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    Clinical Trial Results:
    An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Next-Generation Proteasome Inhibitor, Administered in Combination with a Standard Care Regimen of Melphalan and Prednisone in Patients with Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

    Summary
    EudraCT number
    		 2010-023772-71
    Trial protocol
    		 ES   CZ   GB   IT  
    Global end of trial date
    29 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2018
    First version publication date
    18 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C16006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01335685
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, United States,
    Public contact
    Medical Director, Takeda, +1 8778253327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Takeda, +1 8778253327, 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
    29 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to determine the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of oral ixazomib.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    Czech Republic: 15
    Worldwide total number of subjects
    61
    EEA total number of subjects
    49
    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)
    1
    From 65 to 84 years
    59
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 14 investigative sites in United States, Canada, United Kingdom, Spain and Czech Republic from 27 June 2011 to 29 December 2016.

    Pre-assignment
    Screening details
    		 Participants with a diagnosis of multiple myeloma were enrolled to receive ixazomib orally at various doses in Phase 1. Only Arm B: Ixazomib 4.0 mg continued in Phase 2.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Ixazomib 3.0 mg
    Arm description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 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 3.0 mg, capsule, on Days 1, 4, 8, 11, 22, 25, 29, 32 in 42-day cycle up to 9 cycles

    Arm title
    		 Arm A: Ixazomib 3.7 mg
    Arm description
    		 Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 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 3.7 mg, capsules, on Days 1, 4, 8, 11, 22, 25, 29, 32 in 42-day cycle up to 9 cycles

    Arm title
    		 Arm B: Ixazomib 3.0 mg
    Arm description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 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 3.0 mg, capsules, on Days 1, 8, 15 up to 13 cycles in 28-day cycle

    Arm title
    		 Arm B: Ixazomib 4.0 mg
    Arm description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 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, capsules, orally, on Days 1, 8, 15 up to 13 cycles in 28-day cycle

    Arm title
    		 Arm B: Ixazomib 5.5 mg
    Arm description
    		 Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 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 5.5 mg, capsules, on Days 1, 8, 15 up to 13 cycles in 28-day cycle

    Arm title
    		 Arm C: Ixazomib 3.0 mg
    Arm description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 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 3.0 mg, capsules, on Days 1, 8, 15, 22, and 29 up to 9 cycles in 42-day cycle

    Arm title
    		 Arm C: Ixazomib 4.0 mg
    Arm description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 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, capsules, on Days 1, 8, 15, 22, and 29 up to 9 cycles in 42-day cycle

    Arm title
    		 Arm D: Ixazomib 4.0 mg
    Arm description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 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, capsules, on Days 1, 8, 22, and 29 in 42-day cycle up to 13 cycles

    Number of subjects in period 1
    		Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Started
    7
    4
    3
    26
    5
    6
    4
    6
    Completed
    4
    3
    1
    15
    5
    1
    2
    3
    Not completed
    3
    1
    2
    11
    0
    5
    2
    3
         Consent withdrawn by subject
    1
    -
    -
    1
    -
    -
    -
    -
         Study Terminated by Sponsor
    2
    1
    1
    10
    -
    4
    2
    3
         Reason not Specified
    -
    -
    1
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).

    Reporting group title
    Arm A: Ixazomib 3.7 mg
    Reporting group description
    		 Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).

    Reporting group title
    Arm B: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).

    Reporting group title
    Arm B: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).

    Reporting group title
    Arm B: Ixazomib 5.5 mg
    Reporting group description
    		 Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).

    Reporting group title
    Arm C: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).

    Reporting group title
    Arm C: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).

    Reporting group title
    Arm D: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).

    Reporting group values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg Total
    Number of subjects
    		 7 4 3 26 5 6 4 6 61
    Age, Customized
    Units: Subjects
        <75|
    		 6 0 2 15 2 1 1 4 31
        >=75|
    		 1 4 1 11 3 5 3 2 30
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.0 ( 6.14 ) 79.8 ( 2.87 ) 73.0 ( 7.55 ) 74.5 ( 4.52 ) 74.2 ( 5.63 ) 75.8 ( 4.96 ) 77.0 ( 3.56 ) 73.2 ( 9.66 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 5 3 1 16 5 4 1 3 38
        Male
    		 2 1 2 10 0 2 3 3 23
    Race/Ethnicity, Customized
    Units: Subjects
        Missing|
    		 1 1 1 2 0 0 0 0 5
        Not Hispanic or Latino|
    		 6 3 2 24 5 6 4 6 56
    Race/Ethnicity, Customized
    Units: Subjects
        Asian|
    		 0 0 0 0 0 1 0 0 1
        Black or African American|
    		 0 0 0 1 0 0 0 0 1
        White|
    		 6 4 3 24 5 5 4 6 57
        Other|
    		 1 0 0 1 0 0 0 0 2
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 163.37 ( 8.023 ) 160.25 ( 8.342 ) 160.10 ( 13.286 ) 164.02 ( 12.869 ) 157.52 ( 6.103 ) 161.70 ( 15.361 ) 168.00 ( 1.826 ) 164.50 ( 11.413 ) -
    Weight at Baseline
    Units: kg
        arithmetic mean (standard deviation)
    		 69.41 ( 6.703 ) 72.63 ( 13.972 ) 78.97 ( 18.224 ) 75.23 ( 17.037 ) 60.76 ( 7.747 ) 70.67 ( 25.616 ) 75.93 ( 12.207 ) 66.97 ( 21.404 ) -
    Body Surface Area at Baseline
    Body Surface Area (m^2) = square root [height (cm) x weight (kg) / 3600].
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.773 ( 0.1027 ) 1.798 ( 0.2148 ) 1.870 ( 0.2740 ) 1.843 ( 0.2749 ) 1.630 ( 0.1275 ) 1.734 ( 0.4380 ) 1.880 ( 0.1592 ) 1.718 ( 0.3650 ) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).

    Reporting group title
    Arm A: Ixazomib 3.7 mg
    Reporting group description
    		 Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).

    Reporting group title
    Arm B: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).

    Reporting group title
    Arm B: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).

    Reporting group title
    Arm B: Ixazomib 5.5 mg
    Reporting group description
    		 Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).

    Reporting group title
    Arm C: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).

    Reporting group title
    Arm C: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).

    Reporting group title
    Arm D: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).

    Subject analysis set title
    Arm A: Ixazomib 3.0 - 3.7 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 3.0 - 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles).

    Subject analysis set title
    Arm B: Ixazomib 3.0 - 5.5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 3.0 - 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1-4 for in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles).

    Subject analysis set title
    Arm C: Ixazomib 3.0 - 4.0 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 3.0 - 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles).

    Subject analysis set title
    Arm D: Ixazomib 4.0 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles).

    Subject analysis set title
    Arm B: Ixazomib 4.0 mg (RP2D)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally, on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).

    Primary: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1)

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    End point title
    		 Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Ixazomib (Phase 1) [1]
    End point description
    The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).
    End point type
    Primary
    End point timeframe
    Cycle 1, phase 1 (Up to 42 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not reported as only descriptive analysis was performed as planned.
    End point values
    		 Arm A: Ixazomib 3.0 - 3.7 mg Arm B: Ixazomib 3.0 - 5.5 mg Arm C: Ixazomib 3.0 - 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    11
    34
    10
    6
    Units: mg
        number (not applicable)
    3
    4
    3
    4
    No statistical analyses for this end point

    Primary: Very Good Partial Response (VGPR) or Better Response Rate (Phase 2)

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    End point title
    		 Very Good Partial Response (VGPR) or Better Response Rate (Phase 2) [2]
    End point description
    VGPR or better response rate is defined as percentage of participants with a complete response (CR) and very good partial response (VGPR). Per International Myeloma Working Group Uniform Response Criteria (IMWG), CR: 1) Negative immunofixation on the serum and urine, 2) Disappearance of any soft tissue plasmacytomas and 3) < 5% plasma cells in bone marrow. VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour. The response-evaluable population is defined as participants who received at least 5 of 8 MLN9708 doses in Arm A, at least 2 of 3 MLN9708 doses in Arm B, at least 4 of 5 MLN9708 doses in Arm C, or at least 3 of 4 MLN9708 doses in Arm D and had measurable disease at baseline and at least 1 post-baseline response assessment.
    End point type
    Primary
    End point timeframe
    Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) until death (Up to 5.5 years)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not reported as only descriptive analysis was performed as planned.
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    23
    Units: percentage of participants
        number (not applicable)
    48
    No statistical analyses for this end point

    Secondary: Maximum Inhibition Rate (Emax) (Phase 1)

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    End point title
    		 Maximum Inhibition Rate (Emax) (Phase 1)
    End point description
    Whole blood 20S proteasome inhibition parameters
    End point type
    Secondary
    End point timeframe
    At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    Units: percentage of inhibition
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [3] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [4] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [5] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [6] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [7] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [8] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [9] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [10] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    No statistical analyses for this end point

    Secondary: Time of Occurrence of Emax (TEmax) (Phase 1)

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    End point title
    		 Time of Occurrence of Emax (TEmax) (Phase 1)
    End point description
    Whole blood 20S proteasome inhibition parameters
    End point type
    Secondary
    End point timeframe
    At multiple time points during Cycles 1-3 of each phase and arm of the study, throughout approximately 84-126 days depending on the arm of the study
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: percentage of inhibition
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [11] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [12] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [13] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [14] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [15] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [16] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [17] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    [18] - Assessment of this endpoint was not performed due to the change in the planned analysis.
    No statistical analyses for this end point

    Secondary: Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)

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    End point title
    		 Cmax: Maximum Observed Plasma Concentration for Ixazomib (Phase 1)
    End point description
    The pharmacokinetics (PK) population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 9999=NA (Standard deviation was not estimable for 1 participant) and 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=7,1,2,18,4,6,4,5)|
    26.791 ( 18.2608 )
    39.300 ( 9999 )
    22.950 ( 9999 )
    53.278 ( 41.1963 )
    104.225 ( 46.9148 )
    55.367 ( 43.8052 )
    50.875 ( 20.6487 )
    72.080 ( 54.3984 )
        Cycle 1, Day 11 (n=7,1,0,0,0,0,0,0)|
    69.214 ( 30.1985 )
    22.000 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 15 (n=0,0,1,14,1,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    30.267 ( 13.7173 )
    85.636 ( 64.6346 )
    285.000 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 29 (n=0,0,0,0,0,5,2,4)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    59.560 ( 37.2229 )
    109.000 ( 9999 )
    146.400 ( 90.1703 )
    No statistical analyses for this end point

    Secondary: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)

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    End point title
    		 Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib (Phase 1)
    End point description
    The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: hours
    median (full range (min-max))
        Cycle 1, Day 1 (n=7,1,2,18,4,6, 4,5)|
    1.020 (0.617 to 4.000)
    0.517 (0.517 to 0.517)
    1.750 (1.470 to 2.030)
    1.000 (0.500 to 2.170)
    1.302 (0.533 to 4.000)
    1.560 (0.483 to 4.000)
    1.282 (0.500 to 4.000)
    0.567 (0.417 to 2.150)
        Cycle 1, Day 11 (n=7,1,0,0,0,0,0,0)|
    1.050 (0.500 to 4.000)
    8.000 (8.000 to 8.000)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Cycle 1, Day 15 (n=0,0,3,14,1,0,0,0)|
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0.833 (0.583 to 2.000)
    1.000 (0.500 to 4.000)
    0.500 (0.500 to 0.500)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Cycle 1, Day 29 (n=0,0,0,0,0,5,2,4)|
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.500 (0.500 to 4.030)
    1.275 (0.550 to 2.000)
    0.760 (0.300 to 1.430)
    No statistical analyses for this end point

    Secondary: AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)

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    End point title
    		 AUCtau: Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Ixazomib (Phase 1)
    End point description
    The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 9999=NA (Standard deviation was not estimable for 1 participant) and 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=7,1,2,17,4,6,4, 5)|
    319.714 ( 104.6721 )
    287.000 ( 9999 )
    450.000 ( 9999 )
    806.824 ( 472.7173 )
    1612.250 ( 1009.5816 )
    662.833 ( 414.5178 )
    1037.500 ( 397.8748 )
    934.800 ( 390.2598 )
        Cycle 1, Day 11 (n=7,1,0,0,0,0,0,0)|
    1227.143 ( 338.9550 )
    1180.000 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 15 (n=0,0,3,14,1,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    705.667 ( 92.5005 )
    1610.500 ( 770.2156 )
    1680.000 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 29 (n=0,0,0,0,0,5,2,4)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    1527.800 ( 975.9914 )
    2680.000 ( 9999 )
    2435.000 ( 1107.5047 )
    No statistical analyses for this end point

    Secondary: Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)

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    End point title
    		 Terminal Elimination Rate Constant (λz) for Ixazomib (Phase 1)
    End point description
    Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase. The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 9999=NA (Standard deviation was not estimable for 1 participant) and 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: 1/hour
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (0,0,0,0,0,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 11 (n=0,0,0,0,0,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 15 (n=0,0,1,13,1,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    0.004 ( 99999 )
    0.006 ( 0.0018 )
    0.007 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 29 (n=0,0,0,0,0,4,2,4)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    0.005 ( 0.0021 )
    0.005 ( 9999 )
    0.006 ( 0.0025 )
    No statistical analyses for this end point

    Secondary: Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)

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    End point title
    		 Terminal Phase Elimination Half-life (T1/2) for Ixazomib (Phase 1)
    End point description
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 9999=NA (Standard deviation was not estimable for 1 participant) and 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: hours
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=0,0,0,0,0,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 11(n=0,0,0,0,0,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 15 (n=0,0,1,13,1,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    167.000 ( 9999 )
    130.362 ( 45.0672 )
    98.900 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 29 (0,0,0,0,0,4,2,4)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    140.575 ( 49.3760 )
    163.500 ( 9999 )
    120.050 ( 45.6024 )
    No statistical analyses for this end point

    Secondary: Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)

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    End point title
    		 Observed Accumulation Ratio for AUCtau (Rac) (Phase 1)
    End point description
    Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 14 divided by area under the curve from time zero to end of dosing interval (AUCtau) on Day 1. The PK population consisted of all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Here, 9999=NA (Standard deviation was not estimable for 1 participant) and 99999=NA (Data was not analyzed for this arm group at this time point).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and at multiple timepoints (up to 8 hours) on Day 11 for Arm A, Day 15 for Arm B and Day 29 for Arms C and D
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    1
    3
    20
    4
    6
    4
    5
    Units: ratio
    arithmetic mean (standard deviation)
        Cycle 1, Day 1 (n=0,0,0,0,0,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 11 (n=7,1,0,0,0,0,0,0)|
    4.019 ( 1.1349 )
    4.120 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 15 (n=0,0,2,12,1,0,0,0)|
    99999 ( 99999 )
    99999 ( 99999 )
    1.700 ( 9999 )
    2.288 ( 0.6246 )
    1.970 ( 9999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
        Cycle 1, Day 29 (n=0,0,0,0,0,5,2,4)|
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    2.632 ( 0.6732 )
    2.560 ( 9999 )
    2.540 ( 0.2061 )
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is defined as percentage of participants with overall response including CR, VGPR, and partial response (PR). Per IMWG criteria, CR:1)Negative immunofixation on serum and urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. If serum+urine M-protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.
    End point type
    Secondary
    End point timeframe
    Day 1 of every other cycle from Day 1 of Cycle 2 (each cycle of 28 days) up to 61 cycles, at end of treatment (Up to 5.5 years)
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    3
    3
    23
    5
    5
    3
    4
    Units: percentage of participants
        number (confidence interval 95%)
    86 (42 to 100)
    67 (9 to 99)
    100 (29 to 100)
    65 (43 to 84)
    60 (15 to 95)
    40 (5 to 85)
    67 (9 to 99)
    50 (7 to 93)
    No statistical analyses for this end point

    Secondary: Time to First Response (Phase 2)

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    End point title
    		 Time to First Response (Phase 2)
    End point description
    Response is defined as CR, VGPR and PR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)< 5% plasma cells in bone marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/ 90% or >reduction in serum M-protein + urine M-protein level < 100 mg/ 24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels is required. Else, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. In addition, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment to the date of the first documented response for up to 5.5 years
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    15
    Units: months
        median (confidence interval 95%)
    1.9 (1 to 7)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) (Phase 2)

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    End point title
    		 Duration of Response (DOR) (Phase 2)
    End point description
    DOR: time of first confirmed PR or better to first PD or start of alternative therapy. DOR was presented for those achieving CR+VGPR+PR, CR+VGPR, and CR. Per IMWG criteria, CR:1)Negative immunofixation on serum+urine, 2)Disappearance of any soft tissue plasmacytomas, 3)<5% plasma cells in marrow. VGPR: Serum+urine M-protein detectable by immunofixation but not on electrophoresis/90% or >reduction in serum M-protein+urine M-protein level <100 mg/24-hour. PR:1)≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90%/to <200 mg/24-hour. If serum+urine M-protein are unmeasurable, ≥50% decrease in difference between involved and uninvolved FLC levels OR ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30%. Also, if present at baseline, a ≥50% reduction in size of soft tissue plasmacytomas is required. Here, 9999=NA(value was not reached due to low number of participants with events).
    End point type
    Secondary
    End point timeframe
    From the time from the date of first documentation of PR or better to the date of first documented disease progression for up to 5.5 years
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    23
    Units: months
        median (confidence interval 95%)
    25.2 (4.6 to 9999)
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP) (Phase 2)

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    End point title
    		 Time to Progression (TTP) (Phase 2)
    End point description
    TTP is defined as time from date of enrollment to date of first documented disease progression (PD). Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder. Here, 99999=NA (Lower limit of CI was not reached due to the low number of participants with events.).
    End point type
    Secondary
    End point timeframe
    From the date of enrollment to the date of the first documented disease progression for up to 5.5 years
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    22.1 (8.77 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Next Therapy (Phase 2)

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    End point title
    		 Time to Next Therapy (Phase 2)
    End point description
    Time to Next Therapy is defined as time from the date of enrollment to the date of subsequent antineoplastic therapy.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment to the date of the first documented response for up to 5.5 years
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    0 [19]
    Units: months
        median (confidence interval 95%)
    ( to )
    Notes
    [19] - Time to next therapy was not analyzed due to the change in the planned analysis.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (Phase 2)

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    End point title
    		 Progression Free Survival (Phase 2)
    End point description
    Progression Free Survival is defined as time in months from start of study treatment to first documentation of objective tumor progression per IRF assessment or up to death due to any cause, whichever occurs first. Per IMWG criteria, progressive disease requires any 1 or more of following: Increase of ≥25% from nadir in serum M-component and/or (absolute increase must be ≥0.5 g/dL), urine M-component and/or (absolute increase must be ≥200 mg/24 hour. Participants without measurable serum+urine M-protein levels: difference between involved and uninvolved FLC levels. The absolute increase must be >10 mg/dL. Bone marrow plasma cell percentage: absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia (corrected serum calcium >11.5 mg/dL or 2.85 mmol/L) that can be attributed solely to plasma cell proliferative disorder.
    End point type
    Secondary
    End point timeframe
    From the date of enrollment to the date of the first documented disease progression or death due to any cause for up to 5.5 years
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    18.4 (8.31 to 38.67)
    No statistical analyses for this end point

    Secondary: Overall Survival (Phase 2)

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    End point title
    		 Overall Survival (Phase 2)
    End point description
    Overall Survival is the time in months from start of study treatment to date of death due to any cause. Here, 99999=NA (Median and Lower limit of CI was not reached due to the low number of participants with events).
    End point type
    Secondary
    End point timeframe
    From date of enrollment to date of death, approximately 5.5 years (Approximate median follow-up: 43.6 months)
    End point values
    		 Arm B: Ixazomib 4.0 mg (RP2D)
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    99999 (34.99 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
    End point description
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through 30 days after last dose of study drug or until the start of subsequent antineoplastic therapy for up to 4.9 years
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    7
    4
    3
    26
    5
    6
    4
    6
    Units: participants
        During Entire Study Any Adverse Event|
    7
    4
    3
    26
    5
    6
    4
    6
        Grade 3 or Higher Adverse Event|
    7
    4
    3
    21
    5
    5
    4
    5
        Serious Adverse Event|
    2
    4
    3
    12
    3
    4
    2
    1
        Adverse Event With Any Study Drug Discontinuation|
    0
    0
    0
    8
    2
    2
    1
    2
        Adverse Event With Any Study Drug Reduction|
    4
    2
    1
    13
    3
    3
    2
    4
    No statistical analyses for this end point

    Secondary: Assessments of Quality of Life

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    End point title
    		 Assessments of Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each treatment cycle, and Days 1 and 15 of each maintenance cycle, up to 4.9 years
    End point values
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 3.0 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Number of subjects analysed
    0 [20]
    0 [21]
    0 [22]
    0 [23]
    0 [24]
    0 [25]
    0 [26]
    0 [27]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Notes
    [20] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [21] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [22] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [23] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [24] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [25] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [26] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    [27] - Assessments of quality of life parameters were not analyzed due to change in planned analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study drug through 30 days after the last dose of study drug or until the start of subsequent antineoplastic therapy for up to 5.6 years
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Arm A: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle for up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 23 maintenance cycles; overall up to 32 cycles [34 months]).

    Reporting group title
    Arm A: Ixazomib 3.7 mg
    Reporting group description
    		 Ixazomib 3.7 mg, capsules, orally, on Days 1, 4, 8, 11, 22, 25, 29, 32 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 10 maintenance cycles; overall up to 19 cycles [21 months]).

    Reporting group title
    Arm B: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 15 maintenance cycles; overall up to 27 cycles [25 months]).

    Reporting group title
    Arm B: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15 cycle plus melphalan 6 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 49 maintenance cycles; overall up to 61 cycles [58 months]).

    Reporting group title
    Arm C: Ixazomib 3.0 mg
    Reporting group description
    		 Ixazomib 3.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 30 maintenance cycles; overall up to 39 cycles [40 months]).

    Reporting group title
    Arm B: Ixazomib 5.5 mg
    Reporting group description
    		 Ixazomib 5.5 mg, capsules, orally, on Days 1, 8, 15 plus melphalan 6 mg/m^2, tablets orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1-4 in 28-day cycle for up to 13 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 24 cycles [24 months]).

    Reporting group title
    Arm C: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 15, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 12 maintenance cycles; overall up to 21 cycles [24 months]).

    Reporting group title
    Arm D: Ixazomib 4.0 mg
    Reporting group description
    		 Ixazomib 4.0 mg, capsules, orally, on Days 1, 8, 22, and 29 plus melphalan 9 mg/m^2, tablets, orally on Days 1 to 4 and prednisone 60 mg/m^2, tablets, orally, on Days 1 to 4 in 42-day cycle for up to 9 cycles in induction phase followed by ixazomib at dose last tolerated in induction, orally, on Days 1, 8, 15 in 28-day cycle up to 12 cycles or until disease progression or unacceptable toxicity if deriving benefit in maintenance phase (up to 28 maintenance cycles; overall up to 37 cycles [38 months]).

    Serious adverse events
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm C: Ixazomib 3.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    12 / 26 (46.15%)
    4 / 6 (66.67%)
    3 / 5 (60.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
    0
    3
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
    Additional description: One treatment-emergent death occurred in Arm B during treatment with ixazombib 4.0 mg and is not related.
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Generalised erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Neurogenic bladder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
    Additional description: One treatment-emergent death occurred in Arm B during treatment with ixazombib 4.0 mg and is not related.
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    Additional description: One treatment-emergent death occurred in Arm B during treatment with ixazombib 4.0 mg and is not related.
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A: Ixazomib 3.0 mg Arm A: Ixazomib 3.7 mg Arm B: Ixazomib 3.0 mg Arm B: Ixazomib 4.0 mg Arm C: Ixazomib 3.0 mg Arm B: Ixazomib 5.5 mg Arm C: Ixazomib 4.0 mg Arm D: Ixazomib 4.0 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    3 / 3 (100.00%)
    26 / 26 (100.00%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    0
    0
    Plasmacytoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    6 / 26 (23.08%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    0
    0
    9
    0
    1
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    4 / 26 (15.38%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    5
    0
    1
    0
    0
    Peripheral venous disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    1
    Peripheral coldness
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    9 / 26 (34.62%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
    3 / 6 (50.00%)
         occurrences all number
    1
    3
    1
    14
    1
    3
    4
    4
    Pyrexia
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    6 / 26 (23.08%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    14
    9
    11
    9
    1
    2
    0
    3
    Fatigue
         subjects affected / exposed
    6 / 7 (85.71%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    9 / 26 (34.62%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    17
    0
    1
    18
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 3 (66.67%)
    7 / 26 (26.92%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    3 / 4 (75.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    5
    8
    3
    3
    4
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    15
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    1
    Feeling cold
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    0
    0
    0
    Inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Chest discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Chronic fatigue syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    9 / 26 (34.62%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    2
    1
    10
    2
    0
    0
    1
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    5 / 26 (19.23%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    0
    8
    0
    1
    0
    2
    Catarrh
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    4
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    1
    0
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    1
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Pharyngeal oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    4 / 26 (15.38%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    1
    4
    2
    2
    0
    0
    Depression
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    4 / 26 (15.38%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    4
    0
    1
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    Hallucination
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Disorientation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    0
    1
    1
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    6
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Blood electrolytes decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Liver function test increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    2
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    0
    0
    0
    Clavicle fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Compression fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Face injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Overdose
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Spinal compression fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Synovial rupture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Wrist fracture
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    2
    3
    0
    2
    1
    Atrial flutter
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Atrial tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Cardiac failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    7 / 26 (26.92%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    7
    5
    0
    12
    2
    8
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    4 / 26 (15.38%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    2
    4
    1
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    5 / 26 (19.23%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    4
    0
    5
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 4 (75.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    3
    0
    2
    1
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    5 / 26 (19.23%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    0
    0
    7
    0
    3
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    2
    0
    2
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    3
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    1
    0
    Ataxia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Ageusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Autonomic nervous system imbalance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Burning sensation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Dementia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Dizziness postural
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Polyneuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    7
    0
    0
    0
    0
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Seizure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    6 / 7 (85.71%)
    4 / 4 (100.00%)
    2 / 3 (66.67%)
    16 / 26 (61.54%)
    5 / 6 (83.33%)
    3 / 5 (60.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
         occurrences all number
    18
    41
    15
    84
    18
    17
    19
    38
    Neutropenia
         subjects affected / exposed
    5 / 7 (71.43%)
    4 / 4 (100.00%)
    2 / 3 (66.67%)
    12 / 26 (46.15%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
         occurrences all number
    15
    19
    6
    35
    9
    17
    12
    35
    Anaemia
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    9 / 26 (34.62%)
    3 / 6 (50.00%)
    5 / 5 (100.00%)
    3 / 4 (75.00%)
    4 / 6 (66.67%)
         occurrences all number
    10
    5
    1
    26
    6
    15
    3
    7
    Lymphopenia
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 4 (50.00%)
    1 / 3 (33.33%)
    8 / 26 (30.77%)
    3 / 6 (50.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    19
    4
    33
    12
    15
    9
    9
    Leukopenia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    7 / 26 (26.92%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
    4 / 6 (66.67%)
         occurrences all number
    1
    8
    0
    28
    9
    18
    5
    15
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Eye pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Eye swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 4 (75.00%)
    1 / 3 (33.33%)
    17 / 26 (65.38%)
    2 / 6 (33.33%)
    5 / 5 (100.00%)
    3 / 4 (75.00%)
    3 / 6 (50.00%)
         occurrences all number
    11
    7
    1
    38
    3
    14
    7
    10
    Nausea
         subjects affected / exposed
    6 / 7 (85.71%)
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    11 / 26 (42.31%)
    3 / 6 (50.00%)
    3 / 5 (60.00%)
    2 / 4 (50.00%)
    4 / 6 (66.67%)
         occurrences all number
    11
    3
    4
    19
    4
    3
    2
    7
    Vomiting
         subjects affected / exposed
    4 / 7 (57.14%)
    4 / 4 (100.00%)
    1 / 3 (33.33%)
    11 / 26 (42.31%)
    1 / 6 (16.67%)
    4 / 5 (80.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    9
    2
    18
    4
    5
    1
    6
    Constipation
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    2 / 3 (66.67%)
    6 / 26 (23.08%)
    3 / 6 (50.00%)
    3 / 5 (60.00%)
    3 / 4 (75.00%)
    4 / 6 (66.67%)
         occurrences all number
    2
    5
    2
    6
    4
    3
    4
    8
    Abdominal pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    5 / 26 (19.23%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    12
    1
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    1
    1
    1
    0
    0
    0
    2
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    2 / 6 (33.33%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    4
    2
    0
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    6
    1
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    1
    Dry mouth
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    2
    Haemorrhoids
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Tongue ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Abdominal hernia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Gastric disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Haematemesis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Tongue eruption
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    23
    0
    1
    10
    0
    2
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    3 / 7 (42.86%)
    3 / 4 (75.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    10
    0
    2
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    4 / 26 (15.38%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    1
    7
    0
    0
    0
    2
    Rash pruritic
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    1
    3
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    4 / 26 (15.38%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    2
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Swelling face
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    0
    Eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Erythema nodosum
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Generalised erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Night sweats
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Rash generalised
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Anuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Chromaturia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    10 / 26 (38.46%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    3 / 4 (75.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    14
    0
    1
    5
    0
    Pain in extremity
         subjects affected / exposed
    3 / 7 (42.86%)
    1 / 4 (25.00%)
    2 / 3 (66.67%)
    5 / 26 (19.23%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    3
    6
    2
    1
    1
    1
    Arthralgia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    6 / 26 (23.08%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    5
    0
    0
    9
    5
    0
    0
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    6 / 26 (23.08%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    6
    0
    0
    0
    0
    Arthritis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    1
    2
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    2
    0
    0
    0
    0
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    1
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    0
    0
    0
    Muscular weakness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    Polyarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    8
    0
    0
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Muscle swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    3 / 6 (50.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    0
    4
    6
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    6 / 26 (23.08%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    6
    0
    2
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    2 / 6 (33.33%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    5
    4
    4
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    3
    2
    4
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    0
    Klebsiella infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    Diverticulitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Oesophageal candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Streptococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Urethritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    0
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Wound infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    4 / 26 (15.38%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    0
    6
    1
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 7 (57.14%)
    1 / 4 (25.00%)
    1 / 3 (33.33%)
    8 / 26 (30.77%)
    0 / 6 (0.00%)
    3 / 5 (60.00%)
    2 / 4 (50.00%)
    3 / 6 (50.00%)
         occurrences all number
    12
    1
    2
    9
    0
    4
    4
    4
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    1
    1
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    2 / 26 (7.69%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    1 / 26 (3.85%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    3 / 26 (11.54%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    0
    0
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    0
    0
    Malnutrition
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 3 (0.00%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 3 (33.33%)
    0 / 26 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Aug 2011
    - Standardized Progression Free Survival and Overall Survival (OS) follow-up to 16 weeks - Revised planned dose level 3 from 5.2 mg to 5.5 mg
    29 May 2012
    - Clarified that OS visits will be conducted every 16 weeks after document PD, even if participant goes on to receive subsequent treatment - Added Appendices 15.7, Brief Pain Inventory – Short Form; 15.8, World Health Organization Steps of Analgesics and OME Conversions; and 15.10, EORTC Multiple Myeloma Module (QLQ-MY20)
    22 Mar 2013
    - Removed the twice-weekly arm (Arm A) from the phase 2 portion of the study - Added 2 new once-weekly 6-week cycle treatment arms to the phase 1 portion of the study (Arm C and Arm D) - Revised the design of the phase 2 portion of the study to include 2 once-weekly treatment arms: one 4-week cycle (Arm B) and one 6-week cycle (Arm C or Arm D) - Updated participant numbers to accommodate new study design (i.e., dropping Arm A and adding Arm C and Arm D) - Extended the induction period of Arm B by 1 cycle (up to 13 cycles) - Removed randomization procedures to be able to enroll participants to phase 2 Arm B in parallel with enrollment to phase 1 Arms C and D

    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
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