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    Clinical Trial Results:
    A Phase III, Open-Label, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) in Combination with Bevacizumab versus Sunitinib in Patients with Untreated Advanced Renal Cell Carcinoma

    Summary
    EudraCT number
    		 2014-004684-20
    Trial protocol
    		 ES   GB   DK   CZ   DE   FR   PL   IT  
    Global end of trial date
    13 Dec 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    24 Dec 2022
    First version publication date
    07 Sep 2018
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    WO29637
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02420821
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    13 Dec 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of “Atezolizumab + Bevacizumab” compared with “Sunitinib” as measured by the coprimary endpoints of investigator-assessed progression-free survival (PFS) in the immune cell (IC)1/2/3 population per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) and overall survival (OS) in the Intent-To-Treat (ITT) Population.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP). Approval from the Independent Ethics Committee/Institutional Review Board (IEC/IRB) was obtained before study start and was documented in a letter to the Investigator specifying the date on which the committee met and granted the approval. The Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 61
    Country: Number of subjects enrolled
    Korea, Republic of: 59
    Country: Number of subjects enrolled
    Singapore: 8
    Country: Number of subjects enrolled
    Thailand: 16
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 3
    Country: Number of subjects enrolled
    Czechia: 30
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Russian Federation: 57
    Country: Number of subjects enrolled
    Turkey: 23
    Country: Number of subjects enrolled
    Canada: 59
    Country: Number of subjects enrolled
    United States: 122
    Country: Number of subjects enrolled
    Australia: 51
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Denmark: 33
    Country: Number of subjects enrolled
    Spain: 83
    Country: Number of subjects enrolled
    France: 52
    Country: Number of subjects enrolled
    United Kingdom: 95
    Country: Number of subjects enrolled
    Italy: 82
    Worldwide total number of subjects
    915
    EEA total number of subjects
    324
    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)
    587
    From 65 to 84 years
    327
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 1228 participants were screened, out of which, 915 participants were enrolled into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sunitinib
    Arm description
    		 Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sunitinib
    Investigational medicinal product code
    Other name
    Sutent
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Sunitinib was administered at a dose of 50 mg once daily, orally via capsule, on Day 1 through Day 28 of each 42-day cycle.

    Arm title
    		 Atezolizumab + Bevacizumab
    Arm description
    		 Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Atezolizumab
    Investigational medicinal product code
    Other name
    Tecentriq, MPDL3280A
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Atezolizumab was administered at a fixed dose of 1200 mg via IV infusion on Days 1 and 22 of each 42-day cycle.

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    Other name
    Avastin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bevacizumab was administered at a dose of 15 mg/kg via IV infusion on Days 1 and 22 of each 42-day cycle.

    Number of subjects in period 1
    		Sunitinib Atezolizumab + Bevacizumab
    Started
    461
    454
    Completed
    1
    1
    Not completed
    460
    453
         Physician decision
    6
    2
         Consent withdrawn by subject
    32
    25
         Study Terminated By Sponsor
    145
    149
         Adverse event, non-fatal
    -
    1
         Death
    270
    263
         Progressive Disease
    1
    1
         Non-compliance
    -
    2
         Patient missing record discontinuation
    -
    1
         Patient refused EOT visit due to Covid-19
    -
    1
         Lost to follow-up
    6
    6
         Protinuria
    -
    1
         Disease Progression
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    		 Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    		 Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group values
    		 Sunitinib Atezolizumab + Bevacizumab Total
    Number of subjects
    		 461 454 915
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.9 ± 9.9 61.6 ± 10.4 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 109 137 246
        Male
    		 352 317 669
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 2 3
        Asian
    		 77 94 171
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 4 1 5
        White
    		 334 326 660
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 45 30 75
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 32 25 57
        Not Hispanic or Latino
    		 386 391 777
        Unknown or Not Reported
    		 43 38 81

    End points

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    End points reporting groups
    Reporting group title
    Sunitinib
    Reporting group description
    		 Participants received sunitinib at a dose of 50 milligrams (mg) administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to disease progression (PD) as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    		 Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 milligrams per kilogram (mg/kg) administered via intravenous (IV) infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Primary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Programmed Death-Ligand 1 (PD-L1)-Selected Population

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    End point title
    		 Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Programmed Death-Ligand 1 (PD-L1)-Selected Population [1]
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. The PD was defined as greater than or equal to (>/=) 20 percent (%) relative increase in the sum of diameters (SoD) of all target lesions (TLs), taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 millimeters (mm); >/=1 new lesion(s); and/or unequivocal progression of existing non-TLs. Analysis was performed on the PD-L1-Selected Population, which included all randomized participants whose PD-L1 status was IC1/2/3 at the time of randomization.
    End point type
    Primary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis for this end point.
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    69.6
    58.4
    No statistical analyses for this end point

    Primary: Progression-Free Survival (PFS) as Determined by the Investigator According to RECIST v1.1 in PD-L1-Selected Population

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    End point title
    		 Progression-Free Survival (PFS) as Determined by the Investigator According to RECIST v1.1 in PD-L1-Selected Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Participants with a PFS event who missed >/=2 scheduled assessments immediately prior to the PFS event were censored at the last tumor assessment prior to the missed visits. Median PFS was estimated by Kaplan-Meier method and 95% confidence interval (CI) was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Primary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    7.5 (6.8 to 9.7)
    11.2 (8.6 to 14.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0205
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 0.95
    Notes
    [2] - Hazard ratio was estimated by Cox regression.

    Primary: Percentage of Participants Who Died of Any Cause in ITT Population

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    End point title
    		 Percentage of Participants Who Died of Any Cause in ITT Population [3]
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the ITT Population, which included all randomized participants whether or not the assigned study treatment was received.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis for this end point.
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    55.3
    54.8
    No statistical analyses for this end point

    Primary: Overall Survival (OS) in ITT Population

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    End point title
    		 Overall Survival (OS) in ITT Population
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Primary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    35.3 (28.6 to 42.1)
    36.1 (31.5 to 42.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.2675
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.08
    Notes
    [4] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants Who Died of Any Cause in PD-L1-Selected Population

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    End point title
    		 Percentage of Participants Who Died of Any Cause in PD-L1-Selected Population
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    56.5
    53.9
    No statistical analyses for this end point

    Secondary: OS in PD-L1-Selected Population

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    End point title
    		 OS in PD-L1-Selected Population
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population. The data ‘99999’ in the results signifies that median and/or corresponding 95% CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    31.6 (23.3 to 42.1)
    38.7 (29.0 to 49.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.263
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.13
    Notes
    [5] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by an Independent Review Committee (IRC) According to RECIST v1.1 or Death from Any Cause in ITT Population

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    End point title
    		 Percentage of Participants with PD as Determined by an Independent Review Committee (IRC) According to RECIST v1.1 or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    63.6
    60.4
    No statistical analyses for this end point

    Secondary: PFS as Determined by an IRC According to RECIST v1.1 in ITT Population

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    End point title
    		 PFS as Determined by an IRC According to RECIST v1.1 in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase and >/=5 mm of absolute increase in the SoD of all TLs, taking as reference the smallest SoD recorded since treatment started; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    8.3 (7.0 to 9.7)
    9.6 (8.3 to 11.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.1218
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.04
    Notes
    [6] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by an IRC According to RECIST v1.1 or Death from Any Cause in PD-L1-Selected Population

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    End point title
    		 Percentage of Participants with PD as Determined by an IRC According to RECIST v1.1 or Death from Any Cause in PD-L1-Selected Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: percentage of participants
        number (not applicable)
    64.7
    62.9
    No statistical analyses for this end point

    Secondary: PFS as Determined by an IRC According to RECIST v1.1 in PD-L1-Selected Population

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    End point title
    		 PFS as Determined by an IRC According to RECIST v1.1 in PD-L1-Selected Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the PD-L1-Selected Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    7.2 (6.1 to 11.1)
    8.9 (6.9 to 12.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.6138
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 1.21
    Notes
    [7] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with an Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator According to RECIST v1.1 in Objective Response Rate (ORR)-Evaluable Population

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    End point title
    		 Percentage of Participants with an Objective Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator According to RECIST v1.1 in Objective Response Rate (ORR)-Evaluable Population
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs and (if applicable) normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to less than (<) 10 mm. PR was defined as >/=30% decrease in the SoD of TLs (taking as reference the baseline SoD) or persistence of >/=1 non-TL(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population, which included all participants in the ITT population with measurable disease at baseline, as determined by the investigator.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (28.97 to 37.77)
    36.6 (32.12 to 41.18)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.2733
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.09
         upper limit
    		 9.7
    Notes
    [8] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 in DOR-Evaluable Population

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    End point title
    		 Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 in DOR-Evaluable Population
    End point description
    DOR: the time from the first CR/PR to PD as determined by the investigator per RECIST v1.1 or death from any cause. CR: disappearance of TLs/non-TLs and normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs or persistence of >/=1 non-TL(s) and/or maintenance of tumor marker level above the normal limits. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. DOR-Evaluable Population: all participants with a CR/PR in the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    153 [9]
    166 [10]
    Units: months
        median (confidence interval 95%)
    14.2 (11.3 to 99999)
    16.6 (15.4 to 99999)
    Notes
    [9] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    [10] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Objective Response of CR or PR as Determined by an IRC According to RECIST v1.1 in ORR-Evaluable Population

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    End point title
    		 Percentage of Participants with an Objective Response of CR or PR as Determined by an IRC According to RECIST v1.1 in ORR-Evaluable Population
    End point description
    Tumor response was assessed by an IRC according to RECIST v1.1. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs and (if applicable) normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR was defined as >/=30% decrease in the SoD of TLs (taking as reference the baseline SoD) or persistence of >/=1 non-TL(s) and/or (if applicable) maintenance of tumor marker level above the normal limits. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    31.3 (27.09 to 35.76)
    33.3 (28.94 to 37.80)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.5121
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.32
         upper limit
    		 8.24
    Notes
    [11] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: DOR as Determined by an IRC According to RECIST v1.1 in DOR-Evaluable Population

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    End point title
    		 DOR as Determined by an IRC According to RECIST v1.1 in DOR-Evaluable Population
    End point description
    DOR was defined as the time from the first occurrence of CR/PR to PD as determined by an IRC per RECIST v1.1, or death from any cause, whichever occurred first. CR: disappearance of TLs/non-TLs and normalization of tumor marker level or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs or persistence of >/=1 non-TL(s) and/or maintenance of tumor marker level above the normal limits. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. Analysis was performed on the DOR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    144 [12]
    151 [13]
    Units: months
        median (confidence interval 95%)
    18.6 (13.8 to 99999)
    99999 (16.8 to 99999)
    Notes
    [12] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    [13] - 99999=Median/Upper limit of CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to Immune-Modified RECIST or Death from Any Cause in ITT Population

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    End point title
    		 Percentage of Participants with PD as Determined by the Investigator According to Immune-Modified RECIST or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by the investigator according to immune-modified RECIST. PD was defined as >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    58.1
    55.1
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to Immune-Modified RECIST in ITT Population

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    End point title
    		 PFS as Determined by the Investigator According to Immune-Modified RECIST in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per immune-modified RECIST or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    12.3 (9.8 to 13.7)
    13.9 (12.5 to 15.3)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0606
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 1.01
    Notes
    [14] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with an Objective Response of CR or PR as Determined by the Investigator According to Immune-Modified RECIST in ORR-Evaluable Population

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    End point title
    		 Percentage of Participants with an Objective Response of CR or PR as Determined by the Investigator According to Immune-Modified RECIST in ORR-Evaluable Population
    End point description
    Tumor response was assessed by the investigator according to immune-modified RECIST. Objective response was defined as percentage of participants with a documented CR or PR. CR was defined as disappearance of all TLs/non-TLs or reduction in short axis of any pathological lymph nodes to <10 mm. PR was defined as >/=30% decrease in the SoD of TLs and all new measurable lesions (taking as reference the baseline SoD), in the absence of CR. The 95% CI was computed using Clopper-Pearson approach. Participants without any post-baseline tumor assessments were considered non-responders. Analysis was performed on the ORR-Evaluable Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    460
    454
    Units: percentage of participants
        number (confidence interval 95%)
    35.0 (30.64 to 39.55)
    40.1 (35.55 to 44.76)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    914
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.1011
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response Rates
    Point estimate
    5.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 11.58
    Notes
    [15] - 95% CI for difference in response rates was constructed using Wald method.

    Secondary: DOR as Determined by the Investigator According to Immune-Modified RECIST in DOR-Evaluable Population

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    End point title
    		 DOR as Determined by the Investigator According to Immune-Modified RECIST in DOR-Evaluable Population
    End point description
    DOR was defined as the time from the first occurrence of CR/PR to PD as determined by the investigator per immune-modified RECIST or death from any cause, whichever occurred first. CR: disappearance of TLs/non-TLs or reduction in short axis of any pathological lymph nodes to <10 mm. PR: >/=30% decrease in the SoD of TLs and all new measurable lesions (taking as reference the baseline SoD), in the absence of CR. PD: >/=20% relative increase in the SoD of all TLs and all new measurable lesions, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm. Participants without PD or death after a CR/PR were censored at last tumor assessment. Participants without tumor assessments after a CR/PR were censored at first CR/PR + 1 day. Median DOR was estimated by Kaplan-Meier method and 95% CI by the method of Brookmeyer and Crowley. Analysis was performed on DOR-evaluable population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented CR/PR, PD, or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    161
    182 [16]
    Units: months
        median (confidence interval 95%)
    19.4 (13.1 to 20.0)
    19.4 (16.5 to 99999)
    Notes
    [16] - 99999 = Upper limit of 95% CI could not be estimated due to high number of censored participants.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in ITT Population

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    End point title
    		 Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in ITT Population
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: percentage of participants
        number (not applicable)
    63.8
    60.1
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to RECIST v1.1 in ITT Population

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    End point title
    		 PFS as Determined by the Investigator According to RECIST v1.1 in ITT Population
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Participants with a PFS event who missed >/=2 scheduled assessments immediately prior to the PFS event were censored at the last tumor assessment prior to the missed visits. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    461
    454
    Units: months
        median (confidence interval 95%)
    8.4 (7.5 to 9.7)
    11.2 (9.6 to 13.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    915
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.0254
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 0.98
    Notes
    [17] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Participants with Sarcomatoid Histology

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    End point title
    		 Percentage of Participants with PD as Determined by the Investigator According to RECIST v1.1 or Death from Any Cause in Participants with Sarcomatoid Histology
    End point description
    Tumor response was assessed by the investigator according to RECIST v1.1. PD was defined as >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Analysis was performed on the ITT Population participants with sarcomatoid histology (defined by investigator-assessed conventional histopathology).
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: percentage of participants
        number (not applicable)
    85.1
    67.6
    No statistical analyses for this end point

    Secondary: PFS as Determined by the Investigator According to RECIST v1.1 in Participants with Sarcomatoid Histology

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    End point title
    		 PFS as Determined by the Investigator According to RECIST v1.1 in Participants with Sarcomatoid Histology
    End point description
    PFS was defined as the time from randomization to PD, as determined by the investigator per RECIST v1.1 or death from any cause, whichever occurred first. PD: >/=20% relative increase in the SoD of all TLs, taking as reference the smallest SoD on study, including baseline, and an absolute increase of >/=5 mm; >/=1 new lesion(s); and/or unequivocal progression of non-TLs. Participants without PFS event were censored at the last tumor assessment date. Participants with no post-baseline tumor assessments were censored at the randomization date + 1 day. Median PFS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population participants with sarcomatoid histology.
    End point type
    Secondary
    End point timeframe
    Baseline until documented PD or death, whichever occurred first (until data cut-off date 29 September 2017, up to approximately 24 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: months
        median (confidence interval 95%)
    5.3 (3.3 to 6.7)
    8.3 (5.4 to 12.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.002
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 0.79
    Notes
    [18] - Hazard ratio was estimated by Cox regression.

    Secondary: Percentage of Participants Who Died of Any Cause in Participants with Sarcomatoid Histology

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    End point title
    		 Percentage of Participants Who Died of Any Cause in Participants with Sarcomatoid Histology
    End point description
    Percentage of participants who died of any cause was reported. Analysis was performed on the ITT Population participants with sarcomatoid histology.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: percentage of participants
        number (not applicable)
    77.0
    64.7
    No statistical analyses for this end point

    Secondary: OS in Participants with Sarcomatoid Histology

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    End point title
    		 OS in Participants with Sarcomatoid Histology
    End point description
    OS was defined as the time from randomization to death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley. Analysis was performed on the ITT Population participants with sarcomatoid histology.
    End point type
    Secondary
    End point timeframe
    Baseline until death from any cause (until data cut-off date 14 February 2020, up to approximately 57 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    74
    68
    Units: months
        median (confidence interval 95%)
    15.4 (10.4 to 19.5)
    21.7 (15.3 to 35.6)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: Strata were presence of liver metastases, Motzer score, PD-L1 level per interactive voice/web response system (IxRS).
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.0497
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.06
    Notes
    [19] - Hazard ratio was estimated by Cox regression.

    Secondary: Change from Baseline in Symptom Interference as Determined by M.D. Anderson Symptom Inventory (MDASI) Part II Score

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    End point title
    		 Change from Baseline in Symptom Interference as Determined by M.D. Anderson Symptom Inventory (MDASI) Part II Score
    End point description
    The MDASI is a self-report questionnaire that comprises of 23 items and two subscales: symptom severity (17 items) and symptom interference (6 items). In Part II, participants were asked to rate how much the symptoms have interfered with 6 areas of function (general activity, walking, work, mood, relations with other people, and enjoyment of life) in the last 24 hours. Each item was rated on a scale of 0 (does not interfere) to 10 (interfered completely) and total Part II score was calculated as an average of 6-item scores. Repeated measures model-estimated least-squares (LS) mean score for changes from baseline is reported at each timepoint, where a negative value indicates improvement. Analysis was performed on the patient-reported outcome (PRO)-Evaluable Population, which included all participants with a non-missing baseline PRO assessment and >/=1 post-baseline PRO assessment. Here, 'n’= number of participants evaluable at specified time point for different arms, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); Day 22 Cycle 1; Day 1 and 22 of every cycle from Cycle 2 up to Cycle 19; Cycle length = 42 days
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    359 [20]
    373
    Units: units on a scale
    least squares mean (standard error)
        Change at Cycle1 Day 22 (n=260,301)
    1.28 ± 0.13
    0.54 ± 0.13
        Change at Cycle 2 Day 1 (n=276,305)
    0.76 ± 0.13
    0.56 ± 0.13
        Change at Cycle 2 Day 22 (n=248,284)
    1.58 ± 0.13
    0.56 ± 0.13
        Change at Cycle 3 Day 1 (n=253,297)
    1.05 ± 0.13
    0.53 ± 0.13
        Change at Cycle 3 Day 22 (n=226,279)
    1.63 ± 0.14
    0.61 ± 0.13
        Change at Cycle 4 Day 1 (n=230,266)
    1.02 ± 0.14
    0.59 ± 0.13
        Change at Cycle 4 Day 22 (n=217,252)
    1.55 ± 0.14
    0.57 ± 0.14
        Change at Cycle 5 Day 1 (n=211,238)
    1.18 ± 0.15
    0.72 ± 0.14
        Change at Cycle 5 Day 22 (n=196,238)
    1.56 ± 0.15
    0.78 ± 0.14
        Change at Cycle 6 Day 1 (n=198,224)
    1.03 ± 0.15
    0.82 ± 0.14
        Change at Cycle 6 Day 22 (n=183,207)
    1.44 ± 0.15
    0.80 ± 0.15
        Change at Cycle 7 Day 1 (n=173,200)
    1.15 ± 0.16
    0.72 ± 0.15
        Change at Cycle 7 Day 22 (n=163,191)
    1.43 ± 0.16
    0.66 ± 0.15
        Change at Cycle 8 Day 1 (n=161,192)
    1.06 ± 0.16
    0.76 ± 0.15
        Change at Cycle 8 Day 22 (n=150,186)
    1.34 ± 0.17
    0.69 ± 0.15
        Change at Cycle 9 Day 1 (n=146,185)
    1.05 ± 0.17
    0.67 ± 0.16
        Change at Cycle 9 Day 22 (n=135,172)
    1.46 ± 0.18
    0.56 ± 0.16
        Change at Cycle 10 Day 1 (n=131,169)
    1.24 ± 0.18
    0.61 ± 0.16
        Change at Cycle 10 Day 22 (n=78,151)
    1.61 ± 0.20
    0.60 ± 0.17
        Change at Cycle 11 Day 1 (n=100,134)
    1.12 ± 0.19
    0.62 ± 0.17
        Change at Cycle 11 Day 22 (n=59,122)
    1.45 ± 0.21
    0.61 ± 0.18
        Change at Cycle 12 Day 1 (n=73,110)
    1.02 ± 0.21
    0.53 ± 0.18
        Change at Cycle 12 Day 22 (n=47,93)
    1.45 ± 0.24
    0.69 ± 0.20
        Change at Cycle 13 Day 1 (n=52,81)
    0.79 ± 0.24
    0.80 ± 0.21
        Change at Cycle 13 Day 22 (n=36,72)
    1.09 ± 0.27
    0.73 ± 0.22
        Change at Cycle 14 Day 1 (n=39,57)
    0.86 ± 0.27
    0.73 ± 0.24
        Change at Cycle 14 Day 22 (n=27,54)
    1.22 ± 0.31
    0.83 ± 0.25
        Change at Cycle 15 Day 1 (n=31,43)
    0.93 ± 0.31
    0.78 ± 0.27
        Change at Cycle 15 Day 22 (n=17,36)
    1.67 ± 0.37
    0.88 ± 0.29
        Change at Cycle 16 Day 1 (n=20,27)
    0.90 ± 0.38
    0.98 ± 0.32
        Change at Cycle 16 Day 22 (n=13,22)
    1.30 ± 0.43
    1.32 ± 0.36
        Change at Cycle 17 Day 1 (n=13,19)
    0.80 ± 0.46
    1.18 ± 0.40
        Change at Cycle 17 Day 22 (n=9,11)
    0.92 ± 0.53
    0.95 ± 0.47
        Change at Cycle 18 Day 1 (n=6,9)
    0.75 ± 0.64
    0.75 ± 0.53
        Change at Cycle 18 Day 22 (n=3,6)
    0.65 ± 0.86
    0.87 ± 0.63
        Change at Cycle 19 Day 1 (n=1,5)
    0.29 ± 1.58
    0.80 ± 0.73
        Change at Cycle 19 Day 22 (n=0,2)
    99999 ± 99999
    0.88 ± 1.03
    Notes
    [20] - ‘99999’ = data not available as no participant was evaluable at specified time point.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cycle 1 Day 22 (Actual number of participants included in the analysis = 561): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 -0.43
    Notes
    [21] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1 (Actual number of participants included in the analysis = 581): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.2085
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.11
    Notes
    [22] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Cycle 2 Day 22 (Actual number of participants included in the analysis = 532): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 -0.71
    Notes
    [23] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1 (Actual number of participants included in the analysis = 550): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.0013
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 -0.2
    Notes
    [24] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Cycle 3 Day 22 (Actual number of participants included in the analysis = 505): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 -0.7
    Notes
    [25] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Cycle 4 Day 1 (Actual number of participants included in the analysis = 496): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.0098
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 -0.1
    Notes
    [26] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Cycle 4 Day 22 (Actual number of participants included in the analysis = 469): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 -0.65
    Notes
    [27] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Cycle 5 Day 1 (Actual number of participants included in the analysis = 449): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.008
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.12
    Notes
    [28] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Cycle 5 Day 22 (Actual number of participants included in the analysis = 434): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.13
         upper limit
    		 -0.44
    Notes
    [29] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Cycle 6 Day 1 (Actual number of participants included in the analysis = 422): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.2512
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 0.15
    Notes
    [30] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Cycle 6 Day 22 (Actual number of participants included in the analysis = 390): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.0005
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 -0.28
    Notes
    [31] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    Cycle 7 Day 1 (Actual number of participants included in the analysis = 373): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.0247
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.05
    Notes
    [32] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 13
    Statistical analysis description
    Cycle 7 Day 22 (Actual number of participants included in the analysis = 354): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 -0.39
    Notes
    [33] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 14
    Statistical analysis description
    Cycle 8 Day 1 (Actual number of participants included in the analysis = 353): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.1411
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 0.1
    Notes
    [34] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 15
    Statistical analysis description
    Cycle 8 Day 22 (Actual number of participants included in the analysis = 336): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.0014
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 -0.25
    Notes
    [35] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 16
    Statistical analysis description
    Cycle 9 Day 1 (Actual number of participants included in the analysis = 331): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.0728
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 0.03
    Notes
    [36] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 17
    Statistical analysis description
    Cycle 9 Day 22 (Actual number of participants included in the analysis = 307): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 -0.49
    Notes
    [37] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 18
    Statistical analysis description
    Cycle 10 Day 1 (Actual number of participants included in the analysis = 300): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.0041
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 -0.2
    Notes
    [38] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 19
    Statistical analysis description
    Cycle 10 Day 22 (Actual number of participants included in the analysis = 229): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 -0.55
    Notes
    [39] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 20
    Statistical analysis description
    Cycle 11 Day 1 (Actual number of participants included in the analysis = 234): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.0353
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 -0.03
    Notes
    [40] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 21
    Statistical analysis description
    Cycle 11 Day 22 (Actual number of participants included in the analysis = 181): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.0011
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.35
         upper limit
    		 -0.34
    Notes
    [41] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 22
    Statistical analysis description
    Cycle 12 Day 1 (Actual number of participants included in the analysis = 183): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.0582
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.02
    Notes
    [42] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 23
    Statistical analysis description
    Cycle 12 Day 22 (Actual number of participants included in the analysis = 140): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.0089
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.32
         upper limit
    		 -0.19
    Notes
    [43] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 24
    Statistical analysis description
    Cycle 13 Day 1 (Actual number of participants included in the analysis = 133): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 = 0.9575
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 0.61
    Notes
    [44] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 25
    Statistical analysis description
    Cycle 13 Day 22 (Actual number of participants included in the analysis = 108): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.2745
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.01
         upper limit
    		 0.29
    Notes
    [45] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 26
    Statistical analysis description
    Cycle 14 Day 1 (Actual number of participants included in the analysis = 96): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 = 0.7088
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 0.55
    Notes
    [46] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 27
    Statistical analysis description
    Cycle 14 Day 22 (Actual number of participants included in the analysis = 81): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.3077
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.13
         upper limit
    		 0.36
    Notes
    [47] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 28
    Statistical analysis description
    Cycle 15 Day 1 (Actual number of participants included in the analysis = 74): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.7112
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 0.63
    Notes
    [48] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 29
    Statistical analysis description
    Cycle 15 Day 22 (Actual number of participants included in the analysis = 53): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.0837
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 0.11
    Notes
    [49] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 30
    Statistical analysis description
    Cycle 16 Day 1 (Actual number of participants included in the analysis = 47): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [50]
    P-value
    		 = 0.8655
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.88
         upper limit
    		 1.04
    Notes
    [50] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 31
    Statistical analysis description
    Cycle 16 Day 22 (Actual number of participants included in the analysis = 35): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.9725
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.07
         upper limit
    		 1.11
    Notes
    [51] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 32
    Statistical analysis description
    Cycle 17 Day 1 (Actual number of participants included in the analysis = 32): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [52]
    P-value
    		 = 0.5285
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 1.55
    Notes
    [52] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 33
    Statistical analysis description
    Cycle 17 Day 22 (Actual number of participants included in the analysis = 20): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.9663
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 1.4
    Notes
    [53] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 34
    Statistical analysis description
    Cycle 18 Day 1 (Actual number of participants included in the analysis = 15): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.9914
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 1.63
    Notes
    [54] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 35
    Statistical analysis description
    Cycle 18 Day 22 (Actual number of participants included in the analysis = 9): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 = 0.8345
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 2.3
    Notes
    [55] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 36
    Statistical analysis description
    Cycle 19 Day 1 (Actual number of participants included in the analysis = 6): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [56]
    P-value
    		 = 0.7725
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 3.91
    Notes
    [56] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Change from Baseline in Symptom Severity as Determined by MDASI Part I Score

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    End point title
    		 Change from Baseline in Symptom Severity as Determined by MDASI Part I Score
    End point description
    The MDASI is a cancer-related, multi-symptom, valid, and reliable self-report questionnaire that comprises of 23 items and two subscales: symptom severity (17 items) and symptom interference (6 items). In Part I, participants were asked to rate how severe the symptoms (pain, fatigue, nausea, disturbed sleep, feeling of being distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, feeling sad, vomiting, numbness or tingling, rash/skin changes, headache, mouth/throat sores, and diarrhea) were when “at their worst” in the last 24 hours. Each item was rated on a scale of 0 (not present) to 10 (as bad as you can imagine). Mixed-effects model-estimated LS mean score for change from baseline at the end-of-treatment is reported for each item, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline; End of Treatment (EoT) visit (up to approximately 27 months)
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    337
    358
    Units: units on a scale
    least squares mean (standard error)
        Pain: Change at EoT
    1.41 ± 0.15
    0.92 ± 0.15
        Fatigue: Change at EoT
    1.83 ± 0.15
    1.20 ± 0.15
        Nausea: Change at EoT
    1.20 ± 0.11
    0.29 ± 0.11
        Disturbed sleep: Change at EoT
    0.71 ± 0.14
    0.19 ± 0.14
        Feeling of Being distressed: Change at EoT
    0.82 ± 0.14
    0.25 ± 0.14
        Shortness of breath: Change at EoT
    1.15 ± 0.13
    0.58 ± 0.13
        Remembering things: Change at EoT
    0.93 ± 0.12
    0.60 ± 0.11
        Lack of appetite: Change at EoT
    1.59 ± 0.14
    0.40 ± 0.14
        Drowsy: Change at EoT
    1.32 ± 0.14
    0.79 ± 0.14
        Dry mouth: Change at EoT
    1.67 ± 0.15
    0.67 ± 0.15
        Feeling sad: Change at EoT
    0.88 ± 0.14
    0.28 ± 0.14
        Vomiting: Change at EoT
    0.66 ± 0.09
    0.08 ± 0.09
        Numbness or tingling: Change at EoT
    1.01 ± 0.12
    0.67 ± 0.12
        Rash/skin changes: Change at EoT
    2.08 ± 0.13
    1.00 ± 0.13
        Headache: Change at EoT
    0.70 ± 0.11
    0.66 ± 0.11
        Mouth/throat sores: Change at EoT
    1.76 ± 0.13
    0.74 ± 0.13
        Diarrhea: Change at EoT
    1.37 ± 0.10
    0.29 ± 0.10
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Pain: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 -0.2
    Notes
    [57] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Fatigue: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 -0.34
    Notes
    [58] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Nausea: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.13
         upper limit
    		 -0.69
    Notes
    [59] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Disturbed sleep: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 = 0.0002
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.79
         upper limit
    		 -0.25
    Notes
    [60] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Being distressed: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.29
    Notes
    [61] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Shortness of breath: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [62]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.32
    Notes
    [62] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Remembering things: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.0036
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.11
    Notes
    [63] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Lack of appetite: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [64]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.46
         upper limit
    		 -0.91
    Notes
    [64] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Drowsy: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.81
         upper limit
    		 -0.27
    Notes
    [65] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Dry mouth: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [66]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.28
         upper limit
    		 -0.71
    Notes
    [66] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Feeling sad: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [67]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 -0.33
    Notes
    [67] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    Vomiting: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [68]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.75
         upper limit
    		 -0.41
    Notes
    [68] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 13
    Statistical analysis description
    Numbness or tingling: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [69]
    P-value
    		 = 0.0051
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.1
    Notes
    [69] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 14
    Statistical analysis description
    Rash/Skin Changes: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [70]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.33
         upper limit
    		 -0.83
    Notes
    [70] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 15
    Statistical analysis description
    Headache: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [71]
    P-value
    		 = 0.6541
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.16
    Notes
    [71] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 16
    Statistical analysis description
    Mouth/Throat Sores: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [72]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.28
         upper limit
    		 -0.76
    Notes
    [72] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 17
    Statistical analysis description
    Diarrhea: Mixed-effects model, assuming unstructured covariance matrix, with a term for treatment group, a term for visit time as a continuous variable, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model. The random effects are intercept and slope of visit time.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    695
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [73]
    P-value
    		 < 0.0001
    Method
    		 Mixed Models Analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    -1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.27
         upper limit
    		 -0.88
    Notes
    [73] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Change from Baseline in Symptom Severity as Determined by Brief Fatigue Inventory (BFI) Interference Scale Score

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    End point title
    		 Change from Baseline in Symptom Severity as Determined by Brief Fatigue Inventory (BFI) Interference Scale Score
    End point description
    The BFI is a valid and reliable self-report questionnaire used to assess the severity and impact of cancer-related fatigue. BFI interference subscale (6 items) assessed the impact of fatigue on global domains (general activity, mood, walking ability, normal work, relations with other people, and enjoyment of life) in the last 24 hours. Each item was rated on a scale of 0 (does not interfere) to 10 (interfered completely). Change from baseline in the mean score of all 6 items at each timepoint is reported, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure; 'n’= number of participants evaluable at specified time point for different arms, respectively; ‘9999’ = data not available as no participant was evaluable at specified time point; and ‘99999’ = Standard Deviation (SD) could not be estimated as only 1 participant was evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); every week for first 12 weeks, Days 1 and 22 of each cycle (Cycle 3 up to 19), within 30 days of PD (up to 27 months), at EoT (up to 27 months) and at 6, 12, 24, and 36 weeks after EoT (overall up to 27 months); 1 cycle=42 days
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    368
    381
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=368,381)
    2.11 ± 2.23
    2.08 ± 2.38
        Change at Cycle 1 Day 8 (n=352,356)
    0.30 ± 1.88
    0.37 ± 1.76
        Change at Cycle 1 Day 15 (n=339,352)
    1.26 ± 2.49
    1.06 ± 2.42
        Change at Cycle 1 Day 22 (n=258,298)
    1.34 ± 2.44
    0.57 ± 2.04
        Change at Cycle 1 Day 29 (n=329,348)
    1.48 ± 2.63
    0.66 ± 2.28
        Change at Cycle 1 Day 36 (n=311,344)
    0.95 ± 2.29
    0.74 ± 2.20
        Change at Cycle 2 Day 1 (n=271,293)
    0.38 ± 2.03
    0.43 ± 2.09
        Change at Cycle 2 Day 8 (n=307,336)
    0.63 ± 2.17
    0.68 ± 2.33
        Change at Cycle 2 Day 15 (n=310,319)
    1.10 ± 2.35
    0.55 ± 2.29
        Change at Cycle 2 Day 22 (n=245,277)
    1.24 ± 2.65
    0.26 ± 2.14
        Change at Cycle 2 Day 29 (n=302,303)
    1.45 ± 2.61
    0.51 ± 2.14
        Change at Cycle 2 Day 36 (n=291,311)
    1.11 ± 2.46
    0.43 ± 2.17
        Change at Cycle 3 Day 1 (n=238,278)
    0.76 ± 2.27
    0.21 ± 2.12
        Change at Cycle 3 Day 22 (n=229,279)
    1.43 ± 2.41
    0.36 ± 2.20
        Change at Cycle 4 Day 1 (n=231,266)
    0.76 ± 2.27
    0.38 ± 2.16
        Change at Cycle 4 Day 22 (n=219,252)
    1.47 ± 2.60
    0.44 ± 2.33
        Change at Cycle 5 Day 1 (n=212,239)
    1.01 ± 2.46
    0.52 ± 2.31
        Change at Cycle 5 Day 22 (n=197,238)
    1.38 ± 2.22
    0.61 ± 2.27
        Change at Cycle 6 Day 1 (n=199,224)
    0.88 ± 2.24
    0.59 ± 2.15
        Change at Cycle 6 Day 22 (n=184,207)
    1.25 ± 2.42
    0.52 ± 2.22
        Change at Cycle 7 Day 1 (n=174,200)
    0.82 ± 2.35
    0.61 ± 2.17
        Change at Cycle 7 Day 22 (n=164,191)
    1.05 ± 2.31
    0.47 ± 2.16
        Change at Cycle 8 Day 1 (n=162,192)
    0.87 ± 2.21
    0.63 ± 2.36
        Change at Cycle 8 Day 22 (n=151,186)
    1.22 ± 2.21
    0.52 ± 2.05
        Change at Cycle 9 Day 1 (n=147,185)
    0.93 ± 2.25
    0.57 ± 2.27
        Change at Cycle 9 Day 22 (n=136,172)
    1.35 ± 2.37
    0.37 ± 2.15
        Change at Cycle 10 Day 1 (n=132,169)
    1.09 ± 2.53
    0.56 ± 1.96
        Change at Cycle 10 Day 22 (n=78,151)
    1.62 ± 2.75
    0.52 ± 1.95
        Change at Cycle 11 Day 1 (n=101,134)
    0.95 ± 2.29
    0.60 ± 1.92
        Change at Cycle 11 Day 22 (n=59,122)
    0.88 ± 2.57
    0.57 ± 1.78
        Change at Cycle 12 Day 1 (n=73,111)
    0.89 ± 2.45
    0.35 ± 1.75
        Change at Cycle 12 Day 22 (n=47,93)
    0.97 ± 2.46
    0.58 ± 1.96
        Change at Cycle 13 Day 1 (n=52,81)
    0.84 ± 2.29
    0.36 ± 1.88
        Change at Cycle 13 Day 22 (n=36,72)
    0.76 ± 2.70
    0.56 ± 2.06
        Change at Cycle 14 Day 1 (n=39,57)
    0.80 ± 2.33
    0.73 ± 1.80
        Change at Cycle 14 Day 22 (n=27,54)
    0.69 ± 2.73
    0.94 ± 1.96
        Change at Cycle 15 Day 1 (n=31,43)
    0.95 ± 2.42
    0.61 ± 1.41
        Change at Cycle 15 Day 22 (n=17,36)
    1.05 ± 3.22
    0.91 ± 1.28
        Change at Cycle 16 Day 1 (n=20,27)
    0.13 ± 1.49
    1.02 ± 1.69
        Change at Cycle 16 Day 22 (n=13,22)
    1.05 ± 1.83
    1.55 ± 1.96
        Change at Cycle 17 Day 1 (n=13,19)
    0.53 ± 1.41
    1.25 ± 1.97
        Change at Cycle 17 Day 22 (n=9,11)
    1.43 ± 2.16
    0.41 ± 1.48
        Change at Cycle 18 Day 1 (n=7,9)
    0.79 ± 1.34
    0.35 ± 1.46
        Change at Cycle 18 Day 22 (n=3,6)
    1.28 ± 2.21
    0.17 ± 1.15
        Change at Cycle 19 Day 1 (n=1,5)
    0.00 ± 99999
    -0.80 ± 0.84
        Change at Cycle 19 Day 22 (n=0,2)
    9999 ± 9999
    -0.25 ± 0.82
        Change at 6 weeks after EoT (n=70,42)
    2.31 ± 2.52
    1.83 ± 2.52
        Change at 12 weeks after EoT (n=59,36)
    1.71 ± 2.66
    1.97 ± 2.63
        Change at 24 weeks after EoT (n=31,25)
    2.38 ± 3.11
    2.15 ± 3.30
        Change at 36 weeks after EoT (n=14,18)
    2.40 ± 3.32
    1.15 ± 2.72
        Change at EoT (n=168,127)
    1.57 ± 2.80
    1.62 ± 2.98
        Change Within 30 Days of PD (n=194,184)
    1.74 ± 2.64
    0.74 ± 2.35
    No statistical analyses for this end point

    Secondary: Change from Baseline in Symptom Severity as Determined by BFI Worst Fatigue Item

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    End point title
    		 Change from Baseline in Symptom Severity as Determined by BFI Worst Fatigue Item
    End point description
    The BFI is a valid and reliable self-report questionnaire used to assess the severity and impact of cancer-related fatigue. BFI worst fatigue item assessed the severity of fatigue at its worst in the last 24 hours. The item was rated on a scale of 0 (not present) to 10 (as bad as you can imagine). Change from baseline in the score at each time point is reported, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants evaluable for this outcome measure; 'n’= number of participants evaluable at specified time point for different arms, respectively; ‘9999’ = data not available as no participant was evaluable at specified time point; and ‘99999’ = SD could not be estimated as only 1 participant was evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 Cycle 1); every week for first 12 weeks, Days 1 and 22 of each cycle (Cycle 3 up to 19), within 30 days of PD (up to 27 months), at EoT (up to 27 months) and at 6, 12, 24, and 36 weeks after EoT (overall up to 27 months); 1 cycle=42 days
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    368
    381
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=368,381)
    3.08 ± 2.66
    2.98 ± 2.69
        Change at Cycle 1 Day 8 (n=352,356)
    0.34 ± 2.35
    0.50 ± 2.29
        Change at Cycle 1 Day 15 (n=339,352)
    1.32 ± 2.82
    1.26 ± 2.92
        Change at Cycle 1 Day 22 (n=258,298)
    1.52 ± 2.86
    0.49 ± 2.30
        Change at Cycle 1 Day 29 (n=329,348)
    1.55 ± 2.99
    0.88 ± 2.62
        Change at Cycle 1 Day 36 (n=311,344)
    0.77 ± 2.82
    0.86 ± 2.50
        Change at Cycle 2 Day 1 (n=271,293)
    0.40 ± 2.50
    0.45 ± 2.52
        Change at Cycle 2 Day 8 (n=307,336)
    0.56 ± 2.68
    0.87 ± 2.82
        Change at Cycle 2 Day 15 (n=310,319)
    1.09 ± 2.82
    0.71 ± 2.78
        Change at Cycle 2 Day 22 (n=245,277)
    1.42 ± 3.01
    0.31 ± 2.53
        Change at Cycle 2 Day 29 (n=302,303)
    1.43 ± 3.08
    0.62 ± 2.66
        Change at Cycle 2 Day 36 (n=291,311)
    1.09 ± 3.01
    0.48 ± 2.76
        Change at Cycle 3 Day 1 (n=238,278)
    0.42 ± 2.68
    0.40 ± 2.57
        Change at Cycle 3 Day 22 (n=229,279)
    1.57 ± 2.98
    0.57 ± 2.64
        Change at Cycle 4 Day 1 (n=231,266)
    0.64 ± 2.76
    0.54 ± 2.49
        Change at Cycle 4 Day 22 (n=219,252)
    1.46 ± 3.14
    0.58 ± 2.74
        Change at Cycle 5 Day 1 (n=212,239)
    0.81 ± 2.75
    0.62 ± 2.79
        Change at Cycle 5 Day 22 (n=197,238)
    1.60 ± 2.87
    0.69 ± 2.83
        Change at Cycle 6 Day 1 (n=199,224)
    0.90 ± 2.78
    0.86 ± 2.73
        Change at Cycle 6 Day 22 (n=184,207)
    1.35 ± 2.79
    0.53 ± 2.66
        Change at Cycle 7 Day 1 (n=174,200)
    0.79 ± 2.78
    0.79 ± 2.70
        Change at Cycle 7 Day 22 (n=164,191)
    1.22 ± 2.85
    0.65 ± 2.56
        Change at Cycle 8 Day 1 (n=162,192)
    0.79 ± 2.69
    0.75 ± 2.84
        Change at Cycle 8 Day 22 (n=151,186)
    1.40 ± 2.64
    0.78 ± 2.67
        Change at Cycle 9 Day 1 (n=147,185)
    0.97 ± 2.54
    0.61 ± 2.62
        Change at Cycle 9 Day 22 (n=136,172)
    1.54 ± 2.92
    0.57 ± 2.55
        Change at Cycle 10 Day 1 (n=132,169)
    0.95 ± 2.73
    0.69 ± 2.46
        Change at Cycle 10 Day 22 (n=78,151)
    1.74 ± 3.09
    0.63 ± 2.48
        Change at Cycle 11 Day 1 (n=101,134)
    0.73 ± 2.80
    0.74 ± 2.69
        Change at Cycle 11 Day 22 (n=59,122)
    1.15 ± 3.18
    0.74 ± 2.52
        Change at Cycle 12 Day 1 (n=73,111)
    0.78 ± 2.79
    0.61 ± 2.29
        Change at Cycle 12 Day 22 (n=47,93)
    1.32 ± 2.89
    0.74 ± 2.69
        Change at Cycle 13 Day 1 (n=52,81)
    0.35 ± 2.54
    0.49 ± 2.46
        Change at Cycle 13 Day 22 (n=36,72)
    0.72 ± 3.48
    0.65 ± 2.70
        Change at Cycle 14 Day 1 (n=39,57)
    0.56 ± 2.84
    0.81 ± 2.60
        Change at Cycle 14 Day 22 (n=27,54)
    0.37 ± 3.01
    1.04 ± 2.40
        Change at Cycle 15 Day 1 (n=31,43)
    0.52 ± 3.15
    0.93 ± 2.25
        Change at Cycle 15 Day 22 (n=17,36)
    0.59 ± 4.08
    0.97 ± 1.84
        Change at Cycle 16 Day 1 (n=20,27)
    -0.05 ± 2.61
    1.33 ± 1.92
        Change at Cycle 16 Day 22 (n=13,22)
    0.77 ± 3.70
    1.68 ± 2.10
        Change at Cycle 17 Day 1 (n=13,19)
    -0.62 ± 3.75
    1.68 ± 1.97
        Change at Cycle 17 Day 22 (n=9,11)
    1.44 ± 3.91
    1.18 ± 1.99
        Change at Cycle 18 Day 1 (n=7,9)
    0.00 ± 2.00
    1.33 ± 1.58
        Change at Cycle 18 Day 22 (n=3,6)
    1.00 ± 1.73
    1.00 ± 2.10
        Change at Cycle 19 Day 1 (n=1,5)
    -4.00 ± 99999
    0.60 ± 1.34
        Change at Cycle 19 Day 22 (n=0,2)
    9999 ± 9999
    0.00 ± 0.00
        Change at 6 weeks after EoT (n=70,42)
    2.43 ± 3.25
    2.40 ± 2.89
        Change at 12 weeks after EoT (n=59,36)
    1.56 ± 3.41
    2.06 ± 3.14
        Change at 24 weeks after EoT (n=31,25)
    1.58 ± 3.82
    1.92 ± 3.46
        Change at 36 weeks after EoT (n=14,18)
    1.86 ± 4.37
    0.78 ± 2.86
        Change at EoT (n=168,127)
    1.40 ± 3.13
    1.72 ± 2.84
        Change Within 30 Days of PD (n=194,184)
    1.81 ± 3.16
    0.89 ± 2.58
    No statistical analyses for this end point

    Secondary: Change from Baseline in Treatment Side Effects Burden as Determined by Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-19) General Population 5 (GP5) Item Score

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    End point title
    		 Change from Baseline in Treatment Side Effects Burden as Determined by Functional Assessment of Cancer Therapy Kidney Symptom Index (FKSI-19) General Population 5 (GP5) Item Score
    End point description
    The FKSI-19 is a 19-item tool designed to assess the most important symptoms and concerns related to treatment effectiveness in advanced kidney cancer. The FKSI-19 GP5 item (bothered by the side effect of treatment) assessed side effects burden in the past 7 days on a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Repeated measures model-estimated LS mean score for changes from baseline is reported at each timepoint, where a negative value indicates improvement. Analysis was performed on the PRO-Evaluable Population. Here, 'n’= number of participants evaluable at specified time point for different arms, respectively. ‘99999’ = data not available as no participant was evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1 and 22 of every cycle (Baseline = Day 1 Cycle 1) up to Cycle 19; Cycle length = 42 days
    End point values
    		 Sunitinib Atezolizumab + Bevacizumab
    Number of subjects analysed
    359
    373
    Units: units on a scale
    least squares mean (standard error)
        Change at Cycle1 Day 22 (n=260,301)
    -1.08 ± 0.06
    -0.36 ± 0.06
        Change at Cycle 2 Day 1 (n=276,305)
    -0.87 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 2 Day 22 (n=248,283)
    -1.13 ± 0.06
    -0.43 ± 0.06
        Change at Cycle 3 Day 1 (n=253,297)
    -1.07 ± 0.06
    -0.49 ± 0.06
        Change at Cycle 3 Day 22 (n=226,279)
    -1.22 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 4 Day 1 (n=230,266)
    -1.07 ± 0.06
    -0.45 ± 0.06
        Change at Cycle 4 Day 22 (n=215,252)
    -1.31 ± 0.07
    -0.49 ± 0.06
        Change at Cycle 5 Day 1 (n=210,238)
    -1.17 ± 0.07
    -0.52 ± 0.06
        Change at Cycle 5 Day 22 (n=196,238)
    -1.38 ± 0.07
    -0.55 ± 0.06
        Change at Cycle 6 Day 1 (n=198,223)
    -1.14 ± 0.07
    -0.51 ± 0.06
        Change at Cycle 6 Day 22 (n=183,207)
    -1.27 ± 0.07
    -0.56 ± 0.07
        Change at Cycle 7 Day 1 (n=173,200)
    -1.09 ± 0.07
    -0.61 ± 0.07
        Change at Cycle 7 Day 22 (n=163,191)
    -1.25 ± 0.07
    -0.58 ± 0.07
        Change at Cycle 8 Day 1 (n=161,191)
    -1.08 ± 0.08
    -0.61 ± 0.07
        Change at Cycle 8 Day 22 (n=150,186)
    -1.22 ± 0.08
    -0.62 ± 0.07
        Change at Cycle 9 Day 1 (n=146,185)
    -1.08 ± 0.08
    -0.60 ± 0.07
        Change at Cycle 9 Day 22 (n=135,172)
    -1.23 ± 0.08
    -0.52 ± 0.07
        Change at Cycle 10 Day 1 (n=131,169)
    -1.06 ± 0.08
    -0.53 ± 0.07
        Change at Cycle 10 Day 22 (n=77,150)
    -1.30 ± 0.09
    -0.57 ± 0.08
        Change at Cycle 11 Day 1 (n=100,134)
    -1.16 ± 0.09
    -0.52 ± 0.08
        Change at Cycle 11 Day 22 (n=59,122)
    -1.28 ± 0.11
    -0.54 ± 0.08
        Change at Cycle 12 Day 1 (n=73,110)
    -1.05 ± 0.10
    -0.62 ± 0.09
        Change at Cycle 12 Day 22 (n=47,93)
    -1.17 ± 0.12
    -0.56 ± 0.09
        Change at Cycle 13 Day 1 (n=52,81)
    -1.15 ± 0.12
    -0.62 ± 0.10
        Change at Cycle 13 Day 22 (n=36,72)
    -1.20 ± 0.14
    -0.64 ± 0.11
        Change at Cycle 14 Day 1 (n=39,57)
    -0.94 ± 0.14
    -0.61 ± 0.12
        Change at Cycle 14 Day 22 (n=27,54)
    -1.32 ± 0.16
    -0.65 ± 0.12
        Change at Cycle 15 Day 1 (n=31,43)
    -0.91 ± 0.15
    -0.62 ± 0.13
        Change at Cycle 15 Day 22 (n=17,36)
    -1.16 ± 0.19
    -0.72 ± 0.14
        Change at Cycle 16 Day 1 (n=20,27)
    -1.06 ± 0.19
    -0.58 ± 0.16
        Change at Cycle 16 Day 22 (n=13,22)
    -1.34 ± 0.22
    -0.41 ± 0.18
        Change at Cycle 17 Day 1 (n=13,19)
    -1.10 ± 0.23
    -0.56 ± 0.20
        Change at Cycle 17 Day 22 (n=9,11)
    -1.02 ± 0.27
    -0.44 ± 0.24
        Change at Cycle 18 Day 1 (n=6,9)
    -1.01 ± 0.33
    -0.38 ± 0.27
        Change at Cycle 18 Day 22 (n=3,6)
    -0.81 ± 0.46
    -0.48 ± 0.33
        Change at Cycle 19 Day 1 (n=1,5)
    -1.27 ± 0.84
    -0.75 ± 0.38
        Change at Cycle 19 Day 22 (n=0,2)
    99999 ± 99999
    -0.93 ± 0.55
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Cycle 2 Day 1 (Actual number of participants included in the analysis = 581): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [74]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.57
    Notes
    [74] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Cycle 1 Day 22 (Actual number of participants included in the analysis = 561): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [75]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 0.87
    Notes
    [75] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Cycle 2 Day 22 (Actual number of participants included in the analysis = 531): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [76]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.84
    Notes
    [76] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Cycle 3 Day 1 (Actual number of participants included in the analysis = 550): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [77]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.44
         upper limit
    		 0.73
    Notes
    [77] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Cycle 3 Day 22 (Actual number of participants included in the analysis = 505): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [78]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 0.92
    Notes
    [78] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Cycle 4 Day 1 (Actual number of participants included in the analysis = 496): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [79]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.78
    Notes
    [79] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Cycle 4 Day 22 (Actual number of participants included in the analysis = 467): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [80]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.97
    Notes
    [80] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 9
    Statistical analysis description
    Cycle 5 Day 22 (Actual number of participants included in the analysis = 434): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [81]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 0.99
    Notes
    [81] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 8
    Statistical analysis description
    Cycle 5 Day 1 (Actual number of participants included in the analysis = 448): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [82]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.81
    Notes
    [82] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 10
    Statistical analysis description
    Cycle 6 Day 1 (Actual number of participants included in the analysis = 421): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [83]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.8
    Notes
    [83] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 11
    Statistical analysis description
    Cycle 6 Day 22 (Actual number of participants included in the analysis = 390): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [84]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.89
    Notes
    [84] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 12
    Statistical analysis description
    Cycle 7 Day 1 (Actual number of participants included in the analysis = 373): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [85]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.65
    Notes
    [85] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 14
    Statistical analysis description
    Cycle 8 Day 1 (Actual number of participants included in the analysis = 352): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [86]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.66
    Notes
    [86] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 13
    Statistical analysis description
    Cycle 7 Day 22 (Actual number of participants included in the analysis = 354): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [87]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.86
    Notes
    [87] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 15
    Statistical analysis description
    Cycle 8 Day 22 (Actual number of participants included in the analysis = 336): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [88]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.79
    Notes
    [88] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 16
    Statistical analysis description
    Cycle 9 Day 1 (Actual number of participants included in the analysis = 331): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [89]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.68
    Notes
    [89] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 17
    Statistical analysis description
    Cycle 9 Day 22 (Actual number of participants included in the analysis = 307): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [90]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.91
    Notes
    [90] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 18
    Statistical analysis description
    Cycle 10 Day 1 (Actual number of participants included in the analysis = 300): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [91]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.33
         upper limit
    		 0.73
    Notes
    [91] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 19
    Statistical analysis description
    Cycle 10 Day 22 (Actual number of participants included in the analysis = 227): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [92]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.96
    Notes
    [92] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 20
    Statistical analysis description
    Cycle 11 Day 1 (Actual number of participants included in the analysis = 234): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [93]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.86
    Notes
    [93] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 21
    Statistical analysis description
    Cycle 11 Day 22 (Actual number of participants included in the analysis = 181): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [94]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.99
    Notes
    [94] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 23
    Statistical analysis description
    Cycle 12 Day 22 (Actual number of participants included in the analysis = 140): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [95]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.89
    Notes
    [95] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 22
    Statistical analysis description
    Cycle 12 Day 1 (Actual number of participants included in the analysis = 183): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [96]
    P-value
    		 = 0.001
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.68
    Notes
    [96] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 24
    Statistical analysis description
    Cycle 13 Day 1 (Actual number of participants included in the analysis = 133): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [97]
    P-value
    		 = 0.0005
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.82
    Notes
    [97] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 26
    Statistical analysis description
    Cycle 14 Day 1 (Actual number of participants included in the analysis = 96): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [98]
    P-value
    		 = 0.0591
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.67
    Notes
    [98] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 25
    Statistical analysis description
    Cycle 13 Day 22 (Actual number of participants included in the analysis = 108): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [99]
    P-value
    		 = 0.0008
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.88
    Notes
    [99] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 27
    Statistical analysis description
    Cycle 14 Day 22 (Actual number of participants included in the analysis = 81): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [100]
    P-value
    		 = 0.0005
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 1.05
    Notes
    [100] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 28
    Statistical analysis description
    Cycle 15 Day 1 (Actual number of participants included in the analysis = 74): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [101]
    P-value
    		 = 0.1378
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.68
    Notes
    [101] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 29
    Statistical analysis description
    Cycle 15 Day 22 (Actual number of participants included in the analysis = 53): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [102]
    P-value
    		 = 0.065
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.89
    Notes
    [102] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 30
    Statistical analysis description
    Cycle 16 Day 1 (Actual number of participants included in the analysis = 47): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [103]
    P-value
    		 = 0.0531
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.96
    Notes
    [103] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 31
    Statistical analysis description
    Cycle 16 Day 22 (Actual number of participants included in the analysis = 35): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [104]
    P-value
    		 = 0.0011
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.49
    Notes
    [104] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 32
    Statistical analysis description
    Cycle 17 Day 1 (Actual number of participants included in the analysis = 32): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [105]
    P-value
    		 = 0.0708
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 1.14
    Notes
    [105] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 34
    Statistical analysis description
    Cycle 18 Day 1 (Actual number of participants included in the analysis = 15): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [106]
    P-value
    		 = 0.1487
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 1.47
    Notes
    [106] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 33
    Statistical analysis description
    Cycle 17 Day 22 (Actual number of participants included in the analysis = 20): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [107]
    P-value
    		 = 0.1078
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 1.29
    Notes
    [107] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 35
    Statistical analysis description
    Cycle 18 Day 22 (Actual number of participants included in the analysis = 9): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [108]
    P-value
    		 = 0.5537
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.77
         upper limit
    		 1.43
    Notes
    [108] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.
    Statistical analysis title
    		 Statistical Analysis 36
    Statistical analysis description
    Cycle 19 Day 1 (Actual number of participants included in the analysis = 6): Repeated measures model, assuming 1st order autoregressive covariance structure, with a term for visit as a categorical variable, a term for treatment group, a term for treatment-by-visit interaction, baseline score and stratification factors (presence of liver metastasis, PD-L1 status, and Motzer score) included as covariates in the model.
    Comparison groups
    Sunitinib v Atezolizumab + Bevacizumab
    Number of subjects included in analysis
    732
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [109]
    P-value
    		 = 0.5743
    Method
    		 Repeated measures model
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.29
         upper limit
    		 2.33
    Notes
    [109] - Difference in LS mean score change between arms (Atezolizumab + Bevacizumab minus Sunitinib) was reported.

    Secondary: Number of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab

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    End point title
    		 Number of Participants with Anti-Therapeutic Antibodies (ATAs) Against Atezolizumab [110]
    End point description
    The number of participants with "Treatment-induced ATAs" and "Treatment-enhanced ATA" against atezolizumab at any time during or after treatment was reported. Treatment-induced ATA = a participant with negative or missing Baseline ATA result(s) and at least one positive post-Baseline ATA result. Treatment-enhanced ATA = a participant with positive ATA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result. Analysis was performed on the ATA-Evaluable Population, which included all participants in the Atezolizumab + Bevacizumab arm with a non-missing baseline ATA sample and >/=1 post-baseline ATA sample. Here, ‘Number of Subject Analysed’ = number of participants with a non-missing baseline ATA sample; 'n’= number of participants with a non-missing ATA sample at indicated timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose [Hour 0] at Day 1 Cycle 1); Post-Baseline (Predose at Cycles 2, 4, and 8, and every eight cycles thereafter up to EoT [up to approximately 27 months] and 120 days after EoT [up to approximately 27 months]) (Cycle length=42 days)
    Notes
    [110] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    446
    Units: participants
    number (not applicable)
        Baseline: ATA Positive Participants (n=446)
    16
        Post-Baseline: Treatment-Induced ATA (n=433)
    95
        Post-Baseline: Treatment-Enhanced ATA (n=433)
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with ATAs Against Bevacizumab

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    End point title
    		 Number of Participants with ATAs Against Bevacizumab [111]
    End point description
    The number of participants with "Treatment-induced ATAs" and "Treatment-enhanced ATA" against bevacizumab at any time during or after treatment was reported. Treatment-induced ATA = a participant with negative or missing Baseline ATA result(s) and at least one positive post-Baseline ATA result. Treatment-enhanced ATA = a participant with positive ATA result at Baseline who has one or more post Baseline titer results that are at least 0.60 titer unit greater than the Baseline titer result. Analysis was performed on the ATA-Evaluable Population. Here, ‘Number of Subject Analysed’ = number of participants with a non-missing baseline ATA sample; 'n’= number of participants with a non-missing ATA sample at indicated timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline (Predose [Hour 0] at Day 1 Cycle 1); Post-Baseline (Predose at Cycle 3, at EoT [up to approximately 27 months] and at 120 days after EoT [up to approximately 27 months]) (Cycle length=42 days)
    Notes
    [111] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    444
    Units: participants
    number (not applicable)
        Baseline: ATA Positive Participants (n=444)
    24
        Post-Baseline: Treatment-Induced ATA (n=433)
    4
        Post-Baseline: Treatment-Enhanced ATA (n=433)
    0
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) for Atezolizumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) for Atezolizumab [112]
    End point description
    Cmax for atezolizumab was estimated from plasma concentration versus time data. Analysis was performed on the Atezolizumab Pharmacokinetic (PK) Population, which included all participants who received atezolizumab treatment and had evaluable PK samples. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    30 minutes after the end of bevacizumab infusion (atezolizumab infusion duration: 30-60 min; bevacizumab infusion duration: 30-90 minutes) on Day 1 of Cycle 1 (Cycle length = 42 days)
    Notes
    [112] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    435
    Units: micrograms per milliliter (mcg/mL)
        arithmetic mean (standard deviation)
    376 ± 90.2
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) for Atezolizumab

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    End point title
    		 Minimum Observed Serum Concentration (Cmin) for Atezolizumab [113]
    End point description
    Cmin for atezolizumab was estimated from plasma concentration versus time data. Analysis was performed on the Atezolizumab PK Population. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure; ‘n’ = number of participants evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Predose (Hour 0) on Day 22 of Cycle 1; predose (Hour 0) on Day 1 of Cycles 2; Cycle length = 42 days
    Notes
    [113] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    426
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 22 (n=426)
    85.6 ± 35.3
        Cycle 2 Day 1 (n=407)
    127 ± 49.6
    No statistical analyses for this end point

    Secondary: Cmax for Bevacizumab

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    End point title
    		 Cmax for Bevacizumab [114]
    End point description
    Cmax for bevacizumab was estimated from plasma concentration versus time data. Analysis was performed on the Bevacizumab PK Population, which included all participants who received bevacizumab treatment and had evaluable PK samples. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    30 minutes after the end of bevacizumab infusion (atezolizumab infusion duration: 30-60 min; bevacizumab infusion duration: 30-90 minutes) on Day 1 of Cycle 1 (Cycle length = 42 days)
    Notes
    [114] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    427
    Units: mcg/mL
        arithmetic mean (standard deviation)
    339 ± 104
    No statistical analyses for this end point

    Secondary: Cmin for Bevacizumab

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    End point title
    		 Cmin for Bevacizumab [115]
    End point description
    Cmin for bevacizumab was estimated from plasma concentration versus time data. Analysis was performed on the Bevacizumab PK Population. Here, 'Number of Subject Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Day 1 of Cycle 3 (Cycle length = 42 days)
    Notes
    [115] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis for this end point.
    End point values
    		 Atezolizumab + Bevacizumab
    Number of subjects analysed
    363
    Units: mcg/mL
        arithmetic mean (standard deviation)
    135 ± 56.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to data cut-off date 13 December 2021 (overall approximately 79 months)
    Adverse event reporting additional description
    Analysis was performed on the safety-evaluable (SE) population, which included all randomized participants who received any amount of any component of the study treatments.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Atezolizumab + Bevacizumab
    Reporting group description
    		 Participants received atezolizumab at a dose of 1200 mg and bevacizumab at a dose of 15 mg/kg administered via IV infusions on Day 1 and Day 22 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Reporting group title
    Sunitinib
    Reporting group description
    		 Participants received sunitinib at a dose of 50 mg administered orally via capsules once daily on Days 1 to 28 of each 42-day cycle until loss of clinical benefit in the opinion of the investigator, unacceptable toxicity or symptomatic deterioration attributed to PD as determined by the investigator, withdrawal of consent, or death, whichever occurred first.

    Serious adverse events
    		 Atezolizumab + Bevacizumab Sunitinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    191 / 451 (42.35%)
    169 / 446 (37.89%)
         number of deaths (all causes)
    269
    274
         number of deaths resulting from adverse events
    7
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    CHOLANGIOCARCINOMA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC CANCER STAGE III
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL TUMOUR HAEMORRHAGE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COLON NEOPLASM
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GALLBLADDER CANCER
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    EMBOLISM
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AORTIC DISORDER
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AORTIC DISSECTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PERIPHERAL ARTERY ANEURYSM
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANEURYSM
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK HAEMORRHAGIC
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    HERNIA REPAIR
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    13 / 451 (2.88%)
    8 / 446 (1.79%)
         occurrences causally related to treatment / all
    9 / 14
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 451 (0.22%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    MALAISE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GAIT DISTURBANCE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION SITE EXTRAVASATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
         subjects affected / exposed
    3 / 451 (0.67%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    4 / 451 (0.89%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    3 / 451 (0.67%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SWELLING
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    CYTOKINE RELEASE SYNDROME
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYSTEMIC IMMUNE ACTIVATION
         subjects affected / exposed
    3 / 451 (0.67%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG HYPERSENSITIVITY
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERSENSITIVITY
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    PROSTATITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PULMONARY INFARCTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LARYNGEAL OEDEMA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURISY
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    4 / 451 (0.89%)
    5 / 446 (1.12%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATELECTASIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         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
    5 / 451 (1.11%)
    5 / 446 (1.12%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    INTERSTITIAL LUNG DISEASE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    6 / 451 (1.33%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    7 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    PSYCHOTIC DISORDER
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    DEVICE DISLOCATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD SODIUM DECREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER FUNCTION TEST ABNORMAL
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TROPONIN INCREASED
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIPASE INCREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD PHOSPHORUS DECREASED
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         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
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACCIDENT AT HOME
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND COMPLICATION
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONJUNCTIVAL LACERATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INJURY
         subjects affected / exposed
    1 / 451 (0.22%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFUSION RELATED REACTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER LIMB FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT INJURY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL ANASTOMOTIC LEAK
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAND FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROMA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOOTH INJURY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXICITY TO VARIOUS AGENTS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIB FRACTURE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NECK INJURY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ROAD TRAFFIC ACCIDENT
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TENDON RUPTURE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIOVENTRICULAR BLOCK COMPLETE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY INSUFFICIENCY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRADYCARDIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUS BRADYCARDIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    9 / 451 (2.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    3 / 451 (0.67%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CARDIAC FAILURE
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    HAEMORRHAGIC STROKE
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL SENSORY NEUROPATHY
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL ISCHAEMIA
         subjects affected / exposed
    0 / 451 (0.00%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LETHARGY
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEPRESSED LEVEL OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    2 / 451 (0.44%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APHASIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBOSACRAL PLEXOPATHY
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTRACRANIAL PRESSURE INCREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEADACHE
         subjects affected / exposed
    1 / 451 (0.22%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBRAL INFARCTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    ALTERED STATE OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 451 (0.44%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLIOSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERALISED TONIC-CLONIC SEIZURE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LACUNAR INFARCTION
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAPLEGIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAROTID ARTERY STENOSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROSPINAL FLUID LEAKAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THALAMUS HAEMORRHAGE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (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
    ANAEMIA
         subjects affected / exposed
    2 / 451 (0.44%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 451 (0.00%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACTOR VIII INHIBITION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    DUODENAL ULCER
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    2 / 451 (0.44%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    3 / 451 (0.67%)
    6 / 446 (1.35%)
         occurrences causally related to treatment / all
    0 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 451 (0.00%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ILEUS
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    OESOPHAGEAL PERFORATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC PERFORATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    HAEMORRHOIDS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    GASTRIC HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    4 / 451 (0.89%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    7 / 451 (1.55%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL OBSTRUCTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 451 (0.44%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTOIMMUNE COLITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE-MEDIATED ENTEROCOLITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOLITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    2 / 451 (0.44%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL FISTULA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MECHANICAL ILEUS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL FISTULA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    3 / 451 (0.67%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    LARGE INTESTINE PERFORATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IMMUNE-MEDIATED HEPATITIS
         subjects affected / exposed
    3 / 451 (0.67%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JAUNDICE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER INJURY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    AUTOIMMUNE HEPATITIS
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLANGITIS ACUTE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATOTOXICITY
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC STEATOSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ERYTHEMA MULTIFORME
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULAR
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH MACULO-PAPULAR
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TOXIC EPIDERMAL NECROLYSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    10 / 451 (2.22%)
    11 / 446 (2.47%)
         occurrences causally related to treatment / all
    2 / 10
    5 / 11
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    2 / 451 (0.44%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROTEINURIA
         subjects affected / exposed
    3 / 451 (0.67%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROGENITAL HAEMORRHAGE
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHRITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEPHROTIC SYNDROME
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBULOINTERSTITIAL NEPHRITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETERIC OBSTRUCTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    ADRENAL INSUFFICIENCY
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    HYPERTHYROIDISM
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHYSITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLUCOCORTICOID DEFICIENCY
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHYROIDISM
         subjects affected / exposed
    1 / 451 (0.22%)
    5 / 446 (1.12%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    FLANK PAIN
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GROIN PAIN
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BURSITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SACRAL PAIN
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOSITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JOINT SWELLING
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHABDOMYOLYSIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 451 (0.89%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MOBILITY DECREASED
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 451 (0.00%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACK PAIN
         subjects affected / exposed
    3 / 451 (0.67%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FISTULA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEONECROSIS OF JAW
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATOMA MUSCLE
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTHRALGIA
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (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
    HAEMATOMA INFECTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA VIRAL
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATYPICAL PNEUMONIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    LUNG ABSCESS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMPYEMA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EAR INFECTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABSCESS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS CHRONIC
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA MYCOPLASMAL
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENCEPHALITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COMPLICATED APPENDICITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    3 / 451 (0.67%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIRECTAL ABSCESS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SCROTAL ABSCESS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HERPES ZOSTER
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PILONIDAL CYST
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UROSEPSIS
         subjects affected / exposed
    3 / 451 (0.67%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARONYCHIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENINGITIS ASEPTIC
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    10 / 451 (2.22%)
    6 / 446 (1.35%)
         occurrences causally related to treatment / all
    0 / 11
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    STAPHYLOCOCCAL BACTERAEMIA
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ORCHITIS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS PERFORATED
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    CAMPYLOBACTER INFECTION
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    METABOLIC ACIDOSIS
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CACHEXIA
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    3 / 451 (0.67%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    3 / 451 (0.67%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    HYPERGLYCAEMIA
         subjects affected / exposed
    2 / 451 (0.44%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    4 / 451 (0.89%)
    7 / 446 (1.57%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    2 / 451 (0.44%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DECREASED APPETITE
         subjects affected / exposed
    1 / 451 (0.22%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    1 / 451 (0.22%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    0 / 451 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    1 / 451 (0.22%)
    0 / 446 (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
    		 Atezolizumab + Bevacizumab Sunitinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    437 / 451 (96.90%)
    435 / 446 (97.53%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    183 / 451 (40.58%)
    193 / 446 (43.27%)
         occurrences all number
    304
    349
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    78 / 451 (17.29%)
    56 / 446 (12.56%)
         occurrences all number
    117
    68
    PAIN
         subjects affected / exposed
    25 / 451 (5.54%)
    13 / 446 (2.91%)
         occurrences all number
    27
    15
    FATIGUE
         subjects affected / exposed
    162 / 451 (35.92%)
    170 / 446 (38.12%)
         occurrences all number
    244
    302
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    43 / 451 (9.53%)
    20 / 446 (4.48%)
         occurrences all number
    73
    24
    ASTHENIA
         subjects affected / exposed
    83 / 451 (18.40%)
    113 / 446 (25.34%)
         occurrences all number
    142
    201
    CHEST PAIN
         subjects affected / exposed
    23 / 451 (5.10%)
    29 / 446 (6.50%)
         occurrences all number
    31
    30
    MUCOSAL INFLAMMATION
         subjects affected / exposed
    45 / 451 (9.98%)
    130 / 446 (29.15%)
         occurrences all number
    69
    233
    OEDEMA PERIPHERAL
         subjects affected / exposed
    65 / 451 (14.41%)
    50 / 446 (11.21%)
         occurrences all number
    92
    69
    Respiratory, thoracic and mediastinal disorders
    RHINORRHOEA
         subjects affected / exposed
    32 / 451 (7.10%)
    8 / 446 (1.79%)
         occurrences all number
    43
    8
    DYSPHONIA
         subjects affected / exposed
    66 / 451 (14.63%)
    18 / 446 (4.04%)
         occurrences all number
    75
    19
    DYSPNOEA
         subjects affected / exposed
    60 / 451 (13.30%)
    44 / 446 (9.87%)
         occurrences all number
    79
    62
    EPISTAXIS
         subjects affected / exposed
    76 / 451 (16.85%)
    70 / 446 (15.70%)
         occurrences all number
    98
    93
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    43 / 451 (9.53%)
    18 / 446 (4.04%)
         occurrences all number
    53
    23
    COUGH
         subjects affected / exposed
    114 / 451 (25.28%)
    98 / 446 (21.97%)
         occurrences all number
    159
    120
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    34 / 451 (7.54%)
    15 / 446 (3.36%)
         occurrences all number
    36
    15
    INSOMNIA
         subjects affected / exposed
    45 / 451 (9.98%)
    41 / 446 (9.19%)
         occurrences all number
    48
    44
    Investigations
    PLATELET COUNT DECREASED
         subjects affected / exposed
    2 / 451 (0.44%)
    47 / 446 (10.54%)
         occurrences all number
    2
    82
    NEUTROPHIL COUNT DECREASED
         subjects affected / exposed
    3 / 451 (0.67%)
    28 / 446 (6.28%)
         occurrences all number
    3
    67
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    50 / 451 (11.09%)
    40 / 446 (8.97%)
         occurrences all number
    87
    79
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    28 / 451 (6.21%)
    40 / 446 (8.97%)
         occurrences all number
    45
    58
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    31 / 451 (6.87%)
    38 / 446 (8.52%)
         occurrences all number
    56
    56
    WEIGHT DECREASED
         subjects affected / exposed
    48 / 451 (10.64%)
    26 / 446 (5.83%)
         occurrences all number
    53
    36
    Nervous system disorders
    DYSGEUSIA
         subjects affected / exposed
    27 / 451 (5.99%)
    94 / 446 (21.08%)
         occurrences all number
    31
    129
    HEADACHE
         subjects affected / exposed
    111 / 451 (24.61%)
    78 / 446 (17.49%)
         occurrences all number
    175
    104
    TASTE DISORDER
         subjects affected / exposed
    8 / 451 (1.77%)
    37 / 446 (8.30%)
         occurrences all number
    8
    47
    DIZZINESS
         subjects affected / exposed
    58 / 451 (12.86%)
    28 / 446 (6.28%)
         occurrences all number
    73
    36
    Blood and lymphatic system disorders
    NEUTROPENIA
         subjects affected / exposed
    5 / 451 (1.11%)
    62 / 446 (13.90%)
         occurrences all number
    7
    157
    ANAEMIA
         subjects affected / exposed
    51 / 451 (11.31%)
    104 / 446 (23.32%)
         occurrences all number
    81
    177
    THROMBOCYTOPENIA
         subjects affected / exposed
    15 / 451 (3.33%)
    80 / 446 (17.94%)
         occurrences all number
    36
    172
    LEUKOPENIA
         subjects affected / exposed
    5 / 451 (1.11%)
    31 / 446 (6.95%)
         occurrences all number
    13
    65
    Gastrointestinal disorders
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    15 / 451 (3.33%)
    55 / 446 (12.33%)
         occurrences all number
    15
    65
    CONSTIPATION
         subjects affected / exposed
    86 / 451 (19.07%)
    68 / 446 (15.25%)
         occurrences all number
    106
    87
    DIARRHOEA
         subjects affected / exposed
    150 / 451 (33.26%)
    239 / 446 (53.59%)
         occurrences all number
    273
    632
    VOMITING
         subjects affected / exposed
    59 / 451 (13.08%)
    120 / 446 (26.91%)
         occurrences all number
    106
    210
    NAUSEA
         subjects affected / exposed
    100 / 451 (22.17%)
    177 / 446 (39.69%)
         occurrences all number
    135
    320
    DRY MOUTH
         subjects affected / exposed
    38 / 451 (8.43%)
    25 / 446 (5.61%)
         occurrences all number
    52
    36
    STOMATITIS
         subjects affected / exposed
    50 / 451 (11.09%)
    103 / 446 (23.09%)
         occurrences all number
    67
    170
    ABDOMINAL PAIN
         subjects affected / exposed
    42 / 451 (9.31%)
    42 / 446 (9.42%)
         occurrences all number
    51
    69
    DYSPEPSIA
         subjects affected / exposed
    34 / 451 (7.54%)
    86 / 446 (19.28%)
         occurrences all number
    45
    110
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    22 / 451 (4.88%)
    40 / 446 (8.97%)
         occurrences all number
    24
    67
    TOOTHACHE
         subjects affected / exposed
    30 / 451 (6.65%)
    18 / 446 (4.04%)
         occurrences all number
    38
    20
    Skin and subcutaneous tissue disorders
    PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME
         subjects affected / exposed
    19 / 451 (4.21%)
    200 / 446 (44.84%)
         occurrences all number
    21
    456
    DRY SKIN
         subjects affected / exposed
    47 / 451 (10.42%)
    42 / 446 (9.42%)
         occurrences all number
    58
    47
    PRURITUS
         subjects affected / exposed
    114 / 451 (25.28%)
    35 / 446 (7.85%)
         occurrences all number
    170
    42
    RASH
         subjects affected / exposed
    100 / 451 (22.17%)
    73 / 446 (16.37%)
         occurrences all number
    151
    99
    HAIR COLOUR CHANGES
         subjects affected / exposed
    0 / 451 (0.00%)
    34 / 446 (7.62%)
         occurrences all number
    0
    36
    SKIN DISCOLOURATION
         subjects affected / exposed
    1 / 451 (0.22%)
    28 / 446 (6.28%)
         occurrences all number
    1
    37
    YELLOW SKIN
         subjects affected / exposed
    1 / 451 (0.22%)
    29 / 446 (6.50%)
         occurrences all number
    1
    42
    Renal and urinary disorders
    HAEMATURIA
         subjects affected / exposed
    20 / 451 (4.43%)
    26 / 446 (5.83%)
         occurrences all number
    33
    63
    PROTEINURIA
         subjects affected / exposed
    150 / 451 (33.26%)
    37 / 446 (8.30%)
         occurrences all number
    311
    61
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    31 / 451 (6.87%)
    14 / 446 (3.14%)
         occurrences all number
    32
    16
    HYPOTHYROIDISM
         subjects affected / exposed
    109 / 451 (24.17%)
    130 / 446 (29.15%)
         occurrences all number
    123
    149
    Musculoskeletal and connective tissue disorders
    NECK PAIN
         subjects affected / exposed
    24 / 451 (5.32%)
    10 / 446 (2.24%)
         occurrences all number
    26
    11
    BACK PAIN
         subjects affected / exposed
    82 / 451 (18.18%)
    57 / 446 (12.78%)
         occurrences all number
    95
    76
    ARTHRALGIA
         subjects affected / exposed
    135 / 451 (29.93%)
    79 / 446 (17.71%)
         occurrences all number
    218
    95
    MYALGIA
         subjects affected / exposed
    61 / 451 (13.53%)
    25 / 446 (5.61%)
         occurrences all number
    75
    32
    PAIN IN EXTREMITY
         subjects affected / exposed
    54 / 451 (11.97%)
    38 / 446 (8.52%)
         occurrences all number
    88
    53
    Infections and infestations
    RHINITIS
         subjects affected / exposed
    25 / 451 (5.54%)
    6 / 446 (1.35%)
         occurrences all number
    33
    6
    SINUSITIS
         subjects affected / exposed
    23 / 451 (5.10%)
    11 / 446 (2.47%)
         occurrences all number
    34
    12
    NASOPHARYNGITIS
         subjects affected / exposed
    47 / 451 (10.42%)
    40 / 446 (8.97%)
         occurrences all number
    67
    52
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    52 / 451 (11.53%)
    33 / 446 (7.40%)
         occurrences all number
    81
    38
    URINARY TRACT INFECTION
         subjects affected / exposed
    34 / 451 (7.54%)
    24 / 446 (5.38%)
         occurrences all number
    56
    34
    Metabolism and nutrition disorders
    HYPONATRAEMIA
         subjects affected / exposed
    27 / 451 (5.99%)
    19 / 446 (4.26%)
         occurrences all number
    39
    26
    HYPERGLYCAEMIA
         subjects affected / exposed
    24 / 451 (5.32%)
    17 / 446 (3.81%)
         occurrences all number
    35
    25
    DECREASED APPETITE
         subjects affected / exposed
    94 / 451 (20.84%)
    148 / 446 (33.18%)
         occurrences all number
    115
    213
    HYPERKALAEMIA
         subjects affected / exposed
    35 / 451 (7.76%)
    18 / 446 (4.04%)
         occurrences all number
    54
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2015
    Amendments primarily included the following safety-related changes: information on potential risk of systemic immune activation with Atezolizumab (MPDL3280A) was added, adverse event reporting for serious adverse events (SAEs) and adverse events of special interest (AESIs_ was extended to 90 days after the last dose of Atezolizumab or Bevacizumab, and pregnancy testing was modified to reflect serial monitoring in eligible participants.
    10 Oct 2015
    The following changes were included: The management of gastrointestinal, dermatologic, endocrine, pulmonary toxicity, hepatotoxicity, potential pancreatic or eye toxicity and other immune-mediated adverse events (AEs) was updated; The management recommendations regarding early identification and management of systemic immune activation (SIA) were added; Eligibility criteria for sarcomatoid histology were broadened to allow inclusion of participants whose tumors demonstrated any component of sarcomatoid histology; Participants with treated, asymptomatic, cerebellar metastases were eligible to be enrolled provided that specific criteria were met; Eligibility for participants with malignancies other than RCC within 5 years was clarified.
    10 Dec 2015
    The following changes were included: The primary endpoint was changed from PFS alone in the ITT population to a coprimary endpoint of PFS and OS in the group of participants with IC1/2/3; The number of events required for the analyses of PFS and OS was changed and the total sample size was increased from approximately 550 to approximately 830 participants, including a minimum of approximately 457 participants in the IC1/2/3 PD-L1 expression group.
    14 Jul 2016
    The statistical analysis plan and analysis hierarchy was modified in order to maintain adequate power for the co-primary endpoints.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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