusion criteria allowed participants treated with corticosteroids for reasons other than chemotherapy and premedication to reduce the risk of IRRs as long as the dose didn't exceed 30 mg/day and to clarify that the frequency and period of DNA testing in participants with occult or prior HBV infection and with undetectable HBV DNA would be at least every 3 months for willing participants. The secondary safety endpoint was revised to clarify that it included IRRs linked to any study treatment. The following was clarified: participants who began a prohibited therapy would discontinue the study treatment and the end of induction or end of maintenance visit was performed before any new therapy was started, that 'study treatment' referred to obinutuzumab and chemotherapy during induction and obinutuzumab alone during maintenance, that Beta-2 microglobulin testing would be conducted at screening and EOI, the infusion rates at which obinutuzumab would be restarted following IRRs; premedication that would be given for IRRs, participants with a Grade 4 IRR during induction would discontinue study treatment (and not discontinue the study). This amendment also included additional guidance on when maintenance therapy began, managing suspected anaphylactic reactions, how often to assess vital signs, on tumor and bone marrow assessments and how participant and provided-reported outcome instruments would be administered, the timing of assessments and follow-up period.

    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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