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    Clinical Trial Results:
    Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed or Refractory Multiple Myeloma

    Summary
    EudraCT number
    2013-005525-23
    Trial protocol
    SE   GB   ES   DE   BE   NL   DK   PL   GR  
    Global end of trial date
    30 Sep 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Nov 2023
    First version publication date
    18 Nov 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    54767414MMY3003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02076009
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    1400 McKean Road, PO Box 776 Spring House, United States, 19477
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    30 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to compare the efficacy of daratumumab when combined with lenalidomide and dexamethasone (DRd) to that of lenalidomide and dexamethasone (Rd), in terms of progression-free survival (PFS) in subjects with relapsed or refractory multiple myeloma.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    Spain: 51
    Country: Number of subjects enrolled
    France: 58
    Country: Number of subjects enrolled
    United Kingdom: 51
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Israel: 39
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Sweden: 31
    Country: Number of subjects enrolled
    Taiwan: 20
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    569
    EEA total number of subjects
    247
    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)
    273
    From 65 to 84 years
    292
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 569 subjects were randomised, of which 564 were treated (283 in the daratumumab, lenalidomide, low-dose dexamethasone [DRd] group and 281 in the lenalidomide, low-dose dexamethasone [Rd] group). None of the subjects completed the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lenalidomide, Low-dose Dexamethasone (Rd)
    Arm description
    Subjects received lenalidomide at a dose of 25 milligrams (mg) orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone at a total dose of 40 mg weekly (or 20 mg weekly for subjects greater than [>] 75 years old or with a body mass index less than [<] 18.5 kilograms per meter square [kg/m^2]).
    Arm type
    Active comparator

    Investigational medicinal product name
    Low-dose Dexamethasone (Rd)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low-dose dexamethasone 40 mg weekly (or 20 mg weekly for subjects greater than [>] 75 years old or with a body mass index less than [<] 18.5 kilograms per meter square [kg/m^2]).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenalidomide 25 milligrams (mg) from Day 1 through Day 21 of each 28-day treatment cycle.

    Arm title
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Arm description
    Subjects received daratumumab 16 milligrams per kilogram (mg/kg) as an intravenous (IV) infusion once a week during treatment cycles 1 and 2 (for 8 weeks, each 28-day cycle); every 2 weeks during treatment cycles 3 to 6 (for 16 weeks, each 28-day cycle); once only on Day 1 during treatment cycles 7 onwards (for every 4 weeks). Lenalidomide was administered at a dose of 25 mg orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone was administered at a total dose of 40 mg weekly (or 20 mg weekly for subjects >75 years old or with a body mass index < 18.5 kg/m^2).
    Arm type
    Experimental

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenalidomide 25 mg from Day 1 through Day 21 of each 28-day treatment cycle.

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Subjects received daratumumab 16 mg/kg once a week during treatment cycles 1 and 2 (for 8 weeks, each 28-day cycle); every 2 weeks during treatment cycles 3 to 6 (for 16 weeks, each 28-day cycle); once only on Day 1 during treatment cycles 7 onwards (for every 4 weeks).

    Investigational medicinal product name
    Low-dose Dexamethasone (Rd)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low-dose dexamethasone 40 mg weekly (or 20 mg weekly for subjects >75 years old or with a body mass index <18.5 kg/m^2).

    Number of subjects in period 1
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Started
    283
    286
    Treated (Safety population)
    281
    283
    Completed
    0
    0
    Not completed
    283
    286
         Adverse event, serious fatal
    172
    153
         Consent withdrawn by subject
    16
    12
         Physician decision
    -
    1
         End of data collection
    90
    118
         Lost to follow-up
    4
    2
         Progressive disease
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide, Low-dose Dexamethasone (Rd)
    Reporting group description
    Subjects received lenalidomide at a dose of 25 milligrams (mg) orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone at a total dose of 40 mg weekly (or 20 mg weekly for subjects greater than [>] 75 years old or with a body mass index less than [<] 18.5 kilograms per meter square [kg/m^2]).

    Reporting group title
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Reporting group description
    Subjects received daratumumab 16 milligrams per kilogram (mg/kg) as an intravenous (IV) infusion once a week during treatment cycles 1 and 2 (for 8 weeks, each 28-day cycle); every 2 weeks during treatment cycles 3 to 6 (for 16 weeks, each 28-day cycle); once only on Day 1 during treatment cycles 7 onwards (for every 4 weeks). Lenalidomide was administered at a dose of 25 mg orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone was administered at a total dose of 40 mg weekly (or 20 mg weekly for subjects >75 years old or with a body mass index < 18.5 kg/m^2).

    Reporting group values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd) Total
    Number of subjects
    283 286 569
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    140 133 273
        From 65 to 84 years
    140 152 292
        85 years and over
    3 1 4
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    64.3 ± 8.84 64.4 ± 9.03 -
    Title for Gender
    Units: subjects
        Female
    119 113 232
        Male
    164 173 337

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide, Low-dose Dexamethasone (Rd)
    Reporting group description
    Subjects received lenalidomide at a dose of 25 milligrams (mg) orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone at a total dose of 40 mg weekly (or 20 mg weekly for subjects greater than [>] 75 years old or with a body mass index less than [<] 18.5 kilograms per meter square [kg/m^2]).

    Reporting group title
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Reporting group description
    Subjects received daratumumab 16 milligrams per kilogram (mg/kg) as an intravenous (IV) infusion once a week during treatment cycles 1 and 2 (for 8 weeks, each 28-day cycle); every 2 weeks during treatment cycles 3 to 6 (for 16 weeks, each 28-day cycle); once only on Day 1 during treatment cycles 7 onwards (for every 4 weeks). Lenalidomide was administered at a dose of 25 mg orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone was administered at a total dose of 40 mg weekly (or 20 mg weekly for subjects >75 years old or with a body mass index < 18.5 kg/m^2).

    Primary: Progression-free Survival (PFS)

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    End point title
    Progression-free Survival (PFS) [1]
    End point description
    PFS: time from randomisation to progressive disease(PD)/death. PD, any 1 criteria: >=25% increase in serum M-protein level from lowest response value, absolute increase >=0.5 gram per deciliter(g/dL); >=25% increase in 24hours(h) in urinary light chain excretion (urine M-protein) from lowest response value, absolute increase >=200mg/24h; in subjects without measurable serum and urine M-protein levels: >=25% increase in difference between involved and uninvolved free light chain levels from lowest response value and absolute increase >10 mg/dL; increase in existing bone lesions/soft tissue plasmacytomas size; development of new bone lesions/soft tissue plasmacytomas; development of hypercalcemia(corrected serum calcium >11.5mg/dL) attributed to plasma cell proliferative disorder. Intent-to-treat: subjects randomly assigned to DRd or Rd group. 99999: median, upper and lower limit of 95% CI in DRd arm and upper limit of 95% CI in Rd arm not estimable due to short follow-up by subjects.
    End point type
    Primary
    End point timeframe
    From randomisation to either disease progression or death whichever occurs first (up to 21 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    283
    286
    Units: Months
        median (confidence interval 95%)
    18.43 (13.86 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Disease Progression (TTP)

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    End point title
    Time to Disease Progression (TTP)
    End point description
    TTP: time from date of randomization to date of first documented PD. PD, any 1 criteria:>=25% increase in serum M-protein level from lowest response value, absolute increase >=0.5 g/dL; >=25% increase in 24h in urinary light chain excretion (urine M-protein) from lowest response value, absolute increase >=200mg/24h; in subjects without measurable serum and urine M-protein levels: >=25% increase in difference between involved and uninvolved free light chain (FLC) levels from lowest response value and absolute increase >10 mg/dL; increase in existing bone lesions/soft tissue plasmacytomas size; development of new bone lesions/soft tissue plasmacytomas; development of hypercalcemia(corrected serum calcium >11.5mg/dL) attributed to plasma cell (PC) proliferative disorder. Intent-to-treat: subjects randomly assigned to DRd or Rd group. 99999: median, upper and lower limit of 95% CI in DRd arm and upper limit of 95% CI in Rd arm not estimable due to short follow-up by subjects.
    End point type
    Secondary
    End point timeframe
    From randomisation to disease progression (up to 21 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    283
    286
    Units: Months
        median (confidence interval 95%)
    18.43 (14.78 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Achieved Very Good Partial Response (VGPR) or Better as per International Myeloma Working Group criteria (IMWG)

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    End point title
    Percentage of Subjects who Achieved Very Good Partial Response (VGPR) or Better as per International Myeloma Working Group criteria (IMWG)
    End point description
    VGPR or better: Percentage of subjects who achieved VGPR, complete response(CR) and stringent complete response(sCR) as per IMWG. IMWG criteria: Serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100mg/24h, if serum and urine M-protein are not measurable, decrease of >90% in difference between involved and uninvolved FLC levels is required in place of M-protein criteria. Additionally, >=50% reduction in size of soft tissue plasmacytomas is required at baseline; CR: Negative immunofixation on serum and urine, disappearance of soft tissue plasmacytomas, <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2-4 color flow cytometry. Response-evaluable set: subjects who have confirmed diagnosis of multiple myeloma, measurable disease and must received at least 1 dose of study drug and at least 1 post baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From randomisation to disease progression (up to 21 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    276
    281
    Units: Percentage of subjects
        number (confidence interval 95%)
    44.2 (38.3 to 50.3)
    75.8 (70.4 to 80.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Negative Minimal Residual Disease (MRD)

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    End point title
    Percentage of Subjects With Negative Minimal Residual Disease (MRD)
    End point description
    Minimal residual disease was assessed for all subjects who achieved a complete response (CR) or stringent complete response (sCR). CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and <5% PCs in bone marrow; sCR: CR and normal FLC ratio, absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4 color flow cytometry. The MRD negativity rate was defined as the percentage of subjects who had negative MRD assessment at any time point after the first dose of study drugs by evaluation of bone marrow aspirates or whole blood at 10^ minus (-) 4, 10^-5, 10^-6 threshold. ITT analysis set included all subjects who were randomly assigned to the DRd or Rd group.
    End point type
    Secondary
    End point timeframe
    From randomisation to date of first documented evidence of PD (up to 87.5 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    283
    286
    Units: Percentage of subjects
    number (not applicable)
        MRD negative rate (10^-4)
    10.2
    40.6
        MRD negative rate (10^-5)
    6.7
    33.2
        MRD negative rate (10^-6)
    1.8
    13.3
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    Overall Response Rate
    End point description
    Overall response rate was defined as the percentage of Subjects who achieved a partial response (PR) or better according to the International Myeloma Working Group (IMWG) criteria, during or after study treatment. IMWG criteria for PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours, if the serum and urine M-protein are not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria, in addition to the above criteria, if present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas is also required. Response-evaluable set included subjects who have a confirmed diagnosis of multiple myeloma and measurable disease and must have received at least 1 administration of study treatment and have at least 1 post baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From randomisation to disease progression (up to 21 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    276
    281
    Units: Percentage of subjects
        number (not applicable)
    76.4
    92.9
    No statistical analyses for this end point

    Secondary: Time to Response

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    End point title
    Time to Response
    End point description
    Time to response was defined as the time between the date of randomisation and the first efficacy evaluation that the subject met all criteria for partial response (PR) or better. Response-evaluable set (RES) is defined as subjects who have a confirmed diagnosis of multiple myeloma and measurable disease at baseline or screening visit. In addition, subjects must have received at least 1 administration of study treatment and have at least 1 post baseline disease assessment.
    End point type
    Secondary
    End point timeframe
    From randomisation up to first documented CR or PR (up to 21 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    276
    281
    Units: Months
        median (confidence interval 95%)
    1.3 (1.1 to 1.9)
    1.0 (1.0 to 1.1)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was measured from the date of randomisation to the date of the subject's death. ITT analysis set included all subjects who were randomly assigned to the DRd or Rd group. Here 'N' (number of subjects analyzed) signifies number of subjects who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    From randomisation to date of death due to any cause (up to 87.5 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    175
    153
    Units: Months
        median (confidence interval 95%)
    51.84 (43.99 to 60.02)
    67.58 (53.13 to 80.53)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    Duration of Response (DOR)
    End point description
    DOR: time between first documented confirmed response (PR or better) and disease progression/death due to PD, whichever occurs first. PD, any 1 criteria: >=25% increase in serum M-protein level from lowest response value, absolute increase >=0.5 g/dL; >=25% increase in 24h in urinary light chain excretion (urine M-protein) from lowest response value, absolute increase >=200mg/24h; subjects without measurable serum and urine M-protein levels: >=25% increase in difference between involved and uninvolved FLC levels from lowest response value and absolute increase >10 mg/dL; increase in size of existing and development of new bone lesions/soft tissue plasmacytomas; development of hypercalcemia (corrected serum calcium >11.5mg/dL) attributed to PC proliferative disorder. RES was evaluated. N=subjects who had PR/better response. 99999: median, upper and lower limit of 95% CI in DRd arm and upper limit of 95% CI in Rd arm not estimable due to short follow-up by subjects.
    End point type
    Secondary
    End point timeframe
    From randomisation to the date of first documented evidence of PD (up to 21 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    211
    261
    Units: Months
        median (confidence interval 95%)
    17.4 (17.4 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Subsequent Anticancer Treatment

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    End point title
    Time to Subsequent Anticancer Treatment
    End point description
    Time to subsequent anticancer treatment was defined as the time from randomization to the start of subsequent anticancer treatment or death due to progressive disease (PD), whichever occurs first. ITT analysis set included all subjects who were randomly assigned to the DRd or Rd group, and who started subsequent anticancer therapy or died due to progressive disease, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    From randomisation to date of start of subsequent anticancer treatment or death due to PD, whichever occured first (up to 87.5 months)
    End point values
    Lenalidomide, Low-dose Dexamethasone (Rd) Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Number of subjects analysed
    212
    138
    Units: Months
        median (confidence interval 95%)
    23.1 (18.6 to 26.3)
    69.3 (49.7 to 82.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation up to 30 days after last dose of study treatment (up to 87.5 months)
    Adverse event reporting additional description
    Safety analysis set included all randomised subjects who had at least 1 administration of any study treatment (partial or complete). In arm daratumumab, lenalidomide, low-dose dexamethasone (DRd), 1 subject had death event who was randomised but not treated, therefore, not included in safety analysis set.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd)
    Reporting group description
    Subjects received daratumumab 16 milligrams per kilogram (mg/kg) as an intravenous (IV) infusion once a week during treatment cycles 1 and 2 (for 8 weeks, each 28-day cycle); every 2 weeks during treatment cycles 3 to 6 (for 16 weeks, each 28-day cycle); once only on Day 1 during treatment cycles 7 onwards (for every 4 weeks). Lenalidomide was administered at a dose of 25 mg orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone was administered at a total dose of 40 mg weekly (or 20 mg weekly for subjects >75 years old or with a body mass index < 18.5 kg/m^2).

    Reporting group title
    Lenalidomide, Low-dose Dexamethasone (Rd)
    Reporting group description
    Subjects received lenalidomide at a dose of 25 milligrams (mg) orally on Day 1 through Day 21 of each 28-day treatment cycle and low-dose dexamethasone at a total dose of 40 mg weekly (or 20 mg weekly for subjects greater than [>] 75 years old or with a body mass index less than [<] 18.5 kilograms per meter square [kg/m^2]).

    Serious adverse events
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd) Lenalidomide, Low-dose Dexamethasone (Rd)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    205 / 283 (72.44%)
    148 / 281 (52.67%)
         number of deaths (all causes)
    152
    175
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute monocytic leukaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Adenocarcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoma benign
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign anorectal neoplasm
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus associated lymphoproliferative disorder
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Plasma cell leukaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural mesothelioma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral artery embolism
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombophlebitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic infarction
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous occlusion
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 283 (1.06%)
    3 / 281 (1.07%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    13 / 283 (4.59%)
    5 / 281 (1.78%)
         occurrences causally related to treatment / all
    5 / 17
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Fatigue
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 283 (1.77%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary calcification
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    12 / 283 (4.24%)
    10 / 281 (3.56%)
         occurrences causally related to treatment / all
    11 / 12
    10 / 10
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Influenza B virus test positive
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diagnostic procedure
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Acetabulum fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    4 / 283 (1.41%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peroneal nerve injury
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior capsule rupture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound decomposition
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 283 (0.71%)
    4 / 281 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 283 (1.77%)
    3 / 281 (1.07%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 283 (1.41%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac amyloidosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular failure
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus arrhythmia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systolic dysfunction
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial paralysis
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 283 (1.77%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    5 / 283 (1.77%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    13 / 283 (4.59%)
    4 / 281 (1.42%)
         occurrences causally related to treatment / all
    13 / 16
    4 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sideroblastic anaemia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual field defect
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    4 / 283 (1.41%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    5 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    8 / 283 (2.83%)
    6 / 281 (2.14%)
         occurrences causally related to treatment / all
    6 / 9
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Strangulated umbilical hernia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash papular
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    8 / 283 (2.83%)
    11 / 281 (3.91%)
         occurrences causally related to treatment / all
    0 / 11
    5 / 14
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Azotaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 283 (0.35%)
    5 / 281 (1.78%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urethral haemorrhage
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 283 (1.06%)
    6 / 281 (2.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    3 / 283 (1.06%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral foraminal stenosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    10 / 283 (3.53%)
    7 / 281 (2.49%)
         occurrences causally related to treatment / all
    4 / 12
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brucellosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 283 (1.06%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 283 (0.35%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gingivitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 283 (1.41%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective spondylitis
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 283 (1.06%)
    6 / 281 (2.14%)
         occurrences causally related to treatment / all
    2 / 3
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    14 / 283 (4.95%)
    3 / 281 (1.07%)
         occurrences causally related to treatment / all
    9 / 16
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Legionella infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza
         subjects affected / exposed
    12 / 283 (4.24%)
    7 / 281 (2.49%)
         occurrences causally related to treatment / all
    2 / 14
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratitis fungal
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal abscess
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral fungal infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 283 (0.00%)
    3 / 281 (1.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    48 / 283 (16.96%)
    32 / 281 (11.39%)
         occurrences causally related to treatment / all
    41 / 71
    16 / 42
         deaths causally related to treatment / all
    2 / 2
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    2 / 283 (0.71%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    7 / 283 (2.47%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    3 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 283 (1.77%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonella bacteraemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    3 / 283 (1.06%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    7 / 283 (2.47%)
    8 / 281 (2.85%)
         occurrences causally related to treatment / all
    6 / 9
    1 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Septic shock
         subjects affected / exposed
    4 / 283 (1.41%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 2
         deaths causally related to treatment / all
    2 / 4
    0 / 1
    Sinusitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 283 (1.06%)
    7 / 281 (2.49%)
         occurrences causally related to treatment / all
    3 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 283 (2.47%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine abscess
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 283 (0.35%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 283 (0.00%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    2 / 283 (0.71%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 283 (0.00%)
    2 / 281 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    3 / 283 (1.06%)
    1 / 281 (0.36%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 283 (0.35%)
    0 / 281 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Daratumumab, Lenalidomide, Low-dose Dexamethasone (DRd) Lenalidomide, Low-dose Dexamethasone (Rd)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    278 / 283 (98.23%)
    268 / 281 (95.37%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    26 / 283 (9.19%)
    9 / 281 (3.20%)
         occurrences all number
    32
    10
    Hypertension
         subjects affected / exposed
    31 / 283 (10.95%)
    22 / 281 (7.83%)
         occurrences all number
    41
    24
    Haematoma
         subjects affected / exposed
    15 / 283 (5.30%)
    6 / 281 (2.14%)
         occurrences all number
    15
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    59 / 283 (20.85%)
    47 / 281 (16.73%)
         occurrences all number
    102
    73
    Chills
         subjects affected / exposed
    22 / 283 (7.77%)
    9 / 281 (3.20%)
         occurrences all number
    26
    11
    Influenza like illness
         subjects affected / exposed
    27 / 283 (9.54%)
    20 / 281 (7.12%)
         occurrences all number
    49
    22
    Non-cardiac chest pain
         subjects affected / exposed
    18 / 283 (6.36%)
    5 / 281 (1.78%)
         occurrences all number
    21
    6
    Oedema peripheral
         subjects affected / exposed
    72 / 283 (25.44%)
    50 / 281 (17.79%)
         occurrences all number
    115
    99
    Pyrexia
         subjects affected / exposed
    71 / 283 (25.09%)
    40 / 281 (14.23%)
         occurrences all number
    123
    56
    Fatigue
         subjects affected / exposed
    119 / 283 (42.05%)
    87 / 281 (30.96%)
         occurrences all number
    247
    158
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    18 / 283 (6.36%)
    9 / 281 (3.20%)
         occurrences all number
    18
    9
    Cough
         subjects affected / exposed
    107 / 283 (37.81%)
    43 / 281 (15.30%)
         occurrences all number
    211
    74
    Dyspnoea
         subjects affected / exposed
    65 / 283 (22.97%)
    39 / 281 (13.88%)
         occurrences all number
    107
    59
    Dyspnoea exertional
         subjects affected / exposed
    21 / 283 (7.42%)
    11 / 281 (3.91%)
         occurrences all number
    30
    14
    Epistaxis
         subjects affected / exposed
    11 / 283 (3.89%)
    15 / 281 (5.34%)
         occurrences all number
    13
    18
    Nasal congestion
         subjects affected / exposed
    23 / 283 (8.13%)
    7 / 281 (2.49%)
         occurrences all number
    31
    9
    Oropharyngeal pain
         subjects affected / exposed
    23 / 283 (8.13%)
    17 / 281 (6.05%)
         occurrences all number
    25
    21
    Productive cough
         subjects affected / exposed
    26 / 283 (9.19%)
    11 / 281 (3.91%)
         occurrences all number
    46
    12
    Rhinorrhoea
         subjects affected / exposed
    18 / 283 (6.36%)
    8 / 281 (2.85%)
         occurrences all number
    25
    12
    Rhinitis allergic
         subjects affected / exposed
    21 / 283 (7.42%)
    4 / 281 (1.42%)
         occurrences all number
    27
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    25 / 283 (8.83%)
    13 / 281 (4.63%)
         occurrences all number
    30
    17
    Depression
         subjects affected / exposed
    29 / 283 (10.25%)
    9 / 281 (3.20%)
         occurrences all number
    35
    10
    Insomnia
         subjects affected / exposed
    80 / 283 (28.27%)
    65 / 281 (23.13%)
         occurrences all number
    118
    91
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    19 / 283 (6.71%)
    14 / 281 (4.98%)
         occurrences all number
    36
    34
    Blood creatinine increased
         subjects affected / exposed
    16 / 283 (5.65%)
    17 / 281 (6.05%)
         occurrences all number
    36
    25
    Weight decreased
         subjects affected / exposed
    31 / 283 (10.95%)
    13 / 281 (4.63%)
         occurrences all number
    40
    17
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    25 / 283 (8.83%)
    12 / 281 (4.27%)
         occurrences all number
    37
    15
    Fall
         subjects affected / exposed
    24 / 283 (8.48%)
    12 / 281 (4.27%)
         occurrences all number
    40
    21
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    16 / 283 (5.65%)
    2 / 281 (0.71%)
         occurrences all number
    18
    2
    Atrial fibrillation
         subjects affected / exposed
    17 / 283 (6.01%)
    9 / 281 (3.20%)
         occurrences all number
    21
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    56 / 283 (19.79%)
    23 / 281 (8.19%)
         occurrences all number
    80
    28
    Hypoaesthesia
         subjects affected / exposed
    18 / 283 (6.36%)
    9 / 281 (3.20%)
         occurrences all number
    25
    17
    Neuropathy peripheral
         subjects affected / exposed
    25 / 283 (8.83%)
    18 / 281 (6.41%)
         occurrences all number
    38
    25
    Paraesthesia
         subjects affected / exposed
    17 / 283 (6.01%)
    12 / 281 (4.27%)
         occurrences all number
    24
    22
    Peripheral sensory neuropathy
         subjects affected / exposed
    40 / 283 (14.13%)
    27 / 281 (9.61%)
         occurrences all number
    64
    43
    Tremor
         subjects affected / exposed
    28 / 283 (9.89%)
    26 / 281 (9.25%)
         occurrences all number
    35
    29
    Dizziness
         subjects affected / exposed
    35 / 283 (12.37%)
    30 / 281 (10.68%)
         occurrences all number
    46
    39
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    29 / 283 (10.25%)
    23 / 281 (8.19%)
         occurrences all number
    208
    89
    Anaemia
         subjects affected / exposed
    118 / 283 (41.70%)
    117 / 281 (41.64%)
         occurrences all number
    343
    294
    Neutropenia
         subjects affected / exposed
    185 / 283 (65.37%)
    136 / 281 (48.40%)
         occurrences all number
    1035
    592
    Lymphopenia
         subjects affected / exposed
    20 / 283 (7.07%)
    17 / 281 (6.05%)
         occurrences all number
    91
    111
    Thrombocytopenia
         subjects affected / exposed
    92 / 283 (32.51%)
    90 / 281 (32.03%)
         occurrences all number
    372
    339
    Eye disorders
    Vision blurred
         subjects affected / exposed
    28 / 283 (9.89%)
    17 / 281 (6.05%)
         occurrences all number
    30
    18
    Cataract
         subjects affected / exposed
    59 / 283 (20.85%)
    35 / 281 (12.46%)
         occurrences all number
    71
    41
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    30 / 283 (10.60%)
    16 / 281 (5.69%)
         occurrences all number
    38
    24
    Abdominal pain upper
         subjects affected / exposed
    29 / 283 (10.25%)
    13 / 281 (4.63%)
         occurrences all number
    42
    16
    Constipation
         subjects affected / exposed
    94 / 283 (33.22%)
    77 / 281 (27.40%)
         occurrences all number
    151
    115
    Diarrhoea
         subjects affected / exposed
    169 / 283 (59.72%)
    105 / 281 (37.37%)
         occurrences all number
    474
    216
    Dyspepsia
         subjects affected / exposed
    29 / 283 (10.25%)
    9 / 281 (3.20%)
         occurrences all number
    33
    11
    Nausea
         subjects affected / exposed
    86 / 283 (30.39%)
    53 / 281 (18.86%)
         occurrences all number
    146
    67
    Stomatitis
         subjects affected / exposed
    19 / 283 (6.71%)
    6 / 281 (2.14%)
         occurrences all number
    25
    7
    Toothache
         subjects affected / exposed
    17 / 283 (6.01%)
    10 / 281 (3.56%)
         occurrences all number
    22
    11
    Vomiting
         subjects affected / exposed
    65 / 283 (22.97%)
    19 / 281 (6.76%)
         occurrences all number
    99
    26
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    25 / 283 (8.83%)
    10 / 281 (3.56%)
         occurrences all number
    32
    13
    Pruritus
         subjects affected / exposed
    34 / 283 (12.01%)
    31 / 281 (11.03%)
         occurrences all number
    42
    34
    Rash
         subjects affected / exposed
    51 / 283 (18.02%)
    36 / 281 (12.81%)
         occurrences all number
    65
    48
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    33 / 283 (11.66%)
    15 / 281 (5.34%)
         occurrences all number
    49
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    75 / 283 (26.50%)
    55 / 281 (19.57%)
         occurrences all number
    133
    85
    Back pain
         subjects affected / exposed
    76 / 283 (26.86%)
    56 / 281 (19.93%)
         occurrences all number
    124
    86
    Bone pain
         subjects affected / exposed
    29 / 283 (10.25%)
    16 / 281 (5.69%)
         occurrences all number
    37
    18
    Muscle spasms
         subjects affected / exposed
    87 / 283 (30.74%)
    61 / 281 (21.71%)
         occurrences all number
    128
    106
    Myalgia
         subjects affected / exposed
    22 / 283 (7.77%)
    17 / 281 (6.05%)
         occurrences all number
    25
    25
    Musculoskeletal chest pain
         subjects affected / exposed
    32 / 283 (11.31%)
    24 / 281 (8.54%)
         occurrences all number
    38
    26
    Muscular weakness
         subjects affected / exposed
    29 / 283 (10.25%)
    26 / 281 (9.25%)
         occurrences all number
    49
    35
    Pain in extremity
         subjects affected / exposed
    47 / 283 (16.61%)
    42 / 281 (14.95%)
         occurrences all number
    64
    56
    Neck pain
         subjects affected / exposed
    22 / 283 (7.77%)
    13 / 281 (4.63%)
         occurrences all number
    28
    16
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    30 / 283 (10.60%)
    26 / 281 (9.25%)
         occurrences all number
    62
    37
    Bronchitis
         subjects affected / exposed
    60 / 283 (21.20%)
    45 / 281 (16.01%)
         occurrences all number
    112
    66
    Conjunctivitis
         subjects affected / exposed
    19 / 283 (6.71%)
    6 / 281 (2.14%)
         occurrences all number
    22
    8
    Gastroenteritis
         subjects affected / exposed
    25 / 283 (8.83%)
    9 / 281 (3.20%)
         occurrences all number
    35
    9
    Influenza
         subjects affected / exposed
    34 / 283 (12.01%)
    17 / 281 (6.05%)
         occurrences all number
    38
    19
    Lower respiratory tract infection
         subjects affected / exposed
    22 / 283 (7.77%)
    12 / 281 (4.27%)
         occurrences all number
    49
    24
    Nasopharyngitis
         subjects affected / exposed
    100 / 283 (35.34%)
    62 / 281 (22.06%)
         occurrences all number
    279
    118
    Pneumonia
         subjects affected / exposed
    51 / 283 (18.02%)
    27 / 281 (9.61%)
         occurrences all number
    80
    34
    Respiratory tract infection
         subjects affected / exposed
    38 / 283 (13.43%)
    29 / 281 (10.32%)
         occurrences all number
    73
    49
    Rhinitis
         subjects affected / exposed
    23 / 283 (8.13%)
    5 / 281 (1.78%)
         occurrences all number
    37
    7
    Sinusitis
         subjects affected / exposed
    27 / 283 (9.54%)
    13 / 281 (4.63%)
         occurrences all number
    42
    19
    Upper respiratory tract infection
         subjects affected / exposed
    123 / 283 (43.46%)
    74 / 281 (26.33%)
         occurrences all number
    330
    147
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    50 / 283 (17.67%)
    36 / 281 (12.81%)
         occurrences all number
    81
    50
    Hyperglycaemia
         subjects affected / exposed
    34 / 283 (12.01%)
    22 / 281 (7.83%)
         occurrences all number
    78
    35
    Hypocalcaemia
         subjects affected / exposed
    24 / 283 (8.48%)
    16 / 281 (5.69%)
         occurrences all number
    46
    20
    Hypokalaemia
         subjects affected / exposed
    58 / 283 (20.49%)
    35 / 281 (12.46%)
         occurrences all number
    118
    77
    Hypomagnesaemia
         subjects affected / exposed
    18 / 283 (6.36%)
    17 / 281 (6.05%)
         occurrences all number
    26
    22
    Hypophosphataemia
         subjects affected / exposed
    22 / 283 (7.77%)
    14 / 281 (4.98%)
         occurrences all number
    68
    24

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Jun 2014
    The overall reason for this amendment was 1) The sample size was changed to reflect the median progression-free survival (PFS) assumption for the comparator arm; 2) Lenalidomide global pregnancy prevention plan was added; Feedback from investigators and health authorities was incorporated.
    20 Nov 2014
    The overall reason for this amendment was 1) The requirements for bone marrow sample collection were modified to allow for differences across countries in local clinical practice; 2) Other protocol procedures were clarified based on feedback from investigative sites; 3) Changes from France (FRA)-1 and Japan (JPN)-1 amendments were rolled into the global interim (INT)-2 amendment.
    26 May 2016
    The overall reason for the amendment was to include that following the positive interim analysis of efficacy results, subjects who were randomized to the Rd group and who had sponsor-confirmed disease progression were offered treatment with daratumumab monotherapy. Subjects who received daratumumab monotherapy had a limited schedule of assessments and limited adverse event (AE) collection.
    01 Nov 2016
    The overall reason for the amendment was to include additional time points for collection of bone marrow aspirate, for purposes of minimal residual disease (MRD) assessment, to align with newly defined categories of MRD-negativity.
    22 Jan 2018
    The overall reason for the amendment was to allow disease evaluations to be performed by the central laboratory on the current schedule until median PFS was reached in the daratumumab, lenalidomide, and low-dose dexamethasone (DRd) arm of the randomized portion of the study, for uniformity in data analysis. Thereafter, disease evaluations for all subjects were performed by local laboratories according to each site’s standard of care. In addition, patient reported outcome (PRO) assessments were collected for an extended duration intended to ensure optimal evaluation of long-term health-related quality of life parameters.
    05 Dec 2018
    The overall reason for the amendment was to include changes in response to identification of a new important risk (Hepatitis B Virus reactivation).
    12 Jun 2019
    The overall reason for the amendment was to align guidance on monitoring and management of Hepatitis B Virus reactivation with other daratumumab studies.
    09 Apr 2020
    The overall reason for the amendment was to include changes to provide flexibility for study investigators to prioritize the safety of their patients during the global COVID-19 pandemic. To ensure continuity of study treatment, while limiting subjects’ time spent at the study center, subjects who were receiving daratumumab intravenous (16 milligrams per kilogram [mg/kg]) were given the option to switch to daratumumab subcutaneous (SC) (1800 mg) on Day 1 of any cycle, at the discretion of the investigator. Assessments to evaluate the immunogenicity of recombinant human hyaluronidase PH20 (rHuPH20) were added as part of this protocol amendment.
    06 Apr 2021
    The overall reason for the amendment was to clarify that sites would be notified of the clinical cutoff (CCO) for the final overall survival (OS) analysis, to define the end of the electronic case report form (eCRF) data collection, to amend the end of study, and to clarify that subjects who were benefiting from study treatment would be able to continue to receive study treatment from the final OS analysis until the end of study when alternative access to daratumumab was not available.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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