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    Clinical Trial Results:
    A Phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of copanlisib in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin’s lymphoma (iNHL) – CHRONOS-3

    Summary
    EudraCT number
    		 2013-003893-29
    Trial protocol
    		 IE   PT   DE   ES   BE   LT   HU   AT   DK   FR   BG   LU   GR   SK   IT   RO  
    Global end of trial date
    15 Nov 2024

    Results information
    Results version number
    		 v3(current)
    This version publication date
    04 Sep 2025
    First version publication date
    12 Sep 2021
    Other versions
    		 v1 , v2
    Version creation reason
    • New data added to full data set
    data from final analysis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY80-6946/17067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02367040
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30 300139003, clinical-trials-contact@bayer.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
    15 Nov 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression-free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of ≥ 12 months after completion of the last rituximab-containing treatment, or who are unwilling to receive chemotherapy/for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the participants (or their legally authorized representative according to local legislation). Participating participants (or their legally authorized representative according to local legislation) signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 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
    Argentina: 6
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Brazil: 28
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    China: 81
    Country: Number of subjects enrolled
    Colombia: 9
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Philippines: 4
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 25
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Slovakia: 2
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    Thailand: 6
    Country: Number of subjects enrolled
    Turkey: 26
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Viet Nam: 4
    Worldwide total number of subjects
    458
    EEA total number of subjects
    130
    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)
    255
    From 65 to 84 years
    197
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at multiple centers in North America, South America, South Africa, Europe, Asia, and Australia between 03 August 2015 (first subject first visit) and 15 November 2024 (last subject first visit).

    Pre-assignment
    Screening details
    		 Overall, 652 were screened and total of 458 subjects were randomized in a 2:1 ratio to study treatment: 307 subjects to copanlisib/rituximab and 151 subjects to placebo/rituximab.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Copanlisib + Rituximab
    Arm description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY80-6946
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib was supplied as lyophilized preparation in a 6 ml injection vial. The total amount of copanlisib per vial was 60 mg. The solution for IV infusions was obtained after reconstitution with normal saline solution. Dosing was administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib was administered before rituximab.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituximab dose 375 mg/m^2 body surface weekly during Cycle 1 on Days 1, 8, 15 and 22, and then on Day 1 of Cycles 3, 5, 7 and 9. The solution for IV infusions was obtained after reconstitution of a calculated concentration of 1 to 4 mg/ml rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 mg/ml (0.9%) solution for injection or 5% D-Glucose in water.

    Arm title
    		 Placebo + Rituximab
    Arm description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for emulsion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was supplied as lyophilized preparation in a 6 ml injection vial. The developed placebo lyophilisate was equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing was administered on Days 1, 8 and 15 of each 28-day cycle. Placebo was administered before rituximab.

    Number of subjects in period 1
    		Copanlisib + Rituximab Placebo + Rituximab
    Started
    307
    151
    Received treatment
    304
    149
    Completed
    0
    4
    Not completed
    307
    147
         Progressive disease – radiological progression
    54
    80
         Adverse event, serious fatal
    2
    -
         AE associated with clinical disease progression
    1
    4
         Physician decision
    2
    8
         Non-compliance to study drug
    1
    -
         Drug not administered
    3
    2
         Study terminated by sponsor
    19
    2
         Randomized by mistake with study treatment
    1
    -
         AE not associated clinical disease progression
    117
    12
         Failure to meet continuation criteria
    1
    -
         Progressive disease – clinical progression
    6
    6
         Other reason: Covid-19 pandemic related
    1
    -
         Consent withdrawn by subject
    51
    16
         Patient decision
    40
    14
         Switching to other therapy
    2
    -
         Lost to follow-up
    1
    1
         Patient decision: COVID-19 pandemic related
    1
    -
         Required procedure failed
    1
    -
         Progressive disease
    -
    1
         Lack of efficacy
    1
    -
         Additional primary malignancy
    1
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Reporting group values
    		 Copanlisib + Rituximab Placebo + Rituximab Total
    Number of subjects
    		 307 151 458
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 167 88 255
        From 65-84 years
    		 140 63 203
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.0 ( 12.1 ) 61.5 ( 11.0 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 154 66 220
        Male
    		 153 85 238
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 3 4 7
        Asian
    		 125 50 175
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 4 1 5
        White
    		 164 89 253
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 11 7 18
    Eastern cooperative oncology group (ECOG) Performance Status (PS)
    ECOG PS was measured in a scale from 0 (best) to grade 2, where 0=Fully active, able to carry on all pre-diseases performance without restriction, 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 2=Ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50 percent (%) waking hours (h).
    Units: Subjects
        0 – Fully active
    		 182 95 277
        1 – Restricted active
    		 113 55 168
        2 – Ambulatory and capable of all self-care
    		 12 1 13
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 29 26 55
        Not Hispanic or Latino
    		 262 118 380
        Unknown or Not Reported
    		 16 7 23

    End points

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    End points reporting groups
    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects were included.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All FAS subjects with at least one intake of copanlisib/placebo or rituximab.

    Primary: Progression free survival (PFS) based on independent central review.

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    End point title
    		 Progression free survival (PFS) based on independent central review.
    End point description
    Progression-free survival (PFS) was defined as the time from randomization to progressive disease (PD) or death due to any cause, whichever was earlier according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia.
    End point type
    Primary
    End point timeframe
    From first participant randomization (20-Aug-2015) up to data cut-off date at primary completion (31-Aug-2020), approximately 5 years and 2-year follow-up after primary completion at 31-Aug-2022, up to 7 years and final analysis at 15-Nov-2024
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
    median (confidence interval 95%)
        At data cut-off=31-Aug-2020
    21.5 (17.8 to 33.0)
    13.8 (10.2 to 17.5)
        At data cut-off=31-Aug-2022
    23.2 (19.4 to 33.0)
    13.8 (10.8 to 17.5)
        At data cut-off=15-Nov-2024
    22.4 (19.7 to 30.7)
    14.0 (11.4 to 19.2)
    Statistical analysis title
    		 Progression free survival (PFS)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.000003 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.431
         upper limit
    		 0.722
    Notes
    [1] - PFS was evaluated with the stratified log-rank test. HR and 95% CI were based on stratified Cox Regression Model.
    [2] - 1-sided p-value
    Statistical analysis title
    		 Progression free survival (PFS)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.000002 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.393
         upper limit
    		 0.688
    Notes
    [3] - PFS was evaluated with the stratified log-rank test. HR and 95% CI were based on stratified Cox Regression Model.
    [4] - 1-sided p-value
    Statistical analysis title
    		 Progression free survival (PFS)
    Statistical analysis description
    At final analysis
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.000199 [6]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.643
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.502
         upper limit
    		 0.823
    Notes
    [5] - PFS was evaluated with the stratified log-rank test. HR and 95% CI were based on stratified Cox Regression Model.
    [6] - 1-sided p-value

    Secondary: Objective response rate (ORR)

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    End point title
    		 Objective response rate (ORR)
    End point description
    Objective response rate (ORR) was defined as the percentage of subjects who have a best response rating over the whole duration of the study (i.e. until time of analysis of PFS) of complete response (CR) or partial response (PR) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of CR, very good partial response (VGPR), PR, or minor response (MR) according to the Owen Criteria.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of subjects
    number (not applicable)
        At primary completion date
    80.8
    47.7
        At 2-year follow-up cut-off date
    80.5
    49.7
    Statistical analysis title
    		 Objective response rate (ORR)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.000001 [8]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR
    Point estimate
    30.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.63
         upper limit
    		 39.72
    Notes
    [7] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [8] - 1-sided p-value
    Statistical analysis title
    		 Objective response rate (ORR)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.000001 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in ORR
    Point estimate
    32.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 23.95
         upper limit
    		 42.03
    Notes
    [9] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [10] - 1-sided p-value

    Secondary: Complete response rate (CRR)

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    End point title
    		 Complete response rate (CRR)
    End point description
    Complete response rate (CRR) was defined as the percentage of subjects who had a best response rating over the whole duration of the study (i.e., until the time of analysis of PFS) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) a response rating of Complete Response according to the Owen Criteria.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of subjects
    number (not applicable)
        At primary completion date
    33.9
    14.6
        At 2-year follow-up cut-off date
    34.2
    15.2
    Statistical analysis title
    		 Complete response rate (CRR)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.000001 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in CRR
    Point estimate
    18.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.11
         upper limit
    		 26.73
    Notes
    [11] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [12] - 1-sided p-value
    Statistical analysis title
    		 Complete response rate (CRR)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.000001 [14]
    Method
    		 Logrank
    Parameter type
    		 Difference in CRR
    Point estimate
    19.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.57
         upper limit
    		 26.96
    Notes
    [13] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified.
    [14] - 1-sided p-value

    Secondary: Duration of response (DOR)

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    End point title
    		 Duration of response (DOR)
    End point description
    Duration of response (DOR) was defined as the time (in days) from first observed tumor response Complete Response (CR), Very good partial response (VGPR), Partial Response (PR) or Minor Response (MR) until progression or death from any cause, whichever occurred earlier according to the Owen Criteria. Only patients with response in FAS were included in the analysis.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
    median (confidence interval 95%)
        At primary completion date
    20.4 (17.0 to 30.8)
    17.3 (11.8 to 25.3)
        At 2-year follow-up cut-off date
    25.9 (17.7 to 31.5)
    15.2 (12.3 to 25.3)
    Statistical analysis title
    		 Duration of response (DOR)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.051976 [16]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.761
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.547
         upper limit
    		 1.059
    Notes
    [15] - DOR was evaluated with the stratified log-rank test. HR and 95% CI were based on stratified Cox Regression Model.
    [16] - 1-sided p-value
    Statistical analysis title
    		 Duration of response (DOR)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.058262 [18]
    Method
    		 Logrank
    Parameter type
    		 Difference in DOR
    Point estimate
    0.741
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.508
         upper limit
    		 1.079
    Notes
    [17] - DOR was evaluated with the stratified log-rank test. HR and 95% CI were based on stratified Cox Regression Model.
    [18] - 1-sided p-value

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    Disease control rate was defined as the percentage of subjects who had a best response rating as Complete Response (CR), Partial Response (PR) or stable disease (SD) according to the Lugano Classification and for patients with Waldenström macroglobulinemia (WM) as a response rating of CR, very good partial response (VGPR), PR, minor response (MR) or stable disease (SD) according to the Owen Criteria.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Percentage of subjects
    number (not applicable)
        At primary completion date
    89.3
    84.8
        At 2-year follow-up cut-off date
    89.3
    84.8
    Statistical analysis title
    		 Disease control rate (DCR)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.097339 [20]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 11.12
    Notes
    [19] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [20] - 1-sided p-value
    Statistical analysis title
    		 Disease control rate (DCR)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.097339 [22]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in DCR
    Point estimate
    4.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.26
         upper limit
    		 11.12
    Notes
    [21] - P-value from Cochran-Mantel-Haenszel (CMH) test stratified
    [22] - 1-sided p-value

    Secondary: Time to progression (TTP)

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    End point title
    		 Time to progression (TTP)
    End point description
    Time to progression (TTP) was defined as the time (days) from date of randomization to date of first observed disease progression according to the Lugano Classification and Response criteria in patients affected by Waldenström macroglobulinemia.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
    median (confidence interval 95%)
        At primary completion date
    22.3 (19.4 to 33.2)
    13.8 (10.8 to 18.7)
        At 2-year follow-up cut-off date
    27.7 (21.9 to 33.3)
    13.8 (11.0 to 18.7)
    Statistical analysis title
    		 Time to progression (TTP)
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.000001 [24]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.476
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.357
         upper limit
    		 0.635
    Notes
    [23] - TTP was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [24] - 1-sided p-value
    Statistical analysis title
    		 Time to progression (TTP)
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.000001 [26]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.505
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.387
         upper limit
    		 0.659
    Notes
    [25] - TTP was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [26] - 1-sided p-value

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    Overall survival (OS) was defined as the time (in days) from randomization until death from any cause.
    End point type
    Secondary
    End point timeframe
    From randomization up to the final analysis at 15-Nov-2024
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307 [27]
    151 [28]
    Units: Months
        median (confidence interval 95%)
    99999 (82.2 to 99999)
    99999 (77.3 to 99999)
    Notes
    [27] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    [28] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    Statistical analysis title
    		 Overall survival (OS)
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.436458 [30]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.972
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.691
         upper limit
    		 1.368
    Notes
    [29] - OS was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [30] - 1-sided p-value

    Secondary: Time to deterioration in DRS-P (Disease-Related Symptoms – Physical) of at least three points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.

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    End point title
    		 Time to deterioration in DRS-P (Disease-Related Symptoms – Physical) of at least three points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.
    End point description
    Time to deterioration in DRS-P (Disease-Related Symptoms – Physical) of at least three points was defined as the time (in days) from randomization to DRS-P decline, progression, or death due to any reason, whichever occurred earlier. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    151
    Units: Months
    median (confidence interval 95%)
        At primary completion date
    5.5 (4.2 to 5.9)
    5.5 (4.0 to 7.4)
        At 2-year follow-up cut-off date
    5.5 (4.2 to 5.9)
    5.5 (4.1 to 7.4)
    Statistical analysis title
    		 Time to deterioration in DRS-P
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.661145 [32]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.047
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.841
         upper limit
    		 1.302
    Notes
    [31] - Time to deterioration in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [32] - 1-sided p-value
    Statistical analysis title
    		 Time to deterioration in DRS-P
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.69261 [34]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.843
         upper limit
    		 1.331
    Notes
    [33] - Time to deterioration in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [34] - 1-sided p-value

    Secondary: Time to improvement in DRS-P (Disease-Related Symptoms – Physical) of at least 3 points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.

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    End point title
    		 Time to improvement in DRS-P (Disease-Related Symptoms – Physical) of at least 3 points, as measured by the Functional Assessment of Cancer Therapy Lymphoma Symptom Index-18 (FLymSI-18) questionnaire.
    End point description
    Time to improvement in DRS-P (Disease-Related Symptoms – Physical) was defined as the time (in days) from randomization to DRS-P improvement of at least three points. The Lymphoma Symptom Index-18 (FLymSI-18) questionnaire contains 18 items, each of which utilizes a Likert scale with 5 possible responses ranging from 0 'Not at all' to 4 'Very much' and was divided into a total score.
    End point type
    Secondary
    End point timeframe
    From first subject randomization up to approximately 7 years at data cut-off date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307 [35]
    151 [36]
    Units: Months
    median (confidence interval 95%)
        At primary completion date
    99999 (8.3 to 99999)
    99999 (6.0 to 99999)
        At 2-year follow-up cut-off date
    38.5 (8.2 to 99999)
    35.7 (5.9 to 99999)
    Notes
    [35] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    [36] - 99999 - value cannot be estimated due to censored data (insufficient number of events).
    Statistical analysis title
    		 Time to improvement in DRS-P
    Statistical analysis description
    At primary completion date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.510038 [38]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.996
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.732
         upper limit
    		 1.355
    Notes
    [37] - Time to improvement in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [38] - 1-sided p-value
    Statistical analysis title
    		 Time to improvement in DRS-P
    Statistical analysis description
    At 2-year follow-up cut-off date
    Comparison groups
    Copanlisib + Rituximab v Placebo + Rituximab
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.40597 [40]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.036
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.768
         upper limit
    		 1.398
    Notes
    [39] - Time to improvement in DRS-P was evaluated with the stratified log-rank test. HR and 95% CI were based on Cox Regression Model.
    [40] - 1-sided p-value

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) at primary completion date.

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs) at primary completion date.
    End point description
    Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after end of treatment with study drug, data reporting cut-off at 5 years from the first subject randomization date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    146
    Units: Subjects
        Any TEAEs
    307
    134
        Any copanlisib- or placebo-related TEAE
    293
    95
        Any rituximab-related TEAE
    218
    92
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) at 2-year follow-up cut-off date.

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs) at 2-year follow-up cut-off date.
    End point description
    Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after end of treatment with study drug, data reporting cut-off at 7 years from the first subject randomization date
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    146
    Units: Subjects
        Any TEAEs
    307
    137
        Any copanlisib- or placebo-related TEAE
    295
    98
        Any rituximab-related TEAE
    218
    93
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) at final analysis

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs) at final analysis
    End point description
    Adverse events were considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after end of treatment with study drug, data reporting cut-off at final analysis
    End point values
    		 Copanlisib + Rituximab Placebo + Rituximab
    Number of subjects analysed
    307
    146
    Units: Subjects
        Any TEAEs
    307
    137
        Any copanlisib- or placebo-related TEAE
    295
    98
        Any rituximab-related TEAE
    218
    93
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time frame for Serious and Other Adverse Events - from first administration of study drug until 30 days after the last study drug intake / Time frame for number of death (all causes) - from randomization up to approximately 9 years.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Placebo + Rituximab
    Reporting group description
    		 Placebo was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Placebo was administered before rituximab.

    Reporting group title
    Copanlisib + Rituximab
    Reporting group description
    		 Copanlisib (60 mg) was administered intravenously (IV) (over approximately 1 h) on Days 1, 8, and 15 of each 28-day cycle. Rituximab (375 mg/m^2) was administered weekly during Cycle 1 on Days 1, 8, 15, and 22, and then on Day 1 of Cycles 3, 5, 7, and 9. Copanlisib was administered before rituximab.

    Serious adverse events
    		 Placebo + Rituximab Copanlisib + Rituximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 146 (21.92%)
    161 / 307 (52.44%)
         number of deaths (all causes)
    50
    99
         number of deaths resulting from adverse events
    1
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    0 / 146 (0.00%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arthrodesis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral stent removal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia repair
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Administration site extravasation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 146 (0.00%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (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
    Anaphylactic reaction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 146 (0.00%)
    15 / 307 (4.89%)
         occurrences causally related to treatment / all
    0 / 0
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pleural effusion
         subjects affected / exposed
    4 / 146 (2.74%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 146 (0.00%)
    6 / 307 (1.95%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic interstitial pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 146 (0.68%)
    5 / 307 (1.63%)
         occurrences causally related to treatment / all
    1 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    Fall
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyphaema
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion-related acute lung injury
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Eustachian valve hypertrophy
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve paralysis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tension headache
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure like phenomena
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 146 (2.05%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enteritis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal toxicity
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Panniculitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 146 (0.00%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 146 (3.42%)
    22 / 307 (7.17%)
         occurrences causally related to treatment / all
    4 / 5
    15 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         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
    1 / 146 (0.68%)
    3 / 307 (0.98%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parvovirus B19 infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 146 (1.37%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle abscess
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 146 (1.37%)
    4 / 307 (1.30%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 0
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 146 (2.05%)
    8 / 307 (2.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 307 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 307 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 146 (0.00%)
    21 / 307 (6.84%)
         occurrences causally related to treatment / all
    0 / 0
    27 / 27
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 307 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + Rituximab Copanlisib + Rituximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 146 (86.99%)
    298 / 307 (97.07%)
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    8 / 146 (5.48%)
    13 / 307 (4.23%)
         occurrences all number
    15
    14
    Blood bilirubin increased
         subjects affected / exposed
    2 / 146 (1.37%)
    16 / 307 (5.21%)
         occurrences all number
    4
    31
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 146 (8.22%)
    28 / 307 (9.12%)
         occurrences all number
    22
    37
    Amylase increased
         subjects affected / exposed
    4 / 146 (2.74%)
    16 / 307 (5.21%)
         occurrences all number
    13
    20
    Alanine aminotransferase increased
         subjects affected / exposed
    11 / 146 (7.53%)
    30 / 307 (9.77%)
         occurrences all number
    20
    46
    Blood creatine phosphokinase increased
         subjects affected / exposed
    7 / 146 (4.79%)
    25 / 307 (8.14%)
         occurrences all number
    11
    41
    Neutrophil count decreased
         subjects affected / exposed
    34 / 146 (23.29%)
    102 / 307 (33.22%)
         occurrences all number
    74
    434
    Lymphocyte count decreased
         subjects affected / exposed
    9 / 146 (6.16%)
    42 / 307 (13.68%)
         occurrences all number
    38
    122
    Lipase increased
         subjects affected / exposed
    4 / 146 (2.74%)
    18 / 307 (5.86%)
         occurrences all number
    16
    39
    Blood creatinine increased
         subjects affected / exposed
    6 / 146 (4.11%)
    16 / 307 (5.21%)
         occurrences all number
    7
    26
    Platelet count decreased
         subjects affected / exposed
    12 / 146 (8.22%)
    42 / 307 (13.68%)
         occurrences all number
    23
    121
    Weight decreased
         subjects affected / exposed
    4 / 146 (2.74%)
    47 / 307 (15.31%)
         occurrences all number
    5
    67
    White blood cell count decreased
         subjects affected / exposed
    17 / 146 (11.64%)
    61 / 307 (19.87%)
         occurrences all number
    53
    315
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 146 (21.23%)
    157 / 307 (51.14%)
         occurrences all number
    119
    779
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 146 (1.37%)
    21 / 307 (6.84%)
         occurrences all number
    2
    28
    Dizziness
         subjects affected / exposed
    6 / 146 (4.11%)
    16 / 307 (5.21%)
         occurrences all number
    6
    19
    Headache
         subjects affected / exposed
    10 / 146 (6.85%)
    43 / 307 (14.01%)
         occurrences all number
    20
    73
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 146 (10.96%)
    60 / 307 (19.54%)
         occurrences all number
    62
    139
    Neutropenia
         subjects affected / exposed
    24 / 146 (16.44%)
    64 / 307 (20.85%)
         occurrences all number
    57
    249
    Thrombocytopenia
         subjects affected / exposed
    8 / 146 (5.48%)
    13 / 307 (4.23%)
         occurrences all number
    14
    32
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 146 (9.59%)
    61 / 307 (19.87%)
         occurrences all number
    21
    93
    Mucosal inflammation
         subjects affected / exposed
    2 / 146 (1.37%)
    18 / 307 (5.86%)
         occurrences all number
    2
    23
    Influenza like illness
         subjects affected / exposed
    7 / 146 (4.79%)
    17 / 307 (5.54%)
         occurrences all number
    10
    19
    Fatigue
         subjects affected / exposed
    11 / 146 (7.53%)
    44 / 307 (14.33%)
         occurrences all number
    16
    51
    Chills
         subjects affected / exposed
    7 / 146 (4.79%)
    22 / 307 (7.17%)
         occurrences all number
    10
    33
    Asthenia
         subjects affected / exposed
    5 / 146 (3.42%)
    21 / 307 (6.84%)
         occurrences all number
    7
    27
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 146 (8.22%)
    31 / 307 (10.10%)
         occurrences all number
    14
    37
    Diarrhoea
         subjects affected / exposed
    15 / 146 (10.27%)
    106 / 307 (34.53%)
         occurrences all number
    19
    245
    Mouth ulceration
         subjects affected / exposed
    4 / 146 (2.74%)
    21 / 307 (6.84%)
         occurrences all number
    6
    31
    Nausea
         subjects affected / exposed
    17 / 146 (11.64%)
    70 / 307 (22.80%)
         occurrences all number
    25
    116
    Abdominal pain
         subjects affected / exposed
    6 / 146 (4.11%)
    17 / 307 (5.54%)
         occurrences all number
    7
    23
    Vomiting
         subjects affected / exposed
    5 / 146 (3.42%)
    45 / 307 (14.66%)
         occurrences all number
    5
    62
    Stomatitis
         subjects affected / exposed
    4 / 146 (2.74%)
    41 / 307 (13.36%)
         occurrences all number
    9
    59
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 146 (13.01%)
    47 / 307 (15.31%)
         occurrences all number
    30
    69
    Dyspnoea
         subjects affected / exposed
    14 / 146 (9.59%)
    17 / 307 (5.54%)
         occurrences all number
    18
    17
    Oropharyngeal pain
         subjects affected / exposed
    6 / 146 (4.11%)
    18 / 307 (5.86%)
         occurrences all number
    7
    21
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    2 / 146 (1.37%)
    20 / 307 (6.51%)
         occurrences all number
    2
    22
    Rash maculo-papular
         subjects affected / exposed
    4 / 146 (2.74%)
    21 / 307 (6.84%)
         occurrences all number
    5
    33
    Rash
         subjects affected / exposed
    10 / 146 (6.85%)
    35 / 307 (11.40%)
         occurrences all number
    13
    51
    Pruritus
         subjects affected / exposed
    9 / 146 (6.16%)
    30 / 307 (9.77%)
         occurrences all number
    12
    39
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    5 / 146 (3.42%)
    18 / 307 (5.86%)
         occurrences all number
    5
    19
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    2 / 146 (1.37%)
    19 / 307 (6.19%)
         occurrences all number
    2
    26
    Back pain
         subjects affected / exposed
    13 / 146 (8.90%)
    19 / 307 (6.19%)
         occurrences all number
    17
    21
    Arthralgia
         subjects affected / exposed
    9 / 146 (6.16%)
    21 / 307 (6.84%)
         occurrences all number
    15
    24
    Myalgia
         subjects affected / exposed
    11 / 146 (7.53%)
    8 / 307 (2.61%)
         occurrences all number
    12
    10
    Pain in extremity
         subjects affected / exposed
    5 / 146 (3.42%)
    19 / 307 (6.19%)
         occurrences all number
    6
    27
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 146 (5.48%)
    18 / 307 (5.86%)
         occurrences all number
    9
    30
    Influenza
         subjects affected / exposed
    12 / 146 (8.22%)
    8 / 307 (2.61%)
         occurrences all number
    14
    9
    Nasopharyngitis
         subjects affected / exposed
    7 / 146 (4.79%)
    28 / 307 (9.12%)
         occurrences all number
    12
    41
    Pneumonia
         subjects affected / exposed
    12 / 146 (8.22%)
    36 / 307 (11.73%)
         occurrences all number
    15
    54
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 146 (19.18%)
    62 / 307 (20.20%)
         occurrences all number
    37
    124
    COVID-19
         subjects affected / exposed
    6 / 146 (4.11%)
    21 / 307 (6.84%)
         occurrences all number
    6
    28
    Oral herpes
         subjects affected / exposed
    4 / 146 (2.74%)
    19 / 307 (6.19%)
         occurrences all number
    5
    29
    Urinary tract infection
         subjects affected / exposed
    13 / 146 (8.90%)
    38 / 307 (12.38%)
         occurrences all number
    20
    67
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    35 / 146 (23.97%)
    210 / 307 (68.40%)
         occurrences all number
    93
    940
    Hyperuricaemia
         subjects affected / exposed
    8 / 146 (5.48%)
    20 / 307 (6.51%)
         occurrences all number
    18
    33
    Hypokalaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    25 / 307 (8.14%)
         occurrences all number
    2
    38
    Decreased appetite
         subjects affected / exposed
    4 / 146 (2.74%)
    23 / 307 (7.49%)
         occurrences all number
    4
    28
    Hypertriglyceridaemia
         subjects affected / exposed
    7 / 146 (4.79%)
    21 / 307 (6.84%)
         occurrences all number
    23
    35

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jan 2015
    - The study target population for the efficacy analysis was changed from iNHL patients to FL patients. - The randomization ratio was changed from 1:1 to 2:1 and the stratification factors were changed. - Time to improvement in DRS-P was added as a secondary efficacy variable.
    18 Feb 2016
    - The conservative requirement for blood pressure levels during the evaluation of patient’s eligibility was removed due to feedback from the investigators and lymphoma specialists. - A requirement for prophylactic antiviral therapy to be given to patients who are positive for HBsAg or HBcAb at screening was added. - Copanlisib was added to the list of prohibited previous therapies and medications.
    28 Jul 2016
    - Guidance on dose modification of copanlisib or placebo for hematological toxicity was updated. - Following Health Authority alerts related to safety issues with Zydelig (idelalisib, a PI3K inhibitor) treatment in clinical trials, text was added to provide guidance for monitoring and prophylaxis of opportunistic infections in patients who are at risk for opportunistic infection development while on study treatment.
    02 Feb 2018
    - The total sample size was reduced from 567 patients to 450 patients and the primary efficacy analysis was revised to be performed in the FAS instead of both the FAS and FL subpopulation. - Patients considered unwilling/unfit to receive chemotherapy were bundled to differentiate them in a subgroup different from the long-term responders (i.e., progression-free and treatment-free interval of ≥12 months after completion of the last rituximab-containing treatment).
    08 Oct 2019
    - The statistical assumptions for the primary efficacy analysis of PFS were modified. The required number of PFS events was changed from 288 to 190. - The confirmatory testing strategy was modified.
    22 May 2020
    - Number of events necessary for primary completion analyses was changed to “at least 190 PFS events” to remain flexible. - Removed potential pooling of strata. In order to avoid a too low number of events, only stratification factors “iNHL histology” and “entry criterion” will be adjusted simultaneously in the statistical analyses. - Confirmatory statistical testing strategy for the US was revised and an additional confirmatory statistical testing strategy for the EU was added.
    09 Feb 2023
    - Survival follow-up period extended up to 7 years after the last patient started study treatment. - Reduced efficacy and safety assessments, and other minor changes.

    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.
    The Overall Survival analysis is very immature due to the low number of events. In Subject disposition section, the number of subjects for Completed were ongoing with treatment.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33848462
    http://www.ncbi.nlm.nih.gov/pubmed/39984775
    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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