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    Clinical Trial Results:
    A Phase III, randomized, double-blind, controlled, multicenter study of intravenous PI3K inhibitor copanlisib in combination with standard immunochemotherapy versus standard immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL) - CHRONOS-4

    Summary
    EudraCT number
    		 2015-001088-38
    Trial protocol
    		 FI   DE   BE   CZ   DK   ES   GB   FR   PL   IE   AT   PT   HU   SK   GR   BG   IT   RO  
    Global end of trial date
    10 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Sep 2024
    First version publication date
    27 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY 80-6946/17833
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02626455
    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 Sep 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the safety run-in (SRI) was to determine the recommended phase 3 dose (RP3D) of copanlisib in combination with standard immunochemotherapy [rituximab and bendamustine (R-B) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)] to be used in the subsequent Phase 3 part of the study. The primary objective of the Phase 3 part was to evaluate whether copanlisib in combination with standard immunochemotherapy is superior to standard immunochemotherapy in prolonging PFS in patients with relapsed iNHL, who have received at least 1, but at most 3 lines of treatment, including rituximab, and/or rituximab biosimilars, and/or anti-CD20 monoclonal antibody(MAb)-based immunochemotherapy and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option.
    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 subjects (or their legally authorized representative according to local legislation). Participating subjects (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
    		 R-B and R-CHOP
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 7 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 39
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Chile: 22
    Country: Number of subjects enrolled
    China: 130
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Finland: 13
    Country: Number of subjects enrolled
    France: 33
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 41
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 15
    Country: Number of subjects enrolled
    Romania: 29
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    Slovakia: 5
    Country: Number of subjects enrolled
    South Africa: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 30
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Thailand: 7
    Country: Number of subjects enrolled
    Türkiye: 36
    Country: Number of subjects enrolled
    Ukraine: 25
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    United States: 19
    Worldwide total number of subjects
    714
    EEA total number of subjects
    229
    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)
    438
    From 65 to 84 years
    270
    85 years and over
    6

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 SRI part enrolled 42 subjects from 12 countries, between 06-Jan-2016 (first subject first visit [FPFV]) and 31-Oct-2019 (last subject first visit [LPFV]). LPLV is 28-Aug-2023. Phase 3 part enrolled 672 participants from 35 countries/regions, between 06-Feb-2017 (FPFV) and 31-Mar-2020(LPFV), study terminated on 10-Nov-2023,

    Pre-assignment
    Screening details
    		 SRI: 42 subjects were screened, 15 subjects discontinued screening, 27 subjects were assigned to treatment and administered. Phase 3: 672 subjects were screened, 148 discontinued screening. 4 subjects were randomized to treatment but never administered, 520 subjects randomized treatment.

    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, Monitor, Carer, Data analyst, Assessor
    Blinding implementation details
    SRI part is not randomised, not controlled, not blind. Phase 2 part is randomised-controlled, double blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SRI: Copa+R-B 45 mg
    Arm description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 45 mg on Days 1, 8 and 15 of each cycle, one cycle is 28 days, the maximum duration of treatment is 12 months.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m^2 body surface on D1 and D2 of each cycle, from C1 to C6, one cycle is 28 days

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 body surface on Day 1 (D1), from Cycle 1 (C1) to C6, one cycle is 28 days

    Arm title
    		 SRI: Copa+R-B 60 mg (excluding subjects from Japan)
    Arm description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 60 mg on Days 1, 8 and 15 of each 28-day cycle, the maximum duration of treatment is 12 months.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m^2 body surface on D1 and D2 of each cycle, from C1 to C6, one cycle is 28 days

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 body surface on D1, from C1 to C6, one cycle is 28 days

    Arm title
    		 SRI: Copa+R-CHOP 45 mg
    Arm description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-CHOP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 45 mg on Days 1, 8 and 15 of each cycle, from C1 to C6, one cycle is 21 days, from C7 onward, one cycle is 28 days, the maximum duration of treatment is 12 months

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m^2 body surface (maximum dose 2.0 mg) on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg daily orally (PO) from D2 to D6, from C1 to C6, one cycle is 21 days

    Arm title
    		 SRI: Copa+R-CHOP 60 mg
    Arm description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-CHOP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 60 mg on Days 1, 8 and 15 of each cycle, from C1 to C6, one cycle is 21 days, from C7 onward, one cycle is 28 days, the maximum duration of treatment is 12 months

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg daily orally (PO) from D2 to D6, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m^2 body surface (maximum dose 2.0 mg) on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Arm title
    		 SRI: Japan Copa+R-B 60 mg
    Arm description
    		 In SRI part, subjects from Japan received copanlisib at dose level of 60 mg in combination with R-B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 60 mg on Days 1, 8 and 15 of each cycle, one cycle is 28 days, the maximum duration of treatment is 12 months.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m^2 body surface on D1 and D2 of each cycle, from C1 to C6, one cycle is 28 days

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m^2 body surface on D1, from C1 to C6, one cycle is 28 days

    Arm title
    		 Phase 3: Copa+R-B/R-CHOP
    Arm description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to copanlisib + R-B. Subjects who received R-B as a previous line of therapy were randomized to copanlisib + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to copanlisib + R-B.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Copanlisib
    Investigational medicinal product code
    BAY 80-6946
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib 60 mg on Days 1, 8 and 15 of each cycle, the maximum duration of treatment is 12 months. For Copa+R-B, one cycle is 28 days. For Copa+R-CHOP, from C1 to C6, one cycle is 21 days, from C7 onward, one cycle is 28 days.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m^2 body surface on D1 and D2 of each cycle, from C1 to C6, one cycle is 28 days

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg daily orally (PO) from D2 to D6, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m^2 body surface (maximum dose 2.0 mg) on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    For Copa+R-B, 375 mg/m^2 body surface on D1, from C1 to C6, one cycle is 28 days. For Copa+R-CHOP, 375 mg/m2 body surface on D2, one cycle is 21 days.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Arm title
    		 Phase 3: Pbo+R-B/R-CHOP
    Arm description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to placebo + R-B. Subjects who received R-B as a previous line of therapy were randomized to placebo + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to placebo + R-B.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Copanlisib matching placebo on Days 1, 8 and 15 of each cycle, the maximum duration of treatment is 12 months. For Pbo+R-B, one cycle is 28 days. For Pbo+R-CHOP, from C1 to C6, one cycle is 21 days, from C7 onward, one cycle is 28 days.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    For Pbo+R-B, 375 mg/m^2 body surface on D1, from C1 to C6, one cycle is 28 days. For Pbo+R-CHOP, 375 mg/m2 body surface on D2, one cycle is 21 days.

    Investigational medicinal product name
    Bendamustine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m^2 body surface on D1 and D2 of each cycle, from C1 to C6, one cycle is 28 days

    Investigational medicinal product name
    Prednisone/prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg daily orally (PO) from D2 to D6, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m^2 body surface (maximum dose 2.0 mg) on D2, from C1 to C6, one cycle is 21 days

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m^2 body surface on D2, from C1 to C6, one cycle is 21 days

    Number of subjects in period 1 [1]
    		SRI: Copa+R-B 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-CHOP 45 mg SRI: Copa+R-CHOP 60 mg SRI: Japan Copa+R-B 60 mg Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Started
    3
    7
    5
    6
    6
    262
    262
    Completed
    0
    2
    3
    2
    3
    108
    153
    Not completed
    3
    5
    2
    4
    3
    154
    109
         Progressive disease – radiological progression
    -
    -
    -
    -
    -
    11
    22
         Physician decision
    -
    2
    2
    2
    1
    10
    3
         Logistical reason: COVID-19 pandemic related
    -
    -
    -
    -
    -
    1
    1
         Physician decision: COVID-19 pandemic related
    -
    -
    -
    -
    -
    -
    2
         Study intervention never administered
    -
    -
    -
    -
    -
    1
    3
         AE not related to clinical disease progression
    1
    1
    -
    2
    1
    65
    21
         Progressive disease – clinical progression
    -
    -
    -
    -
    -
    1
    2
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    10
    6
         Patient decision
    -
    1
    -
    -
    1
    36
    22
         Other
    1
    1
    -
    -
    -
    17
    23
         AE related to clinical disease progression
    -
    -
    -
    -
    -
    1
    2
         Lost to follow-up
    -
    -
    -
    -
    -
    1
    -
         Patient decision: COVID-19 pandemic related
    -
    -
    -
    -
    -
    -
    1
         Protocol deviation
    -
    -
    -
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: SRI: 42 subjects were screened, 15 subjects discontinued screening, 27 subjects were assigned to treatment and administered. Phase 3: 672 subjects were screened, 148 discontinued screening. 4 subjects were randomized to treatment but never administered, 520 subjects randomized treatment.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    SRI: Copa+R-B 45 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-B.

    Reporting group title
    SRI: Copa+R-B 60 mg (excluding subjects from Japan)
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-B.

    Reporting group title
    SRI: Copa+R-CHOP 45 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-CHOP.

    Reporting group title
    SRI: Copa+R-CHOP 60 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-CHOP.

    Reporting group title
    SRI: Japan Copa+R-B 60 mg
    Reporting group description
    		 In SRI part, subjects from Japan received copanlisib at dose level of 60 mg in combination with R-B.

    Reporting group title
    Phase 3: Copa+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to copanlisib + R-B. Subjects who received R-B as a previous line of therapy were randomized to copanlisib + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to copanlisib + R-B.

    Reporting group title
    Phase 3: Pbo+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to placebo + R-B. Subjects who received R-B as a previous line of therapy were randomized to placebo + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to placebo + R-B.

    Reporting group values
    		 SRI: Copa+R-B 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-CHOP 45 mg SRI: Copa+R-CHOP 60 mg SRI: Japan Copa+R-B 60 mg Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP Total
    Number of subjects
    		 3 7 5 6 6 262 262 551
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 2 4 4 2 6 160 162 340
        From 65-84 years
    		 1 3 1 4 0 99 98 206
        85 years and over
    		 0 0 0 0 0 3 2 5
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.3 ( 12.1 ) 65.1 ( 13.3 ) 61.0 ( 6.4 ) 65.5 ( 13.0 ) 49.5 ( 5.2 ) 59.6 ( 12.8 ) 60.2 ( 11.4 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 3 5 4 1 2 103 128 246
        Male
    		 0 2 1 5 4 159 134 305
    Race
    Units: Subjects
        White
    		 2 5 3 6 0 144 168 328
        Black or African American
    		 0 0 1 0 0 4 1 6
        Asian
    		 1 2 0 0 6 98 82 189
        American Indian or Alaska Native
    		 0 0 0 0 0 0 1 1
        Multiple
    		 0 0 0 0 0 1 0 1
        Not reported
    		 0 0 1 0 0 15 10 26
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 0 24 32 56
        Not Hispanic or Latino
    		 3 7 5 5 6 223 215 464
        Not reported
    		 0 0 0 1 0 15 15 31

    End points

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    End points reporting groups
    Reporting group title
    SRI: Copa+R-B 45 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-B.

    Reporting group title
    SRI: Copa+R-B 60 mg (excluding subjects from Japan)
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-B.

    Reporting group title
    SRI: Copa+R-CHOP 45 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 45 mg in combination with R-CHOP.

    Reporting group title
    SRI: Copa+R-CHOP 60 mg
    Reporting group description
    		 In SRI part, subjects received copanlisib at dose level of 60 mg in combination with R-CHOP.

    Reporting group title
    SRI: Japan Copa+R-B 60 mg
    Reporting group description
    		 In SRI part, subjects from Japan received copanlisib at dose level of 60 mg in combination with R-B.

    Reporting group title
    Phase 3: Copa+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to copanlisib + R-B. Subjects who received R-B as a previous line of therapy were randomized to copanlisib + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to copanlisib + R-B.

    Reporting group title
    Phase 3: Pbo+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to placebo + R-B. Subjects who received R-B as a previous line of therapy were randomized to placebo + R-CHOP or, if progression-free interval after the last R-B treatment was ≥ 24 months, to placebo + R-B.

    Subject analysis set title
    SRI: Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects in the SRI part who received at least 1 dose of study intervention.

    Subject analysis set title
    SRI: Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the SRI part who received at least 1 dose of study intervention

    Subject analysis set title
    Phase 3: Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects in Phase 3.

    Subject analysis set title
    Phase 3: Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized subjects in Phase 3 who received at least 1 dose of study intervention (either copanlisib/placebo, R-B, or R-CHOP).

    Primary: SRI: Occurrence of dose-limiting toxicities (DLT)

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    End point title
    		 SRI: Occurrence of dose-limiting toxicities (DLT) [1] [2]
    End point description
    Dose-limiting toxicity is defined as any of the following occurring during Cycle 1 at a given dose level and regarded by the investigator and/or the sponsor to be possibly, probably, or definitely related to copanlisib given in combination with R-B or R-CHOP. General: any grade 5 hematologic or non-hematologic toxicity or any delay of >2 weeks of Cycle 2 due to study treatment-related toxicity; Non-hematologic DLT: any non-hematologic toxicity grade ≥ 3; Hematologic DLT: grade 4 absolute neutrophil count decrease lasting >7 days, or grade 4 febrile neutropenia, or grade 4 platelet count decreased or grade 3 platelet count decreased with serious bleeding, or signs of serious bleeding and/or international normalized ratio (INR) increased or partial thromboplastin time (PTT) prolonged of grade 3.
    End point type
    Primary
    End point timeframe
    At Cycle 1: 28 days for Copa+R-B or 21 days for Copa+R-CHOP
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    [2] - 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: This endpoint analysis is only for SRI part arms.
    End point values
    		 SRI: Copa+R-B 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-CHOP 45 mg SRI: Copa+R-CHOP 60 mg SRI: Japan Copa+R-B 60 mg
    Number of subjects analysed
    3 [3]
    7 [4]
    5 [5]
    6 [6]
    6 [7]
    Units: Percentage
        number (not applicable)
    0
    0
    0
    0
    16.7
    Notes
    [3] - SAF
    [4] - SAF
    [5] - SAF
    [6] - SAF
    [7] - SAF
    No statistical analyses for this end point

    Primary: Phase 3: Progression-free survival (PFS) by independent central review

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    End point title
    		 Phase 3: Progression-free survival (PFS) by independent central review [8]
    End point description
    PFS is defined as the time from randomization to progressive disease (PD) or death from any cause (if no progression is documented).
    End point type
    Primary
    End point timeframe
    Approximately to 6 years 4 months
    Notes
    [8] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [9]
    262 [10]
    Units: Months
        median (confidence interval 95%)
    32.9 (24.4 to 38.6)
    33.3 (27.8 to 42.8)
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Comparison of PFS
    Statistical analysis description
    PFS was evaluated with the unstratified log-rank test. HR and 95% CI are based on the unstratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.827974 [12]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.881
         upper limit
    		 1.437
    Notes
    [11] - Stratification is by baseline randomization factors
    [12] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors

    Secondary: SRI: Best overall response

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    End point title
    		 SRI: Best overall response [13]
    End point description
    Best overall response is defined as the best response achieved during the treatment and active follow-up periods; prior to end of study or start of new anti-tumor treatment, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Approximately 7 years 8 months.
    Notes
    [13] - 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: This endpoint analysis is only for SRI part arms.
    End point values
    		 SRI: Copa+R-B 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-CHOP 45 mg SRI: Copa+R-CHOP 60 mg SRI: Japan Copa+R-B 60 mg
    Number of subjects analysed
    3 [14]
    7 [15]
    5 [16]
    6 [17]
    6 [18]
    Units: Percentage
    number (confidence interval 95%)
        Best response (BR) -Complete response (CR)
    33.3 (0.8 to 90.6)
    71.4 (29.0 to 96.3)
    60.0 (14.7 to 94.7)
    16.7 (0.4 to 64.1)
    50.0 (11.8 to 88.2)
        BR - Very good partial response (VGPR)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        BR - Partial response (PR)
    66.7 (9.4 to 99.2)
    28.6 (3.7 to 71.0)
    20.0 (0.5 to 71.6)
    83.3 (35.9 to 99.6)
    33.3 (4.3 to 77.7)
        BR - Minor response (MR)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        BR - Stable disease
    0 (0 to 0)
    0 (0 to 0)
    20.0 (0.5 to 71.6)
    0 (0 to 0)
    0 (0 to 0)
        BR - Progressive disease (PD)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        BR - Unconfirmed early stable disease (uSD)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        BR - Not evaluable
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    16.7 (0.4 to 64.1)
        BR - Not available
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        Response rate - Objective response rate (ORR)
    100.0 (29.2 to 100.0)
    100.0 (59.0 to 100.0)
    80.0 (28.4 to 99.5)
    100.0 (54.1 to 100.0)
    83.3 (35.9 to 99.6)
        Response rate - Disease control rate (DCR)
    100.0 (29.2 to 100.0)
    100.0 (59.0 to 100.0)
    100.0 (47.8 to 100.0)
    100.0 (54.1 to 100.0)
    83.3 (35.9 to 99.6)
        Response rate - Complete response rate (CRR)
    33.3 (0.8 to 90.6)
    71.4 (29.0 to 96.3)
    60.0 (14.7 to 94.7)
    16.7 (0.4 to 64.1)
    50.0 (11.8 to 88.2)
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    [17] - FAS
    [18] - FAS
    No statistical analyses for this end point

    Secondary: SRI: Number of subjects with treatment-emergent adverse event (TEAE)

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    End point title
    		 SRI: Number of subjects with treatment-emergent adverse event (TEAE) [19]
    End point description
    A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.
    End point type
    Secondary
    End point timeframe
    Approximately 4 years 10 months
    Notes
    [19] - 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: This endpoint analysis is only for SRI part arms.
    End point values
    		 SRI: Copa+R-B 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-CHOP 45 mg SRI: Copa+R-CHOP 60 mg SRI: Japan Copa+R-B 60 mg
    Number of subjects analysed
    3 [20]
    7 [21]
    5 [22]
    6 [23]
    6 [24]
    Units: Subjects
        Any TEAE
    3
    7
    5
    6
    6
        TESAEs
    2
    3
    3
    6
    3
    Notes
    [20] - SAF
    [21] - SAF
    [22] - SAF
    [23] - SAF
    [24] - SAF
    No statistical analyses for this end point

    Secondary: Phase 3: Objective tumor response rate (ORR) - Independent central review

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    End point title
    		 Phase 3: Objective tumor response rate (ORR) - Independent central review [25]
    End point description
    ORR, as assessed by independent central review, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [25] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [26]
    262 [27]
    Units: Percentage
        number (confidence interval 95%)
    85.5 (80.6 to 89.5)
    86.6 (81.9 to 90.5)
    Notes
    [26] - FAS
    [27] - FAS
    Statistical analysis title
    		 Difference in ORR
    Statistical analysis description
    ORR of Copa+R-B/R-CHOP minus ORR of Pbo+R-B/R-CHOP was evaluated using a one-sided stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.658652 [28]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.25
         upper limit
    		 4.75
    Notes
    [28] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: ORR-Investigator assessment

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    End point title
    		 Phase 3: ORR-Investigator assessment [29]
    End point description
    ORR, as assessed by investigator, is defined as the percentage of participants who had a best response rating of CR or PR according to the Lugano classification and for subjects with LPL/WM, a response rating of CR, VGPR, PR, or MR according to the Owen criteria, over the whole duration of the study (i.e., until time of analysis of PFS).
    End point type
    Secondary
    End point timeframe
    Up to 6 years 4 months
    Notes
    [29] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [30]
    262 [31]
    Units: Percentage
        number (confidence interval 95%)
    85.5 (80.6 to 89.5)
    86.6 (81.9 to 90.5)
    Notes
    [30] - FAS
    [31] - FAS
    Statistical analysis title
    		 Difference in ORR
    Statistical analysis description
    ORR of Copa+R-B/R-CHOP minus ORR of Pbo+R-B/R-CHOP was evaluated using a one-sided stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.605183 [32]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.64
         upper limit
    		 5.05
    Notes
    [32] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors

    Secondary: Phase 3: Duration of tumor response (DOR) -Independent central review

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    End point title
    		 Phase 3: Duration of tumor response (DOR) -Independent central review [33]
    End point description
    DOR, as assessed by independent central review, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [33] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP Phase 3: Full analysis set (FAS)
    Number of subjects analysed
    224 [34]
    227 [35]
    451 [36]
    Units: Months
        median (confidence interval 95%)
    32.2 (22.8 to 38.8)
    32.4 (27.7 to 42.0)
    32.4 (28.1 to 38.4)
    Notes
    [34] - FAS
    [35] - FAS
    [36] - Best overall response (BOR) of CR or PR
    Statistical analysis title
    		 Comparison of DOR
    Statistical analysis description
    DOR was evaluated with the stratified log-rank test. HR and its 95% CI were based on the Cox regression model
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP v Phase 3: Full analysis set (FAS)
    Number of subjects included in analysis
    902
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.846204 [38]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.145
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.883
         upper limit
    		 1.484
    Notes
    [37] - The total number of subjects analyzed was 451. Below "Subjects in this analysis: 902" was erroneously calculated by database due to database constraints.
    [38] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: DOR-Investigator assessment

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    End point title
    		 Phase 3: DOR-Investigator assessment [39]
    End point description
    DOR, as assessed by investigator, is defined as the time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until progression or death from any cause, whichever occurred earlier. The DOR was only defined for patients with at least 1 CR, VGPR, PR, or MR.
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [39] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP Phase 3: Full analysis set (FAS)
    Number of subjects analysed
    227 [40]
    229 [41]
    456 [42]
    Units: Months
        median (confidence interval 95%)
    32.4 (24.3 to 38.8)
    30.9 (24.8 to 42.0)
    32.4 (27.6 to 38.5)
    Notes
    [40] - FAS
    [41] - FAS
    [42] - BOR of CR or PR
    Statistical analysis title
    		 Comparison of DOR
    Statistical analysis description
    DOR was evaluated with a one-side stratified log-rank test. HR and its 95% CI were based on the stratified Cox regression model
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP v Phase 3: Full analysis set (FAS)
    Number of subjects included in analysis
    912
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.801735 [44]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.865
         upper limit
    		 1.443
    Notes
    [43] - The total number of subjects analyzed was 456. Below "Subjects in this analysis: 912" was erroneously calculated by database due to database constraints.
    [44] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: Complete tumor response rate (CRR) -Independent central review

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    End point title
    		 Phase 3: Complete tumor response rate (CRR) -Independent central review [45]
    End point description
    CRR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [45] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [46]
    262 [47]
    Units: Percentage
        number (confidence interval 95%)
    38.5 (32.6 to 44.7)
    41.2 (35.2 to 47.4)
    Notes
    [46] - FAS
    [47] - FAS
    Statistical analysis title
    		 Difference in CRR
    Statistical analysis description
    CRR of Copa+R-B/R-CHOP minus CRR of Pbo+R-B/R-CHOP was evaluated using a one-side stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.741153 [48]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.06
         upper limit
    		 5.57
    Notes
    [48] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: CRR-Investigator assessment

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    End point title
    		 Phase 3: CRR-Investigator assessment [49]
    End point description
    CRR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR according to the Lugano classification, and for patients with LPL/WM, a response rating of CR according to the Owen criteria, over the whole duration of the study (i.e., until the time of analysis of PFS).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [49] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [50]
    262 [51]
    Units: Percentage
        number (confidence interval 95%)
    39.7 (33.7 to 45.9)
    42.0 (35.9 to 48.2)
    Notes
    [50] - FAS
    [51] - FAS
    Statistical analysis title
    		 Difference in CRR
    Statistical analysis description
    CRR of Copa+R-B/R-CHOP minus CRR of Pbo+R-B/R-CHOP was evaluated using a one-side stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.696482 [52]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.62
         upper limit
    		 6.2
    Notes
    [52] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: Disease control rate (DCR) - Independent central review

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    End point title
    		 Phase 3: Disease control rate (DCR) - Independent central review [53]
    End point description
    DCR, as assessed by independent central review, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [53] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [54]
    262 [55]
    Units: Percentage
        number (confidence interval 95%)
    88.5 (84.1 to 92.1)
    92.4 (88.5 to 95.3)
    Notes
    [54] - FAS
    [55] - FAS
    Statistical analysis title
    		 Difference in DCR
    Statistical analysis description
    DCR of Copa+R-B/R-CHOP minus DCR of Pbo+R-B/R-CHOP was evaluated using a one-sided stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.936009 [56]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -3.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.04
         upper limit
    		 1.14
    Notes
    [56] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: DCR-Investigator assessment

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    End point title
    		 Phase 3: DCR-Investigator assessment [57]
    End point description
    DCR, as assessed by investigator, is defined as the proportion of patients who had a best response rating of CR, VGPR, PR, MR, or stable disease (excluding unconfirmed early stable disease).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [57] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [58]
    262 [59]
    Units: Percentage
        number (confidence interval 95%)
    88.5 (84.1 to 92.1)
    92.4 (88.5 to 95.3)
    Notes
    [58] - FAS
    [59] - FAS
    Statistical analysis title
    		 Difference in DCR
    Statistical analysis description
    DCR of Copa+R-B/R-CHOP minus DCR of Pbo+R-B/R-CHOP was evaluated using a one-sided stratified Cochran-Mantel-Haenszel (CMH) test. Point estimate and 95% CI are based on Mantel-Haenszel weighted treatment difference.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.944242 [60]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    -3.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.68
         upper limit
    		 0.9
    Notes
    [60] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: Time to tumor progression (TTP) - Independent central review

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    End point title
    		 Phase 3: Time to tumor progression (TTP) - Independent central review [61]
    End point description
    TTP, as assessed by independent central review, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of “other” as reason (which excludes PD).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [61] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [62]
    262 [63]
    Units: Months
        median (confidence interval 95%)
    36.1 (30.3 to 44.0)
    35.0 (30.4 to 44.8)
    Notes
    [62] - FAS
    [63] - FAS
    Statistical analysis title
    		 Comparison of TTP
    Statistical analysis description
    TTP was evaluated with a one-sided stratified log- rank test. HR and its 95% CI are based on the stratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.517849 [64]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.006
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.777
         upper limit
    		 1.303
    Notes
    [64] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: TTP-Investigator assessment

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    End point title
    		 Phase 3: TTP-Investigator assessment [65]
    End point description
    TTP, as assessed by investigator, is defined as the time from randomization to progression or death related to progression, whichever occurred earlier. Death related to progression was any death except for: death due to an AE unrelated to progression; or death with a specification of “other” as reason (which excludes PD).
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [65] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [66]
    262 [67]
    Units: Months
        median (confidence interval 95%)
    36.1 (30.3 to 44.0)
    35.0 (30.4 to 44.8)
    Notes
    [66] - FAS
    [67] - FAS
    Statistical analysis title
    		 Comparison of TTP
    Statistical analysis description
    TTP was evaluated with a one-sided stratified log- rank test. HR and its 95% CI are based on the stratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.411398 [68]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.971
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.257
    Notes
    [68] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors

    Secondary: Phase 3: Time to next anti-lymphoma treatment (TTNT)

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    End point title
    		 Phase 3: Time to next anti-lymphoma treatment (TTNT) [69]
    End point description
    A new anti-lymphoma therapy is any new systemic anticancer treatment or radiotherapy for lymphoma, with a consolidation intent. TTNT was defined as the time from the date of randomization to the start of new anti-lymphoma therapy, where the date of randomization was considered Day 1. '99999' denotes value could not be estimated due to censored data
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [69] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [70]
    262 [71]
    Units: Months
        median (confidence interval 95%)
    99999 (50.1 to 99999)
    99999 (99999 to 99999)
    Notes
    [70] - FAS
    [71] - FAS
    Statistical analysis title
    		 Comparison of TTNT
    Statistical analysis description
    TTNT was evaluated with a one-sided stratified log-rank test. HR and its 95% CI are based on the stratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.955865 [72]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.289
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.962
         upper limit
    		 1.728
    Notes
    [72] - Significance level IS 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: Overall survival (OS)

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    End point title
    		 Phase 3: Overall survival (OS) [73]
    End point description
    Overall survival is defined as the time from randomization until death from any cause. The OS for patients alive at the time of the database cut-off date was censored to the last date they were known to be alive. Deaths that occurred after the database cut-off date, reported during data cleaning, were considered for establishing the last known alive date at data cut-off. '99999' denotes value could not be estimated due to censored data.
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [73] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [74]
    262 [75]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [74] - FAS
    [75] - FAS
    Statistical analysis title
    		 Comparison of OS
    Statistical analysis description
    OS was evaluated with a one-sided stratified log-rank test. HR and 95% CI are based on the unstratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.758563 [76]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.132
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.603
    Notes
    [76] - Significance level is 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: time to deterioration in disease-related symptoms-physical (DRS-P) of at least 3 points of lymphoma

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    End point title
    		 Phase 3: time to deterioration in disease-related symptoms-physical (DRS-P) of at least 3 points of lymphoma [77]
    End point description
    Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated in all patients. It is defined as the time from randomization to DRS-P decline, progression, or death from any reason, whichever occurred earlier.
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [77] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [78]
    262 [79]
    Units: Months
        median (confidence interval 95%)
    2.7 (1.9 to 3.3)
    6.3 (4.6 to 8.3)
    Notes
    [78] - FAS
    [79] - FAS
    Statistical analysis title
    		 Comparison of time to deterioration in DRS-P
    Statistical analysis description
    Time to deterioration in DRS-P was evaluated with a one-sided stratified log-rank test.HR and its 95% CI are based on the stratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.999695 [80]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.394
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.149
         upper limit
    		 1.691
    Notes
    [80] - Significance level IS 0.025. P-values are descriptive (nominal) due to multiplicity testing. Stratification is by baseline randomization factors.

    Secondary: Phase 3: time to improvement in disease-related symptoms-physical (DRS-P) of at least 3 points of lymphoma

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    End point title
    		 Phase 3: time to improvement in disease-related symptoms-physical (DRS-P) of at least 3 points of lymphoma [81]
    End point description
    Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, was evaluated for all patients. It is defined as the time from randomization to DRS-P improvement of at least 3 points.
    End point type
    Secondary
    End point timeframe
    Approximately 6 years 4 months
    Notes
    [81] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [82]
    262 [83]
    Units: Months
        median (confidence interval 95%)
    12.8 (6.7 to 36.1)
    5.1 (2.8 to 8.3)
    Notes
    [82] - FAS
    [83] - FAS
    Statistical analysis title
    		 Comparison of time to improvement in DRS-P
    Statistical analysis description
    Time to improvement in DRS-P was evaluated with a one-sided stratified log-rank test. HR and its 95% CI are based on the stratified Cox regression model.
    Comparison groups
    Phase 3: Copa+R-B/R-CHOP v Phase 3: Pbo+R-B/R-CHOP
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.965639 [84]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.642
         upper limit
    		 1.02
    Notes
    [84] - Significance level is 0.025. P-value is descriptive (nominal) due to multiplicity testing. Analysis is stratified by baseline randomization factors.

    Secondary: Phase 3: Number of subjects with treatment-emergent adverse event (TEAE)

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    End point title
    		 Phase 3: Number of subjects with treatment-emergent adverse event (TEAE) [85]
    End point description
    A treatment-emergent AE is defined as any event arising or worsening after start of study drug administration until 30 days after the last study drug intake.
    End point type
    Secondary
    End point timeframe
    Approximately 4 years
    Notes
    [85] - 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: This endpoint analysis is only for phase 3 part arms.
    End point values
    		 Phase 3: Copa+R-B/R-CHOP Phase 3: Pbo+R-B/R-CHOP
    Number of subjects analysed
    262 [86]
    257 [87]
    Units: Subjects
        Any TEAE
    263
    250
        TESAEs
    161
    54
        Any copanlisib or placebo related TEAE
    250
    214
        Any copanlisib or placebo related TESAEs
    118
    26
        Any R-B/R-CHOP related TEAE
    245
    224
        Any R-B/R-CHOP related TESAEs
    109
    26
    Notes
    [86] - Actual number is 263. One subject was not valid. Two Pbo+R-B/R-CHOP were analyzed as they took Copa.
    [87] - Three subjects were not valid. Two subjects were analyzed under Copa+R-B/R-CHOP as they took Copa.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first study intervention up to 30 days after the end of study intervention. For SRI, this is over a period of approximately 4 years 10 months and for phase 3, over a period of approximately 4 years.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    SRI: Copa+R-CHOP 45 mg
    Reporting group description
    		 In SRI part, subjects received 45 mg of copanlisib in combination with R-CHOP.

    Reporting group title
    SRI: Copa+R-B 60 mg (excluding subjects from Japan)
    Reporting group description
    		 In SRI part, subjects received 60 mg of copanlisib in combination with R-B.

    Reporting group title
    SRI: Copa+R-B 45 mg
    Reporting group description
    		 In SRI part, subjects received 45 mg of copanlisib in combination with R-B.

    Reporting group title
    Phase 3: Copa+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to copanlisib + R-B. Subjects who received R-B as a previous line of therapy were randomized to copanlisib + R-CHOP or, if progression-free interval after the last R-B treatment was >= 24 months, to copanlisib + R-B.

    Reporting group title
    SRI: Japan Copa+R-B 60 mg
    Reporting group description
    		 In SRI part, Subjects from Japan only received 60 mg of copanlisib in combination with R-B.

    Reporting group title
    Phase 3: Pbo+R-B/R-CHOP
    Reporting group description
    		 In Phase 3 part, subjects who never received R-B as a previous line of therapy were randomized to placebo + R-B. Subjects who received R-B as a previous line of therapy were randomized to placebo + R-CHOP or, if progression-free interval after the last R-B treatment was >= 24 months, to placebo + R-B.

    Reporting group title
    SRI: Copa+R-CHOP 60 mg
    Reporting group description
    		 In SRI part, subjects received 60 mg of copanlisib in combination with R-CHOP.

    Serious adverse events
    		 SRI: Copa+R-CHOP 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-B 45 mg Phase 3: Copa+R-B/R-CHOP SRI: Japan Copa+R-B 60 mg Phase 3: Pbo+R-B/R-CHOP SRI: Copa+R-CHOP 60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 7 (42.86%)
    2 / 3 (66.67%)
    161 / 263 (61.22%)
    3 / 6 (50.00%)
    54 / 257 (21.01%)
    6 / 6 (100.00%)
         number of deaths (all causes)
    0
    0
    1
    68
    0
    62
    1
         number of deaths resulting from adverse events
    0
    0
    0
    8
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kaposi's sarcoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 7 (28.57%)
    0 / 3 (0.00%)
    22 / 263 (8.37%)
    1 / 6 (16.67%)
    4 / 257 (1.56%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    13 / 26
    1 / 1
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion related hypersensitivity reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    7 / 263 (2.66%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 4
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    7 / 263 (2.66%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 8
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Norovirus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    18 / 263 (6.84%)
    0 / 6 (0.00%)
    8 / 257 (3.11%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    14 / 18
    0 / 0
    6 / 8
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    Eosinophilia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelosuppression
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    5 / 257 (1.95%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    5 / 5
    0 / 0
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Uveitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 6
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin toxicity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    12 / 263 (4.56%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    15 / 16
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated cryptococcosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis cryptococcal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    34 / 263 (12.93%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    28 / 38
    0 / 0
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    1 / 6 (16.67%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    4 / 5
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 5
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ludwig angina
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection fungal
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    10 / 263 (3.80%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    11 / 11
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    5 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SRI: Copa+R-CHOP 45 mg SRI: Copa+R-B 60 mg (excluding subjects from Japan) SRI: Copa+R-B 45 mg Phase 3: Copa+R-B/R-CHOP SRI: Japan Copa+R-B 60 mg Phase 3: Pbo+R-B/R-CHOP SRI: Copa+R-CHOP 60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    7 / 7 (100.00%)
    3 / 3 (100.00%)
    259 / 263 (98.48%)
    6 / 6 (100.00%)
    250 / 257 (97.28%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Secondary hypertension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Phlebitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    11 / 263 (4.18%)
    0 / 6 (0.00%)
    6 / 257 (2.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    12
    0
    6
    0
    Hypotension
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    18
    0
    9
    1
    Hypertension
         subjects affected / exposed
    4 / 5 (80.00%)
    2 / 7 (28.57%)
    1 / 3 (33.33%)
    114 / 263 (43.35%)
    3 / 6 (50.00%)
    42 / 257 (16.34%)
    3 / 6 (50.00%)
         occurrences all number
    6
    10
    1
    328
    3
    90
    3
    Vasculitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    3 / 6 (50.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    2
    0
    Surgical and medical procedures
    Ureteral stent insertion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    18 / 263 (6.84%)
    0 / 6 (0.00%)
    6 / 257 (2.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    24
    0
    9
    0
    Asthenia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 7 (28.57%)
    0 / 3 (0.00%)
    18 / 263 (6.84%)
    0 / 6 (0.00%)
    21 / 257 (8.17%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    20
    0
    28
    0
    Face oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0
    1
    0
    Injection site reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    2 / 3 (66.67%)
    51 / 263 (19.39%)
    3 / 6 (50.00%)
    49 / 257 (19.07%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    3
    65
    4
    63
    2
    Malaise
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    26 / 263 (9.89%)
    0 / 6 (0.00%)
    15 / 257 (5.84%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    47
    0
    26
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    9 / 263 (3.42%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences all number
    0
    6
    1
    14
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    2 / 5 (40.00%)
    4 / 7 (57.14%)
    1 / 3 (33.33%)
    87 / 263 (33.08%)
    2 / 6 (33.33%)
    34 / 257 (13.23%)
    2 / 6 (33.33%)
         occurrences all number
    2
    6
    1
    130
    4
    51
    2
    Oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    1 / 6 (16.67%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    3
    0
    Swelling face
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    3
    0
    Reproductive system and breast disorders
    Vulvovaginal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    41 / 263 (15.59%)
    0 / 6 (0.00%)
    37 / 257 (14.40%)
    3 / 6 (50.00%)
         occurrences all number
    2
    1
    0
    59
    0
    47
    3
    Nasal congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    5
    0
    3
    1
    Hypoxia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    6
    0
    0
    1
    Hiccups
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    1 / 6 (16.67%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    14 / 263 (5.32%)
    0 / 6 (0.00%)
    11 / 257 (4.28%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    15
    0
    12
    2
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    11 / 263 (4.18%)
    0 / 6 (0.00%)
    10 / 257 (3.89%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    12
    0
    10
    0
    Productive cough
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    9 / 263 (3.42%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    10
    0
    10
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    23 / 263 (8.75%)
    1 / 6 (16.67%)
    13 / 257 (5.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    29
    1
    13
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
    1 / 3 (33.33%)
    34 / 263 (12.93%)
    3 / 6 (50.00%)
    18 / 257 (7.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    2
    51
    4
    27
    0
    Amylase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    13 / 263 (4.94%)
    1 / 6 (16.67%)
    10 / 257 (3.89%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    15
    1
    17
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
    1 / 3 (33.33%)
    38 / 263 (14.45%)
    3 / 6 (50.00%)
    22 / 257 (8.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    1
    62
    3
    38
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    19 / 263 (7.22%)
    1 / 6 (16.67%)
    13 / 257 (5.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    33
    1
    27
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    12 / 263 (4.56%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    23
    0
    8
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    9 / 263 (3.42%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    11
    0
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    9 / 263 (3.42%)
    1 / 6 (16.67%)
    14 / 257 (5.45%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    11
    2
    17
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    27 / 263 (10.27%)
    0 / 6 (0.00%)
    11 / 257 (4.28%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    53
    0
    14
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    13
    0
    3
    2
    CD4 lymphocytes decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    16 / 263 (6.08%)
    1 / 6 (16.67%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    16
    1
    2
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    1 / 6 (16.67%)
    6 / 257 (2.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    6
    1
    7
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    15 / 263 (5.70%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    16
    0
    9
    0
    Lipase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    18 / 263 (6.84%)
    1 / 6 (16.67%)
    13 / 257 (5.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    21
    1
    18
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    72 / 263 (27.38%)
    4 / 6 (66.67%)
    50 / 257 (19.46%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    232
    6
    145
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
    1 / 3 (33.33%)
    109 / 263 (41.44%)
    3 / 6 (50.00%)
    82 / 257 (31.91%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    1
    489
    5
    301
    6
    Platelet count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    72 / 263 (27.38%)
    1 / 6 (16.67%)
    52 / 257 (20.23%)
    3 / 6 (50.00%)
         occurrences all number
    5
    1
    0
    209
    1
    126
    3
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    64 / 263 (24.33%)
    1 / 6 (16.67%)
    21 / 257 (8.17%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    74
    1
    29
    2
    White blood cell count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    0 / 3 (0.00%)
    78 / 263 (29.66%)
    3 / 6 (50.00%)
    65 / 257 (25.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    386
    6
    272
    1
    Ejection fraction decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    3
    0
    Cytomegalovirus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    20 / 263 (7.60%)
    3 / 6 (50.00%)
    13 / 257 (5.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    28
    3
    22
    0
    Troponin I increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    20 / 263 (7.60%)
    1 / 6 (16.67%)
    7 / 257 (2.72%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    28
    2
    11
    0
    Norovirus test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pseudomonas test positive
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Inflammatory marker increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Patella fracture
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    0
    3
    1
    Infusion related reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    9 / 263 (3.42%)
    2 / 6 (33.33%)
    15 / 257 (5.84%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    13
    3
    17
    0
    Wound
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    Tooth fracture
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    5
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    18 / 263 (6.84%)
    0 / 6 (0.00%)
    12 / 257 (4.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    22
    0
    17
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    35 / 263 (13.31%)
    2 / 6 (33.33%)
    29 / 257 (11.28%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    2
    44
    2
    42
    3
    Dysgeusia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    9 / 263 (3.42%)
    2 / 6 (33.33%)
    10 / 257 (3.89%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    21
    2
    11
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    6
    0
    5
    0
    Sciatica
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    4
    0
    Presyncope
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    3 / 6 (50.00%)
         occurrences all number
    0
    0
    0
    2
    0
    3
    4
    Paraesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    5
    0
    2
    0
    Taste disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    4
    0
    1
    1
    Vagus nerve disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 7 (42.86%)
    2 / 3 (66.67%)
    85 / 263 (32.32%)
    0 / 6 (0.00%)
    64 / 257 (24.90%)
    3 / 6 (50.00%)
         occurrences all number
    3
    10
    2
    166
    0
    147
    5
    Febrile neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    1 / 6 (16.67%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    11
    1
    2
    0
    Leukopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    13 / 263 (4.94%)
    0 / 6 (0.00%)
    21 / 257 (8.17%)
    0 / 6 (0.00%)
         occurrences all number
    1
    8
    2
    18
    0
    39
    0
    Eosinophilia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    9
    0
    5
    0
    Lymphopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    15 / 263 (5.70%)
    0 / 6 (0.00%)
    22 / 257 (8.56%)
    1 / 6 (16.67%)
         occurrences all number
    1
    2
    1
    29
    0
    42
    1
    Neutropenia
         subjects affected / exposed
    4 / 5 (80.00%)
    5 / 7 (71.43%)
    2 / 3 (66.67%)
    86 / 263 (32.70%)
    1 / 6 (16.67%)
    88 / 257 (34.24%)
    1 / 6 (16.67%)
         occurrences all number
    20
    24
    5
    213
    1
    232
    1
    Thrombocytopenia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 7 (42.86%)
    2 / 3 (66.67%)
    44 / 263 (16.73%)
    0 / 6 (0.00%)
    28 / 257 (10.89%)
    1 / 6 (16.67%)
         occurrences all number
    8
    7
    3
    68
    0
    57
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Uveitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    12 / 263 (4.56%)
    1 / 6 (16.67%)
    13 / 257 (5.06%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    0
    13
    1
    14
    2
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    14 / 263 (5.32%)
    0 / 6 (0.00%)
    14 / 257 (5.45%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    17
    0
    17
    0
    Constipation
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 7 (28.57%)
    1 / 3 (33.33%)
    36 / 263 (13.69%)
    0 / 6 (0.00%)
    49 / 257 (19.07%)
    1 / 6 (16.67%)
         occurrences all number
    5
    4
    1
    43
    0
    57
    1
    Diarrhoea
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 7 (42.86%)
    1 / 3 (33.33%)
    88 / 263 (33.46%)
    2 / 6 (33.33%)
    38 / 257 (14.79%)
    4 / 6 (66.67%)
         occurrences all number
    5
    5
    4
    137
    4
    45
    4
    Dry mouth
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    5 / 257 (1.95%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    11
    0
    5
    0
    Dysphagia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    4
    0
    Dyspepsia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    8 / 257 (3.11%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    10
    0
    13
    0
    Enterocolitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    8
    0
    7
    1
    Gastrointestinal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    Gingival pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    6
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    Periodontal disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 5 (60.00%)
    5 / 7 (71.43%)
    3 / 3 (100.00%)
    112 / 263 (42.59%)
    4 / 6 (66.67%)
    92 / 257 (35.80%)
    1 / 6 (16.67%)
         occurrences all number
    3
    8
    6
    208
    4
    156
    1
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 7 (57.14%)
    2 / 3 (66.67%)
    25 / 263 (9.51%)
    1 / 6 (16.67%)
    10 / 257 (3.89%)
    2 / 6 (33.33%)
         occurrences all number
    0
    5
    2
    31
    4
    10
    2
    Mouth ulceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    16 / 263 (6.08%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    21
    0
    5
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    0 / 3 (0.00%)
    59 / 263 (22.43%)
    2 / 6 (33.33%)
    31 / 257 (12.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    123
    3
    44
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    0
    3
    1
    Drug eruption
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Erythema multiforme
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    1 / 6 (16.67%)
    6 / 257 (2.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    7
    1
    6
    0
    Eczema asteatotic
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    0
    Eczema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    1 / 6 (16.67%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    14
    1
    3
    0
    Nail dystrophy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    2 / 3 (66.67%)
    30 / 263 (11.41%)
    0 / 6 (0.00%)
    24 / 257 (9.34%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    2
    39
    0
    29
    1
    Purpura
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    1 / 6 (16.67%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 7 (57.14%)
    1 / 3 (33.33%)
    59 / 263 (22.43%)
    1 / 6 (16.67%)
    26 / 257 (10.12%)
    1 / 6 (16.67%)
         occurrences all number
    0
    8
    1
    75
    1
    33
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    25 / 263 (9.51%)
    3 / 6 (50.00%)
    14 / 257 (5.45%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    38
    3
    16
    0
    Toxic skin eruption
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    5
    0
    3
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    2 / 263 (0.76%)
    0 / 6 (0.00%)
    5 / 257 (1.95%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    5
    1
    Nephrolithiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    4
    0
    1
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    7 / 263 (2.66%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    8
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    6 / 263 (2.28%)
    1 / 6 (16.67%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    6
    1
    3
    0
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    11 / 263 (4.18%)
    1 / 6 (16.67%)
    23 / 257 (8.95%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    12
    1
    31
    1
    Arthralgia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    15 / 257 (5.84%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    11
    0
    20
    1
    Limb mass
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    8
    0
    7
    1
    Myositis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    14 / 263 (5.32%)
    0 / 6 (0.00%)
    7 / 257 (2.72%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    16
    0
    10
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    47 / 263 (17.87%)
    1 / 6 (16.67%)
    14 / 257 (5.45%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    70
    2
    14
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    1 / 6 (16.67%)
    5 / 257 (1.95%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    4
    1
    5
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    3 / 263 (1.14%)
    0 / 6 (0.00%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    3
    0
    2
    0
    Genital herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    9 / 263 (3.42%)
    1 / 6 (16.67%)
    1 / 257 (0.39%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    9
    2
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    14 / 263 (5.32%)
    0 / 6 (0.00%)
    11 / 257 (4.28%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    16
    0
    15
    2
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    1 / 6 (16.67%)
    5 / 257 (1.95%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    10
    1
    7
    0
    Herpes zoster
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    13 / 263 (4.94%)
    0 / 6 (0.00%)
    15 / 257 (5.84%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    14
    0
    16
    0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    31 / 263 (11.79%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    34
    0
    4
    0
    Pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    10 / 263 (3.80%)
    1 / 6 (16.67%)
    7 / 257 (2.72%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    12
    2
    7
    0
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    1 / 6 (16.67%)
    9 / 257 (3.50%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    5
    1
    10
    2
    Tinea pedis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    44 / 263 (16.73%)
    3 / 6 (50.00%)
    37 / 257 (14.40%)
    2 / 6 (33.33%)
         occurrences all number
    1
    1
    0
    63
    4
    51
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    19 / 263 (7.22%)
    0 / 6 (0.00%)
    17 / 257 (6.61%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    0
    32
    0
    22
    1
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    14 / 263 (5.32%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    29
    0
    6
    0
    Borrelia infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    8 / 263 (3.04%)
    0 / 6 (0.00%)
    4 / 257 (1.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    10
    0
    7
    2
    Device related sepsis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    1 / 3 (33.33%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Erythema migrans
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Candida infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Herpes simplex reactivation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    0 / 263 (0.00%)
    0 / 6 (0.00%)
    0 / 257 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    5 / 5 (100.00%)
    6 / 7 (85.71%)
    1 / 3 (33.33%)
    150 / 263 (57.03%)
    4 / 6 (66.67%)
    53 / 257 (20.62%)
    3 / 6 (50.00%)
         occurrences all number
    8
    15
    2
    318
    4
    145
    3
    Diabetes mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    5 / 263 (1.90%)
    0 / 6 (0.00%)
    1 / 257 (0.39%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    5
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 7 (14.29%)
    1 / 3 (33.33%)
    11 / 263 (4.18%)
    0 / 6 (0.00%)
    3 / 257 (1.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    16
    0
    3
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    13 / 263 (4.94%)
    1 / 6 (16.67%)
    2 / 257 (0.78%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    16
    1
    3
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    4 / 263 (1.52%)
    1 / 6 (16.67%)
    21 / 257 (8.17%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    6
    1
    34
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    26 / 263 (9.89%)
    1 / 6 (16.67%)
    17 / 257 (6.61%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    40
    1
    24
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 7 (0.00%)
    0 / 3 (0.00%)
    1 / 263 (0.38%)
    1 / 6 (16.67%)
    5 / 257 (1.95%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    5
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 7 (14.29%)
    0 / 3 (0.00%)
    44 / 263 (16.73%)
    0 / 6 (0.00%)
    9 / 257 (3.50%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    62
    0
    13
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 7 (28.57%)
    1 / 3 (33.33%)
    24 / 263 (9.13%)
    0 / 6 (0.00%)
    8 / 257 (3.11%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    1
    29
    0
    10
    0
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 7 (42.86%)
    0 / 3 (0.00%)
    43 / 263 (16.35%)
    1 / 6 (16.67%)
    32 / 257 (12.45%)
    0 / 6 (0.00%)
         occurrences all number
    0
    7
    0
    54
    2
    40
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2015
    Clarification of exclusion criteria for patients who had received bendamustine-based therapy. Clarification of timing of blood count collection for dosing criteria. Addition of an additional plasma collection for non-genetic biomarker analysis for patients in the R-CHOP treatment arm.
    18 Jul 2016
    The allowed prior immunochemotherapy regimens and treatment assignment were clarified. Text describing the rules for randomization based on prior immunochemotherapy and exclusion criterion 29 regarding the prior treatment with bendamustine was modified in accordance with the standard treatment for iNHL. Updated inclusion criteria to remove requirement for the absolute lymphocyte count at diagnosis, clarified screening requirements for WM patients who do not have a radiologically measurable lesion, updated text referring to platelet count in patients with confirmed lymphomatous bone marrow infiltration, and updated criterion for the use of effective contraception. Modified exclusion criterion related to arterial hypertension to eliminate the conservative requirement for blood pressure levels during eligibility evaluation. Exclusion of patients based on plasma glucose levels was removed to eliminate the eligibility evaluation requirement for plasma glucose testing and to ensure enrollment of patients with diabetes mellitus in a compensation state confirmed by HbA1c testing at Screening. Clarification added that the HbA1c >8.5% level concerns all patients, not only patients with diabetes mellitus. Allowed for inclusion of patients with a chronic HCV or HBV infection; prophylaxis for HBV and monitoring of HBV and HCV were added as patients with HBV and HCV are at risk of recurrence while receiving rituximab. Exclusion criterion related to proteinuria was modified to allow proteinuria assessment using a method other than UPCR. Clarification was added for how the tests should be performed and reported. Clarification added for corticosteroid therapy use prior to and during the study. Added prior treatment with copanlisib to the list of prohibited previous therapies and medications. An updated guidance for the management of transient glucose increases was provided to ensure patient safety. Table continued.
    30 Mar 2017
    Study eligibility criteria and treatment allocation language were modified to include patients who have received prior treatment with rituximab-based immunochemotherapy and alkylating agents. Study design was modified to allow patients who have received R-B as a previous line of therapy to be randomized to study intervention plus R-B arm when there is ≥24 months progression-free interval after the last R-B treatment; exclusion criteria modified to reflect this change. Total sample size was reduced from 676 patients to 520 patients, with primary efficacy analysis to be performed in the FAS instead of both FAS and FL subgroups. Clarification was added that patients recruited into the SRI part were not to be evaluated as part of the Phase 3 part of the study. RP3D for copanlisib in combination with R-B was determined in accordance with the DMC, and clarification was added to allow starting the Phase 3 part of the study. A new exclusion criterion was added to exclude patients who had received live vaccination within 6 months before the start of study treatment. Language was modified to allow patients beyond progression to continue treatment with copanlisib if, in the investigator’s opinion, treatment is providing clinical benefit. Clarifications were made to the bone marrow assessments relating to confirmation of WM diagnosis and biomarker analysis in patients with WM, local assessment of bone marrow biopsies prior to central pathology review, and modified text for platelet count values in patients with lymphomatous bone marrow infiltration to consider values at study entry. Clarifications were made for the radiological tumor assessments regarding timing and calculation of time points for tumor assessments, the use of PET-CT imaging and modification of withdrawal criteria to clarify the assessment of disease progression leading to the discontinuation of study treatment. Guidance regarding drug–drug interactions was updated based on new data.
    14 Aug 2017
    Language was modified to not allow patients to continue treatment in CHRONOS-4 beyond disease progression
    25 Sep 2018
    Updated guidance for the management of glucose increases regarding dose reduction guidance and withdrawal criterion, fasting requirements, glucose monitoring, the timing of post-infusion glucose measurements, and the schedule for HbA1c measurements. Guidance related to blood pressure measurements on infusion days was clarified to be aligned with copanlisib and rituximab labeling information. Updated guidance for dermatologic to align with copanlisib labeling information, and hematological toxicity was modified to clarify the use of G-CSF. Inclusion criteria were modified for the use of prior line of rituximab-based immunochemotherapy and alkylating agents and for assessment requirements for nodal and extranodal involvement in patients with splenic MZL. Exclusion criteria were modified to remove study participation restrictions, including the exclusion of patients with a history of current autoimmune disease, and to clarify the definition of rituximab resistance. Clarification of the administration of study treatment regarding permanent discontinuation and drug administration delay of any of the study treatment and prohibition of the use of rituximab biosimilars during the study. Eligibility criteria modifications for laboratory assessments included criterion for total bilirubin, testing criterion for CMV and HBV/HCV, and criterion to perform blood cultures. Clarification of tumor assessments regarding bone marrow biopsy requirements, PET functional imaging preference, and timing and requirements for CT/MRI scans. Clarification was added that patients would be stratified by the duration of progression-free interval from the last rituximab-containing regimen (previously duration of treatment-free interval). Change to prohibited concomitant therapy prohibiting use of biotin at least 72 hours prior to immunoassay test collection.
    14 Aug 2019
    The eligibility criterion was modified to allow prior anticancer therapies with rituximab biosimilars, and/or anti-CD20 MAb. Change from use of electronic PRO to paper PRO and updated version. Other changes included corrections of the descriptive text for excluding blood count test at Cycle(x), Day 8 and removal of BP measurement at Day 2 (Cycles 1–6).
    21 Mar 2023
    Changed the number of PFS events for primary completion from approximately 256 events to approximately 280 events, and detailed that confirmatory statistical testing strategies will be provided in SAP. Changed the end of the active follow-up period to extend up to 2 years after study primary completion. Changed the time for collecting survival follow-up data from 5 to 10 years after the last patient started study treatment. Added disease control rate as a secondary objective and defined the respective analyses. Revised information for FLymSI questionnaire to change the version of the form being used from version 4 to version 2 and the timing of the form to be completed for up to at least 1 year after study primary completion or until sponsor’s decision to terminate form completion. Provided guidance to specify the tumor assessments beyond Year 5 study period. Removed text that required submission of a tumor sample from a biopsy or excision occurring during the study based on medical need. Added text to clarify that central pathology would be analyzed only as an exploratory analysis. Changed the post-baseline bone marrow biopsy assessment central review to local assessment to confirm the first CR. Added text regarding disclosure of study results. Added text for participant visits, assessments, and monitoring in the event of study continuity issues. Aligned text throughout to state that disease progression is assessed by blinded independent central review.

    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.
    NA

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34389273
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