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    Clinical Trial Results:
    A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone [DRd] vs Lenalidomide and Dexamethasone [Rd] in Subjects with Previously Untreated Multiple Myeloma who are Ineligible for High Dose Therapy

    Summary
    EudraCT number
    		 2014-002273-11
    Trial protocol
    		 SE   AT   NL   GB   DK   IE   DE   BE   IT  
    Global end of trial date
    02 Oct 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Oct 2025
    First version publication date
    23 Oct 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    54767414MMY3008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252172
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical registry group, Janssen-Cilag International N.V., ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical registry group, Janssen-Cilag International N.V., 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
    29 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trail 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 newly diagnosed myeloma who were not candidates for high dose chemotherapy and autologous stem cell transplant.
    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
    10 Mar 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 89 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 35
    Country: Number of subjects enrolled
    Austria: 14
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Canada: 52
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    France: 312
    Country: Number of subjects enrolled
    United Kingdom: 67
    Country: Number of subjects enrolled
    Ireland: 7
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Sweden: 22
    Country: Number of subjects enrolled
    United States: 151
    Worldwide total number of subjects
    737
    EEA total number of subjects
    424
    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)
    8
    From 65 to 84 years
    704
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 737 subjects were enrolled (368 subjects in the Daratumumab + Lenalidomide + Dexamethasone [DRd] group and 369 in the Lenalidomide + Dexamethasone [Rd] group) of which 729 were treated (364 subjects in the DRd group and 365 in the Rd group) and none 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 + Dexamethasone (Rd)
    Arm description
    		 Subjects received Lenalidomide 25 milligrams (mg) capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously (IV) once a week (QW) until disease progression or unacceptable toxicity up to 77.5 months. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group [IMWG] criteria).
    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 capsule orally daily on Day 1 through Day 21 of each 28-day cycle until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Dexamethasone 40 mg IV QW until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Dexamethasone 40 mg oral tablet QW until disease progression or unacceptable toxicity.

    Arm title
    		 Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Arm description
    		 Subjects received Daratumumab 16 milligrams per kilograms (mg/kg) IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days), Lenalidomide 25 mg capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or IV QW until disease progression or unacceptable toxicity up to 77.3 months. After implementation of Amendment 8, subjects who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab subcutaneous (SC) injection on Day 1 of any cycle, as per investigator’s discretion. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria).
    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 capsule orally daily on Day 1 through Day 21 of each 28-day cycle until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    JNJ-54767414
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Daratumumab 16 mg/kg IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days) until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Daratumumab
    Investigational medicinal product code
    JNJ-54767414
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Daratumumab 16 mg/kg SC QW for the first 8 weeks (cycles 1-2) and then Q2W for 16weeks (Cycle 3-6), then Q4W (from Cycle 7 and beyond) (each cycle of 28 days).

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Dexamethasone 40 mg IV QW until disease progression or unacceptable toxicity.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Dexamethasone 40 mg oral QW until disease progression or unacceptable toxicity.

    Number of subjects in period 1
    		Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Started
    369
    368
    Treated
    365
    364
    Completed
    0
    0
    Not completed
    369
    368
         Adverse event, serious fatal
    218
    175
         Consent withdrawn by subject
    20
    15
         Physician decision
    -
    1
         End of data collection
    122
    170
         Lost to follow-up
    9
    6
         Site closure
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenalidomide + Dexamethasone (Rd)
    Reporting group description
    		 Subjects received Lenalidomide 25 milligrams (mg) capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously (IV) once a week (QW) until disease progression or unacceptable toxicity up to 77.5 months. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group [IMWG] criteria).

    Reporting group title
    Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Reporting group description
    		 Subjects received Daratumumab 16 milligrams per kilograms (mg/kg) IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days), Lenalidomide 25 mg capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or IV QW until disease progression or unacceptable toxicity up to 77.3 months. After implementation of Amendment 8, subjects who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab subcutaneous (SC) injection on Day 1 of any cycle, as per investigator’s discretion. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria).

    Reporting group values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd) Total
    Number of subjects
    		 369 368 737
    Age categorical
    Units: Subjects
        In Utero
    		 0 0 0
        Preterm newborn infants (gestional age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days - 23 months)
    		 0 0 0
        Children (2 - 11 years)
    		 0 0 0
        12 - 17 years
    		 0 0 0
        Adults (18 - 64 years)
    		 4 4 8
        From 65 - 84 years
    		 349 355 704
        85 years and over
    		 16 9 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.2 ( 5.66 ) 74.0 ( 5.44 ) -
    Gender categorical
    Units: Subjects
        Male
    		 195 189 384
        Female
    		 174 179 353
    Stage of Disease (ISS)
    The International Staging System (ISS) consists of following 3 stages - Stage I: serum beta2-microglobulin less than (<) 3.5 milligrams per liter (mg/L) and albumin greater than or equal to (>=) 3.5 grams per 100 Milliliter (g/100 mL); Stage II: neither stage I nor stage III and Stage III: serum beta2-microglobulin >= 5.5 mg/L.
    Units: Subjects
        Stage I
    		 103 98 201
        Stage II
    		 156 163 319
        Stage III
    		 110 107 217
    Time from Multiple Myeloma (MM) diagnosis
    Time from MM diagnosis is the time from diagnosis of multiple myeloma to randomization in each treatment group.
    Units: Months
        arithmetic mean (standard deviation)
    		 1.3 ( 1.4 ) 1.4 ( 1.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Lenalidomide + Dexamethasone (Rd)
    Reporting group description
    		 Subjects received Lenalidomide 25 milligrams (mg) capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously (IV) once a week (QW) until disease progression or unacceptable toxicity up to 77.5 months. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group [IMWG] criteria).

    Reporting group title
    Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Reporting group description
    		 Subjects received Daratumumab 16 milligrams per kilograms (mg/kg) IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days), Lenalidomide 25 mg capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or IV QW until disease progression or unacceptable toxicity up to 77.3 months. After implementation of Amendment 8, subjects who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab subcutaneous (SC) injection on Day 1 of any cycle, as per investigator’s discretion. After completion of treatment, subjects entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria).

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS: Time from date of randomization to either progressive disease (PD) or death, whichever occurred first based on computerized algorithm as per IMWG criteria. PD: An increase of 25 percent (%) from the lowest response value in one of the following: serum and urine M-component (absolute increase must be greater than or equal to [>=] 0.5 gram per deciliter [g/dL] and >=200 mg/24 hours [h] respectively); Only in subjects without measurable serum and urine M-protein levels the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be greater than [>]10 mg/dL); development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia attributed solely to Plasma cell (PC) proliferative disorder. Intent-to-treat (ITT) population included all randomized subjects. '99999' signifies median and 95% CI was not estimable due to insufficient number of events.
    End point type
    Primary
    End point timeframe
    From randomization (Day -3) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 3.5 years)
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Months
        median (confidence interval 95%)
    31.87 (28.94 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.73

    Primary: Time to Response

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    End point title
    		 Time to Response [1]
    End point description
    Time to first response, VGPR or better, CR or better, best response was reported for this endpoint. Time to response: time from date of randomization to first efficacy evaluation that met criteria for PR/better as their best response (PR, CR, or better) based on IMWG criteria. PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours. If serum and urine M-protein were not measurable, a decrease of >=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. Based on computerized algorithm, according to IMWG response criteria, VGPR or better: proportion of subjects with a response of VGPR or better (i.e., VGPR, CR or sCR), CR or better: proportion of subjects with a response of CR or better (i.e., CR or sCR). Here, 'N'=number of subjects evaluable for this end point; 'n'= number of subjects analyzed at specified timepoints.
    End point type
    Primary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    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 + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    301
    342
    Units: Months
    median (full range (min-max))
        Time to first response (n= 301, 342)
    1.05 (0.3 to 22.3)
    1.05 (0.2 to 12.1)
        Time to VGPR or better (n= 210, 300)
    4.70 (0.9 to 43.3)
    3.01 (0.9 to 60.9)
        Time to CR or better (n=111, 188)
    13.17 (2.8 to 54.6)
    10.66 (1.0 to 46.7)
        Time to best response (n=301, 342)
    6.31 (0.9 to 55.2)
    9.97 (0.9 to 60.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Complete Response (CR) or Better

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    End point title
    		 Percentage of Subjects With Complete Response (CR) or Better
    End point description
    Percentage of subjects with a CR or better (CR or stringent complete response [sCR]) based on computerized algorithm as per IMWG criteria was reported. CR was defined as negative immunofixation on the serum and urine, and disappearance of any soft tissue plasmacytomas, and less than (<) 5 percent (%) PCs in bone marrow. In subjects with only measurable disease by serum FLC levels a normal serum FLC ratio was required. sCR was defined as in addition to CR a normal FLC ratio, and absence of clonal PCs by immunohistochemistry (IHC), immunofluorescence, 2-4 color flow cytometry (FC). ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Percentage of subjects
        number (confidence interval 95%)
    30.1 (25.4 to 35.0)
    51.1 (45.9 to 56.3)
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 3.3

    Secondary: Percentage of Subjects With Very Good Partial Response (VGPR) or Better

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    End point title
    		 Percentage of Subjects With Very Good Partial Response (VGPR) or Better
    End point description
    VGPR or better rate was defined as the percentage of subjects who achieved VGPR or better (VGPR, CR or sCR) according to the IMWG criteria during or after the study treatment. VGPR: Serum and urine component detectable by immunofixation but not on electrophoresis, or >= 90% reduction in serum M-protein plus urine M-protein level less than (<) 100 milligram (mg) per 24 hour; CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and < 5% plasms cells (PCs) in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Percentage of subjects
        number (confidence interval 95%)
    56.9 (51.7 to 62.0)
    81.5 (77.2 to 85.4)
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.42
         upper limit
    		 4.77

    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
    MRD negativity rate is defined as the percentage of subjects who had negative MRD at any time point after the date of randomization and prior to subsequent antimyeloma therapy. MRD was assessed in subjects who achieved CR or better. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Percentage of subjects
        number (confidence interval 95%)
    11.1 (8.1 to 14.8)
    32.1 (27.3 to 37.1)
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.55
         upper limit
    		 5.59

    Secondary: Percentage of Subjects With Stringent Complete Response (sCR)

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    End point title
    		 Percentage of Subjects With Stringent Complete Response (sCR)
    End point description
    sCR as per IMWG criteria is CR plus normal free light chain (FLC) ratio and absence of clonal PCs by immunohistochemistry, immunofluorescence or 2- to 4-color flow cytometry. CR: Negative immunofixation on the serum and urine; Disappearance of any soft tissue plasmacytomas; <5% plasma cells (PCs) in bone marrow. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Percentage of subjects
        number (confidence interval 95%)
    15.7 (12.2 to 19.8)
    35.6 (30.7 to 40.7)
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 4.24

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was the percentage of subjects who achieved partial response (PR) or better (PR, VGPR, CR or sCR) based on computerized algorithm as per IMWG criteria. PR: >=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >=90% or to <200 mg/24 hours. If serum and urine M-protein were not measurable, a decrease of >=50% in the difference between involved and uninvolved FLC levels was required in place of the M-protein criteria. If present at baseline, a >=50% reduction in the size of soft tissue plasmacytomas was also required. VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein <100 mg/24 hours. CR: negative immunofixation on the serum and urine, Disappearance of any soft tissue plasmacytomas and < 5% PCs in bone marrow; sCR: CR in addition to having a normal FLC ratio and an absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. ITT was used.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Percentage of subjects
        number (confidence interval 95%)
    81.6 (77.2 to 85.4)
    92.9 (89.8 to 95.3)
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.85
         upper limit
    		 4.86

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was measured from the date of randomization to the date of the death. Median OS was estimated by using the Kaplan-Meier method. ITT population included all randomized subjects. '99999' signifies that upper limit of 95% CI was not estimable due to an insufficient number of events.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 8.7 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Months
        number (confidence interval 95%)
    64.07 (55.98 to 70.80)
    90.25 (80.76 to 99999)
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.82

    Secondary: Time to Disease Progression (TTP)

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    End point title
    		 Time to Disease Progression (TTP)
    End point description
    TTP was defined as the time from the date of randomization to date of first documented evidence of PD or death due to PD, whichever occurred first. PD per IMWG criteria- Increase of 25 % from lowest response value in one of following: Serum M-component (absolute increase >=0.5 g/dL); Urine M-component (absolute increase >=200 mg/24 hours); Only in subjects without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels (absolute increase >10 milligram per deciliter [mg/dL]); Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the PC proliferative disorder. ITT population included all randomized subjects. Here '99999' signifies median, upper and lower limit of 95% CI was not estimable due to an insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Months
        median (confidence interval 95%)
    40.87 (35.81 to 48.79)
    99999 (99999 to 99999)
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.62

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    DoR was defined for subjects with confirmed response (PR or better) as time between first documentation of response and disease progression per IMWG response criteria, or death due to PD, whichever occurs first. PD per IMWG criteria- Increase of 25% from lowest response value in one of following: Serum M-component; Urine M-component; Only in subjects without measurable serum and urine M-protein levels: difference between involved and uninvolved FLC levels; Definite development of new bone lesions/soft tissue plasmacytomas or definite increase in size of existing bone lesions/soft tissue plasmacytomas and Development of hypercalcemia that can be attributed solely to the PC proliferative disorder. Response evaluable population were used. Here '99999' signifies median, upper and lower of 95% CI was not estimable due to an insufficient number of subjects with events. Here, 'N' (Overall number of subjects analyzed) signifies number of subjects evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    152
    119
    Units: Months
        median (confidence interval 95%)
    43.7 (36.8 to 52.6)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Subsequent Anti-myeloma Treatment

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    End point title
    		 Time to Subsequent Anti-myeloma Treatment
    End point description
    Time to subsequent anti-myeloma treatment was defined as the time from randomization to the start of subsequent anti-myeloma treatment. Kaplan-Meier method was used for the analysis. Here '99999' signifies median and upper limit of 95% CI was not estimable due to an insufficient number of subjects with events. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 8.7 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Months
        median (confidence interval 95%)
    42.4 (33.5 to 50.6)
    99999 (84.1 to 99999)
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 0.63

    Secondary: Progression-free Survival on Next Line of Therapy (PFS2)

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    End point title
    		 Progression-free Survival on Next Line of Therapy (PFS2)
    End point description
    PFS2 was defined as the time from randomization to progression on next line of therapy or death, whichever comes first. Disease progression on next line of treatment was based on investigator judgment. ITT population included all randomized subjects. Here '99999' signifies upper limit of 95% CI was not estimable due to an insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    369
    368
    Units: Months
        median (confidence interval 95%)
    48.89 (44.09 to 56.57)
    73.72 (73.72 to 99999)
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    737
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.76

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status (GHS) Score

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 Global Health Status (GHS) Score
    End point description
    EORTC QLQ-C30 is 30 items self-reporting questionnaire, with 1 week recall period, resulting in 5 functional scales (physical, role, emotional , cognitive and social functioning), 1 GHS scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Questionnaire included 28 items with 4-point Likert type responses from “1-not at all” to “4-very much” to assess functioning and symptoms. Scores were transformed to 0 to 100 scale, with higher scores representing better GHS, better functioning, and more symptoms. Negative change from baseline values showed deterioration in quality of life or functioning and reduction in symptom and positive values indicated improvement and worsening of symptoms. ITT was used. Here 'N' signifies number of subjects who were evaluable in this endpoint; 'n' signifies number of subjects analyzed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    295
    314
    Units: Score on scale
    least squares mean (confidence interval 95%)
        Cycle 3 Day 1 (n= 295, 314)
    1.4 (-0.7 to 3.5)
    3.8 (1.7 to 5.8)
        Cycle 6 Day 1 (n= 267, 304)
    4.8 (2.6 to 7)
    6.3 (4.3 to 8.4)
        Cycle 9 Day 1 (n= 229, 278)
    5.7 (3.4 to 8)
    7.5 (5.4 to 9.7)
        Cycle 12 Day 1 (n= 231, 274)
    4.5 (2.2 to 6.8)
    7.8 (5.6 to 9.9)
        Cycle 18 Day 1 (n= 186, 253)
    4.7 (2.2 to 7.2)
    6.4 (4.1 to 8.6)
        Cycle 24 Day 1 (n= 161, 238)
    4.7 (2.1 to 7.4)
    6.3 (4.1 to 8.6)
        Cycle 30 Day 1 (n= 140, 213)
    4.5 (1.7 to 7.3)
    5.5 (3.1 to 7.9)
        Cycle 36 Day 1 (n= 119, 207)
    5 (2 to 8)
    7.7 (5.3 to 10.1)
        Cycle 42 Day 1 (n= 100, 184)
    3.8 (0.6 to 7)
    5.6 (3.1 to 8.1)
        Cycle 48 Day 1 (n= 80, 170)
    3.4 (-0.1 to 6.9)
    4.2 (1.6 to 6.7)
        Cycle 54 Day 1 (n= 64, 145)
    6.1 (2.2 to 9.9)
    4.8 (2 to 7.5)
        Cycle 60 Day 1 (n=46, 114)
    4.9 (0.4 to 9.4)
    4.1 (1.1 to 7.1)
        Cycle 66 Day 1 (n= 26, 78)
    7.1 (1.3 to 12.8)
    7.7 (4.2 to 11.2)
    Statistical analysis title
    		 Statistical Analysis 11; Cycle 3 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0986
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 5.2
    Statistical analysis title
    		 Statistical Analysis 12, Cycle 6 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3042
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 4.4
    Statistical analysis title
    		 Statistical Analysis 13 ; Cycle 9 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2339
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 4.9
    Statistical analysis title
    		 Statistical Analysis 14; Cycle 12 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0365
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 6.3
    Statistical analysis title
    		 Statistical Analysis 15; Cycle 18 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3093
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 4.9
    Statistical analysis title
    		 Statistical Analysis 16; Cycle 24 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3481
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 5
    Statistical analysis title
    		 Statistical Analysis 17; Cycle 30 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5825
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 4.6
    Statistical analysis title
    		 Statistical Analysis 21; Cycle 54 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5793
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 3.3
    Statistical analysis title
    		 Statistical Analysis 18; Cycle 36 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1566
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 6.4
    Statistical analysis title
    		 Statistical Analysis 19; Cycle 42 Day 1
    Comparison groups
    Daratumumab + Lenalidomide + Dexamethasone (DRd) v Lenalidomide + Dexamethasone (Rd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3858
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 5.7
    Statistical analysis title
    		 Statistical Analysis 20; Cycle 48 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7296
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 5
    Statistical analysis title
    		 Statistical Analysis 22; Cycle 60 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7756
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.1
         upper limit
    		 4.5
    Statistical analysis title
    		 Statistical Analysis 23; Cycle 66 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8458
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 7.4

    Secondary: Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS)

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    End point title
    		 Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS)
    End point description
    EQ-5D-5L is a standardized, subject-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state profile (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the subject's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state. ITT population included all randomized subjects. Here 'N' (overall number of subjects analyzed) signifies number of subjects who were evaluable in this endpoint; 'n' (number analyzed) signifies number of subjects analyzed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    286
    301
    Units: Score on scale
    least squares mean (confidence interval 95%)
        Cycle 3 Day 1 (n= 286, 301)
    2.1 (0.3 to 4)
    4.2 (2.3 to 6)
        Cycle 6 Day 1 (n= 252, 287)
    4.8 (2.8 to 6.8)
    7.6 (5.8 to 9.5)
        Cycle 9 Day 1 (n= 221, 267)
    7 (5 to 9.1)
    9.6 (7.7 to 11.5)
        Cycle 12 Day 1 (n= 227, 261)
    3.6 (1.6 to 5.7)
    9.4 (7.4 to 11.3)
        Cycle 18 Day 1 (n= 180, 242)
    5.4 (3.2 to 7.6)
    7.4 (5.4 to 9.4)
        Cycle 24 Day 1 (n=154, 227)
    4.3 (2 to 6.7)
    7 (5 to 9)
        Cycle 30 Day 1 (n= 133, 198)
    4.6 (2.1 to 7)
    6.9 (4.8 to 9.1)
        Cycle 36 Day 1 (n= 115, 195)
    4.9 (2.3 to 7.5)
    8.1 (6 to 10.2)
        Cycle 42 Day 1 (n= 99, 178)
    4.6 (1.8 to 7.3)
    5.6 (3.4 to 7.8)
        Cycle 48 Day 1 (n= 79, 162)
    5.5 (2.4 to 8.5)
    6.7 (4.5 to 9)
        Cycle 54 Day 1 (n= 64, 141)
    3.4 (0.1 to 6.7)
    5.8 (3.4 to 8.2)
        Cycle 60 Day 1 (n= 44, 112)
    5.8 (1.9 to 9.6)
    5.2 (2.6 to 7.8)
        Cycle 66 Day 1 (n= 26, 74)
    6.9 (2 to 11.8)
    5.6 (2.5 to 8.7)
    Statistical analysis title
    		 Statistical Analysis 25; Cycle 6 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0336
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 5.4
    Statistical analysis title
    		 Statistical Analysis 24; Cycle 3 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1176
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 4.5
    Statistical analysis title
    		 Statistical Analysis 28; Cycle 18 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1805
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 4.8
    Statistical analysis title
    		 Statistical Analysis 29; Cycle 24 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0783
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 5.7
    Statistical analysis title
    		 Statistical Analysis 27; Cycle 12 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3
         upper limit
    		 8.5
    Statistical analysis title
    		 Statistical Analysis 26; Cycle 9 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0653
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 5.3
    Statistical analysis title
    		 Statistical Analysis 30; Cycle 30 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1422
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 5.5
    Statistical analysis title
    		 Statistical Analysis 31; Cycle 36 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0575
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 6.5
    Statistical analysis title
    		 Statistical Analysis 32; Cycle 42 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5339
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 4.5
    Statistical analysis title
    		 Statistical Analysis 33; Cycle 48 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5015
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 5
    Statistical analysis title
    		 Statistical Analysis 34; Cycle 54 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2512
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 6.3
    Statistical analysis title
    		 Statistical Analysis 35; Cycle 60 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8246
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 4.1
    Statistical analysis title
    		 Statistical Analysis 36; Cycle 66 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    587
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.664
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 4.5

    Secondary: Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score

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    End point title
    		 Change From Baseline in EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Utility Score
    End point description
    EQ-5D-5L is standardized, subject-reported questionnaire to assess health-related QoL. It includes 2 components: EQ-5D-5L health state profile (descriptive system) and EQ-5D-5L VAS. EQ-5D-5L descriptive system provides a profile of subject’s health state 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. Responses to 5D scores were combined and converted into single preference-weighted health utility index score 0 (0.0- worst health state) to 1 (1.0- better health state) representing the general health status of individual (but allows for values less than 0 by United kingdom [UK] scoring algorithm). ITT was used. Here 'N' signifies number of subjects who were evaluable in this endpoint; 'n' signifies number of subjects analyzed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline (Day -24) and Day 1 of Cycles 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, 60 and 66 (each Cycle of 28 days)
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    286
    302
    Units: Score on scale
    least squares mean (confidence interval 95%)
        Cycle 3 Day 1 (n= 286, 302)
    0.081 (0.058 to 0.103)
    0.097 (0.074 to 0.119)
        Cycle 6 Day 1 (n= 252, 287)
    0.111 (0.087 to 0.135)
    0.13 (0.107 to 0.152)
        Cycle 9 Day 1 (n= 221, 267)
    0.113 (0.088 to 0.138)
    0.124 (0.101 to 0.147)
        Cycle 12 Day 1 (n= 227, 261)
    0.103 (0.078 to 0.128)
    0.132 (0.108 to 0.155)
        Cycle 18 Day 1 (n= 180, 242)
    0.089 (0.062 to 0.116)
    0.116 (0.092 to 0.14)
        Cycle 24 Day 1 (n=154, 227)
    0.088 (0.059 to 0.116)
    0.121 (0.096 to 0.145)
        Cycle 30 Day 1 (n= 133, 198)
    0.088 (0.058 to 0.118)
    0.102 (0.076 to 0.127)
        Cycle 36 Day 1 (n= 115, 195)
    0.099 (0.067 to 0.131)
    0.109 (0.083 to 0.135)
        Cycle 42 Day 1 (n= 99, 178)
    0.062 (0.028 to 0.096)
    0.113 (0.086 to 0.14)
        Cycle 48 Day 1 (n=79, 162)
    0.075 (0.038 to 0.112)
    0.082 (0.055 to 0.11)
        Cycle 54 Day 1 (n= 64, 141)
    0.05 (0.01 to 0.091)
    0.087 (0.058 to 0.116)
        Cycle 60 Day 1 (n= 44, 112)
    0.068 (0.02 to 0.115)
    0.079 (0.047 to 0.111)
        Cycle 66 Day 1 (n= 26, 74)
    0.041 (-0.019 to 0.102)
    0.111 (0.073 to 0.148)
    Statistical analysis title
    		 Statistical Analysis 38; Cycle 6 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2472
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.019
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.013
         upper limit
    		 0.05
    Statistical analysis title
    		 Statistical Analysis 37; Cycle 3 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3069
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.016
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.015
         upper limit
    		 0.046
    Statistical analysis title
    		 Statistical Analysis 41; Cycle 18 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1296
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.008
         upper limit
    		 0.062
    Statistical analysis title
    		 Statistical Analysis 42; Cycle 24 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0762
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.07
    Statistical analysis title
    		 Statistical Analysis 40; Cycle 12 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0841
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.029
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.004
         upper limit
    		 0.062
    Statistical analysis title
    		 Statistical Analysis 39; Cycle 9 Day 1
    Statistical analysis description
    NA
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4972
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.044
    Statistical analysis title
    		 Statistical Analysis 43; Cycle 30 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4859
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.014
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.025
         upper limit
    		 0.052
    Statistical analysis title
    		 Statistical Analysis 44; Cycle 36 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6031
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.029
         upper limit
    		 0.051
    Statistical analysis title
    		 Statistical Analysis 45; Cycle 42 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0178
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.051
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.009
         upper limit
    		 0.093
    Statistical analysis title
    		 Statistical Analysis 46; Cycle 48 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.746
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.053
    Statistical analysis title
    		 Statistical Analysis 47; Cycle 54 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1394
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.037
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.012
         upper limit
    		 0.086
    Statistical analysis title
    		 Statistical Analysis 48; Cycle 60 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6982
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.045
         upper limit
    		 0.068
    Statistical analysis title
    		 Statistical Analysis 49; Cycle 66 Day 1
    Comparison groups
    Lenalidomide + Dexamethasone (Rd) v Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects included in analysis
    588
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0543
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.069
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.001
         upper limit
    		 0.14

    Secondary: Sub-group Analysis: Progression-free Survival (PFS)

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    End point title
    		 Sub-group Analysis: Progression-free Survival (PFS)
    End point description
    PFS for subjects with cytogenic high risk was reported. PFS: time from date of randomization to either PD/death, whichever occurred first based on computerized algorithm per IMWG criteria. PD: An increase of 25% from lowest response value in 1 of following: serum and urine M-component (absolute increase must be >=0.5g/dL and >=200mg/24h respectively); Only in subjects without measurable serum and urine M-protein levels, difference between involved and uninvolved FLC levels (absolute >10 mg/dL); Development of new bone lesions or soft tissue plasmacytomas or increase in size of existing bone lesions or soft tissue plasmacytomas; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that could be attributed solely to PC proliferative disorder. High risk was defined as positive for any of del17p, t(14;16) or t(4;14) by (corrected serum calcium >11.5 mg/dL) Fluorescence In Situ Hybridization (FISH)/Karyotype. ITT was used. 'N' = number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) to disease progression, death, subsequent anti-myeloma therapy, withdrawal of consent to study participation or clinical cut-off (CCO) whichever occurs first (up to 3.5 years)
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    31
    28
    Units: Months
        median (confidence interval 95%)
    29.6 (15.6 to 34.5)
    45.3 (18.4 to 61.9)
    No statistical analyses for this end point

    Secondary: Sub-group Analysis: Overall Response Rate (ORR)

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    End point title
    		 Sub-group Analysis: Overall Response Rate (ORR)
    End point description
    ORR for subjects with cytogenic high risk was reported. ORR: percentage of subjects who achieved PR/better per IMWG criteria. PR: >=50% reduction of serum M-protein, reduction in 24h urinary M-protein by >=90% or <200mg/24h. If serum/urine M-protein were not measurable, decrease of >=50% in difference between involved and uninvolved FLC levels was required in place of M-protein criteria. If present at baseline, >=50% reduction in size of soft tissue plasmacytomas was required. VGPR: serum/urine M-component detectable by immunofixation but not on electrophoresis or >=90% reduction in serum and urine M-protein <100mg/24h. CR: negative immunofixation on serum/urine, Disappearance of soft tissue plasmacytomas, <5% PCs in bone marrow; sCR: CR in addition to normal FLC ratio, absence of clonal cells in bone marrow by IHC, immunofluorescence, 2-4 color FC. High risk: positive for any of del17p, t(14;16) or t(4;14) by FISH/Karyotype. ITT used. N=number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomization (Day -3) up to 6.6 years
    End point values
    		 Lenalidomide + Dexamethasone (Rd) Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Number of subjects analysed
    44
    48
    Units: Percentage of subjects
        number (not applicable)
    75.0
    91.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious and Other AEs: From start of treatment (Day 1) up to 6.6 years
    Adverse event reporting additional description
    Serious and Other AEs: Safety population was defined as subjects who have received at least 1 administration of any study treatment (partial or complete).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Daratumumab + Lenalidomide + Dexamethasone (DRd)
    Reporting group description
    		 Participants received Daratumumab 16 milligrams per kilograms (mg/kg) IV QW for the first 8 weeks (cycles 1-2) and then every 2 weeks (Q2W) for 16 weeks (Cycle 3-6), then every 4 weeks (Q4W) (from Cycle 7 and beyond) (each cycle of 28 days), Lenalidomide 25 mg capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or IV QW until disease progression or unacceptable toxicity up to 77.3 months. After implementation of Amendment 8, participants who were ongoing with daratumumab IV treatment were given an option to switch to daratumumab subcutaneous (SC) injection on Day 1 of any cycle, as per investigator’s discretion. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by IMWG criteria).

    Reporting group title
    Lenalidomide + Dexamethasone (Rd)
    Reporting group description
    		 Participants received Lenalidomide 25 milligrams (mg) capsule orally daily on Day 1 through Day 21 of each 28-day cycle, Dexamethasone 40 mg orally or intravenously (IV) once a week (QW) until disease progression or unacceptable toxicity up to 77.5 months. After completion of treatment, participants entered follow-up phase and were not started on subsequent anti-myeloma therapy without confirmed disease progression (assessed by the International Myeloma Working Group [IMWG] criteria).

    Serious adverse events
    		 Daratumumab + Lenalidomide + Dexamethasone (DRd) Lenalidomide + Dexamethasone (Rd)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    287 / 364 (78.85%)
    259 / 365 (70.96%)
         number of deaths (all causes)
    287
    259
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Adrenal adenoma
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B precursor type acute leukaemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    6 / 364 (1.65%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    5 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Breast cancer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal neoplasm
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Leiomyosarcoma
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucinous adenocarcinoma of appendix
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Porocarcinoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Primary pulmonary melanoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    7 / 364 (1.92%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    5 / 8
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 364 (0.27%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    6 / 364 (1.65%)
    10 / 365 (2.74%)
         occurrences causally related to treatment / all
    6 / 6
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Air embolism
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteritis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    5 / 364 (1.37%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 364 (0.00%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    7 / 364 (1.92%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 364 (0.55%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Malaise
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granuloma
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 364 (0.82%)
    12 / 365 (3.29%)
         occurrences causally related to treatment / all
    0 / 4
    6 / 18
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Fatigue
         subjects affected / exposed
    4 / 364 (1.10%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    20 / 364 (5.49%)
    12 / 365 (3.29%)
         occurrences causally related to treatment / all
    11 / 24
    7 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Sudden death
         subjects affected / exposed
    1 / 364 (0.27%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Procedural failure
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical deconditioning
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterocele
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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
    Cough
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial disorder
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    4 / 364 (1.10%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    3 / 364 (0.82%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 364 (1.65%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    3 / 7
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 364 (0.27%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    16 / 364 (4.40%)
    14 / 365 (3.84%)
         occurrences causally related to treatment / all
    14 / 17
    14 / 14
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    6 / 364 (1.65%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    6 / 8
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Personality change
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    3 / 364 (0.82%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eating disorder
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    4 / 364 (1.10%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Agitation
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radial pulse abnormal
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occult blood positive
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hip fracture
         subjects affected / exposed
    4 / 364 (1.10%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    8 / 364 (2.20%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    7 / 364 (1.92%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    2 / 364 (0.55%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fever
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound necrosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Corneal dystrophy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 364 (0.27%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 364 (0.82%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    10 / 364 (2.75%)
    15 / 365 (4.11%)
         occurrences causally related to treatment / all
    6 / 16
    8 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 364 (0.00%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 364 (0.55%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 364 (0.82%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    1 / 2
    1 / 2
    Cardiac failure chronic
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    5 / 364 (1.37%)
    11 / 365 (3.01%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac amyloidosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocarditis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 364 (0.55%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Mitral valve incompetence
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 364 (0.82%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain oedema
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    3 / 364 (0.82%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 364 (1.37%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    4 / 6
    6 / 6
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Nervous system disorder
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 364 (0.55%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperaesthesia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    4 / 364 (1.10%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Occipital neuralgia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    5 / 364 (1.37%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 364 (0.55%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIth nerve paralysis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar stroke
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    11 / 364 (3.02%)
    9 / 365 (2.47%)
         occurrences causally related to treatment / all
    10 / 11
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 364 (1.65%)
    12 / 365 (3.29%)
         occurrences causally related to treatment / all
    3 / 6
    9 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 364 (0.82%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 364 (0.55%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deafness bilateral
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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 / 364 (1.10%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    2 / 6
    6 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 364 (1.37%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 364 (0.55%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 364 (1.10%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    11 / 364 (3.02%)
    7 / 365 (1.92%)
         occurrences causally related to treatment / all
    8 / 12
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    5 / 364 (1.37%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 364 (0.55%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Gastric ulcer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Inguinal hernia strangulated
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    7 / 364 (1.92%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    5 / 364 (1.37%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis acute
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 7
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    4 / 6
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    6 / 364 (1.65%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 364 (0.82%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ecchymosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 364 (0.00%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 364 (0.00%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    14 / 364 (3.85%)
    15 / 365 (4.11%)
         occurrences causally related to treatment / all
    4 / 17
    9 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder neck sclerosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder stenosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal disorder
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    6 / 364 (1.65%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    2 / 6
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral caruncle
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 364 (0.55%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adrenal insufficiency
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Crystal arthropathy
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    4 / 364 (1.10%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone sequestrum
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    4 / 364 (1.10%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    14 / 364 (3.85%)
    9 / 365 (2.47%)
         occurrences causally related to treatment / all
    2 / 18
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    4 / 364 (1.10%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fistula
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    5 / 364 (1.37%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 364 (0.55%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    4 / 364 (1.10%)
    5 / 365 (1.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal synovial cyst
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    3 / 364 (0.82%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal sepsis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial diarrhoea
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    15 / 364 (4.12%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    14 / 18
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    6 / 364 (1.65%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    4 / 364 (1.10%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    5 / 364 (1.37%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    3 / 5
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis staphylococcal
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis viral
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    7 / 364 (1.92%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 364 (0.00%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    11 / 364 (3.02%)
    12 / 365 (3.29%)
         occurrences causally related to treatment / all
    7 / 16
    6 / 18
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    16 / 364 (4.40%)
    8 / 365 (2.19%)
         occurrences causally related to treatment / all
    6 / 16
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis infectious
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         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 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    68 / 364 (18.68%)
    39 / 365 (10.68%)
         occurrences causally related to treatment / all
    66 / 89
    31 / 51
         deaths causally related to treatment / all
    2 / 3
    2 / 3
    Pneumonia bacterial
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nocardiosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 364 (0.82%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    3 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mycosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    11 / 364 (3.02%)
    10 / 365 (2.74%)
         occurrences causally related to treatment / all
    5 / 11
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sepsis syndrome
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic arthritis staphylococcal
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic embolus
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    6 / 364 (1.65%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    4 / 7
    3 / 4
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Skin infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 364 (0.27%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    12 / 364 (3.30%)
    7 / 365 (1.92%)
         occurrences causally related to treatment / all
    6 / 16
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteritis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    4 / 8
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval abscess
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    2 / 364 (0.55%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (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 / 364 (0.82%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 364 (1.65%)
    4 / 365 (1.10%)
         occurrences causally related to treatment / all
    2 / 7
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    3 / 364 (0.82%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 364 (0.82%)
    2 / 365 (0.55%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 364 (0.55%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 364 (0.27%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 364 (0.27%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 364 (0.27%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 364 (0.82%)
    6 / 365 (1.64%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 364 (0.55%)
    3 / 365 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 364 (0.27%)
    0 / 365 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 364 (0.00%)
    1 / 365 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daratumumab + Lenalidomide + Dexamethasone (DRd) Lenalidomide + Dexamethasone (Rd)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    362 / 364 (99.45%)
    358 / 365 (98.08%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    21 / 364 (5.77%)
    9 / 365 (2.47%)
         occurrences all number
    29
    17
    Vascular disorders
    Haematoma
         subjects affected / exposed
    31 / 364 (8.52%)
    23 / 365 (6.30%)
         occurrences all number
    36
    31
    Deep vein thrombosis
         subjects affected / exposed
    31 / 364 (8.52%)
    29 / 365 (7.95%)
         occurrences all number
    35
    30
    Hypertension
         subjects affected / exposed
    64 / 364 (17.58%)
    31 / 365 (8.49%)
         occurrences all number
    133
    51
    Hypotension
         subjects affected / exposed
    41 / 364 (11.26%)
    33 / 365 (9.04%)
         occurrences all number
    46
    37
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    134 / 364 (36.81%)
    98 / 365 (26.85%)
         occurrences all number
    261
    154
    Chills
         subjects affected / exposed
    49 / 364 (13.46%)
    6 / 365 (1.64%)
         occurrences all number
    55
    8
    Fatigue
         subjects affected / exposed
    163 / 364 (44.78%)
    114 / 365 (31.23%)
         occurrences all number
    370
    206
    Influenza like illness
         subjects affected / exposed
    21 / 364 (5.77%)
    17 / 365 (4.66%)
         occurrences all number
    37
    20
    Non-cardiac chest pain
         subjects affected / exposed
    23 / 364 (6.32%)
    21 / 365 (5.75%)
         occurrences all number
    26
    26
    Peripheral swelling
         subjects affected / exposed
    16 / 364 (4.40%)
    24 / 365 (6.58%)
         occurrences all number
    24
    32
    Pyrexia
         subjects affected / exposed
    85 / 364 (23.35%)
    63 / 365 (17.26%)
         occurrences all number
    122
    95
    Oedema peripheral
         subjects affected / exposed
    155 / 364 (42.58%)
    117 / 365 (32.05%)
         occurrences all number
    300
    210
    Immune system disorders
    Hypogammaglobulinaemia
         subjects affected / exposed
    19 / 364 (5.22%)
    3 / 365 (0.82%)
         occurrences all number
    23
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    122 / 364 (33.52%)
    65 / 365 (17.81%)
         occurrences all number
    207
    104
    Dysphonia
         subjects affected / exposed
    29 / 364 (7.97%)
    19 / 365 (5.21%)
         occurrences all number
    33
    22
    Dyspnoea
         subjects affected / exposed
    115 / 364 (31.59%)
    63 / 365 (17.26%)
         occurrences all number
    171
    88
    Dyspnoea exertional
         subjects affected / exposed
    29 / 364 (7.97%)
    25 / 365 (6.85%)
         occurrences all number
    31
    32
    Epistaxis
         subjects affected / exposed
    21 / 364 (5.77%)
    20 / 365 (5.48%)
         occurrences all number
    26
    32
    Nasal congestion
         subjects affected / exposed
    22 / 364 (6.04%)
    9 / 365 (2.47%)
         occurrences all number
    22
    10
    Oropharyngeal pain
         subjects affected / exposed
    31 / 364 (8.52%)
    10 / 365 (2.74%)
         occurrences all number
    37
    16
    Productive cough
         subjects affected / exposed
    23 / 364 (6.32%)
    11 / 365 (3.01%)
         occurrences all number
    29
    13
    Rhinorrhoea
         subjects affected / exposed
    30 / 364 (8.24%)
    12 / 365 (3.29%)
         occurrences all number
    32
    14
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    19 / 364 (5.22%)
    10 / 365 (2.74%)
         occurrences all number
    23
    12
    Anxiety
         subjects affected / exposed
    39 / 364 (10.71%)
    38 / 365 (10.41%)
         occurrences all number
    51
    48
    Confusional state
         subjects affected / exposed
    29 / 364 (7.97%)
    20 / 365 (5.48%)
         occurrences all number
    35
    26
    Depression
         subjects affected / exposed
    36 / 364 (9.89%)
    38 / 365 (10.41%)
         occurrences all number
    42
    44
    Insomnia
         subjects affected / exposed
    125 / 364 (34.34%)
    116 / 365 (31.78%)
         occurrences all number
    176
    184
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 364 (5.77%)
    15 / 365 (4.11%)
         occurrences all number
    45
    20
    Blood alkaline phosphatase increased
         subjects affected / exposed
    20 / 364 (5.49%)
    9 / 365 (2.47%)
         occurrences all number
    37
    15
    Blood creatinine increased
         subjects affected / exposed
    35 / 364 (9.62%)
    21 / 365 (5.75%)
         occurrences all number
    62
    27
    Weight decreased
         subjects affected / exposed
    112 / 364 (30.77%)
    69 / 365 (18.90%)
         occurrences all number
    162
    103
    Weight increased
         subjects affected / exposed
    28 / 364 (7.69%)
    8 / 365 (2.19%)
         occurrences all number
    34
    9
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    36 / 364 (9.89%)
    32 / 365 (8.77%)
         occurrences all number
    52
    40
    Fall
         subjects affected / exposed
    40 / 364 (10.99%)
    25 / 365 (6.85%)
         occurrences all number
    63
    30
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    27 / 364 (7.42%)
    33 / 365 (9.04%)
         occurrences all number
    36
    40
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    79 / 364 (21.70%)
    64 / 365 (17.53%)
         occurrences all number
    112
    87
    Dysgeusia
         subjects affected / exposed
    28 / 364 (7.69%)
    17 / 365 (4.66%)
         occurrences all number
    35
    17
    Hypoaesthesia
         subjects affected / exposed
    22 / 364 (6.04%)
    17 / 365 (4.66%)
         occurrences all number
    30
    27
    Memory impairment
         subjects affected / exposed
    20 / 364 (5.49%)
    11 / 365 (3.01%)
         occurrences all number
    25
    14
    Paraesthesia
         subjects affected / exposed
    67 / 364 (18.41%)
    31 / 365 (8.49%)
         occurrences all number
    95
    42
    Peripheral sensory neuropathy
         subjects affected / exposed
    111 / 364 (30.49%)
    66 / 365 (18.08%)
         occurrences all number
    182
    101
    Sciatica
         subjects affected / exposed
    26 / 364 (7.14%)
    19 / 365 (5.21%)
         occurrences all number
    33
    24
    Taste disorder
         subjects affected / exposed
    14 / 364 (3.85%)
    19 / 365 (5.21%)
         occurrences all number
    15
    20
    Tremor
         subjects affected / exposed
    64 / 364 (17.58%)
    52 / 365 (14.25%)
         occurrences all number
    97
    70
    Headache
         subjects affected / exposed
    79 / 364 (21.70%)
    43 / 365 (11.78%)
         occurrences all number
    127
    57
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    224 / 364 (61.54%)
    166 / 365 (45.48%)
         occurrences all number
    1199
    707
    Lymphopenia
         subjects affected / exposed
    72 / 364 (19.78%)
    48 / 365 (13.15%)
         occurrences all number
    281
    129
    Leukopenia
         subjects affected / exposed
    73 / 364 (20.05%)
    42 / 365 (11.51%)
         occurrences all number
    285
    110
    Anaemia
         subjects affected / exposed
    154 / 364 (42.31%)
    148 / 365 (40.55%)
         occurrences all number
    498
    381
    Thrombocytopenia
         subjects affected / exposed
    80 / 364 (21.98%)
    76 / 365 (20.82%)
         occurrences all number
    276
    227
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    22 / 364 (6.04%)
    19 / 365 (5.21%)
         occurrences all number
    27
    26
    Eye disorders
    Vision blurred
         subjects affected / exposed
    30 / 364 (8.24%)
    19 / 365 (5.21%)
         occurrences all number
    32
    24
    Cataract
         subjects affected / exposed
    88 / 364 (24.18%)
    78 / 365 (21.37%)
         occurrences all number
    109
    94
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    41 / 364 (11.26%)
    30 / 365 (8.22%)
         occurrences all number
    63
    35
    Constipation
         subjects affected / exposed
    156 / 364 (42.86%)
    136 / 365 (37.26%)
         occurrences all number
    259
    190
    Diarrhoea
         subjects affected / exposed
    237 / 364 (65.11%)
    186 / 365 (50.96%)
         occurrences all number
    683
    453
    Dry mouth
         subjects affected / exposed
    14 / 364 (3.85%)
    21 / 365 (5.75%)
         occurrences all number
    15
    22
    Dyspepsia
         subjects affected / exposed
    30 / 364 (8.24%)
    30 / 365 (8.22%)
         occurrences all number
    38
    33
    Gastrooesophageal reflux disease
         subjects affected / exposed
    23 / 364 (6.32%)
    24 / 365 (6.58%)
         occurrences all number
    26
    26
    Haemorrhoids
         subjects affected / exposed
    19 / 364 (5.22%)
    11 / 365 (3.01%)
         occurrences all number
    21
    14
    Nausea
         subjects affected / exposed
    132 / 364 (36.26%)
    87 / 365 (23.84%)
         occurrences all number
    224
    137
    Stomatitis
         subjects affected / exposed
    25 / 364 (6.87%)
    13 / 365 (3.56%)
         occurrences all number
    28
    16
    Toothache
         subjects affected / exposed
    20 / 364 (5.49%)
    20 / 365 (5.48%)
         occurrences all number
    21
    21
    Vomiting
         subjects affected / exposed
    77 / 364 (21.15%)
    48 / 365 (13.15%)
         occurrences all number
    110
    65
    Abdominal pain
         subjects affected / exposed
    59 / 364 (16.21%)
    43 / 365 (11.78%)
         occurrences all number
    84
    56
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    72 / 364 (19.78%)
    70 / 365 (19.18%)
         occurrences all number
    126
    89
    Pruritus
         subjects affected / exposed
    41 / 364 (11.26%)
    35 / 365 (9.59%)
         occurrences all number
    52
    45
    Night sweats
         subjects affected / exposed
    14 / 364 (3.85%)
    20 / 365 (5.48%)
         occurrences all number
    18
    23
    Hyperhidrosis
         subjects affected / exposed
    23 / 364 (6.32%)
    5 / 365 (1.37%)
         occurrences all number
    27
    5
    Dry skin
         subjects affected / exposed
    30 / 364 (8.24%)
    20 / 365 (5.48%)
         occurrences all number
    37
    26
    Erythema
         subjects affected / exposed
    30 / 364 (8.24%)
    22 / 365 (6.03%)
         occurrences all number
    38
    25
    Rash maculo-papular
         subjects affected / exposed
    23 / 364 (6.32%)
    10 / 365 (2.74%)
         occurrences all number
    27
    16
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    20 / 364 (5.49%)
    11 / 365 (3.01%)
         occurrences all number
    22
    12
    Acute kidney injury
         subjects affected / exposed
    34 / 364 (9.34%)
    17 / 365 (4.66%)
         occurrences all number
    44
    24
    Chronic kidney disease
         subjects affected / exposed
    37 / 364 (10.16%)
    23 / 365 (6.30%)
         occurrences all number
    55
    36
    Renal impairment
         subjects affected / exposed
    34 / 364 (9.34%)
    35 / 365 (9.59%)
         occurrences all number
    61
    45
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    105 / 364 (28.85%)
    78 / 365 (21.37%)
         occurrences all number
    173
    111
    Back pain
         subjects affected / exposed
    146 / 364 (40.11%)
    107 / 365 (29.32%)
         occurrences all number
    208
    163
    Bone pain
         subjects affected / exposed
    41 / 364 (11.26%)
    35 / 365 (9.59%)
         occurrences all number
    49
    49
    Muscle spasms
         subjects affected / exposed
    110 / 364 (30.22%)
    86 / 365 (23.56%)
         occurrences all number
    162
    154
    Muscular weakness
         subjects affected / exposed
    38 / 364 (10.44%)
    25 / 365 (6.85%)
         occurrences all number
    46
    37
    Musculoskeletal chest pain
         subjects affected / exposed
    39 / 364 (10.71%)
    45 / 365 (12.33%)
         occurrences all number
    49
    59
    Musculoskeletal pain
         subjects affected / exposed
    73 / 364 (20.05%)
    57 / 365 (15.62%)
         occurrences all number
    91
    66
    Myalgia
         subjects affected / exposed
    34 / 364 (9.34%)
    28 / 365 (7.67%)
         occurrences all number
    42
    35
    Neck pain
         subjects affected / exposed
    31 / 364 (8.52%)
    32 / 365 (8.77%)
         occurrences all number
    40
    40
    Osteoarthritis
         subjects affected / exposed
    29 / 364 (7.97%)
    21 / 365 (5.75%)
         occurrences all number
    36
    32
    Pain in extremity
         subjects affected / exposed
    81 / 364 (22.25%)
    59 / 365 (16.16%)
         occurrences all number
    109
    85
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    119 / 364 (32.69%)
    85 / 365 (23.29%)
         occurrences all number
    235
    150
    Cystitis
         subjects affected / exposed
    23 / 364 (6.32%)
    10 / 365 (2.74%)
         occurrences all number
    27
    12
    Gastroenteritis
         subjects affected / exposed
    36 / 364 (9.89%)
    22 / 365 (6.03%)
         occurrences all number
    41
    27
    Influenza
         subjects affected / exposed
    31 / 364 (8.52%)
    22 / 365 (6.03%)
         occurrences all number
    36
    22
    Lower respiratory tract infection
         subjects affected / exposed
    21 / 364 (5.77%)
    18 / 365 (4.93%)
         occurrences all number
    57
    35
    Nasopharyngitis
         subjects affected / exposed
    92 / 364 (25.27%)
    66 / 365 (18.08%)
         occurrences all number
    159
    104
    Pneumonia
         subjects affected / exposed
    64 / 364 (17.58%)
    36 / 365 (9.86%)
         occurrences all number
    76
    46
    Rhinitis
         subjects affected / exposed
    38 / 364 (10.44%)
    23 / 365 (6.30%)
         occurrences all number
    52
    36
    Sinusitis
         subjects affected / exposed
    26 / 364 (7.14%)
    17 / 365 (4.66%)
         occurrences all number
    34
    22
    Upper respiratory tract infection
         subjects affected / exposed
    93 / 364 (25.55%)
    52 / 365 (14.25%)
         occurrences all number
    197
    87
    Urinary tract infection
         subjects affected / exposed
    76 / 364 (20.88%)
    44 / 365 (12.05%)
         occurrences all number
    159
    88
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    93 / 364 (25.55%)
    65 / 365 (17.81%)
         occurrences all number
    126
    87
    Dehydration
         subjects affected / exposed
    23 / 364 (6.32%)
    18 / 365 (4.93%)
         occurrences all number
    36
    19
    Gout
         subjects affected / exposed
    19 / 364 (5.22%)
    17 / 365 (4.66%)
         occurrences all number
    24
    22
    Hyperglycaemia
         subjects affected / exposed
    54 / 364 (14.84%)
    28 / 365 (7.67%)
         occurrences all number
    174
    71
    Hyperkalaemia
         subjects affected / exposed
    19 / 364 (5.22%)
    10 / 365 (2.74%)
         occurrences all number
    26
    10
    Hypocalcaemia
         subjects affected / exposed
    59 / 364 (16.21%)
    35 / 365 (9.59%)
         occurrences all number
    123
    69
    Hypokalaemia
         subjects affected / exposed
    98 / 364 (26.92%)
    71 / 365 (19.45%)
         occurrences all number
    214
    150
    Hypomagnesaemia
         subjects affected / exposed
    30 / 364 (8.24%)
    32 / 365 (8.77%)
         occurrences all number
    76
    46
    Hyponatraemia
         subjects affected / exposed
    20 / 364 (5.49%)
    16 / 365 (4.38%)
         occurrences all number
    48
    26
    Hypophosphataemia
         subjects affected / exposed
    22 / 364 (6.04%)
    10 / 365 (2.74%)
         occurrences all number
    41
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2014
    The overall reason for the amendment was to make clarifications to MRD monitoring and investigator feedback was incorporated into the protocol.
    13 Apr 2015
    The overall reason for the amendment was to revise the exclusion criterion for hepatitis, based on feedback from the German PEI (Paul-Ehrlich-Institute) on a related ongoing daratumumab protocol.
    26 Aug 2015
    The overall reason for the amendment was to update the criteria for treatment discontinuation, based on feedback from the UK Medicines and Healthcare Products Regulatory Agency (MHRA).
    28 Aug 2015
    The overall reason for the amendment was to incorporate the Country specific change from from UK-1 into INT-2.
    17 Feb 2016
    The overall reason for the amendment was to incorporate feedback from the French National Ethics Committee regarding duration of contraceptive use from 4 to 3 months per Investigator’s Brochure (IB) and informed consent form (ICF) risk language.
    26 Aug 2016
    The overall reason for the amendment was to make revisions to clarify blood typing assessment during the screening phase by incorporating Indirect Antiglobulin (Coombs) Testing (IAT) due to the risk of daratumumab interference with blood typing. Also, further defined the exclusion criteria for hepatitis B and C, and Human Immunodeficiency Virus (HIV).
    02 Nov 2016
    The overall reason for the amendment was to revise the timepoints for the assessment of MRD-negativity to align with newly defined International Myeloma Working Group (IMWG) categories.
    14 Nov 2016
    The overall reason for the amendment was to incorporate country specific change from UK-1 into INT-3.
    22 May 2017
    The overall reason for the amendment was to make revision for subjects in the DRd group to continue treatment with lenalidomide and dexamethasone until disease progression or unacceptable toxicity based on continuous lenalidomide treatment emerging as the standard of care and consistent with the approved lenalidomide prescribing information. Previous version had lenalidomide and dexamethasone stopping at 2 years in the DRd group. Two subjects in the DRd group had treatment disruption due to implementing the amendment. One subject had met the 2-year mark while waiting for Institutional Review Board (IRB) approval of the amendment and received one month of treatment with daratumumab alone. The second subject signed the ICF for amendment 4 but Rd was discontinued at the 2-year mark in error.
    01 Jun 2017
    The overall reason for the amendment was to incorporate country specific change from UK-1 into INT-4.
    15 Jan 2019
    The overall reason for the amendment was following review of data from the second interim analysis by the Independent Data Monitoring Committee (IDMC), the study was amended to allow subjects in Arm A (Rd treatment group) access to daratumumab after sponsor confirmation of progressive disease (PD) per IMWG criteria.
    12 Jun 2019
    The overall reason for the amendment was to add or modify the text for identification of HBV reactivation, testing, and management of subjects with the potential for Hepatitis B Virus (HBV) reactivation in response to identification of a new important risk (HBV reactivation).
    17 Jan 2020
    The overall reason for the amendment was to make clarifications to study conduct to align with updates in daratumumab program. Quantitative immunoglobulin testing was no longer required. Confirmation of disease progression by sponsor was no longer required, except for subjects who progress on the Rd arm and then requested subsequent therapy with daratumumab.
    03 Apr 2020
    The overall reason for the amendment was to provide flexibility for study investigators to prioritize the safety of their patients during the global Coronavirus Disease 2019 (COVID-19) pandemic, and to ensure continuity of study treatment, while limiting subjects’ time spent at the study center, subjects were given the option to switch from daratumumab IV to daratumumab SC. Disease evaluations were to be performed locally per the site’s standard of care.
    20 Jul 2021
    The overall reason for the amendment was to define the clinical cutoff for the updated PFS analysis which marks the start of the long-term survival follow-up during which subjects will continue to receive study treatment and will be followed for OS.

    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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