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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Multicenter Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma

    Summary
    EudraCT number
    		 2013-000326-54
    Trial protocol
    		 FR   BE  
    Global end of trial date
    24 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2023
    First version publication date
    07 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C16014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01850524
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    95 Hayden Avenue, Lexington, MA, United States, 02421
    Public contact
    Study Director, Takeda, TrialDisclosures@takeda.com
    Scientific contact
    Study Director, Takeda, TrialDisclosures@takeda.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
    24 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to provide continued access to ixazomib and/or lenalidomide to participants who are continuing to have clinical benefit and to continue collecting relevant safety data to monitor safety in participants with Newly Diagnosed Multiple Myeloma (NDMM) who are not eligible for stem cell transplant.
    Protection of trial subjects
    Each participant signed an informed consent form before participating in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 262
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Japan: 59
    Country: Number of subjects enrolled
    Belgium: 73
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    United States: 147
    Country: Number of subjects enrolled
    Canada: 122
    Worldwide total number of subjects
    705
    EEA total number of subjects
    335
    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)
    19
    From 65 to 84 years
    658
    85 years and over
    28

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 238 investigative sites in multiple countries from 29 April 2013 to 24 June 2022.

    Pre-assignment
    Screening details
    		 Participants with newly diagnosed multiple myeloma were enrolled in 1:1 ratio to receive ixazomib or placebo in addition to the background therapy of Lenalidomide and Dexamethasone (LenDex) in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + LenDex
    Arm description
    		 Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo matching Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 for the first 18 cycles (each cycle was of 28 days).

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22 for the first 18 cycles (each cycle was of 28 days).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg capsules orally on Days 1-21.

    Arm title
    		 Ixazomib + LenDex
    Arm description
    		 Participants who were randomly assigned to receive Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ixazomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 for the first 18 cycles (each cycle was of 28 days). Following cycle 18 participants received 3.0 mg ixazomib capsule as a single oral dose on Days 1, 8 and 15 in each 28-day cycle.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22 for the first 18 cycles (each cycle was of 28 days).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide 25 mg capsules orally on Days 1-21 for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, Participants received lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle.

    Number of subjects in period 1
    		Placebo + LenDex Ixazomib + LenDex
    Started
    354
    351
    Intent-to-Treat (ITT) Population
    354
    351
    Completed Study Treatment Per Protocol
    283
    284
    Per Protocol (PP) Population
    293
    296
    Participants With Exposure of ≥ 19 Cycle
    189
    191
    Response-evaluable Population
    347
    335
    Completed
    183
    178
    Not completed
    171
    173
         Withdrawal by Subject
    24
    22
         Lost to follow-up
    5
    10
         Reason not specified
    142
    141

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + LenDex
    Reporting group description
    		 Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Reporting group title
    Ixazomib + LenDex
    Reporting group description
    		 Participants who were randomly assigned to receive Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Reporting group values
    		 Placebo + LenDex Ixazomib + LenDex Total
    Number of subjects
    		 354 351 705
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.7 ( 5.91 ) 73.5 ( 6.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 172 179 351
        Male
    		 182 172 354
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 14 12 26
        Not Hispanic or Latino
    		 340 337 677
        Unknown or Not Reported
    		 0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 2 3
        Asian
    		 52 44 96
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 13 11 24
        White
    		 285 291 576
        Unknown or Not Reported
    		 3 2 5
    Height
    'n= 341, 339'. 'n' indicates number of participants available for analysis at baseline
    Units: centimetre
        arithmetic mean (standard deviation)
    		 164.7 ( 10.04 ) 164.3 ( 10.13 ) -
    Body Surface Area (BSA)
    'n= 341, 339'. 'n' indicates number of participants available for analysis at baseline. BSA = square root of (height x weight/3600)
    Units: square metre
        arithmetic mean (standard deviation)
    		 1.789 ( 0.2306 ) 1.810 ( 0.2456 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 70.53 ( 15.353 ) 72.67 ( 16.995 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo + LenDex
    Reporting group description
    		 Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib matching placebo capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Reporting group title
    Ixazomib + LenDex
    Reporting group description
    		 Participants who were randomly assigned to receive Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) for the first 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Subject analysis set title
    Placebo + LenDex (Exposure Up to 18 Cycles)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days).

    Subject analysis set title
    Ixazomib+ LenDex (Exposure Up to 18 Cycles)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomly assigned to receive Ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days).

    Subject analysis set title
    Placebo + LenDex (Exposure ≥19 Cycles)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomly assigned to receive placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib placebo matching capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Subject analysis set title
    Ixazomib + LenDex (Exposure ≥19 Cycles)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomly assigned to receive Ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Subject analysis set title
    Ixazomib
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were randomly assigned to receive Ixazomib 4.0 mg capsules orally once on Days 1,8,15 and lenalidomide 25 mg capsules orally on days 1-21 and dexamethasone 40 mg tablets orally on Days 1,8, 15 and 22, during every 28-day cycle for the first 18 cycles. After Cycle 18 dexamethasone was discontinued and participants continued to receive ixazomib capsule and lenalidomide at reduced doses until progressive disease or unacceptable toxicity, whichever comes first, up to end of study (up to approximately 109 months).

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death due to any cause according to International Myeloma Working Group (IMWG) criteria whichever occurs first. PD required one of the following: Increase of >=25% from nadir in: Serum M-component and/or (the absolute increase must be >=0.5 g/dL); Urine M-component and/or (the absolute increase must be >=200 mg/24 hours); in participants without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels (absolute increase must be > 10 mg/dL); Bone marrow plasma cell percentage: the absolute % must be >10%; development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.85 mmol/L). ITT population included all participants who were randomized.
    End point type
    Primary
    End point timeframe
    Up to approximately 79 months
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    21.8 (19.65 to 30.78)
    35.3 (26.45 to 43.70)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.073 [1]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 1.018
    Notes
    [1] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization to the date of death. Participants without documented death at the time of analysis are censored at the date last known to be alive. ITT population included all participants who were randomized. 99999 indicates that Median and Upper limit of Confidence Interval (CI) was not estimable due to censoring of participants as most participants were still alive during last contact.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to death due to any cause (Up to approximately 9 years)
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    99999 (58.71 to 99999)
    99999 (63.18 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Ixazomib + LenDex v Placebo + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.988 [3]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.998
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.261
    Notes
    [2] - Hazard ratio is based on an Unadjusted Cox’s proportional hazard regression model is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [3] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use

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    End point title
    		 Pain Response Rate as Assessed by the Brief Pain Inventory- Short Form (BPI-SF) and Analgesic Use
    End point description
    Pain response rate was defined as percentage of participants with pain response. Pain response was defined as the occurrence of at least a 30% reduction from baseline in BPI-SF worst pain score over the last 24 hours without an increase in analgesic use for 2 consecutive measurements > 28 days apart, were reported. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable). Percentages are rounded off to the nearest single decimal. ITT population included all participants who were randomized. 'N' indicates overall number of participants with baseline worst pain score>=4 as assessed by m-BPI-SF.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    195
    190
    Units: percentage of participants
        number (not applicable)
    51.3
    50.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.9195 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.656
         upper limit
    		 1.463
    Notes
    [4] - Odds ratio > 1 favors Ixazomib+LenDex versus LenDex alone.
    [5] - Logistic regression model with prognostic factor: age (<75 years vs >=75) and ISS (stage I or II vs stage III).

    Secondary: Complete Response (CR) Rate

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    End point title
    		 Complete Response (CR) Rate
    End point description
    CR rate was defined as the percentage of participants who achieve CR assessed by an IRC relative to the intent-to-treat (ITT) population during the treatment period. Percentage of participants with CR, as assessed by IMWG disease assessment criteria were reported. CR was defined as negative immunofixation of serum and urine along with the disappearance of any soft tissue plasmacytomas and <5 % plasma cells (PC’s) in bone marrow. ITT population included all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: percentage of participants
        number (not applicable)
    14
    26
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001 [7]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.43
         upper limit
    		 3.09
    Notes
    [6] - Odds ratio and confidence interval are based on logistic regression model with treatment group as categorical predictor variable,age(<75 years vs >=75), ISS(stage I or II vs stage III),and BPI-SF worst pain score(<4 vs >=4)at screening as covariates.
    [7] - CMH test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants who achieved CR + partial response (PR) + very good partial response (VGPR) (including sCR) or better relative to the ITT population during treatment period. CR was defined as negative immunofixation of serum and urine along with the disappearance of any soft tissue plasmacytomas and <5 % PC’s in bone marrow. PR was defined as ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% along with ≥50% reduction in the size of soft tissue plasmacytomas. VGPR was defined as ≥90% in serum M-component plus urine M-component <100 mg/24. sCR is defined as stringent complete response. Percentages are rounded off to nearest whole numbers. ITT population included all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: percentage of participants
        number (not applicable)
    80
    82
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.436 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.7
    Notes
    [8] - Odds ratio and confidence interval are based on logistic regression model with treatment group as categorical predictor variable,age(<75 years vs >=75), ISS(stage I or II vs stage III),and BPI-SF worst pain score(<4 vs >=4)at screening as covariates.
    [9] - CMH test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response was defined as the time from the date of randomization to the first documentation of PR or better, as measured by IMWG criteria. ITT population included all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    1.87 (1.15 to 1.87)
    1.02 (0.99 to 1.08)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.001 [11]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.402
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.185
         upper limit
    		 1.659
    Notes
    [10] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [11] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Progression Free Survival (PFS)-2

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    End point title
    		 Progression Free Survival (PFS)-2
    End point description
    PFS2 was defined as the time from the date of randomization to the date of documentation of disease progression on the subsequent line of anticancer therapy, as assessed by the investigator in accordance with IMWG criteria, or death due to any cause, whichever occurs first. ITT population included all participants who were randomized. 99999 indicated that Upper limit of CI was not estimable to due insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    52.2 (45.21 to 61.90)
    63.2 (54.70 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.189 [13]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.859
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 1.078
    Notes
    [12] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [13] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression was defined as the time from randomization to the date of first documented disease progression. ITT population included all participants who were randomized.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    26.8 (21.22 to 37.91)
    45.8 (31.84 to 56.25)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.008 [15]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.738
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.589
         upper limit
    		 0.925
    Notes
    [14] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [15] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response was measured as the time from the date of first documentation of PR or better to the date of first documented progression (PD) for responders, as measured by IMWG criteria. Response-evaluable population was defined as all participants in the ITT population who receive at least 1 dose of any study drug, have measurable disease at baseline, and at least 1 post baseline response assessment assessed by an IRC. Overall number of participants analyzed are the number of responders. 99999 indicates that Upper limit of CI was not estimable as participants without documentation of PD at the date of last response assessment that is stable disease (SD) or better were censored.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    281
    287
    Units: months
        median (confidence interval 95%)
    37.5 (25.69 to 50.27)
    50.6 (39.98 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline to Worst Value in Eastern Cooperative Oncology Group (ECOG) Performance Score

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    End point title
    		 Number of Participants With Shifts From Baseline to Worst Value in Eastern Cooperative Oncology Group (ECOG) Performance Score
    End point description
    Eastern Cooperative Oncology Group (ECOG) scale score ranged from 0 to 5, where 0 indicated normal activity and 5 indicated death. The data is reported for those categories where at least 1 participant had worst post-baseline value for each ECOG score. Safety population is defined as all participants who receive at least 1 dose of any study drug. 'N' indicates overall number of participants available for analysis.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    344
    340
    Units: participants
        Baseline Score 0, Post-Baseline Score 0
    23
    23
        Baseline Score 0, Post-Baseline Score 1
    57
    52
        Baseline Score 0, Post-Baseline Score 2
    20
    23
        Baseline Score 0, Post-Baseline Score 3
    2
    10
        Baseline Score 1, Post-Baseline Score 0
    1
    1
        Baseline Score 1, Post-Baseline Score 1
    96
    104
        Baseline Score 1, Post-Baseline Score 2
    72
    57
        Baseline Score 1, Post-Baseline Score 3
    18
    9
        Baseline Score 1, Post-Baseline Score 4
    6
    4
        Baseline Score 2, Post-Baseline Score 1
    12
    8
        Baseline Score 2, Post-Baseline Score 2
    28
    35
        Baseline Score 2, Post-Baseline Score 3
    7
    11
        Baseline Score 2, Post-Baseline Score 4
    2
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.Safety population= participants who receive at least 1 dose of any study drug. Data for safety is summarized as per duration of exposure to study treatment (exposure up to 18 cycles; exposure ≥19 cycles)
    End point type
    Secondary
    End point timeframe
    From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)
    End point values
    		 Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
    Number of subjects analysed
    160
    163
    189
    191
    Units: participants
        TEAEs
    160
    163
    189
    191
        SAEs
    105
    119
    119
    125
    No statistical analyses for this end point

    Secondary: Number of Participants With Abnormal Serum Chemistry and Hematology Laboratory Values Based on Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants With Abnormal Serum Chemistry and Hematology Laboratory Values Based on Treatment-emergent Adverse Events (TEAEs)
    End point description
    Laboratory values assessment included serum chemistry and hematology. Serum chemistry assessment - blood urea nitrogen(BUN), creatinine, bilirubin(total), urate, lactate dehydrogenase, phosphate, albumin, alkaline phosphatase(ALP), aspartate aminotransferase(AST), alanine aminotransferase(ALT), glucose, sodium, potassium, calcium, chloride, carbon dioxide(CO2), magnesium, thyroid stimulating hormone(TSH). Hematology assessment - hemoglobin, hematocrit, platelet(count), leukocytes with differential neutrophils(ANC). Participants with abnormal serum chemistry and hematology values reported as TEAEs are reported. TEAEs: events that occurred after administration of first dose of any agent in study drug regimen and through 30 days after last dose of any agent in study drug regimen. Safety population:participants who receive at least 1 dose of any study drug. Data for safety is summarized as per duration of exposure to study treatment(exposure up to 18 cycles; exposure ≥19 cycles).
    End point type
    Secondary
    End point timeframe
    From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)
    End point values
    		 Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
    Number of subjects analysed
    160
    163
    189
    191
    Units: participants
        Hypokalaemia
    16
    33
    33
    39
        Blood creatinine increased
    9
    6
    12
    16
        Hypophosphataemia
    2
    9
    3
    9
        Hypomagnesaemia
    8
    6
    11
    15
        Hyponatraemia
    7
    10
    8
    7
        Hyperglycaemia
    4
    7
    16
    6
        Hypocalcaemia
    13
    6
    12
    4
        Hyperkalaemia
    3
    7
    3
    3
        Alanine aminotransferase increased
    1
    1
    4
    10
        Iron deficiency
    2
    1
    2
    7
        Hypercalcaemia
    6
    2
    1
    5
        Creatinine renal clearance decreased
    2
    1
    7
    4
        Hypoalbuminaemia
    5
    2
    1
    3
        Aspartate aminotransferase increased
    1
    0
    3
    5
        Hyperuricaemia
    2
    2
    1
    2
        Anaemia
    57
    53
    52
    58
        Thrombocytopenia
    15
    34
    14
    24
        Neutropenia
    36
    15
    48
    39
        Neutrophil count decreased
    11
    5
    13
    18
        Platelet count decreased
    6
    6
    4
    15
        Lymphopenia
    0
    7
    2
    4
        Febrile neutropenia
    5
    7
    2
    2
        Leukopenia
    3
    6
    4
    2
        International normalised ratio increased
    1
    4
    0
    4
        Pancytopenia
    2
    3
    1
    2
        Iron deficiency anaemia
    1
    1
    1
    4
        White blood cell count decreased
    5
    1
    3
    2
        Lymphocyte count decreased
    1
    2
    3
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score

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    End point title
    		 Change From Baseline in Health-Related Quality of Life (HRQOL) Measured by European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C30 Scale Total Score
    End point description
    EORTC-QLQ-C30 scale (30 items) was used to assess HRQOL. Subscale with individual items:physical functioning items 1-5, role functioning items 6-7, emotional functioning items 21-24, cognitive functioning items 20, 25, social functioning items 26-27, quality of life items 29-30, fatigue items 10, 12, 18, nausea and vomiting items 14-15, pain items 9, 19, dyspnoea item 8, insomnia item 11, appetite loss item 13, constipation item 16, diarrhoea item 17, financial difficulties item 28. Raw scores were converted into scale scores ranging from 0 to 100. Functional scales and global health status(GHS) scale:higher scores=better HRQOL. Symptom scales:lower scores=better HRQOL. Positive change in functional and global health status scale=improvement; negative change for symptom scales=improvement. ITT population. 'N' indicates overall number of participants available for analyses. 'n' indicates number of participants available for analysis at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    353
    351
    Units: score on a scale
    arithmetic mean (standard deviation)
        GHS/QOL Baseline (n= 352, 351)
    55.2 ( 23.53 )
    56.4 ( 23.66 )
        GHS/QOL End of Treatment (EOT) (n= 220, 217)
    -2.2 ( 26.03 )
    -4.1 ( 29.48 )
        Physical Functioning: Baseline (n= 353, 350)
    60.0 ( 28.73 )
    61.4 ( 27.96 )
        Physical Functioning: EOT (n= 223, 217)
    1.7 ( 26.81 )
    0.3 ( 28.23 )
        Role Functioning: Baseline (n= 352, 350)
    54.9 ( 36.52 )
    56.5 ( 36.60 )
        Role Functioning: EOT (n= 223, 217)
    -0.3 ( 36.25 )
    -1.8 ( 36.74 )
        Emotional Functioning: Baseline (n= 353, 351)
    73.5 ( 23.09 )
    72.6 ( 24.84 )
        Emotional Functioning: EOT (n= 222, 217)
    -2.4 ( 21.70 )
    -0.5 ( 24.35 )
        Cognitive Functioning: Baseline (n= 353, 351)
    77.8 ( 22.97 )
    78.3 ( 25.92 )
        Cognitive Functioning: EOT (n= 222, 217)
    -3.2 ( 25.14 )
    -5.1 ( 24.70 )
        Social Functioning: Baseline (n= 351, 351)
    69.1 ( 32.54 )
    69.5 ( 33.01 )
        Social Functioning: EOT (n= 220, 217)
    -2.9 ( 31.56 )
    -2.5 ( 36.57 )
        Fatigue: Baseline (n= 353, 350)
    44.6 ( 28.30 )
    40.8 ( 27.69 )
        Fatigue: EOT (n= 223, 218)
    -2.3 ( 27.75 )
    4.5 ( 31.04 )
        Pain: Baseline (n= 353, 351)
    45.6 ( 34.04 )
    42.5 ( 33.51 )
        Pain: EOT (n= 225, 218)
    -5.5 ( 33.77 )
    -3.5 ( 34.55 )
        Nausea and Vomiting: Baseline (n= 353, 350)
    7.1 ( 15.75 )
    8.1 ( 18.49 )
        Nausea and Vomiting: EOT (n= 224, 218)
    -0.5 ( 19.80 )
    1.6 ( 25.22 )
        Dyspnoea: Baseline (n= 352, 350)
    26.2 ( 30.25 )
    24.0 ( 29.35 )
        Dyspnoea: EOT (n= 222, 217)
    -3.6 ( 30.86 )
    2.8 ( 33.83 )
        Insomnia: Baseline (n= 353, 350)
    30.3 ( 30.31 )
    34.3 ( 32.20 )
        Insomnia: EOT (223, 217)
    -1.5 ( 35.06 )
    -1.1 ( 36.06 )
        Appetite Loss: Baseline (n= 353, 350)
    25.4 ( 33.14 )
    25.5 ( 33.04 )
        Appetite Loss: EOT (n= 223, 218)
    -1.2 ( 37.42 )
    3.4 ( 38.65 )
        Constipation: Baseline (n= 352, 351)
    25.9 ( 32.94 )
    24.9 ( 32.19 )
        Constipation: EOT (n= 222, 218)
    -7.1 ( 39.03 )
    -5.7 ( 35.83 )
        Diarrhoea: Baseline (n= 352, 351)
    8.2 ( 19.45 )
    6.7 ( 16.58 )
        Diarrhoea: EOT (n= 221, 217)
    10.7 ( 27.72 )
    18.3 ( 31.73 )
        Financial Difficulties: Baseline (n= 352, 351)
    12.5 ( 24.04 )
    12.3 ( 24.03 )
        Financial Difficulties: EOT (n= 220, 216)
    2.0 ( 27.42 )
    0.8 ( 25.61 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in HRQOL Measured by EORTC-QLQ-MY20 Scale

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    End point title
    		 Change From Baseline in HRQOL Measured by EORTC-QLQ-MY20 Scale
    End point description
    EORTC QLQ-MY20 was a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. The scale has 20 questions. Subscale and individual items include future perspective items 18-20, body image item 17, disease symptoms items 1-6, side effects of treatment items 7-16. Raw scores are averaged, and transformed to 0-100 scale, where higher score is better quality of life. Positive change indicates improvement. ITT population included all participants who were randomized. 'N' indicates overall number of participants available for analyses. 'n' indicates the number of participants available for analysis at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    352
    350
    Units: score on a scale
    arithmetic mean (standard deviation)
        Disease Symptoms: Baseline (n= 352, 350)
    30.3 ( 23.76 )
    29.2 ( 22.97 )
        Disease Symptoms: EOT (222, 215)
    -3.1 ( 20.74 )
    -5.3 ( 22.44 )
        Side-Effects: Baseline (352, 350)
    18.0 ( 14.53 )
    17.6 ( 15.04 )
        Side-Effects: EOT (n= 222, 214)
    1.7 ( 14.52 )
    3.3 ( 15.91 )
        Body Image: Baseline (n= 346, 346)
    81.7 ( 27.67 )
    81.2 ( 29.11 )
        Body Image: EOT (n= 215, 207)
    -7.8 ( 31.93 )
    -2.3 ( 29.66 )
        Future Perspective: Baseline (n= 350, 349)
    57.3 ( 25.95 )
    55.0 ( 28.47 )
        Future Perspective: EOT (220, 211)
    4.4 ( 24.85 )
    6.0 ( 25.69 )
    No statistical analyses for this end point

    Secondary: OS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations

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    End point title
    		 OS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations
    End point description
    OS was defined as the time from the date of randomization to the date of death, as assessed in high-risk population carrying del(17p), t(4;14), or t(14;16) mutations. High risk category includes t(4;14), t(14;16), or del(17) abnormalities. ITT population included all participants who were randomized. 'N' indicates overall number of participants from the high-risk category. 99999 indicated that upper range of CI was not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to death due to any cause (Up to approximately 9 years)
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    63
    60
    Units: months
        median (confidence interval 95%)
    43.1 (33.84 to 57.82)
    39.0 (25.43 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    OS in High-risk Population Carrying Del(17p), Amp(1q21), t(4;14), or t(14;16) Mutations
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.662 [17]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.118
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.678
         upper limit
    		 1.845
    Notes
    [16] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [17] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: PFS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations

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    End point title
    		 PFS in High-risk Population Carrying Del(17p), t(4;14), or t(14;16) Mutations
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of progressive disease based on central laboratory results and IMWG criteria as evaluated by an independent review committee (IRC) or death due to any cause, whichever occurs first, as assessed in high-risk population carrying del(17p), t(4;14), or t(14;16) mutations. ITT population included all participants who were randomized. 'N' indicates overall number of participants from the high-risk category.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    63
    60
    Units: months
        median (confidence interval 95%)
    17.5 (12.12 to 20.30)
    22.4 (12.16 to 42.84)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    PFS in High-risk Population Carrying del(17p), t(4;14), or t(14;16) Mutations
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.271 [19]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.466
         upper limit
    		 1.24
    Notes
    [18] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [19] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Time to Pain Progression

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    End point title
    		 Time to Pain Progression
    End point description
    Time to pain progression was assessed as the time from randomization to the date of initial progression classification. Pain progression was defined as the occurrence of 1 of the following and confirmed by 2 consecutive evaluations (To qualify as progression, the participant must have a BPI-SF worst pain score > 4 during pain progression): 1) a ≥ 2 point and 30% increase from Baseline in BPI-SF worst pain score without an increase in analgesic use, or 2) a 25% or more increase in analgesic use from Baseline without a decrease in BPI-SF worst pain score from Baseline. Brief Pain Inventory - Short Form (m-BPI-SF) is a participant rated 11-point Likert rating scale ranged from 0 (no pain) to 10 (worst pain imaginable). ITT population included all participants who were randomized. 99999 indicates that Median, upper limit and/or lower limit of CI was not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    354
    351
    Units: months
        median (confidence interval 95%)
    47.1 (30.88 to 99999)
    99999 (57.59 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Time to Pain Progression
    Comparison groups
    Placebo + LenDex v Ixazomib + LenDex
    Number of subjects included in analysis
    705
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.26 [21]
    Method
    		 Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.661
         upper limit
    		 1.12
    Notes
    [20] - Hazard ratio is based on an unadjusted Cox’s proportional hazard regression model stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.
    [21] - Log-rank test is stratified by age (<75 years vs >=75), ISS (stage I or II vs stage III), and BPI-SF worst pain score (<4 vs >=4) at screening.

    Secondary: Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry

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    End point title
    		 Percentage of Participants With MRD-Negative Status as Assessed by Flow Cytometry
    End point description
    The absence of minimal residual disease (MRD negativity) was tested in all participants who achieve a CR and maintained it until Cycle 18, using bone marrow aspirates. Response-evaluable population includes all participants in the ITT population who receive at least 1 dose of any study drug, have measurable disease at baseline, and at least 1 post baseline response assessment assessed by an IRC.
    End point type
    Secondary
    End point timeframe
    Up to approximately 9 years
    End point values
    		 Placebo + LenDex Ixazomib + LenDex
    Number of subjects analysed
    347
    335
    Units: percentage of participants
        number (not applicable)
    50
    59
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Plasma Concentration for Ixazomib

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    End point title
    		 Cmax: Maximum Plasma Concentration for Ixazomib
    End point description
    Pharmacokinetic (PK) analysis population is defined as subjects with at least one PK sample that was collected and analyzed. 'N' indicates overall number of participants available for analyses. 'n' indicates number of participants available for analysis at the given timepoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: Post-dose at multiple timepoints up to 4 hours; Pre-dose at Cycle 1 Day 14, Cycles 2-3 Day 1 and Day 14, Cycles 4-11 Day 1 (Each cycle length = 28 days)
    End point values
    		 Ixazomib
    Number of subjects analysed
    331
    Units: millilitre(s)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 1 Hour Post-dose (n= 331)
    44.745 ( 35.9404 )
        Cycle 1 Day 1: 4 Hours Post-dose (n= 320)
    16.253 ( 17.0407 )
        Cycle 1 Day 14: Pre-dose (n= 327)
    7.867 ( 15.4420 )
        Cycle 2 Day 1: Pre-dose (n= 320)
    2.664 ( 2.2770 )
        Cycle 2 Day 14: Pre-dose (n= 302)
    8.521 ( 14.7411 )
        Cycle 3 Day 1: Pre-dose (n= 300)
    2.763 ( 1.6318 )
        Cycle 3 Day 14: Pre-dose (n= 275)
    8.490 ( 17.6720 )
        Cycle 4 Day 1: Pre-dose (n= 284)
    3.284 ( 6.1116 )
        Cycle 5 Day 1: Pre-dose (n= 270)
    3.594 ( 13.2046 )
        Cycle 6 Day 1: Pre-dose (n= 260)
    2.603 ( 1.5242 )
        Cycle 7 Day 1: Pre-dose (n= 258)
    2.598 ( 1.4658 )
        Cycle 8 Day 1: Pre-dose (n= 251)
    2.539 ( 1.5549 )
        Cycle 9 Day 1: Pre-dose (n= 242)
    2.593 ( 2.0867 )
        Cycle 10 Day 1: Pre-dose (n= 238)
    2.536 ( 1.7431 )
        Cycle 11 Day 1: Pre-dose (n=224)
    2.667 ( 4.5448 )
        Cycle 12 Day 1: Pre-dose (n=217)
    2.686 ( 1.8949 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs)

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    End point title
    		 Percentage of Participants With New or Worsening of Existing Skeletal-related Events (SREs)
    End point description
    SRE is defined as new fractures [including vertebral compression fractures], irradiation of or surgery on bone, or spinal cord compression. Safety population is defined as all participants who receive at least 1 dose of any study drug. Data for safety is summarized as per the duration of exposure to study treatment (exposure up to 18 cycles; exposure ≥19 cycles).
    End point type
    Secondary
    End point timeframe
    From the date of randomization through 30 days after the last dose of study drug up to end of study (up to approximately 9 years)
    End point values
    		 Placebo + LenDex (Exposure Up to 18 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles)
    Number of subjects analysed
    160
    163
    189
    191
    Units: percentage of participants
        number (not applicable)
    14
    10
    28
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of randomization through 30 days after the last dose of study drug up to end of study (approximately 9 years)
    Adverse event reporting additional description
    Safety population.4 participants randomized to placebo received ixazomib during study and were included in ixazomib arm for safety population. 1 participant randomized to each arm withdrew from study and was not included. Data for safety is summarized per the duration of exposure to study treatment (exposure up to 18 cycles;exposure ≥19 cycles).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Placebo + LenDex (Exposure Up to 18 Cycles)
    Reporting group description
    		 -

    Reporting group title
    Placebo + LenDex (Exposure ≥19 Cycles)
    Reporting group description
    		 Participants who were randomly assigned to receive Placebo were administered ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib placebo matching capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Reporting group title
    Ixazomib + LenDex (Exposure ≥19 Cycles)
    Reporting group description
    		 Participants who were randomly assigned to receive Ixazomib were administered ixazomib 4.0 mg placebo matching capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days). Following Cycle 18, participants received 3.0 mg ixazomib capsule as single oral dose on Days 1, 8 and 15 along with lenalidomide 10 mg capsules orally on Days 1-21 in each 28-day cycle until progressive disease or unacceptable toxicity, whichever comes first up to end of study (up to approximately 109 months).

    Reporting group title
    Ixazomib+ LenDex (Exposure Up to 18 Cycles)
    Reporting group description
    		 Participants who were randomly assigned to receive Ixazomib were administered ixazomib 4.0 mg capsule single oral dose on Days 1, 8 and 15 along with standard regimen of LenDex (lenalidomide 25 mg capsules orally on Days 1-21 and dexamethasone 40 mg tablets orally on Days 1, 8, 15 and 22) up to 18 cycles (each cycle was of 28 days).

    Serious adverse events
    		 Placebo + LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    105 / 160 (65.63%)
    119 / 189 (62.96%)
    125 / 191 (65.45%)
    119 / 163 (73.01%)
         number of deaths (all causes)
    107
    63
    63
    95
         number of deaths resulting from adverse events
    17
    5
    7
    21
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute erythroid leukaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 160 (0.63%)
    6 / 189 (3.17%)
    12 / 191 (6.28%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    6 / 6
    8 / 15
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal adenocarcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung carcinoma cell type unspecified stage I
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large granular lymphocytosis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcomatoid carcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    4 / 191 (2.09%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    Plasma cell leukaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 160 (0.63%)
    4 / 189 (2.12%)
    5 / 191 (2.62%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
    5 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    3 / 160 (1.88%)
    5 / 189 (2.65%)
    4 / 191 (2.09%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
    3 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    5 / 160 (3.13%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    4 / 8
    1 / 3
    1 / 4
    1 / 6
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 2
    Complication associated with device
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 160 (1.88%)
    3 / 189 (1.59%)
    4 / 191 (2.09%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 4
    2 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stent-graft endoleak
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    3 / 191 (1.57%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
    1 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular oedema
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystocele
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    3 / 191 (1.57%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 160 (4.38%)
    5 / 189 (2.65%)
    2 / 191 (1.05%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    7 / 7
    6 / 6
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis aspiration
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 160 (0.63%)
    5 / 189 (2.65%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Obsessive thoughts
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blast cells present
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 160 (1.88%)
    2 / 189 (1.06%)
    4 / 191 (2.09%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic injury
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    3 / 189 (1.59%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 160 (0.63%)
    4 / 189 (2.12%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb traumatic amputation
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    3 / 160 (1.88%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    3 / 189 (1.59%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 160 (1.88%)
    3 / 189 (1.59%)
    4 / 191 (2.09%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    2 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    Hypertensive heart disease
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    5 / 160 (3.13%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 3
    0 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    2 / 191 (1.05%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prosthetic cardiac valve malfunction
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Demyelinating polyneuropathy
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    3 / 191 (1.57%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Embolic stroke
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperaesthesia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Senile dementia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 160 (0.63%)
    5 / 189 (2.65%)
    4 / 191 (2.09%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
    1 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thalamus haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    4 / 4
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Angle closure glaucoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Amaurosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    0 / 160 (0.00%)
    3 / 189 (1.59%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic nerve sheath haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    7 / 191 (3.66%)
    8 / 163 (4.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    6 / 7
    7 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric volvulus
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pancreatitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periodontal disease
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    4 / 191 (2.09%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermal cyst
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash macular
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash papular
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    8 / 160 (5.00%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 2
    2 / 3
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myeloma cast nephropathy
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 160 (1.88%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 160 (1.88%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone lesion
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kyphosis
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crystal arthropathy
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    4 / 160 (2.50%)
    4 / 189 (2.12%)
    2 / 191 (1.05%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 4
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcopenia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bartholinitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 160 (0.00%)
    5 / 189 (2.65%)
    4 / 191 (2.09%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    1 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis bacterial
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 189 (1.06%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis staphylococcal
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 160 (1.88%)
    3 / 189 (1.59%)
    2 / 191 (1.05%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 3
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    3 / 191 (1.57%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal oesophagitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Erysipelas
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    16 / 160 (10.00%)
    13 / 189 (6.88%)
    22 / 191 (11.52%)
    22 / 163 (13.50%)
         occurrences causally related to treatment / all
    7 / 18
    7 / 13
    15 / 26
    11 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    2 / 191 (1.05%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis Escherichia coli
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 160 (2.50%)
    4 / 189 (2.12%)
    1 / 191 (0.52%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    3 / 4
    2 / 5
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    1 / 1
    Sepsis syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis aspergillus
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    4 / 160 (2.50%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    4 / 163 (2.45%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 0
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 1
    Superinfection bacterial
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic shock syndrome staphylococcal
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 160 (0.63%)
    3 / 189 (1.59%)
    6 / 191 (3.14%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
    1 / 6
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral uveitis
         subjects affected / exposed
    0 / 160 (0.00%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    5 / 191 (2.62%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    5 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    4 / 160 (2.50%)
    1 / 189 (0.53%)
    1 / 191 (0.52%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    4 / 191 (2.09%)
    6 / 163 (3.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    2 / 4
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 160 (0.63%)
    2 / 189 (1.06%)
    3 / 191 (1.57%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    2 / 189 (1.06%)
    0 / 191 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    1 / 191 (0.52%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 189 (0.00%)
    0 / 191 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 189 (0.53%)
    0 / 191 (0.00%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + LenDex (Exposure Up to 18 Cycles) Placebo + LenDex (Exposure ≥19 Cycles) Ixazomib + LenDex (Exposure ≥19 Cycles) Ixazomib+ LenDex (Exposure Up to 18 Cycles)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    159 / 160 (99.38%)
    189 / 189 (100.00%)
    191 / 191 (100.00%)
    162 / 163 (99.39%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 160 (5.63%)
    18 / 189 (9.52%)
    29 / 191 (15.18%)
    6 / 163 (3.68%)
         occurrences all number
    10
    20
    32
    7
    Hypotension
         subjects affected / exposed
    12 / 160 (7.50%)
    11 / 189 (5.82%)
    15 / 191 (7.85%)
    17 / 163 (10.43%)
         occurrences all number
    12
    12
    20
    19
    Haematoma
         subjects affected / exposed
    1 / 160 (0.63%)
    7 / 189 (3.70%)
    10 / 191 (5.24%)
    2 / 163 (1.23%)
         occurrences all number
    1
    9
    12
    2
    Flushing
         subjects affected / exposed
    5 / 160 (3.13%)
    12 / 189 (6.35%)
    6 / 191 (3.14%)
    4 / 163 (2.45%)
         occurrences all number
    5
    15
    6
    5
    Deep vein thrombosis
         subjects affected / exposed
    15 / 160 (9.38%)
    13 / 189 (6.88%)
    4 / 191 (2.09%)
    5 / 163 (3.07%)
         occurrences all number
    16
    14
    4
    5
    Hot flush
         subjects affected / exposed
    2 / 160 (1.25%)
    14 / 189 (7.41%)
    4 / 191 (2.09%)
    0 / 163 (0.00%)
         occurrences all number
    2
    15
    4
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 160 (12.50%)
    29 / 189 (15.34%)
    33 / 191 (17.28%)
    30 / 163 (18.40%)
         occurrences all number
    22
    43
    45
    53
    Peripheral swelling
         subjects affected / exposed
    8 / 160 (5.00%)
    12 / 189 (6.35%)
    17 / 191 (8.90%)
    8 / 163 (4.91%)
         occurrences all number
    12
    14
    23
    8
    Oedema peripheral
         subjects affected / exposed
    52 / 160 (32.50%)
    64 / 189 (33.86%)
    106 / 191 (55.50%)
    66 / 163 (40.49%)
         occurrences all number
    71
    103
    170
    91
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 160 (1.25%)
    10 / 189 (5.29%)
    14 / 191 (7.33%)
    4 / 163 (2.45%)
         occurrences all number
    2
    11
    17
    4
    Malaise
         subjects affected / exposed
    3 / 160 (1.88%)
    16 / 189 (8.47%)
    17 / 191 (8.90%)
    6 / 163 (3.68%)
         occurrences all number
    4
    18
    18
    6
    Influenza like illness
         subjects affected / exposed
    4 / 160 (2.50%)
    11 / 189 (5.82%)
    16 / 191 (8.38%)
    1 / 163 (0.61%)
         occurrences all number
    4
    13
    23
    1
    Fatigue
         subjects affected / exposed
    53 / 160 (33.13%)
    52 / 189 (27.51%)
    69 / 191 (36.13%)
    41 / 163 (25.15%)
         occurrences all number
    71
    80
    115
    61
    Chills
         subjects affected / exposed
    10 / 160 (6.25%)
    7 / 189 (3.70%)
    12 / 191 (6.28%)
    11 / 163 (6.75%)
         occurrences all number
    12
    7
    15
    14
    Asthenia
         subjects affected / exposed
    44 / 160 (27.50%)
    53 / 189 (28.04%)
    58 / 191 (30.37%)
    36 / 163 (22.09%)
         occurrences all number
    56
    76
    84
    47
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    6 / 160 (3.75%)
    7 / 189 (3.70%)
    15 / 191 (7.85%)
    2 / 163 (1.23%)
         occurrences all number
    6
    7
    17
    3
    Productive cough
         subjects affected / exposed
    8 / 160 (5.00%)
    5 / 189 (2.65%)
    12 / 191 (6.28%)
    2 / 163 (1.23%)
         occurrences all number
    8
    7
    13
    2
    Oropharyngeal pain
         subjects affected / exposed
    4 / 160 (2.50%)
    12 / 189 (6.35%)
    12 / 191 (6.28%)
    3 / 163 (1.84%)
         occurrences all number
    5
    12
    19
    3
    Hiccups
         subjects affected / exposed
    6 / 160 (3.75%)
    10 / 189 (5.29%)
    5 / 191 (2.62%)
    2 / 163 (1.23%)
         occurrences all number
    10
    19
    6
    4
    Epistaxis
         subjects affected / exposed
    11 / 160 (6.88%)
    16 / 189 (8.47%)
    12 / 191 (6.28%)
    7 / 163 (4.29%)
         occurrences all number
    13
    20
    14
    8
    Dyspnoea exertional
         subjects affected / exposed
    7 / 160 (4.38%)
    14 / 189 (7.41%)
    12 / 191 (6.28%)
    8 / 163 (4.91%)
         occurrences all number
    7
    16
    15
    11
    Dyspnoea
         subjects affected / exposed
    32 / 160 (20.00%)
    26 / 189 (13.76%)
    39 / 191 (20.42%)
    21 / 163 (12.88%)
         occurrences all number
    39
    36
    64
    29
    Dysphonia
         subjects affected / exposed
    4 / 160 (2.50%)
    12 / 189 (6.35%)
    4 / 191 (2.09%)
    5 / 163 (3.07%)
         occurrences all number
    4
    16
    4
    5
    Cough
         subjects affected / exposed
    24 / 160 (15.00%)
    37 / 189 (19.58%)
    53 / 191 (27.75%)
    28 / 163 (17.18%)
         occurrences all number
    26
    50
    85
    33
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 160 (1.88%)
    10 / 189 (5.29%)
    11 / 191 (5.76%)
    4 / 163 (2.45%)
         occurrences all number
    3
    11
    13
    4
    Anxiety
         subjects affected / exposed
    15 / 160 (9.38%)
    25 / 189 (13.23%)
    26 / 191 (13.61%)
    22 / 163 (13.50%)
         occurrences all number
    17
    35
    32
    22
    Confusional state
         subjects affected / exposed
    15 / 160 (9.38%)
    11 / 189 (5.82%)
    11 / 191 (5.76%)
    16 / 163 (9.82%)
         occurrences all number
    18
    13
    11
    19
    Irritability
         subjects affected / exposed
    3 / 160 (1.88%)
    11 / 189 (5.82%)
    4 / 191 (2.09%)
    1 / 163 (0.61%)
         occurrences all number
    3
    13
    4
    1
    Insomnia
         subjects affected / exposed
    27 / 160 (16.88%)
    68 / 189 (35.98%)
    70 / 191 (36.65%)
    30 / 163 (18.40%)
         occurrences all number
    33
    85
    84
    36
    Depression
         subjects affected / exposed
    10 / 160 (6.25%)
    14 / 189 (7.41%)
    26 / 191 (13.61%)
    18 / 163 (11.04%)
         occurrences all number
    10
    15
    29
    19
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 160 (0.63%)
    4 / 189 (2.12%)
    10 / 191 (5.24%)
    1 / 163 (0.61%)
         occurrences all number
    1
    5
    12
    2
    Blood creatinine increased
         subjects affected / exposed
    8 / 160 (5.00%)
    12 / 189 (6.35%)
    16 / 191 (8.38%)
    6 / 163 (3.68%)
         occurrences all number
    9
    18
    18
    6
    Neutrophil count decreased
         subjects affected / exposed
    11 / 160 (6.88%)
    13 / 189 (6.88%)
    18 / 191 (9.42%)
    5 / 163 (3.07%)
         occurrences all number
    17
    45
    47
    12
    Platelet count decreased
         subjects affected / exposed
    6 / 160 (3.75%)
    4 / 189 (2.12%)
    15 / 191 (7.85%)
    6 / 163 (3.68%)
         occurrences all number
    13
    4
    40
    7
    Weight decreased
         subjects affected / exposed
    20 / 160 (12.50%)
    30 / 189 (15.87%)
    35 / 191 (18.32%)
    24 / 163 (14.72%)
         occurrences all number
    24
    40
    51
    29
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 160 (4.38%)
    20 / 189 (10.58%)
    19 / 191 (9.95%)
    3 / 163 (1.84%)
         occurrences all number
    7
    25
    23
    4
    Fall
         subjects affected / exposed
    9 / 160 (5.63%)
    35 / 189 (18.52%)
    45 / 191 (23.56%)
    8 / 163 (4.91%)
         occurrences all number
    10
    67
    68
    10
    Procedural pain
         subjects affected / exposed
    2 / 160 (1.25%)
    11 / 189 (5.82%)
    6 / 191 (3.14%)
    1 / 163 (0.61%)
         occurrences all number
    2
    11
    6
    1
    Skin laceration
         subjects affected / exposed
    4 / 160 (2.50%)
    10 / 189 (5.29%)
    8 / 191 (4.19%)
    2 / 163 (1.23%)
         occurrences all number
    5
    10
    10
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    8 / 160 (5.00%)
    11 / 189 (5.82%)
    7 / 191 (3.66%)
    6 / 163 (3.68%)
         occurrences all number
    9
    12
    7
    6
    Cardiac failure
         subjects affected / exposed
    3 / 160 (1.88%)
    2 / 189 (1.06%)
    1 / 191 (0.52%)
    9 / 163 (5.52%)
         occurrences all number
    3
    2
    1
    9
    Palpitations
         subjects affected / exposed
    1 / 160 (0.63%)
    8 / 189 (4.23%)
    11 / 191 (5.76%)
    2 / 163 (1.23%)
         occurrences all number
    1
    8
    13
    2
    Nervous system disorders
    Tremor
         subjects affected / exposed
    23 / 160 (14.38%)
    27 / 189 (14.29%)
    19 / 191 (9.95%)
    14 / 163 (8.59%)
         occurrences all number
    27
    39
    20
    18
    Syncope
         subjects affected / exposed
    2 / 160 (1.25%)
    6 / 189 (3.17%)
    14 / 191 (7.33%)
    4 / 163 (2.45%)
         occurrences all number
    2
    8
    20
    4
    Sciatica
         subjects affected / exposed
    3 / 160 (1.88%)
    11 / 189 (5.82%)
    16 / 191 (8.38%)
    4 / 163 (2.45%)
         occurrences all number
    3
    12
    18
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    27 / 160 (16.88%)
    57 / 189 (30.16%)
    85 / 191 (44.50%)
    23 / 163 (14.11%)
         occurrences all number
    29
    93
    152
    31
    Paraesthesia
         subjects affected / exposed
    13 / 160 (8.13%)
    21 / 189 (11.11%)
    25 / 191 (13.09%)
    9 / 163 (5.52%)
         occurrences all number
    14
    33
    34
    10
    Neuropathy peripheral
         subjects affected / exposed
    3 / 160 (1.88%)
    9 / 189 (4.76%)
    14 / 191 (7.33%)
    2 / 163 (1.23%)
         occurrences all number
    3
    11
    16
    2
    Memory impairment
         subjects affected / exposed
    3 / 160 (1.88%)
    10 / 189 (5.29%)
    7 / 191 (3.66%)
    4 / 163 (2.45%)
         occurrences all number
    3
    10
    11
    4
    Hypoaesthesia
         subjects affected / exposed
    7 / 160 (4.38%)
    11 / 189 (5.82%)
    14 / 191 (7.33%)
    6 / 163 (3.68%)
         occurrences all number
    7
    16
    17
    7
    Headache
         subjects affected / exposed
    22 / 160 (13.75%)
    36 / 189 (19.05%)
    33 / 191 (17.28%)
    15 / 163 (9.20%)
         occurrences all number
    25
    50
    46
    21
    Dysgeusia
         subjects affected / exposed
    14 / 160 (8.75%)
    12 / 189 (6.35%)
    32 / 191 (16.75%)
    9 / 163 (5.52%)
         occurrences all number
    15
    13
    35
    12
    Dizziness
         subjects affected / exposed
    31 / 160 (19.38%)
    36 / 189 (19.05%)
    31 / 191 (16.23%)
    27 / 163 (16.56%)
         occurrences all number
    38
    75
    42
    34
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    56 / 160 (35.00%)
    51 / 189 (26.98%)
    58 / 191 (30.37%)
    51 / 163 (31.29%)
         occurrences all number
    92
    85
    107
    85
    Thrombocytopenia
         subjects affected / exposed
    15 / 160 (9.38%)
    14 / 189 (7.41%)
    24 / 191 (12.57%)
    32 / 163 (19.63%)
         occurrences all number
    30
    25
    41
    77
    Neutropenia
         subjects affected / exposed
    36 / 160 (22.50%)
    48 / 189 (25.40%)
    39 / 191 (20.42%)
    15 / 163 (9.20%)
         occurrences all number
    92
    135
    99
    27
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 160 (0.00%)
    6 / 189 (3.17%)
    10 / 191 (5.24%)
    1 / 163 (0.61%)
         occurrences all number
    0
    7
    11
    1
    Vertigo
         subjects affected / exposed
    4 / 160 (2.50%)
    18 / 189 (9.52%)
    22 / 191 (11.52%)
    3 / 163 (1.84%)
         occurrences all number
    4
    21
    26
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    6 / 160 (3.75%)
    41 / 189 (21.69%)
    54 / 191 (28.27%)
    1 / 163 (0.61%)
         occurrences all number
    7
    55
    74
    1
    Dry eye
         subjects affected / exposed
    1 / 160 (0.63%)
    6 / 189 (3.17%)
    17 / 191 (8.90%)
    5 / 163 (3.07%)
         occurrences all number
    1
    7
    19
    5
    Vision blurred
         subjects affected / exposed
    6 / 160 (3.75%)
    22 / 189 (11.64%)
    25 / 191 (13.09%)
    6 / 163 (3.68%)
         occurrences all number
    6
    22
    26
    7
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 160 (3.75%)
    11 / 189 (5.82%)
    11 / 191 (5.76%)
    1 / 163 (0.61%)
         occurrences all number
    6
    14
    14
    1
    Abdominal pain
         subjects affected / exposed
    10 / 160 (6.25%)
    38 / 189 (20.11%)
    30 / 191 (15.71%)
    7 / 163 (4.29%)
         occurrences all number
    15
    48
    44
    7
    Abdominal pain upper
         subjects affected / exposed
    13 / 160 (8.13%)
    29 / 189 (15.34%)
    23 / 191 (12.04%)
    8 / 163 (4.91%)
         occurrences all number
    13
    39
    27
    8
    Constipation
         subjects affected / exposed
    61 / 160 (38.13%)
    82 / 189 (43.39%)
    92 / 191 (48.17%)
    59 / 163 (36.20%)
         occurrences all number
    78
    128
    120
    71
    Dental caries
         subjects affected / exposed
    2 / 160 (1.25%)
    11 / 189 (5.82%)
    6 / 191 (3.14%)
    0 / 163 (0.00%)
         occurrences all number
    2
    15
    8
    0
    Diarrhoea
         subjects affected / exposed
    48 / 160 (30.00%)
    115 / 189 (60.85%)
    147 / 191 (76.96%)
    68 / 163 (41.72%)
         occurrences all number
    82
    292
    378
    115
    Nausea
         subjects affected / exposed
    35 / 160 (21.88%)
    63 / 189 (33.33%)
    78 / 191 (40.84%)
    55 / 163 (33.74%)
         occurrences all number
    49
    100
    128
    77
    Dyspepsia
         subjects affected / exposed
    16 / 160 (10.00%)
    22 / 189 (11.64%)
    21 / 191 (10.99%)
    5 / 163 (3.07%)
         occurrences all number
    17
    34
    29
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 160 (1.88%)
    10 / 189 (5.29%)
    13 / 191 (6.81%)
    4 / 163 (2.45%)
         occurrences all number
    3
    13
    15
    5
    Haemorrhoids
         subjects affected / exposed
    6 / 160 (3.75%)
    15 / 189 (7.94%)
    12 / 191 (6.28%)
    1 / 163 (0.61%)
         occurrences all number
    7
    16
    13
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 160 (0.00%)
    10 / 189 (5.29%)
    5 / 191 (2.62%)
    0 / 163 (0.00%)
         occurrences all number
    0
    13
    5
    0
    Dry mouth
         subjects affected / exposed
    14 / 160 (8.75%)
    12 / 189 (6.35%)
    13 / 191 (6.81%)
    11 / 163 (6.75%)
         occurrences all number
    15
    14
    16
    11
    Toothache
         subjects affected / exposed
    4 / 160 (2.50%)
    15 / 189 (7.94%)
    8 / 191 (4.19%)
    3 / 163 (1.84%)
         occurrences all number
    4
    16
    11
    4
    Stomatitis
         subjects affected / exposed
    9 / 160 (5.63%)
    8 / 189 (4.23%)
    15 / 191 (7.85%)
    10 / 163 (6.13%)
         occurrences all number
    9
    9
    21
    10
    Vomiting
         subjects affected / exposed
    13 / 160 (8.13%)
    33 / 189 (17.46%)
    66 / 191 (34.55%)
    41 / 163 (25.15%)
         occurrences all number
    23
    53
    170
    59
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    8 / 160 (5.00%)
    22 / 189 (11.64%)
    31 / 191 (16.23%)
    11 / 163 (6.75%)
         occurrences all number
    8
    26
    35
    13
    Alopecia
         subjects affected / exposed
    3 / 160 (1.88%)
    8 / 189 (4.23%)
    13 / 191 (6.81%)
    3 / 163 (1.84%)
         occurrences all number
    3
    8
    14
    4
    Urticaria
         subjects affected / exposed
    1 / 160 (0.63%)
    5 / 189 (2.65%)
    10 / 191 (5.24%)
    2 / 163 (1.23%)
         occurrences all number
    3
    6
    12
    2
    Rash papular
         subjects affected / exposed
    8 / 160 (5.00%)
    4 / 189 (2.12%)
    12 / 191 (6.28%)
    8 / 163 (4.91%)
         occurrences all number
    8
    5
    13
    12
    Rash maculo-papular
         subjects affected / exposed
    18 / 160 (11.25%)
    22 / 189 (11.64%)
    43 / 191 (22.51%)
    37 / 163 (22.70%)
         occurrences all number
    35
    40
    111
    69
    Rash macular
         subjects affected / exposed
    3 / 160 (1.88%)
    11 / 189 (5.82%)
    27 / 191 (14.14%)
    11 / 163 (6.75%)
         occurrences all number
    7
    14
    39
    27
    Rash erythematous
         subjects affected / exposed
    10 / 160 (6.25%)
    3 / 189 (1.59%)
    18 / 191 (9.42%)
    6 / 163 (3.68%)
         occurrences all number
    12
    3
    32
    10
    Rash
         subjects affected / exposed
    9 / 160 (5.63%)
    7 / 189 (3.70%)
    18 / 191 (9.42%)
    11 / 163 (6.75%)
         occurrences all number
    12
    7
    25
    11
    Pruritus
         subjects affected / exposed
    13 / 160 (8.13%)
    29 / 189 (15.34%)
    37 / 191 (19.37%)
    16 / 163 (9.82%)
         occurrences all number
    15
    42
    59
    23
    Night sweats
         subjects affected / exposed
    9 / 160 (5.63%)
    9 / 189 (4.76%)
    5 / 191 (2.62%)
    9 / 163 (5.52%)
         occurrences all number
    9
    11
    6
    10
    Erythema
         subjects affected / exposed
    2 / 160 (1.25%)
    20 / 189 (10.58%)
    16 / 191 (8.38%)
    11 / 163 (6.75%)
         occurrences all number
    2
    21
    21
    14
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    29 / 160 (18.13%)
    50 / 189 (26.46%)
    50 / 191 (26.18%)
    18 / 163 (11.04%)
         occurrences all number
    34
    78
    73
    24
    Osteoarthritis
         subjects affected / exposed
    4 / 160 (2.50%)
    13 / 189 (6.88%)
    24 / 191 (12.57%)
    1 / 163 (0.61%)
         occurrences all number
    4
    16
    25
    1
    Neck pain
         subjects affected / exposed
    9 / 160 (5.63%)
    25 / 189 (13.23%)
    22 / 191 (11.52%)
    7 / 163 (4.29%)
         occurrences all number
    9
    26
    25
    9
    Myalgia
         subjects affected / exposed
    9 / 160 (5.63%)
    24 / 189 (12.70%)
    33 / 191 (17.28%)
    5 / 163 (3.07%)
         occurrences all number
    13
    32
    40
    10
    Musculoskeletal pain
         subjects affected / exposed
    0 / 160 (0.00%)
    14 / 189 (7.41%)
    13 / 191 (6.81%)
    1 / 163 (0.61%)
         occurrences all number
    0
    19
    15
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 160 (7.50%)
    27 / 189 (14.29%)
    25 / 191 (13.09%)
    12 / 163 (7.36%)
         occurrences all number
    14
    33
    31
    13
    Muscle spasms
         subjects affected / exposed
    27 / 160 (16.88%)
    50 / 189 (26.46%)
    52 / 191 (27.23%)
    15 / 163 (9.20%)
         occurrences all number
    38
    82
    96
    21
    Joint swelling
         subjects affected / exposed
    1 / 160 (0.63%)
    11 / 189 (5.82%)
    12 / 191 (6.28%)
    7 / 163 (4.29%)
         occurrences all number
    1
    12
    14
    7
    Bone pain
         subjects affected / exposed
    10 / 160 (6.25%)
    24 / 189 (12.70%)
    20 / 191 (10.47%)
    4 / 163 (2.45%)
         occurrences all number
    10
    30
    24
    4
    Back pain
         subjects affected / exposed
    34 / 160 (21.25%)
    67 / 189 (35.45%)
    64 / 191 (33.51%)
    26 / 163 (15.95%)
         occurrences all number
    36
    101
    90
    30
    Arthritis
         subjects affected / exposed
    0 / 160 (0.00%)
    4 / 189 (2.12%)
    16 / 191 (8.38%)
    2 / 163 (1.23%)
         occurrences all number
    0
    5
    17
    2
    Arthralgia
         subjects affected / exposed
    23 / 160 (14.38%)
    81 / 189 (42.86%)
    76 / 191 (39.79%)
    23 / 163 (14.11%)
         occurrences all number
    34
    155
    143
    31
    Muscular weakness
         subjects affected / exposed
    12 / 160 (7.50%)
    19 / 189 (10.05%)
    18 / 191 (9.42%)
    9 / 163 (5.52%)
         occurrences all number
    13
    22
    25
    13
    Pathological fracture
         subjects affected / exposed
    5 / 160 (3.13%)
    20 / 189 (10.58%)
    10 / 191 (5.24%)
    7 / 163 (4.29%)
         occurrences all number
    7
    23
    11
    8
    Pain in jaw
         subjects affected / exposed
    3 / 160 (1.88%)
    8 / 189 (4.23%)
    10 / 191 (5.24%)
    5 / 163 (3.07%)
         occurrences all number
    3
    10
    11
    5
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 160 (1.25%)
    5 / 189 (2.65%)
    18 / 191 (9.42%)
    2 / 163 (1.23%)
         occurrences all number
    2
    9
    20
    2
    Cellulitis
         subjects affected / exposed
    5 / 160 (3.13%)
    3 / 189 (1.59%)
    11 / 191 (5.76%)
    2 / 163 (1.23%)
         occurrences all number
    5
    3
    15
    3
    Bronchitis
         subjects affected / exposed
    13 / 160 (8.13%)
    51 / 189 (26.98%)
    74 / 191 (38.74%)
    13 / 163 (7.98%)
         occurrences all number
    15
    109
    168
    14
    Cystitis
         subjects affected / exposed
    2 / 160 (1.25%)
    12 / 189 (6.35%)
    13 / 191 (6.81%)
    2 / 163 (1.23%)
         occurrences all number
    2
    20
    19
    2
    Urinary tract infection
         subjects affected / exposed
    14 / 160 (8.75%)
    27 / 189 (14.29%)
    30 / 191 (15.71%)
    19 / 163 (11.66%)
         occurrences all number
    18
    44
    56
    33
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 160 (10.63%)
    47 / 189 (24.87%)
    48 / 191 (25.13%)
    10 / 163 (6.13%)
         occurrences all number
    29
    88
    97
    14
    Tooth infection
         subjects affected / exposed
    2 / 160 (1.25%)
    11 / 189 (5.82%)
    10 / 191 (5.24%)
    2 / 163 (1.23%)
         occurrences all number
    2
    24
    10
    2
    Sinusitis
         subjects affected / exposed
    1 / 160 (0.63%)
    6 / 189 (3.17%)
    18 / 191 (9.42%)
    5 / 163 (3.07%)
         occurrences all number
    1
    7
    24
    5
    Pneumonia
         subjects affected / exposed
    6 / 160 (3.75%)
    20 / 189 (10.58%)
    24 / 191 (12.57%)
    7 / 163 (4.29%)
         occurrences all number
    6
    21
    31
    7
    Pharyngitis
         subjects affected / exposed
    1 / 160 (0.63%)
    10 / 189 (5.29%)
    10 / 191 (5.24%)
    2 / 163 (1.23%)
         occurrences all number
    1
    13
    11
    2
    Nasopharyngitis
         subjects affected / exposed
    13 / 160 (8.13%)
    71 / 189 (37.57%)
    62 / 191 (32.46%)
    13 / 163 (7.98%)
         occurrences all number
    16
    137
    133
    16
    Influenza
         subjects affected / exposed
    3 / 160 (1.88%)
    22 / 189 (11.64%)
    13 / 191 (6.81%)
    3 / 163 (1.84%)
         occurrences all number
    3
    24
    18
    3
    Herpes zoster
         subjects affected / exposed
    4 / 160 (2.50%)
    4 / 189 (2.12%)
    24 / 191 (12.57%)
    4 / 163 (2.45%)
         occurrences all number
    4
    4
    27
    4
    Gastroenteritis
         subjects affected / exposed
    4 / 160 (2.50%)
    15 / 189 (7.94%)
    15 / 191 (7.85%)
    4 / 163 (2.45%)
         occurrences all number
    4
    21
    18
    4
    Rhinitis
         subjects affected / exposed
    5 / 160 (3.13%)
    21 / 189 (11.11%)
    23 / 191 (12.04%)
    2 / 163 (1.23%)
         occurrences all number
    5
    31
    29
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 160 (28.13%)
    35 / 189 (18.52%)
    45 / 191 (23.56%)
    34 / 163 (20.86%)
         occurrences all number
    55
    47
    69
    39
    Dehydration
         subjects affected / exposed
    11 / 160 (6.88%)
    5 / 189 (2.65%)
    12 / 191 (6.28%)
    10 / 163 (6.13%)
         occurrences all number
    14
    7
    18
    13
    Gout
         subjects affected / exposed
    4 / 160 (2.50%)
    14 / 189 (7.41%)
    10 / 191 (5.24%)
    1 / 163 (0.61%)
         occurrences all number
    5
    24
    19
    1
    Hyperglycaemia
         subjects affected / exposed
    3 / 160 (1.88%)
    15 / 189 (7.94%)
    6 / 191 (3.14%)
    7 / 163 (4.29%)
         occurrences all number
    3
    20
    8
    12
    Hypocalcaemia
         subjects affected / exposed
    13 / 160 (8.13%)
    12 / 189 (6.35%)
    4 / 191 (2.09%)
    6 / 163 (3.68%)
         occurrences all number
    19
    13
    5
    10
    Hypokalaemia
         subjects affected / exposed
    16 / 160 (10.00%)
    33 / 189 (17.46%)
    39 / 191 (20.42%)
    33 / 163 (20.25%)
         occurrences all number
    25
    50
    67
    46
    Hypomagnesaemia
         subjects affected / exposed
    8 / 160 (5.00%)
    11 / 189 (5.82%)
    15 / 191 (7.85%)
    6 / 163 (3.68%)
         occurrences all number
    16
    16
    23
    6
    Hyponatraemia
         subjects affected / exposed
    6 / 160 (3.75%)
    7 / 189 (3.70%)
    4 / 191 (2.09%)
    10 / 163 (6.13%)
         occurrences all number
    6
    8
    5
    27
    Hypophosphataemia
         subjects affected / exposed
    2 / 160 (1.25%)
    3 / 189 (1.59%)
    9 / 191 (4.71%)
    9 / 163 (5.52%)
         occurrences all number
    4
    8
    10
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Aug 2019
    The following changes were implemented as per Amendment 4: 1. Updated statistical procedures to modify the number of events for the final PFS analysis. 2. Clarified the statistical boundary for PFS at the second IA. 3. Clarified that REVLIMID or generic lenalidomide may be administered as part of the study treatment regimen. 4. Removed the requirement to document adverse events that require breaking the blind in the eCRF. 5. Updated the SAE reporting contact information in Japan to BI Medical. 6. Clarified the duration of new primary malignancy AE assessment. 7. Clarified the locations of study centers.
    09 Jul 2020
    The following changes were implemented as per Amendment 5: 1. Added language to clarify ongoing treatment of participants—participants should be moved off study and onto commercial supply of ixazomib and/or lenalidomide, if available, and otherwise kept on study. 2. Updated Schedule of Events. 3. Revised Study Period Definitions. 4. Added explanatory text to Study Objectives. 5. Added explanatory text to Study Endpoints. 6. Added explanatory text to Overview of Study Design and removed language regarding the previous Schedule of Events. 7. Revised information regarding the interim analyses in the Overview of Study Design. 8. Revised thrombocytopenia text in Management of Clinical Events. 9. Revised Blinding and Unblinding text. 10. Revised language in Preparation, Reconstitution, and Dispensing. 11. Added a sentence to Packaging and Labeling. 12. Added language in Storage, Handling, and Accountability. 13. Added language regarding alternative methods for administering study procedures/assessments when it is not possible for the patient to come to the study site due to extenuating circumstances (eg, due to the COVID-19 pandemic). 14. Removed or revised several study procedures. 15. Revised language regarding unscheduled visits. 16. Revised language regarding completion of treatment. 17. Revised language regarding completion of study. 18. Revised language regarding discontinuation of treatment with the study drug regimen, and patient replacement. 19. Revised language regarding withdrawal of patients from study. 20. Revised language regarding statistical and quantitative analyses. 22. Added language to Independent Review Committee section. 23. Added language to Procedures for Recording and Reporting Adverse Events and Serious Adverse Events.

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

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